The May Voice

VOICE

THE CENTER FOR HUMAN REPRODUCTION

MAY 2024

IN THIS MONTH’S ISSUE THE CHR LETTER

2

FEUILLETON

4

TESTING THE TESTS: TESTING THE ENDOMETRIUM FOR IMPLANTATION FAILURE?

7

THINK DIFFERENTLY A CHR OPINION

11

DR. ALBERTINI’S PHOTO GALLERY

15

MONTHLY NEWS

16

OBITUARY

31

PATIENT QUESTIONS

34

CASE REPORT OF THE MONTH

37

A PIECE OF MY MIND: SOMETIMES HOW OTHER FERTILITY CLINICS TREAT PATIENTS BECOMES PERSONAL

41

NON-TRADITIONAL TREATMENTS TO OVERCOME THE ADVERSE IMPACT OF OBESITY ON FERTILITY

45

THE CHR’S FAVORITE NYC RESTAURANTS

50

LITERATURE REVIEW

56

1 | THE VOICE

To Our Readers,

May 2024

After an amazingly successful March-April issue, we welcome you to the May issue. Because the preceding double issue left us with a two-months window to cover, this issue of the VOICE offers practically double the usual page number. We hope that this volume of information is not too overwhelming but with performance criteria of this electronic newsletter (which you can also receive in print by subscribing at social@thechr.com) from issue to issue getting better, we feel encouraged to continue feeding the demand in an attempt of becoming an increasingly important source of information for worldwide reproductive medicine. With an opening rate for the preceding issue of 29.3%, and with an average reading time of 12 minutes and 26 seconds, we not only set new records, but established seemingly almost impossible to exceed goals toward further improvement.

VOICE

Achieving the unexpected is, however, in our blood. We, therefore, will continue to strive for even better results and this issue is, hopefully, a good next step.

This time only a one-month issue, we again are trying to impress with the originality and variety of subjects addressed and, indeed dare to suggest that the combination of materials our readers find in the VOICE is unique in reproductive medicine not only in content, but also in format and presentation.

Considering the diversity of our readership, this issue, as always, attempts to address all the various interests, with the content starting with materials of more general interest and progressively moving toward more science-based subjects and is therefore obviously more restricted to smaller subgroups of our readership.

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As always, we invite you to, nevertheless, browse through the complete issue and let us know what you especially liked (and, of course, disliked). We also want to remind our readers that we are welcoming contributions to the VOICE. Please send us a query at social@thechr.com if you have something to say and you will have a response in hand within one week. Though we are not a medical journal, as a registered in principle electronic publication, articles in the VOICE are citable.

We are very please to welcome in this issue a new – hopefully steady – in-house contributor to the newsletter in Sònia Gayete Lafuente, MD, PhD, who just joined the CHR as a Foundation for Reproductive Medicine Clinical Research Fellow and has already started contributing to the center’s research program in a variety of ways.

Sònia Gayete Lafuente, MD, PhD

Sonia is a trained Obstetrician Gynecologist with a subspecialty in REI with extensive clinical and translational research experience in Spain, and since 2021, as a Clinical Research Fellow funded by a Spanish grant in the OB/GYN department of Yale University School of Medicine in New Haven, CT. There, her main themes were fertility preservation in young women with cancer and other causes of early ovarian insufficiency. As ovarian aging, of course, has also been a main subject of pursuit of the CHR’s research for many years, her becoming a FRM fellow in collaboration with the CHR was a natural evolution when her international support ended, and she decided to remain in the US to continue pursuing her research interests in this country. She is passionate about women’s health and fluent in Spanish and English, and we look forward to her many contributions to the CHR’s research effort.

The Editorial Team of the VOICE We love eggs!

33 || THE THE VOICE VOICE

FEUILLETON

SOME UNDERREPORTED ASPECTS OF ENDOMETRIOSIS: Comments and advocacy Sònia Gayete Lafuente, MD, PhD FRM Research fellow at the CHR

BRIEFING: This article addresses some issues of importance for endometriosis patients which often receive short thrift in the literature.

Some Basics About Endometriosis Endometriosis is a complex, dynamic, chronic condition affecting 5-10% of fertile and 25-40% of infertile women of reproductive age. The disease is defined by the presence of endometrial tissue outside the uterine cavity.

It can be anywhere in the abdominal cavity, but can also reach beyond that into the lungs, rectum, and umbilicus. Endometrial implants usually develop due to the menstrual cycle hormone-dependent changes, similar to those of the uterine lining, triggering local bleeding when the endometrium menstruates which,

in turn, often leads to inflammation, pain, and impaired fertility.

If these symptoms sound familiar, you may be dealing with endometriosis. Living with chronic pain and infertility often results in heightened stress, anxiety, and frustration. The condition can disrupt sleep, impair cognitive function, and diminish enjoyment in daily activities and relationships, impacting overall well-being. Fortunately, women with endometriosis and fertility specialists are no longer the only ones talking about the topic. Given its high prevalence and its implications for women’s health and quality of life, endometriosis has increasingly attracted medical and social attention. The consequences have been more dedicated research, public awareness, and advocacy efforts.

Spain, for instance, in June of 2023 became the first European country to implement government-paid work leaves for incapacitating menstrual pain associated with conditions like endometriosis.

Roughly 1 in 10 women, independent of race and ethnic background, suffers from endometriosis.

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Continued on page 6 Other countries around the world, including Japan, South Korea, Taiwan, and Zambia offer different menstrual pain leave policies, recognizing the notable distress this condition can cause.

Despite such increased awareness and understanding of endometriosis, considerable controversy regarding its impact on fertility still exists, and treatments in different clinical scenarios have remained controversial.

Those include pharmacological and surgical strategies aimed at slowing down or pausing the natural course of the disease and/or reducing its extent. Based on the need to alleviate the severity of symptoms, strategies should always be individualized based on each woman’s treatment target. Early diagnosis and appropriate management can vastly improve reproductive outcomes, but less mindful approaches can also aggravate symptoms as well as infertility.

Ovarian endometriomas are ovarian cysts containing ectopic endometrial tissue. They are among the most common findings in endometriosis, affecting up to 45% of endometriosis patients. Based on their distinctive brownish-blackish color, they are also called “chocolate cysts.” The toxic inflammatory content of these cysts has been shown to cause fibrosis, structural distortion, and vascular deterioration, which damages the surrounding ovarian tissue. This, in turn, results in significant follicle loss (decline in functional ovarian reserve, FOR) and, likely, decreased oocyte quality.

Approximately 30% of women with diagnosed endometriomas are infertile.

Some underreported and rarely discussed issues

Logically severity of disease should correlate to severity of symptomatology! However, this is paradoxically not the case with endometriosis: Mild disease (stage I) can be extremely painful while another woman with stage IV (the most severe form) may not even know she has disease.

Some patients with so-called deep endometriosis may not experience any symptoms at all, while others with small focal and superficial implants may suffer from very severe symptoms. Those symptoms, among others, can include excruciating pelvic pain and/or excessive bleeding before, during, or after periods; pain with intercourse (especially with deep penetration); pain with bowel movements or urination; and typical symptoms of inflammation, such as brain fog and severe fatigue.

The effects of endometriosis on fertility can also be multifactorial. To date, plausible risk factors for endometriosis-related infertility suggested in the literature include altered ovarian folliculogenesis leading to poor oocyte quality, dysfunction of the tubal-ovarian anatomy with mechanical interference of oocyte uptake and transport by fallopian tubes, exposure to a hostile inflammatory environment, oxidative damage, and immune reactions that may impair embryo implantation.

The pain can be excruciating

Endometriomas, moreover, decrease ovarian reserve directly and indirectly. Directly, through the above-noted mechanism, and indirectly because ovarian surgeries that remove endometriomas always also remove healthy ovarian tissue containing still viable follicles. The latter fact has initiated a classical and still unresolved debate about the surgical removal of endometriomas before attempting fertility treatments.

The CHR has found itself in this debate for decades at the very extreme of conservatism, supporting surgery only in the most extreme cases when an endometrioma, for example, threatens to rupture or, because of its weight, threatens to twist the ovary, which can lead to complete ovarian loss.

5 | THE VOICE

Continued from page 5 Because of the almost complete lack of robust data, physician recommendations concerning this subject are almost always subjective. While in the past, the trend favored surgical removal of endometriomas prior to IVF, the majority opinion has in recent years changed much more toward the CHR’s traditional conservatism which appears to preserve ovarian reserve. Recent data, moreover, strongly suggest that women with endometriomas can still confidently pursue IVF and will often still obtain oocytes with comparable fertility as women of identical age without endometriosis. Before undergoing ovarian surgery for endometriosis, we, therefore, always recommend a second opinion (and sometimes a third opinion may also help!).

Integrating counseling into endometriosis care Awareness that endometriosis not only causes physical suffering but also stress and uncertainty regarding a patient’s general reproductive health and future, is essential. An early consultation with a fertility expert with special expertise in endometriosis is, therefore, highly recommended whenever a diagnosis of endometriosis is suspected or has just been confirmed. And by that, we do not mean a consultation with an endometriosis surgeon, - even though those colleagues very often are valuable collaborators in a final treatment plan that attempts to secure a young woman’s FOR over the long term if she suffers from endometriosis.

In addition to reducing the severity of symptoms, treatments in women who are still desirous of future fertility must concentrate on the preservation of maximal fertility. This means that treatments must be aimed at halting the progression of endometriosis and prioritizing non-surgical approaches that could result in irreversible diminished ovarian reserve. Within such a context, Egg Freezing for fertility preservation has assumed an increasingly important role and is bridging the divide between “social” and “medical” egg-freezing. Especially when extensive ovarian surgery cannot be avoided, egg-freezing must be considered before such surgery, not dissimilar to situations where young women are threatened to lose their FOR because of other non-surgical treatments (i.e., for example, treatments with ovary-toxic medications or radiation therapy to the ovaries).

ADVERTISEMENT Fertility counseling is, therefore, always timely in endometriosis, as it enables informed decision-making and empowers women to choose the best reproductive and family planning options for them. Early holistic counseling ultimately optimizes the patient’s autonomy regarding treatment strategies to balance disease management with fertility preservation and family goals.

Reading list Gayete-Lafuente et al. Indirect markers of oocyte quality in patients with ovarian endometriosis undergoing IVF/ICSI: A systematic review and meta-analysis. Reprod Biomed Online.2024; 23-00981R2; ahead of print.

González-Comadran M, Schwarze JE, Zegers-Hochschild F, Souza MD, Carreras R, Checa MÁ. The impact of endometriosis on the outcome of Assisted Reproductive Technology. Reprod Biol Endocrinol. 2017;15(1):8.

Li A, Zhang J, Kuang Y, Yu C. Analysis of IVF/ICSI-FET outcomes in women with advanced endometriosis: Influence on ovarian response and oocyte competence. Front Endocrinol (Lausanne). 2020;11:427 Senapati S, Sammel MD, Morse C, Barnhart KT. Impact of endometriosis on in vitro fertilization outcomes: an evaluation of the Society for Assisted Reproductive Technologies Database. Fertil Steril.106(1):164-171.e1. doi: 10.1016/j.fertnstert.2016.03.037. Epub 2016 Apr 7. PMID: 27060727; PMCID: PMC5173290.

THE VOICE | 6

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Continued on page 7

TESTING THE TESTS

Testing the endometrium for implantation failure?

David Barad, MD MS Head, Clinical IVF and Clinical Research at the CHR BRIEFING: This is the first article in a new series in the VOICE called “Testing the Tests.” The purpose of this series is simple: Large numbers of dubious tests have entered infertility practice, often heavily marketed by industry despite limited or even no clinical value, significant costs, and sometimes, moreover, even causing harm to sub-groups in the infertile patient population. As so-called laboratory-developed tests, many in the U.S., unfortunately, also escape FDA review and they only very rarely face scrutiny by professional organizations like the ASRM. In this first article on the subject, the CHR’s David Barad, MD reviews the use of several tests of the endometrium in attempts to diagnose implantation failure.

There is no greater disappointment for infertile couples in treatment than learning that embryos, produced after weeks of treatment and transferred with great hopes, have failed to implant. The disappointment grows even further if couples also invested in chromosomal testing (PGT-A) and were told that their transferred embryos had been not only chromosomal-normal but also of high morphological grade. Looking at such cases desperately for an explanation, it is easy to conclude that the problem must lie elsewhere and – seemingly – must be unrelated to transferred embryos, which brings us to the subject of “implantation failure” (IF).

This diagnosis, however, carries with it several major problems: (i) Nobody really knows how to accurately define IF or even diagnose this condition. Most of the literature defines IF as failure to establish pregnancy with transfer of 2-3 good quality embryos, but it seems rather obvious to us that this represents a rather low threshold (we would argue that under this definition a very large percentage of infertile women in IVF treatments suffer from IF). (ii) We, moreover, know that as women age, the chance of conception per embryo declines. Consequently, it seems rather puzzling that no IF study in the literature ever adjusted for female age (i.e., increased with advancing age the number good quality embryos transferred to qualify for the diagnosis of IF).

Putting all of this aside, once a diagnosis of IF is sus-

pected, an initial area of investigation in such cases must be the endometrium. Throughout menstrual cycles, women of reproductive age undergo growth and development of this lining which serves in protecting and supporting newly implanting embryos. Proper endometrial development is, therefore, a necessary step in allowing normal implantation.

Fertilization takes place at the distal end of the fallopian tube (see figure below), the organ in which the zygote (the fertilized egg) is retained for another three to five days after fertilization and starts dividing into an ever-greater number of cells. By the time an embryo reaches the endometrial cavity, it has developed into a blastocyst (ca. 250 cells), a spherical structure composed of an outer trophectoderm (the future placenta), and an inner cell mass that, hopefully, will become the fetus.

The endometrium can be evaluated using ultrasound to assess its thickness and structure. Under ideal circumstances, during the follicular phase (first half) of the menstrual cycle, a triple-line pattern is seen in preovulatory endometrium. Following ovulation, the endometrium, however, turns hyperechoic, which means that it becomes a single pale bright stripe without defined lines. Using saline contrast, the endometrial cavity can be evaluated to rule out the presence of an endometrial polyp or submucous myoma. Hysteroscopy (inserting a scope and inspecting the endometrial 7 | THE VOICE

Continued from page 7

The figure depicts a right fallopian tube, with its fimbriae now adjacent to the ovary and allowing an ovulating egg to escape into the distal end of the fallopian tube. There it is fertilized, becoming a zygote, which then starts dividing and developing until it is a blastocyst by the time it reaches the endometrial cavity. After 48 hours, it remains free-floating in the mostly mucous fluid of the cavity, the embryo hopefully implants, - leading to pregnancy.

cavity directly) may also be used to identify abnormalities such as polys, fibroids, or adhesions that could interfere with embryo implantation.

Under the influence of hormones produced by the ovaries, the endometrium goes through progressive developmental changes making it “receptive” for implantation of the newly formed embryo. Failure to undergo these changes properly will lower the chance of embryo implantation. One way of evaluating the endometrium further is to obtain an endometrial biopsy.

What is an endometrial biopsy?

Histological dating of the endometrium was developed and defined in the early 20th century. It was associated with fertility in 1950 with a report in the very first issue of Fertility and Sterility by Noyes, Hertig, and Rock.1 In that report the authors found that an endometrial biopsy could give a “rough idea of the quantitative progesterone effect” and on the time of ovulation.

They also noted that the presence of plasma cells could distinguish the presence of endometritis.

Until 20 years ago, routine evaluation of the luteal phase with histologic examination of the endometrium obtained by endometrial biopsy was part of the recommended work-up for all infertile couples. Before the availability of inexpensive and rapid hormonal assays, endometrial histology offered a bioassay that could prove ovulation and an adequate luteal phase when a predictable pattern of morphological changes was known to occur. If a two-day lag of those changes was observed, the cycle was said to be “out of phase.” Once associated with a shortened luteal phase, these findings were thought to be a cause of failed embryo implantation.

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“Out of phase” endometria were observed in some series in between 5% and 50% of patients, with validity of histologic dating being questioned in part because of this high degree of variability. Later, a large prospective multicenter study found that histological dating of endometrial biopsies could not differentiate between fertile and infertile couples and concluded that endometrial biopsies should no longer be used as part of a routine evaluation of infertility.2 While hematoxylin and eosin–stained endometrial biopsies are no longer recommended, the concept that disruption of orderly endometrial development through the luteal phase could lead to poor receptivity and failed embryo implantation has now moved on to investigations on the molecular level.3 Chronic endometritis, characterized by endometrial inflammation, has now also been associated with recurrent miscarriage.4 The immunohistochemical detection of plasma cells (CD138) in endometrial samples is seen as an objective marker of chronic endometritis.5 While a single course of antibiotic (doxycycline) has been reported to resolve histologic findings of endometrial inflammation in 92% of cases, evidence is limited that such treatment can make a difference in ongoing pregnancy and live birth rate, as randomized studies are lacking and published cohort studies are small. Moreover, it is now also widely accepted that only approximately half of endometritis diagnoses are bacterial, with the other half being inflammatory and, therefore, not responsive to antibiotics.

Despite this lack of evidence for objective effectiveness, testing for endometritis and/or antibiotic therapy is often prescribed for recurrent miscarriage and/or alleged IF attributed to chronic endometritis. While there are numerous studies that support the use of antibiotic coverage to improve implantation and ongoing pregnancy rates, the evidence is not of high quality and, indeed, no randomized controlled trials proving the effectiveness of antibiotic treatment have so far, to the best of our knowledge, been published.6 A large multicenter randomized clinical trial in the U.K. is anticipated to complete recruitment this month (April 2024). Its findings are anxiously awaited.7

Continued on page 10

The endometrial microbiome

A microbiome is a community of microorganisms, including bacteria, viruses, fungi, and archaea that live in a particular environment. While in the past the upper female reproductive tract, including the endometrium, was thought to be sterile, recent studies have suggested that there exists an endometrial microbiome - the composition of which may influence implantation and pregnancy outcomes.8 It is thought that the presence of microorganisms in the endometrial environment could lead to inflammation of the endometrium, altering embryo receptivity as well as the immune tolerance needed to avoid immunological rejection of the early pregnancy.9 The suggestion that endometrial microbiota before embryo transfer is a biomarker predictive of IVF outcomes has led to the promotion of commercial testing of microbiota by Igenomix USA (Jersey City, NJ, producing EMMA and ALICE tests).10 Together EMMA and ALICE testing can cost upwards of $1,000, although the clinical utility and cost-effectiveness of these two tests are far from proven. Igenomix is also one of the principal PGT-A laboratories in the U.S. (and elsewhere) and, as further discussed below, is one of the principal merchants of endometrial receptivity testing. The company, indeed, appears to specialize in bringing to market controversial tests. Interestingly, if EMMA testing is positive, the company recommends treatment with vaginal probiotics (Lactobacillus), which only cost a fraction of the cost of the original testing. One could therefore easily argue, why not offer patients inexpensive vaginal probiotics without testing if an inflammatory process is suspected?

Studies of the endometrial microbiome are easily subject to cross-contamination from microorganisms in the vagina, as any instrument used to sample the endometrial compartment must pass through the vagina which has a rich natural composition of native microorganisms, primarily Lactobacilli. A recent study reported that vaginal Lactobacillus was associated with improved pregnancy outcomes following frozen embryo transfer but found no difference in the endometrial macrobiotic flora between successful and failed IVF cycles.11 As a general criticism of microbiome studies, it has been proposed that modern techniques that amplify the genetic signals associated with specific micro-

organisms might simply be detecting contaminants found in clinical or laboratory environments. Recent studies have found evidence in endometrial microbiome studies of microorganisms commonly found in plants but never found in humans, which, indeed, is supportive of the argument that microbiome studies may be contaminated from their environments.

Studies have also claimed that alterations in vaginal and endometrial microbiome compositions (such as lower prevalence of Lactobacillus) are associated with early pregnancy loss. Whether these associations, however, denote cause or result of pregnancy loss is still unclear. Moreover, antibiotics generally decrease vaginal Lactobacillus and such treatment, therefore, may be counterproductive.

Endometrial Receptivity Array (ERA)

It is widely assumed that the endometrium is receptive to embryo implantation only between 2 and 4 days in the mid-secretory phase of the menstrual cycle.12 The so-called ERA test, again marketed by Igenomix, is a test based on transcriptomic genetic analysis to identify this period of endometrial receptivity. It involves a biopsy of the endometrium and then analyzes the expression of a panel of genes associated with receptivity looking at 238 genes. The test report results the endometrium as allegedly being non-receptive, pre-receptive, receptive, or post-receptive.13 Meta-analyses based on retrospective studies have reached varying conclusions regarding the efficacy of ERA testing in improving embryo implantation. One well designed double-blind, randomized clinical trial of 767 participants conducted at 30 sites in the Eastern US found no evidence that ERA testing could improve the rate of livebirth following IVF and transfer of PGT-A tested euploid blastocyst.14 A later publication reanalyzed the data and, indeed, concluded that ERA testing actually significantly reduced live birth rates and, likely, already led to the failure of thousands of IVF embryo transfers.15

ReceptivaDx testing

The so-called ReceptivaDx test is offered by Cicero Diagnostic Inc (NV). It is advertised as “a path forward for unexplained infertility, failed IVF, and recurrent pregnancy loss” (https://receptivadx.com/).

9 | THE VOICE

Continued from page 9 By way of background, integrin adhesion molecules are known to play a significant role in all mammalian pregnancies. In endometrial biopsy samples, they were found to be abnormal in women with unexplained infertility.13,16 Testing for integrin was, therefore, one of the first commercial tests of endometrial receptivity.

The test, however, was also the first to demonstrate its insufficiency in differentiating between good and poor receptivity. Astutely, the test was then redeveloped to another application.

As it was discovered that the endometrium of women with endometriosis often demonstrates inflammation, it became obvious that these endometria differed from controls by demonstrating more estrogen receptors and fewer other components, including specific proteins. Screening of genes expressed in the endometrium subsequently found that women with endometriosis expressed a very distinct gene profile compared to controls. From this observation arose the hypothesis that those genes induce progesterone resistance, producing an endometrium incapable of supporting pregnancy.

The test is also referred to as the BCL6 test and is now alleged after a diagnostic biopsy procedure to simultaneously assess patients for endometriosis, progesterone resistance, and endometritis. It does so by focusing on detecting the presence of the BCL6 protein, an indicator of inflammation.

BCL6 is found in more than 50% of women with unexplained infertility. Women with low levels of BCL6 demonstrated significantly higher clinical pregnancy rates following embryo transfer.18 That BCL6 is associated with endometriosis and poor implantation, however, does not mean that endometriosis is the cause of BCL6 expression; in fact, it may mean that women with an abnormally high level may, simply, be more susceptible to developing endometriosis. The test is, nevertheless, now used for the tentative diagnosis of endometriosis.

If BCL6 is positive, current published data recommends two options: surgical laparoscopy to remove endometriosis or 60 days of hormone suppression therapy. Both approaches, however, presume that treating endometriosis will decrease BCL6 expression.

Prospective case control studies have, indeed, found significant improvement of pregnancy rates following medical or surgical treatments.19 However, no controlled trials investigating this hypothesis have been performed (though that, of course, does not prevent use of this test and unproven follow-up treatments).

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Conclusions

From the presented data, it should not be surprising that the CHR does not use any of the tests discussed here. While many other fertility clinics often, unfortunately, demonstrate little hesitance in increasing already exorbitant IVF cycle costs by adding unneeded and/or unproven tests and treatments, the CHR has always been very careful in introducing new diagnostic and therapeutic tools into routine clinical practice. We, indeed, almost never introduce a new treatment into routine care without first confirming its efficiency in our center’s unique patient population. In this process, we also always consider our patient’s pocketbooks.

The mostly molecular tests described here, as of this point, cannot and should not be considered as “established.” They, indeed, often have been demonstrated not to improve IVF outcomes. Under most favorable assessments, such testing and resulting treatments represent a waste of time, hope, and resources; in a worstcase scenario, such testing can, however, additionally result in misleading results which in turn can lead to harmful treatments.

While the CHR fully supports investigations that can help with better understanding the complicated physiology of embryo implantation, the current utilization in reproductive medicine of many tests (going far beyond the tests of the endometrium and the problem of IF addressed here) and consequential treatments with no established benefits and often significant downsides for at least sub-populations, is highly disturbing. This subject, therefore, deserves more attention!

REFERENCES 1. Noyes et al., Fertil Steril; 19501; (1): 3-25 2. Coutifaris et al., Fertil Steril 2004; 82(5): 1264-1272 3. Kliman, H. J. F&S Reports 2020; 1(1): 2-4.

4. Cicinelli, et al., Reproductive Sciences 2014;21(5): 640-647 5. McQueen et al., Fertil Steril 2015 104(4): 927-931 6. Buzzaccarini, et al., J Assist Reprod Genet 2020; 37(12): 2897-2911 7. Odendaal et al., BMJ Open 2023;13(12): e081470.

8. Odendaal,et al., Hume Reprod 2024; 39(4): 638-646.

9. Blazheva, et al., Microorganisms 2024; 12(3): 547 10. Moreno, et al., Microbioma 2022;10(1):1 11. Wei, et al., J Assist Reprod Genet 2024; https://doi.org/10.1007/s10815-02403066-0; ahead of print.

12. Wilcox, et al., N Engl J Med 1999; 340(23): 1796-1799.

13. Díaz-Gimeno, et al., Fertil Steril 2011; 95(1): 50-60.e15.

14. Doyle, et al., JAMA 2022; 328(21): 2117-2125

15. Richter, et al. Hum Reprod 2023;38(7): 1239-1244.

16. Johnson, et al., J Animal Sci Biotech 2023;14:1 17. Lessey,et al., Fertil Steril 1995;63(3): 535-542.

18. Almquist, et al., 2017; Fertil Steril 108(6): 1063-1069.

19. Likes, et al., J Assist Reprod Genet 2019 36(3): 483-490.

Continued on page 12

THINK DIFFERENTLY – A CHR OPINION

ONCE MORE CHOOSES POLITICAL CORRECTNESS OVER REALITY: The real U.S. maternal mortality rate!

BRIEFING: The impression of many members of the ACOG in recent months has been that, like many other academic and professional not-for-profit organizations, ACOG no longer appears to act in accordance with its members’ values. This current low point may be, at least partially, the consequence of the absence of permanent and competent leadership. The CEO is unfortunately only in an acting capacity and the current (physician) President seems unable or unwilling to stand up to a highly politicized bureaucracy within the organization, which for all practical purposes, has assumed control over the ACOG. One can only hope that the upcoming election of a new President will change things. Like in so many other not-for-profits (including major prominent universities and medical schools), political ideologues, primarily driven by the slogan of the current political moment, “Diversity, Equity, and Inclusion” (DEI), have taken over at ACOG. While ACOG has not yet recovered from the resignation of substantial numbers of Jewish and non-Jewish members because of the college’s shameful refusal (under current leadership) to condemn the Hamas atrocities against Israeli women on October 7, 2023, we here point out the most recent example of shameful behavior of ACOG (under current leadership). This time, an attack letter was executed by the currently acting CEO of ACOG against highly qualified Canadian colleagues who, based on an excellent study, had dared to demonstrate that widely distributed U.S. national maternal mortality data were, based on negligent data collection, unreliable and incorrect. Too high and increasing maternal mortality rates, however, have not only been at the core of ACOG’s drive for more financial support from the government, but have also been a key argument in its DEI-dependent policies.

It does not happen often that the American College of Obstetrics and Gynecology (ACOG) formally criticizes a paper that appeared in the OB/GYN literature, but this is exactly what recently occurred. Even before the article appeared in print in the American Journal of Obstetrics and Gynecology (AJOG),1 ACOG was already “upset” enough to publish a rebuttal by Christopher M. Zahn, MD, Interim CEO and in his usual job, unsurprisingly, Chief of Clinical Practice and Health Equity and Quality of ACOG.2 The CHR has not been very happy with the decision-making process at ACOG under his authority (which also included no response – not even an acknowledgment - to personal notes sent to him and other members of the current leadership). But, maybe, we should make it less personal and just note that we have not been very happy with many of the recent decisions made by ACOG, culminating with the shameful silence of ACOG (as probably the only professional society serving primarily women) in response to the occurrences of October 7 in Israel involving mass-rape and murder of so many innocent women and children

(and let us also not forget the men who also, allegedly, often were sexually assaulted), - a situation, at the time of this writing, still unresolved for over 130 abducted hostages, even including a baby (many, if not most, very likely already murdered by their abductors, as recent media reports suggest). This not being the subject of this column, let us, however, return to the matter that quite obviously attracted more of Dr. Zahn’s attention than October 7 ever could have, - a recent article from a team of highly qualified Canadian colleagues published in the AJOG, the longstanding competitor to ACOG’s own journal, Obstetrics & Gynecology.

Though it would be interesting to know whether this manuscript had been submitted and rejected by Obstetrics & Gynecology before acceptance by AJOG, we do not wish to imply that ACOG’s reaction to the impact this paper has had on media and the public may have been influenced by the decades-long competitive jealousy between these two journals (the AJOG clearly emerged as the winner). However, it is important to point out that the authors of this paper have considerable expertise in study design and statistical analysis of complex data sets.

11 | THE VOICE

Continued from page 11 This is of importance, considering the criticism directed at the study by ACOG and other representatives of the political OB/GYN establishment for whom a rising maternal mortality rate, of course, is the perfect pitch for more funding for obstetrical interests. Dr. Zahn, if he does not assume the CEO position at ACOG permanently, is, of course, in principle the Chief of Clinical Practice, Health Equity, and Quality of ACOG. This background information is important to understand, considering that we are here addressing a study that aimed to assess why maternal mortality rates were so high in the U.S. and increasing. Might this be caused by newly arising obstetrical factors (including new practice patterns)? Were those rates, possibly, the consequence of more maternal medical diseases (as older women represent the most rapidly growing age group having children)? Or, and here is where this study became such a threat to the obstetrical establishment, have mortality rate assessments over time maybe changed in ways that led to incorrect assessments?

That this was important to ask is indisputable because how could anybody otherwise understand the underlying causes of increasing maternal mortality rates?

And the study, indeed, offered a very clear answer: The high and climbing U.S. maternal mortality rate in the U.S., according to a quite simple but brilliant investigation, turned out to be “fake news.”1 Alysia Finley in The Wall Street Journal called it the “phony pregnancy crisis.”3

So, what, then, is going on here?

The answer is rather straightforward: Like in so many other fields of medicine (one only has to look back at the COVID-19 pandemic), self-interested “experts,” in this case in a relatively small and poorly funded medical specialty field, recognized the unique opportunity of a professional lifetimes to financially benefit the specialty (and, of course, themselves) by arguing that a high – and even increasing – maternal mortality rate in pregnancy represented an inexcusable stain on U.S. medicine that, of course, required immediate remedies (i.e., additional funding). The argument, moreover, was further strengthened by the long-known observation that obstetrical outcomes in minority populations lagged behind those of Caucasian women.

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Efforts of improving obstetrical outcomes in minority populations – an obvious universally desired goal in the profession - therefore, also were reflective of the current social “Zeitgeist” in medicine which in recent years developed a rapidly growing “equity” industry, probably nobody more so than ACOG (we recommend you visit the ACOG website and browse through “Diversity, Equity, and Inclusive Excellence at ACOG”4 to appreciate how radical ACOG’s political positions have become under its current leadership). High and growing maternal mortality rates, therefore, became a practically irresistible symbol for the big theme of inequity in clinical medicine, which now no longer allows for doubts about the alleged associations between systemic racism and systemic inequities in obstetrical care and increasing maternal mortality in pregnancy (we again recommend above referenced ACOG website). Consequently, not only was there no longer an incentive to further investigate whether these alleged associations were really factual but attempts to do so would undoubtedly - as the ACOG reaction addressed here so well demonstrated – not only be disincentivized but met with derision and excommunication from the community. Unsurprisingly, it, therefore, took Canadian colleagues to demonstrate to their U.S. colleagues how poor their insights into obstetrical practice in the U.S. really were.

How various self-interests can affect medical practice, has been a steady subject in the VOICE for many years.

Closing one’s eyes to inconvenient truth is one way of serving one’s own interests rather than serving the community as a whole. Obstetrics over many years, indeed, did absolutely nothing to reconfirm the annual reports from the Centers for Disease Control (CDC) that regurgitated year after year (as we now learned) incorrect reports of increasing maternal mortality rates in the U.S. That the CDC cannot always be trusted in its reporting is, of course, nothing new: False interpretations over the years of national IVF outcomes have occurred (and been criticized in these pages) repeatedly. And, who, of course, can forget the many misleading statements from this federal agency during the COVID pandemic? It took Canadian colleagues to study what was really going on with U.S. maternal mortality rates. One, therefore, must ask, where were U.S. organizations like the CDC, ACOG, the NIH, and U.S. obstetrical academia in general?

Continued on page 14 It is difficult to believe that nobody in the U.S. was suspicious of these published maternal mortality data and that nobody was at least considering the possibility that the national data collection may be at fault.

But that, of course, might have turned off the spigot of financial support and would have weakened the allegation of widespread institutional racism and inequity in obstetrical practice, and that cannot be allowed to happen!

CHR, however, is – and always will be – an in-principle data-driven organization. The CHR, therefore, does not bias its conclusions based on what is considered a politically correct answer in a given time period, but, like our here-addressed Canadian colleagues, follows the numbers of well-executed studies, wherever they may lead us.

With all of this as a backdrop, it now is time to let Dr. Zahn and ACOG speak, allowing them We, of course, do not wish to suggest that inequities in to offer their reply. We, indeed, will give them obstetrical practice based on race, ethnicity, and many the last word by simply reprinting ACOG’s other factors do not exist. Very much to the contrary, the CHR for decades has been at the forefront of trying News Release of March 13 2 because it so well speaks for itself in how eerily similar in tone to bring equitable care to economically poor patient populations. After all, the CHR was founded in 1981 and excuses this formal ACOG statement was as the academic OB/GYN practice of an inner-city to what Dr. Anthony Fauci’s had to offer as hospital in Chicago which, in a majority, served miexcuses for all of his misrepresentations during norities. CHR investigators were among the first in the COVID-19 pandemic. the world to point out racial outcome differences in association with IVF and tried to explain them.5 The

HEADING: ACOG NEWS RELEASES March 13, 2024 Despite New Manuscript, Incontrovertible Evidence Proves the Unacceptably High U.S. Maternal Mortality Rate The following statement is from Christopher M. Zahn, MD, FACOG, interim CEO and chief of clinical practice and health equity and quality of the American College of Obstetricians and Gynecologists: A new manuscript published in the American Journal of Obstetrics & Gynecology regarding U.S. maternal mortality rates and surveillance confirms what we know, which is that we need data to drive change.

However, this publication paints an incomplete picture and fails to highlight what we should be focusing on regarding maternal deaths—preventability. Discrepancies exist when data are derived from multiple sources, and overall, all our data systems could be improved. We live in a country with a fragmented health care system, and it will take continued and significant investment to make improvements to our surveillance systems. To reduce the U.S. maternal mortality crisis to an ‘overestimation’ is irresponsible and minimizes the many lives lost and the families that have been deeply affected.

Using their methodology, the authors found that there had been decreases in maternal death rates for some conditions, such as hypertension, hemorrhage, and preeclampsia. This shows that nationwide and regional programs to eliminate deaths from preventable pregnancy-related conditions, such as the Alliance for Innovation on Maternal Health, are working. But where we still fall short is in successfully addressing significant, existing racial health disparities, which were mentioned only briefly in this manuscript. Additionally, the authors pointed out that mortality rates had increased for several conditions, including placenta accreta syndrome, cardiomyopathy, and preexisting hypertension. So, there is still a lot of work to do.

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Continued from page 13 The authors have created discrete categories to discredit the pregnancy checkbox, which, while somewhat flawed in its implementation, was not created to fabricate a problem. It was created to address an existing one. It is one of multiple sources of data we have—each with its own pros and cons, showing different aspects of maternal health outcomes—that help to provide information so that we can create actionable solutions.

For instance, data that come from maternal mortality review committees are broader and more in-depth and reflect a longer period of time. These multidisciplinary committees examine maternal deaths well beyond 42 days postpartum and instead look up to a year after pregnancy—a critical time. Based on Centers for Disease Control and Prevention data, approximately 30% of pregnancy-related deaths from 2017 to 2019 occurred from 43 to 365 days postpartum because of several factors, including ones that the authors have discounted, such as mental health conditions, which include suicide and substance use disorder.

REFERENCES 1. Joseph et al., Am J Obstet Gynecol 2024; https://doi.org/10.1016/j.ajog.2023.12.038; Online ahead of print.

2. Zahn CM. ACOG News Release; March 13, 2024. https://www.acog.org/news/news-releases/2024/03/despite-new-manuscript-incontrovertible-evidence-proves-unacceptably-high-us-maternal-mortality-rate 3. Finley A.. The Wall Street Journal. March 25, 2024. pA17 4. ACOG. https://www.acog.org/about/diversity-equity-and-inclusive-excellence.

5. Gleicher et al., PLoS One 2011;6(4):e18781

IVF CLINICAL COORDINATOR, CURRENT NEW YORK RN LICENSE

at the CHR

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As a Nurse coordinator, you’re responsible for all aspects of patient care, egg donors, complete patient assessment, this position collaborates with the physician to coordinate care and consult with patients regarding treatment and protocols, medications and/or required testing procedures. The IVF nurse coordinator is expected to function independently in the role, seeking assistance from the physicians, the manager and team members as needed.

The CHR offers a unique practice model by being a privately owned independent infertility center with strong academic links, and a strictly academic discipline in practicing medicine and conducting important research. If you are the nursecoordinator we are looking for, please send your CV to Ms. Jolanta Tapper, COO (jtapper@thechr.com). All submissions are considered confidential correspondence.

THE VOICE | 14

IMAGE 1: Research at CHR relies heavily on peering into the details of our genetic heritage, a subject our readership has heard much about when it comes to the genetic testing of embryos. But understanding more about the health and integrity of DNA-containing nuclei can be learned from using the cells residing inside the follicles we obtain during ovum pickup. Here, several granulosa cells are shown with odd shapes in the nuclei (blue) indicating an early stage of cell aging or senescence.

IMAGE 2: Using special labeling tricks, our research also allows us to explore the degree to which DNA is damaged in granulosa cells we obtain from patients of different ages. Here, you see many small yellow spots in the nucleus of a cell that is undergoing repair of breaks in the DNA molecules found in the nucleus. In both images, the actin cytoskeleton is shown in red.

15 15 || THE THE VOICE VOICE

MONTHLY NEWS MONTHLY NEWS MONTHLY NEWS BRIEFING: Here, we offer brief notes regarding news that in the preceding months caught our attention as relevant to the practice of reproductive medicine and infertility.

ASRM announces termination of affiliation with Springer Nature’s Journal of Assisted Reproduction and Genetics (JARG) In a terse, short three-paragraph announcement to membership by e-mail (see below reference 1), the ASRM on March 21, 2024, made public that insiders for quite some time expected a “strategic decision to focus on the development of the society’s own new family of Fertility and Sterility journals,”1 in addition to the mothership, Fertility and Sterility, now also including F&S Science, F&S Reports, and F&S Reviews, all launched in 2019. As a consequence of this decision, the ASRM as of that same date terminated the society’s affiliation with the JARG, owned and published what is likely the world’s most prestigious medical and science publisher, Springer Nature. JARG had served as the ASRM’s principal basic science journal since January of 2009. The e-mail further stated that, “as a result, effective immediately, JARG access will no longer be offered as part of ASRM membership.”

The ASRM-Springer Nature arrangement had been initiated after ESHRE already in 1995 had expanded its publishing empire beyond the society’s initial Human Reproduction journal to Molecular Human Reproduction (as its basic science journal), later to be followed by Human Reproduction Open, and Human Reproduction Update.

Founded by the medical publisher Alan List in 1982 as the Journal of In Vitro Fertilization and Embryo Transfer (IVF-ET) with the CHR’s Norbert Gleicher, MD, (in those days located in Chicago) as founding Editor-in-Chief, and in 1984 with the advent of chromosomal testing of human embryos during IVF at the urging of Yuri Verlinsky, PhD (credited with having conceived the idea of genetic testing of embryos as an initial Associate Editor of the journal), renamed the JARG,2 the new sponsorship by the ASRM was a welcome opportunity to expand the readership of the journal, as the agreement offered ASRM members free access to the journal. At the time it was also a very beneficial arrangement for the ASRM, by David Adamson, MD (then ASRM President), described as follows: ”Springer’s journal JARG, in conjunction with our existing publications, will significantly enhance our Society’s ability to bring scientific advances in reproduction and genetics to our members.” 3 Left unsaid was that JARG offered the ASRM an immediate counterpart to the ESHRE’s Molecular Human Reproduction journal without any investment. Springer, moreover, in addition, paid the ASRM a quite significant annual licensing fee and allowed the ASRM to choose a new Editor-in-Chief.

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Continued on page 18 Purely coincidentally, David F Albertini, PhD, who several years later joined the CHR as Director of the CHR’s Laboratory Division, and to this day is still an active Visiting Senior Scientist at CHR, assumed this position to considerable acclaim, significantly expanding submissions to the JARG and turning the journal into a fierce competitor in an ever-expanding sea of medical journals in reproductive endocrinology and infertility by significantly improving its impact factor.

It will now be his responsibility to transition the JARG with help from the publisher into independence from the ASRM. Though the cut-off from the membership of ASRM may somewhat hurt, opportunities for the JARG will also arise from this break-up, including the freedom to compete more aggressively with the family of F&S Journals and Fertility and Sterility itself.

REFERENCES: 1.

Well-summarized in a recent editorial in The Wall Street Journal, the government-mandated lockdowns resulted in almost no benefits but caused very significant economic and health-related damages.2 The authors described health benefits achieved from the lockdowns as “tiny,” apparently preventing only between 4,000-16,000 COVID deaths. To define “tiny,” they noted that this referred to in comparison to annually approximately 37,000 people dying from the flu in the U.S. On the other side of the equation, they defined economic, social, educational, and health harms as “enormous,” suggesting at least 400,000 additional deaths were caused by mandated or recommended interventions (and excluding deaths directly caused by the SARS-CoV-2 virus), which likely included the approximately 40,000 additional deaths in New York State from sending infected patients back into nursing homes. Sourced from a paper in the Proceedings of the National Academy of Sciences (PNAS),­3 the article summarized well the most basic message: In comparison to other developed nations, the U.S. did very poorly!

2. Friberg J, Gleicher N. JARG 1984;1(1):1 3. Springer Newsreleas. https://www.eurekalert.org/news-releases/607120

Lessons learned from the COVID-19 pandemic - better late than never So, we all know by now that this country (and most, though not all, of the world) did not manage the COVID-19 pandemic very well (to say it politely).

Now, over four years later, organized objective critique has finally started to trickle out as a result of congressional hearings, investigative journalism (yes, it does still exist to a degree), and legal proceedings even involving the Supreme Court in Murthy v. Missouri, in which Jay Bhattacharya, MD, a brilliant professor of health research policy at Stanford University, is one of the plaintiffs in accusing the Biden administration of policing (his) free speech.1 The final verdict on how the U.S. managed the COVID-19 pandemic is not pretty. Almost nothing we were told to do was worth the effort, and much of what we ended up doing was actually harmful.

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Continued from page 17 This becomes most apparent in a comparison of all causes of death experienced during the COVID pandemic between 2020 and 2023, including COVID-related as well as lockdown- and other government-related deaths in comparison to expected death rates in non-COVID times (see figure above). As the figure demonstrates, among developed nations, the U.S. experienced the overall highest excessive death rate of 12.7% during the pandemic, followed by the U.K.

hospital-based services. As the article noted, emergency room visits, for example, dropped between 40% and 50%, while hundreds of thousands of chemotherapy patients did not get their required treatments for prolonged periods of time because hospitals basically shut down non-pandemic related services. As the article also noted, some medical services have still not recovered to pre-pandemic levels.

The article then also addressed the economic damage caused by the nation’s mandated lockdown. Among other factors, at its peak in May of 2020, 49 million Americans were out of work. The authors note that the shock of unemployment carries with it significant health consequences and is predicted over the next 15-20 years to lead to an additional 840,000 to 1.22 million excess deaths, especially affecting women and minority populations.

But, as already widely reported earlier, the likely most significant long-lasting damage to the country came from the prolonged school closings in most states.

Total excess deaths during the COVID-19 pandemic: The U.S. leads They are expected to reduce the earnings of significant and Sweden was by far the best. SOURCE: Reference 3 populations for decades and will most affect those who (10.5%), Spain (8.2%), France (8.1%), South Korea can least afford it. The authors note that by one eco(8.1%), Germany (7.5%), and Sweden (3.5%). Sweden, nomic estimate, the affected generation of children in indeed, demonstrated the lowest rate by far and, parthe country will lose $17 trillion in lifetime earnings. adoxically, during the pandemic was widely criticized Though school closings ultimately did not offer any by public health experts all over the world for being public health benefit (except maybe to the pocketbooks the only country that did not lock down at any stage of of teachers’ union members), they produced signifithe COVID pandemic and did not shut down schools. cant additional adverse medical consequences for the Public health experts in the U.S. who supported similar longer-term wellbeing of the children, including - here measures to Sweden during the pandemic were practi- they use the term “massive” - increases in psychiatric cally ostracized by the public health establishment and illnesses, self-harm, obesity, and substance abuse. the U.S. government (more on this below).

Into all this accounting one also must include the subThough these differences in percentages on first imstantial loss of faith in health experts and government pression may not appear too impressive, what they in general. Both groups have lost considerable esteem mean, however, is indeed, “enormous:” Had the U.S and are seen by many as coalition partners in attempts followed the Swedish model, the country would have to deceive the public. experienced 1.60 million fewer deaths between 2020 and 2023, 1.07 million fewer had it followed Finland’s, To regain this trust, it will take work and much more and 910,00 fewer had it followed France’s management commitment to transparency and clear separation patterns. between science advisors and the politicians they are advising. In addition to other remedies (among those, One major contributing factor to these excess deaths first and foremost, the recognition that so many miswas the excessive fear of contagion communicated takes were made), the authors of The Wall Street Jourby the government and media to the general popnal article suggested term limits for senior positions in ulation, which prevented people from seeking out health agencies. non-COVID-related healthcare services, especially THE VOICE | 18

Continued on page 20 Considering that some very prominent agency leaders during the COVID pandemic actively (and at times even aggressively) attempted to shut down dissenting professional opinions, it is not surprising that even some very prominent voices were muzzled. One of The Wall Street Journal article’s authors, Scott W. Atlas, MD, indeed, became one of the most prominent among a small group of these “outcasts,” all mostly restricted to the Stanford and John Hopkins campuses.

Both groups were outright ostracized by the medical public health establishment for speaking out against what they felt were erroneous and harmful public health policies.

Then the subjects of often harsh criticism, they are now widely appreciated, as their original opinions are fully recognized as correct and, often, precise insights, while most of the academic public health establishment not only refused to listen but aggressively attempted to shut down those colleagues’ rights to free speech.

Fittingly, Atlas, initially a clinical department chair and professor at Stanford, had given up clinical practice and had assumed the research position of the Robert Wesson Senior Fellow at Stanford’s Hoover Institute by the time the pandemic hit. Steve H. Hanke, PhD, his co-author on the article, is a professor of applied economics at John Hopkins.

Scott W. Atlas, MD SOURCE: The Mercury News

We cannot help ourselves but contrast their brief but important commentary with an earlier commentary of approximately equal length from the World Health Organization (WHO) titled: “Lessons learned from COVID-19: how the pandemic affected children’s health and habits?”4 In that commentary, the WHO offered three lessons: COVID-19 led to (i) “increased frequency of home cooking;” (ii) “increased consumption of sweets;” and (iii) “decreased levels of active play for children.”

After reading these three main “lessons” the WHO took home from COVID-19 and considered important enough to be formally published, can anybody still be surprised about this agency’s incompetent performance during the COVID pandemic? It took the WHO over two weeks to recognize that there was a pandemic brewing in China before announcing it to the world. Then its leader criticized the U.S. for shutting down air traffic from China. This was followed by the WHO’s purposefully, and to this day, obfuscated the likely origin of the pandemic from the Wuhan Institute of Virology in Wuhan, China. As Nicholas Wade recently opined in The Wall Street Journal,5 new documents bolster the theory that the SARSCoV-2 virus not only escaped from this laboratory but was, indeed, developed there, finally explaining the genesis of the COVID-19 pandemic that killed millions.

Within this context, a recent report from the non-profit Committee to Unleash Prosperity (CTUP), 6 which sharply criticized the government’s response to the COVID pandemic, describing lockdowns, school closures, and vaccine mandates as “catastrophic errors, resulting in many Americans losing faith in public health institutions,” suggested that the U.S. halt all binding agreements and/or pledges to the WHO, supported term limits for senior health agency positions, and recommended that powers of health agencies be limited to make certain that they remain strictly advisory and not be given the power of making law or setting mandates. Atlas and Hanke were two of the four authors of this report.

REFERENCES 1.Wiseman O. The Free Press, March 20, 2024. <bariweiss@substack. com> 2. Atlas SW, Hanke SH. The Wall Street Journal. March 19, 2024, pA17 3. Paglino et al., PNAS 2024;121(6):e2313661121 4. WHO. May 22, 2023. https://www.who.int/europe/news/item/22-052023-lessons-learned-from-covid-19--how-did-the-pandemic-affectchildren-s-health-and-habits 5. Wade N. The Wall Street Journal. February 29, 2024; pA17 6. Atlas et al., Committee to Unleash Prosperity. https://committeetounleashprosperity.com/wp-content/uploads/2024/03/240313_CTUP_ COVIDCommitteeReport_Doc.pdf

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Continued from page 19

Will DEI in medical schools have the same effects as at Boeing and Google?

Opinions about the concept of DEI (diversity, equity, inclusion), which in recent years has found widespread applications at all levels of our education system, the media, Hollywood, and even in corporate America, may, of course, widely vary; but the popularity of DEI in almost all of those spheres of life is now, surprisingly, quickly losing popularity. One can argue why that is, but it is difficult to deny that only the most committed DEI supporters would choose the pilot flying their plane or the physician operating on their bodies to have qualified for their jobs based on DEI criteria rather than the degree of their competence.

These two companies were recently reported to have been adversely affected by their radical DEI policies

The spreading of this sentiment is well documented by increasing numbers of media reports on this subject.

Some recent ones, for example, quoted Elon Musk suggesting that a federal filing by the Boeing company demonstrated that over the recent years the company initiated in its hiring DEI goals incentives for company executive compensations in place of prior incentives that had been primarily directed at safety and quality control.1 The principal implication of these comments, of course, was that Boeing prioritized DEI over safety and that this represented a major reason for the many mishaps the Boeing company – once the pride of the country’s industrial sector - has recently experienced.

A recent article by Francesca Block and Olivia Reingold in The Free Press offered an even more telling example for the argument that DEI-driven hiring will ultimately always adversely affect the overall performance of even very large companies. The recent chatbot disaster that befell Google after launching its new AI program was directly tracible to biased data inclusions in building their chatbot by staff Google hired in one of the most radical DEI hiring programs in the industry.2 The practice of medicine as well as medical education have, of course, not been spared from widespread implementation of DEI. Despite the cliché that most people would rather choose their physician based on THE VOICE | 20

qualifications than DEI, medical education and clinical practice adopted DEI with wide open arms and considerable vengeance. These developments, however, recently have been generating increasing concern, as expressed in an editorial in The Wall Street Journal under the rather provocative title “Ban DEI quackery in medical schools.”3 The article claimed that accreditation institutions are “pushing” all 158 accredited medical schools to train their students in political activism instead of using time and resources on “rigorous coursework and prep for medical practice.” In analogy to above above-noted corporate examples at Boeing and Google, the authors feared a similar fate of deterioration in the quality of the product (in this case “less qualified physicians”) to become the consequence.

Like almost all aspects of society, medicine has now for several years been in the midst of revolutionary (in the full sense of this word) changes. What in the 1970s still was an almost pure male profession and since has come to produce medical school classes with usually female majorities, is now on the way to becoming a female profession in practically all specialty areas. Unsurprisingly, women, therefore, are also quickly assuming leadership positions in all areas of medical practice and administration.

Why especially male racial and ethnic minorities are lagging in similar accomplishments is, therefore, somewhat of a puzzle. Clearly, women would not have progressed so quickly had they not earned this progress, as unearned progress in fulfillment of only idealistic slogans and social theory cannot succeed in the long run. In medicine (and, of course, in many other academic endeavors), careers primarily based on “social welfare” quickly become obvious. They then also carry with them the danger of delegitimizing demonstrated excellence by members of minority groups.

To address current DEI influences in medical schools and “to return medical education to its life-saving mission,” the articles suggested several interventions into current medical school operations and practices: (i) ending attempts at teaching medical students to treat patients differently based on race, sex, or gender identity and to define individuals either as “oppressor” or “oppressed,” (ii) stop offering scholarships, classes, and programming exclusively or preferably only to students with selected identities, races, or ethnicities, (iii) ending mandates for students and faculty to write

Continued on page 22 (iii) ending mandates for students and faculty to write DEI statements as preconditions for acceptance/employment, and (iv) close down DEI offices in medical schools. The article also suggests that these changes should be legislated by Congress as a condition of federal funding of medical schools.4

ly reported that five publications from this group of investigators have been tagged so far. Four had to be withdrawn, and the fifth, in a comment by the journal, was accused of “severe abuse of the scientific publishing system.”1 This scandal involves the Chief of the cancer surgery division at Columbia University’s medical center. The hospital and medical school have, A California lawsuit by a Black female Los Angeles-based anesthesiologist, who has practiced for 50 however, failed to comment on years, was filed because she considered “calling doctors this growing scandal so far, nor have there apparently been any out for implicit bias as divisive, arguing that the state disciplinary actions taken against cannot legally require her to teach the idea in her con5 involved individuals. One can tinuing education classes.” only hope that a proper investiWith the country quite obviously in the midst of a very gation is underway because, as intense “culture war,” it is only too obvious that medinoted in last month’s VOICE, the number of retracted cine must be and will be affected. The pushback against papers in even prominent journals has been skyrocketing, further contributing to the growing lack of confiDEI in health care and medical education appears at dence in medical science (and other academic fields) least partially inspired by the recent Supreme Court decision that barred affirmative action in higher educa- by the general public after the COVID-19 pandemic.` That this increasing lack of tion. It is, furthermore, equally obvious that since the 1990s medicine has radically changed, with most prac- trust in academia goes beyond just the medical field is titioners in those years philosophically and politically well demonstrated by a recent being conservative, to now becoming a much more article in the Free Beacon,2 progressive profession. Where the field ultimately sets boundaries will determine the future of medicine in which alleged that a Stanford this country and the world.

University professor whose research led to a major change REFERENCES in how the city of San Francis1. Thaler S. New York Post. January 11, 2024. https://nypost. co taught 8th-grade algebra (it com/2024/01/11/business/elon-musk-rips-boeing-they-prioritized-deiover-safety/ axed it!) is now (after the experiment very obviously 2. Block F, Reingold O. The Free Press. March 19, 2024; bariweiss@ failed) accused of “reckless disregard for accuracy,” substack.com according to an academic complaint filed with the 3. Murphy G, Goldfarb S. The Wall Street Journal. March 19, 2024, pA15 4. Weber S. Medscaped Medical News. March 21, 2024. https://www.

Stanford University provost, when in 52 instances medscaped.com/viewarticle/proposed-bill-could-end-student-aid-usmisrepresented supporting research she cited in her med-schools-dei-2024a100059t publications to support her conclusions. She also owns 5. Cohen R, KFF Health News. February 28, 2024. https://kffhealthnews. org/news/article/anti-bias-training-health-...OMUL7edkfV2gcrBFPaa company through which she, according to another Khy3tbjnfnF7fKuwTjA7DYRBYgMIaQBAvZU8EACIm-M3KE4 recent opinion article,3 has become “one of the biggest influencers of math education in the nation.” The comIncreasing doubt about academic integrity pany’s website allegedly in its first sentence defines the More retracted publications purpose of the company as “how equity is promoted in mathematics.” Obviously, something is very wrong in We in these pages in the preceding issue of the VOICE academia, and some of the most prominent and prestireported on the rapidly increasing number of pubgious universities are smack in the middle of it! lished studies that are being withdrawn by journals because of obvious irregularities in published data. We REFERENCES 1. Mueller S. The New York Times. March 22, 2024. pA13 also noted that some of these scandals involved prom- 2. Luthi S. Free Beacon. March 20, 2024; https://freebeacon.com/califorinent scientists, including leaders of major institutions. nia/san-francisco-cited-this-professor-to-end-8th-grade-algebra-her-research-had-reckless-disregard-for-accuracy-complaint-alleges/ One local scandal involved a prominent cancer lab at 3. Chin WW. New York Post, March 22, 2024. P27 Columbia University and The New York Times recent21 | THE VOICE

Continued from page 20

Self-promoting science leads to self-promoting practice But returning to medicine, Britain’s National Health Service recently announced a ban on the use of puberty blockers for the treatment of gender dysphoria in transgender minors. As the New York Post in that regard noted in an editorial, at the same time the U.S. medical establishment and government have remained mum and, indeed, appear committed to this treatment which the editorial describes as “junk science.”1 The article notes that in the U.S., medical practice in this area is dominated by the so-called World Professional Association for Transgender Health (WPATH), made up of alleged “experts” in the field - all, however, of course have significant financial as well as career interests linked to the medical practices in the field.

Without having the expertise to comment on this very specific subject, the activities ascribed by the editorial to the WPATH, however, sound very familiar to us and it works the following way: A few clinical researchers discover an allegedly new and useful treatment; they publish several, often rather poorly executed studies in usually not very prominent medical journals and establish “a new area of medical expertise,” and in parallel, “a new specialty society” for the field, often also accompanied by a “new specialty journal;” and from this point on, the process starts feeding upon itself. Papers are written, usually poorly reviewed by “experts in the field” from the same club of interested players with (as noted above) strong personal interests. The society, with its members as the “leading” experts, publishes practice guidelines for the new field – of course, also in strong support of the procedure(s) involved - exactly as reported in the New York Post.

If this sounds familiar to readers of the VOICE, then this was, indeed, the intent. It, indeed, exactly mimics the process of how, for example, the Preimplantation Genetic Diagnosis International Society (PGDIS) 2 came into existence and the principal source for guidelines addressing the practice of genetic testing of human embryos, even though the society’s guidelines lack even minimum standards for how clinical practice guidelines must be developed.3 Very clearly, the medical establishment and government in the U.S., apparently care much less about very obvious conflicts of interest in medical practice than, for example, medical THE VOICE | 22

establishments in the U.K. and Sweden. One has to wonder, why?

As the disastrous management of the COVID-19 pandemic in most countries once again so well demonstrated, because of the very obvious self-interests (and limited worldview) of every “expert” concentrated on only his/her own field of special interest and expertise, the behavioral literature has for decades offered irrefutable evidence that “expert” opinion in every field must be consumed with caution and should never be trusted as the only (or even principal) decision maker.

(See also the preceding discussion on the COVID-19 pandemic literature). Because of their inherent biases, experts can serve as advisers but should never be entrusted with making final decisions!

REFERENCES 1. Editrorial, New York Post. March 17, 2024. P38 2. https://pgdis.org/ 3. Gleicher et al., J Assist Reprod Genet 2023;40(4):817-826

Is China the main problem, or is it academia and the medical publishing industry?

Nobody can argue any longer about the enormous progress medical research has achieved in China over recent decades, reflected not only in the numbers of Chinese papers in virtually all medical journals including highly ranked journals, but also the stellar quality of many of those papers. At the same time, China has, however, also become central for many problems that have befallen the medical and scientific publishing industry, starting with paper mill publishing and all of its terrible consequences, and a, seemingly, above average paper retraction rate for Chinese publications. But there are also additional problems: Science magazine, for example, recently pointed out a newly arising issue that resulted in the retraction of 18 papers from China in a genetics journal (Molecular Genetics & Genomics Medicine) over concerns that informed consents were improperly obtained from study participants, mostly minorities, considered vulnerable to state oppression.1 This mass retraction by one journal points out a bigger and systemic problem to which Chinese papers have

Continued on page 24 been, and still are, the principal contributors and which the short note in Science did not address: New journals with relatively low Impact Factors (in this case the journal has a 2022 Impact Factor of only 3.1), are always on the hunt for publishable papers, especially in “open-access” journals where revenues exclusively come from accepted papers for publication. Their criteria for acceptance, therefore, are often low in comparison to more established journals and, indeed, can be very low. This of course makes them attractive targets of Chinese paper mills because papers in English-language journals are more “valuable” to authors than local Chinese publications. It, therefore, is not uncommon to see in such English language journals a large proportion of whole issues being made up of poor-quality papers of mostly Chinese origin.

Interestingly, it is China’s government (and not the Western scientific publishing industry) that appears to have finally noticed the problem. A recent news article in Nature magazine reported that Chinese universities have been mandated by the Chinese government to complete a nationwide audit of retracted research papers.2 This order came about after Hindawi, a subsidiary of Wiley (recently shut down by the publisher, as reported in the February-March issue of the VOICE), had to retract large numbers of Chinese papers. Wiley’s problems, thus appear not only restricted to Hindawi, which raises serious questions not only about how Wiley conducts its business but about the current publication model in medical sciences in general.

China also started publishing a list of suspect journals, called the “Early Warning Journal List,” which just recently was updated, as reported in Nature magazine, and included 24 journals from several publishing houses.3

this to happen in the first place.

That this subject is reaching a boiling point is also suggested by a recent feature article in the British Medical Journal, which basically questioned the integrity of one of the world’s largest Open Access scientific publishers with 230 journals under its guidance, including Frontiers, which recently found itself retracting not less than 38 papers that all involved buying and selling authorship on research papers.4 The publisher’s PR manager is quoted in the article as stating that “authorship for sale” represents an industry-wide problem, potentially affecting more than 10,000 papers. Amazing!

REFERENCES 1.

Brainard J. Science 2024;383(6685):800 2.

Mallapaty S. Nature 2024;626:700-701 3.

News in focus: Nature 2024;627:252 4.

Owens B. BMJ 2024;384:q659

Ghost research

SOURCE: pixabay

A recent study of clinical trials in several Scandinavian countries (so far published only as a preprint) revealed that results from 475 of those trials were never published (therefore, the term “ghost trials”), wasting public money, harming patients, and undermining public health.1 The article cited here also points out that such ghost studies are, of course, not only restricted to Scandinavian countries but represent a worldwide problem.

Though in the U.S. the article claims trial results (at least of federally funded trials) under the law must be made public, here too, there appears to be “rampant noncompliance,” with FDA and NIH sharing the blame for not following up on this mandate after funding trials. The FDA, according to this article, indeed, can fine non-compliant grant recipients up to $10,000 but has, as of January 2023, sent only 92 preliminary notices and 4 final notices of noncompliance.

What the article, however, does not address is the motivation for noncompliance, while that may, indeed, be the more important story. What is usually not Nature’s analysis of only English language papers published are negative trial results, for two principal concluded that since January 1st, 2021, more than 17,000 retraction notices for papers by Chinese authors reasons: (i) Negative trials have a much smaller chance of being accepted for publication than positive trials; have been issued, an obviously staggering number!2 and (ii) unpublished negative trials support (often It remains to be seen how this Chinese government commercial) interests of parties who benefit from initiative will be executed. At least theoretically, universities are within only a short three months mandat- non-publication of trial results (often manufacturers of products used in medical practice). ed to determine which of these retractions were based on misconduct and punish authors accordingly. Let’s wait and see whether that will really happen, but the Chinese government deserves kudos for at least trying. One is, however, left wondering how the Western scientific publication industry could have allowed all of 23 | THE VOICE

Continued from page 23

Is “Long COVID” just a fantasy?

Which returns us to the subject of “Long COVID.” Just in time for the “International Long COVID Day,” celebrated on March 22, several newspapers, including The Guardian,1 reported on a yet unpublished Australian study by the state of Queensland’s chief health officer as senior author, Dr. John Gerrad. The study involved 5,112 adults with obvious respiratory disease who between May and June of 2022 underwent PCR testing: 2,399 positives for COVID, 995 positives for influenza, and 1,718 negatives for both. One year after testing, participants were queried about ongoing symptoms and impairments, and there was practically no difference between those with or without COVID-19.

This is a surprising finding since, as discussed in the most recent issue of the VOICE, several recent studies demonstrated quite distinctive immune profiles in individuals with so-called Long COVID. What these findings, however, may confirm is the old dictum that association does not equate with causation. In other words, patients are not to be doubted in their symptoms, but just because they suffered at some point before from COVID-19 does not mean that those symptoms represent late sequelae of their COVID infection.

REFERENCE 1. Reed B. The Guardian. March 16, 2024. https://www.theguardian.com/ society/2024/mar/15/long-covid-symptoms-flu-cold

More on Alabama’ Supreme Court’s decision LePage v. Center for Reproductive Medicine As the state’s legislature passed a law to protect IVF clinics from legal exposure for harm that may come to embryos from the IVF process, the worst regarding Alabama’s Supreme Court’s bizarre decision of assigning embryos personhood appears to be over; however, concerns remain. IVF clinics in Alabama and companies shipping embryos in and out of the state, which had paused their services after the court’s decision, mostly resumed their work but, as an opinion paper by colleagues from NYU in JAMA recently concluded, “remaining (clinical) policy implications are real and dire.”1 Potential legal ramifications were well dissected in a separate paper in JAMA by I. Glenn Cohen’s group from the Petrie-Flom Center for Health Law, Biotechnology, and Bioethics at Harvard Law School. It correctly predicted that a local legislative intervention THE VOICE | 24

would be able to at least restore IVF practice in Alabama.2 An opinion piece in Science then also pointed out that the Alabama IVF ruling may in addition have other secondary consequences beyond just IVF practice, citing as an example the halting of uterine transplants in a hospital in Alabama.3 As The New York Times reported on March 6, 2024, Alabama lawmakers on that day passed a law “to protect IVF treatments,”4 which the state’s governor then immediately signed into law. It became obvious that the Republican majority wanted to clearly separate IVF from the abortion debate. Though most IVF clinics in the state apparently resumed IVF service, the law failed to address important questions (the NYT described them as “existential”) stemming from the state’s Supreme Court decision, thereby, leaving open the prospect of legal challenges. Whether an embryo conceived outside of a woman’s body should be considered a person under Alabama law, therefore, remained unresolved. All the law did was shield IVF clinics (and their staff) from civil and criminal liabilities. It also limited the liability of gamete and embryo shipping companies to pay for the costs of the IVF cycle that potentially adversely impacted embryos during their transport.

As the article also noted, the IVF clinic that was the defendant in the lawsuit that ultimately reached the Alabama Supreme Court and where embryos were ‘”lost” (the Center for Reproductive Medicine within the Infirmary Health System), has so far not resumed IVF services. The published explanation was: “At this time, we believe the law falls short of addressing the fertilized eggs currently stored across the state and leaves challenges to physicians and fertility clinics trying to help deserving families have children of their own.”

What also remains of concern is that 11 states currently have broad personhood laws similar to the Alabama law which could potentially extend to embryos and the practice of IVF. Moreover, 13 states have personhood-related bills moving through the legislative process. Though not specifically addressing IVF, concern has been expressed that they may end up affecting IVF after all.5 REFERENCES 1. Bayefsky et al., JAMA 2024. doi: 10.1001/jama.2024.3726. Online ahead of print.

2. Feinberg et al., JAMA 2024; doi: 10.1001/jama.2024.3559. Online ahead of print.

3. Wadman M. Science 2024;383: 936 4. Cochran E. The New York Times. March 6, 2024. https://www. nytimes.com/2024/03/06/us/politics/alabama-ivf-law.html?smid=nytcore-los-share&referringSource=articleShare 5. Lieber R, Siegel Bernard T. The New York Times. March 5, 2024; pB6

Continued on page 26

The treatment authorization process by medical insurance companies We in these pages have repeatedly criticized the excesses of insurance companies’ mandated approval processes for specific medical treatments in the infertility field which, in our opinion, in several instances have crossed the boundary into “practice of medicine,” for which insurance companies are not licensed. Similar complaints have, of course, been voiced in other medical specialty areas as well. The Centers for Medicare & Medicaid Services (CMS) now in a “final rule” (CMS0057-F),1 at least to a small part, addressed some of the most obvious issues, though Medicare and Medicaid cover infertility only marginally. These new rules will affect fertility services more indirectly, as newly defined principles of service authorizations of physician requests, of course, cannot differ between medical specialties and between government or non-government payors. Mandated changes in attempts to improve prior authorization processes for Medicare and Medicaid services can also be expected to become the rule for patients covered by private insurance. Here are a few of those changes, with insurance companies generally given until 2026 to implement these changes: • Prior authorization decisions must be sent within 72 hours if expedited (urgent) and within 7 days if standard (non-urgent).

• Payors must provide a specific reason for denial of authorization decisions, regardless of how the authorization request had been submitted (with authorizations of drugs being an exception).

• Payors are mandated to publicly report prior authorization metrics annually by posting them on their websites.

As the AMA New Wire already reported last fall (and we previously noted in the VOICE), even more important were announcements from UnitedHealthcare (UHC), the nation’s largest private health insurer, and Cigna Healthcare, another very large national health insurance company, which announced tentative steps to reduce the volume of care-delaying and time-wasting prior authorizations.2 In conjunction with the announcement, the AMA noted that “prior authorization is costly, inefficient, and responsible for patient care delays. The AMA stands up to insurance companies to eliminate care delays, patient harm, and practice hassles.” We, of course, couldn’t agree more!

REFERENCES 1. CMS Interoperatibility an prior Autorization Final Rule CMS-0057-F. January17, 2024. https://www.cms.gov/newsroom/fact-sheets/cms-interoperatibility-and-prior-authorization-final-rule-cms-0057-f 2. O’Reilly KB. AMA News Wire. September 18, 2023; https://www. ama-assn.org/practice-management/prior-authorization/2-big-insurers-take-small-steps-ease-prior-authorization

Griffin Jones’ always interesting e-mails Readers of the VOICE by now must be very familiar with the periodic News Digest we receive by e-mail from Griffin Jones, Founder and Owner of Fertility Bridge, a consulting company serving the infertility field. This month we report on three of these mailings.

In a first, on March 14, 2024, Ron Shinkman reported that thousands of IVF payments from insurance companies to IVF clinics were delayed after Change Healthcare, a subsidiary of UnitedHealth Group, a major payment processor for the health insurance industry, was basically shut down by cyber-attack. The company was reported to have paid $22 million in bitcoin as ransom to the hackers to regain access to their own data. eIVF, a company that serves approximately 140 IVF clinics and offers billing services for many among them, worked through Change. Its clients, therefore, were greatly delayed in their payments.

On February 15, 2023, the News Digest reported in an article by Lisa Munger that Boston-based Northstar Fertility had acquired Surrogacy.com and Everie (a frozen egg bank), adding to the company’s already existing portfolio of companies, including Circle Surrogacy, Growing Generations, and Reproductive Possibilities - all surrogacy agencies. Owned by the CortecGroup, Northstar was established in 2019 and, beyond surrogacy services (and now frozen egg-banking) also offers other services to fertility clinics, like insurance coordination, financing, and escrow management.

Finally in a March 21 e-mail, Rosemary Scott followed up on earlier reports about the Chapter 11 bankruptcy protection filing of the genetic testing company Invitae on February 13, 2024 (previously reported in the VOICE), which at filing reported assets worth $500 million to $1 billion and debt of $1 billion to $10 billion. Shortly before its filing, it now announced to have sold its reproductive health assets, made up of carrier screening and non-invasive prenatal testing, to Natera for $10 million and, possibly, additionally up to 42.5 million in milestone payments and litigation credits over time.

25 | THE VOICE

Continued from page 25

Federal agencies are probing the effects of private - equity investments in healthcare There are only very few specialty areas in medicine where private equity has been as actively involved as in reproductive endocrinology and infertility (REI). A short article by Chris Cumming and Maria Armental in The Wall Street Journal caught our attention because it was the first time we learned that the federal government was looking at the effects of private-equity investments in healthcare. Because of the rapidly growing impact of private equity on REI, this has, of course, been a steady subject of discussion in recent years here in the VOICE and will, likely, remain one for some time to come.

Announced for the first time, the effort of the government involves antitrust regulators at the Justice Department, the Federal Trade Commission, and the Department for Health and Human Services with the goal of determining whether private-equity investments in health care potentially increase consolidation (amazing how long it took!). They apparently are also interested in corporate profits from such investments and want to determine whether private-equity investments increase prices while producing poorer quality of care. The last three questions have recently been the subjects of several published studies with rather disturbing results.

Investigators at those agencies, therefore, could just go to the literature and get answers very quickly!

As the article also noted, private-equity investments in healthcare have “soared” because of the industry’s high growth rates and resistance to downturns, which have made this sector one of the most attractive areas for investments in the U.S. economy.

REFERENCE 1. Cumming C, Armental M. The Wall Street Journal. March 6, 2024; pA3

New York State alleges that Mount Sinai Beth Israel violated “cease and desist” order In prior issues of the VOICE, we on two occasions reported on the Mount Sinai Health System announcement about the closing of the Mount Sinai Beth Israel Hospital and the “cease and desist” order issued by New York State prohibiting the closure of any beds and services without prior state approval. Based on an initial report by Politico, Becker’s Hospital Review, THE VOICE | 26

now reported that the New York State Department of Health accused Mount Sinai Beth Israel of having violated this order. Specifically, investigators found that the hospital, following December 21, 2023, when the order was issued, stopped accepting some stroke patients in the ER, ended on-call MRI services, and stopped outpatient surgeries. Moreover, they found nursing staffing levels to be inadequate, overall concluding that the hospital failed to ensure that “appropriate resources for delivery of patient care were maintained. Mount Sinai announced that it plans to dispute the findings in a court case filed over the hospital’s closure, and previously announced plans to close the hospital down by July of 2024. And it, indeed, asked the judge in the case to reject attempts to block the closure of the hospital.2 As Becker’s Hospital Review then, however, reported,3 the New York Department of Health advised the Mount Sinai System that their submitted plan of closure for Beth Israel was incomplete and required a more comprehensive submission. This would also require a change in the tentative date of closure on July 12.

REFERENCES 1. Bean M. Becker’s Hospital Review. https://wwwshospitalreview. co/legal-regulatory-issues/beth-israel-violated-cease-and-desist-order-state-alleges.html 2. Cass A. Becker’s Hospital Review.; March 27, 2024.https://www.beckershospitalreview.com/legal-regulatory-issues/mount-sinai-asks-judge-toreject-attempt-to-block-beth-israel-closure.html 3. Cass A. Becker’s Hospital review, April 3, 2024; https://www.beckerhospitalreview.com/finance/mount-siani-beth-israel-closure-plan-hitsspeed-bump.html.

Measles - the old new threat!

After being eliminated in the U.S. since 2000, Reuters® on March 22, 2024, reported that, according to the CDC, by that date, the U.S. had already experienced 62 measles cases, a number larger than in all of 2023.

Concomitantly, the CDC issued a health advisory urging unvaccinated children and international travelers (where measles may be even more prevalent) to get vaccinated (or re-vaccinated) with the MMR vaccine.

Although not specifically noted in the CDC advisory, measles is not a good disease to catch while pregnant.

It increases the risk of stillbirth and premature birth as well as low birth weight and, if occurring in later pregnancy, can also lead to infected newborns.

Continued on page 28 In a medical news article in JAMA, Melissa Suran, PhD, MSJ, quoted an expert when pointing out that even a single case was worrisome because of measles’ highly contagious features, not even requiring direct contact with an infected person. The article further notes that 9 out of 10 non-immune people exposed to the virus will become infected, among the highest rates of contagiousness among viruses. Moreover, 1 in 5 unvaccinated people who become infected end up in the hospital.

A further recommendation circulating is that older people check whether they still have measles immunity. If not, individuals above age 65 and/or immunocompromised patients should be reimmunized with the MMR vaccine as well. A single dose of MMR vaccine is approximately 93% effective at preventing measles. After 2 doses, the protection reaches 93%.

REFERENCE 1. Reuters. March 22, 2024; https://www.reuters.com/world/us/meslescases-us-rise-62-thursday-says-cdc-2024-03-22/

Smoking leaves a lasting effect on the adaptive immune system

Smoking. Image by karosieben from Pixab

A recent paper in Nature magazine suggested that smoking not only changes adaptive immune function but does so with long-persisting effects.1 Smoking, indeed, initially affects innate as well as adaptive immune systems, but the effect on innate immunity very quickly dissipates after cessation of smoking. In contrast, adaptive responses remain affected for long times after smoking has been stopped and are associated with epigenetic memory mediated by DNA methylation that modifies DNA sequences in the nucleus.2 The authors concluded that their findings likely have clinical implications for the risk of developing infections, cancers, and/or autoimmune diseases. More evidence that smoking is not good for you!

REFERENCES 1. Saint André V et al., Nature 2024;626:827-835 2. Luo Y, Stent S. Nature 2024;626:724-725

Are we surrounded by sentience?

This is likely the first time we are featuring a book review in these pages, but one by Philip Ball in Science magazine recently caught our attention. In it, he reviewed the multi-authored book The Sentient Cell: The Cellular Foundation of Consciousness, (Oxford University Press 2024). The basis of the book is the provocative proposition that even individual cells express evidence of consciousness. Plants, for example, have by some scientists been considered sentient for that reason since the early 2000s. In this book (which we have not yet gotten our hands on), according to Ball, cognitive psychologist Arthur Reber, plant biologist Frantisek Baluska, and medical scientist William Miller offer the claim that in life we are surrounded by consciousness, down to single cells.

As we learned about this concept, which was first proposed by German “Naturphilosophie” in the late 18th century from this brief book review, observing the “intelligence” of the SARS-CoV-2 virus in its ability to mutate during the COVID-19 pandemic (and ever since) in order to survive was in a way eye-opening.

As the author of the book review asks, are the sophisticated responses of bacteria to stimuli evidence of bacterial “intelligence”? This kind of thinking increasingly does look less and less strange. And how about the ability for self-organization of the ultimate single cell, the zygote, in producing a complete human being?

How “intelligent” must this first cell be to accomplish this goal?

Book and reviewers agree that the proper language for discussing consciousness (or other properties) of living systems is not that of machines or computers but of cognition. He also concludes that we (still) lack the vocabulary to talk about the complex competencies and agency of living things without anthropomorphizing.

What a fascinating concept!

REFERENCE 1. Ball P. Science 2024;383(6688):1186

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Why are so many young people suddenly getting cancer?

sants, especially among female adolescents is exploding. Those who do not see the connection must be really blind!

Cancer rates, especially gastro-intestinal malignancies, for younger people (under age 50) appear to be spiraling out of control. Why this is happening has mostly remained unclear, but some hypotheses are surfacing and were recently discussed in a feature article in Nature magazine by Heidi Ledford.1 Consensus appears to be developing that the gastro-intestinal microbiome may play a central role, mostly the result of dietary changes and increasing antibiotic exposure, both linked to the development of inflammatory bowel diseases which, in turn, increase cancer risks.

Investigators, however, also agree that there must be more reasons for such drastic changes in cancer susceptibility at young ages. Another hypothesis pursued by some investigators is prenatal in-utero exposure to carcinogens. One such possible association has been reported between early colon-rectal cancer and a particular form of progesterone prescribed to prevent premature labor.2 The article also notes that cancers in younger individuals create new treatment-related problems. For example, secondary cancers are more common and some of these cancers in young women may be associated with pregnancies, with the latter, of course, producing highly complex new issues to be dealt with. All in all, it seems that the understanding of why we are witnessing a worldwide epidemic in early cancer rates is still rather limited, and further studies to better understand the underlying especially epigenetic conditions leading to early cancers are urgently needed.

REFERENCES 1. Ledford H. Nature 2024;627:258-260 2. Murphy et al., J Endocr Soc 2021;%:A496-A497

Why are we having less sex and more depression?

According to an article in the Free Press by Nellie Bowles,1 it seems we – at all ages – have less sex. Why that is, is unclear, but we would not be surprised if the decline correlated with the time spent on our portable phones. And at the same time, the use of antidepresTHE VOICE | 28

REFERENCE 1.Bowles N. Free Press. April 2, 2024; https://www.thefp.com/p/nelliebowles-welcome-to-free-press-health?utm_source=substack&publication_id=260347&post_id=143174105&utm_medium=email&utm_content=share&utm_campaign=email-share&action=share&triggerShare=true&isFreemail=false&r=2p8a8u&triedRedirect=true ADVERTISEMENT

NEWS from the CHR Preparations for the 2024 FRMC are in full swing

We are pleased to report that preparations for the 2024 Foundation for Reproductive Medicine Conference (FRMC) in NYC, which the CHR co-sponsors, are fully underway. Registration has, indeed, opened, including hotel reservations. A preliminary program has also been established with several new themes receiving added attention this year.

Among those, facilitated by the widespread availability of very effective new weight loss medications, are the subjects of “Obesity as an Infertility Diagnosis,” several new ethical issues arising from rapid progress in basic research and the development of new technologies in the laboratory, “The Business of Infertility,” and others.

As always, the conference will attempt to recruit many of the most important contributors to the field in the preceding year, whether in research or clinical practice, and we are pleased to announce that among several prominent speakers who have already confirmed their participation are Katsuhiko Hayashi, PhD, from Japan who’s recent study published in Nature magazine1 in 2023 was named one of 10 papers the magazine annually declares to have “shaped science in the year.” In addition, we are honored to welcome this year Paula Amato, MD, Professor of OB/GYN at OHSU in Oregon and current President of the ASRM, who will share her opinions about the current status of infertility practice, and Nanette Santoro, MD, Professor and Chair of OB/GYN at the University of Colorado Anschutz Medical Campus who will address the effects of weight loss on female and male infertility, a subject receiving considerable coverage (as noted above).

Prof. Paula Amato, MD. Oregon Health & Science University (OHSU), Anschutz Medical Campus, and current President of the ASRM

Prof. Katsuhiko Hayashi, PhD. University, Osaka, Japan

Prof. Nanette Santoro, MD. University of Colorado, Anshutz 29 | THE VOICE

The CHR’s

Norbert Gleicher, MD on a short professional trip to Thailand Originally Dr. Gleicher was supposed to deliver two lectures from the offices of the CHR electronically to the 28th annual meeting of the Thai Society for Reproductive Medicine Annual Scientific Meeting, this year scheduled in Pattaya, a beautiful seaside resort, roughly a two-hour drive from Bangkok (see below).

A view from above on the beautiful sand beach of Pattaya

But then, just a few weeks before the conference, plans changed and Dr. Gleicher agreed to attend the conference in person. After a 21-hour-long journey via Dubai, he spent a short night in Bangkok and was then invited the next morning to tour Bangkok’s newest private hospital, a quite spectacular place called MedPark Hospital, located in a beautiful modern high rise in the center of the city. And believe it or not, it had its own Starbucks in the entrance lobby and a gourmet restaurant in the building, serving patients and staff exquisite Thai as well as European cuisine.

Dr. Gleicher is welcomed at the entrance of MedPark Hospital by the hospital’s head administrator and the Medical Director of MedPark’s IVF unit, Assoc Prof Dr. Suphakde Julavijitphong, (in white coat) who also was the Vice-President of the Thai Fertility Society which hosted the conference in Pattaya. The female physician was a member of the IVF team at the hospital. A picture of the hospital is visible on the screen in the background.

The hospital describes itself as a high-acuity, multi-specialty medical center that serves patients from all over Asia. Bangkok has, indeed, been one of the principal centers for medical tourism in Asia (and beyond) since the days of the Vietnam War. The IVF unit, like the whole hospital, is brand-new and an extremely generously designed space with only the most modern equipment (see below).

From there it went after lunch (yes, in the gourmet restaurant at the hospital) by car to Pattaya, where the conference was already underway. Gleicher presented two talks: (i) “Management of mosaic embryos in PGT-A” and (ii) “Management of women with DOR” and, as the final photo (with Dr. Julavijitphong) demonstrates, had a wonderful time doing this.

THE VOICE | 30

The entrance into the gorgeous IVF unit with its proud Medical Director …

… and the view from the IVF unit over Bangkok

… after one of the lectures

ORBITUARY: Jan Friberg, MD, PhD 1943 - 2024

According to an announcement on March 21, 2024, from the ASRM,1 JAN FRIBERG, MD, PhD, recently passed away. The cause of death and the date were not announced.

He was born in Kartineholm, Sweden to Carl and Helga Friberg and was married in 1969 to Inger Friberg, MD, a gynecologist with REI subspecialty. He started his career in Sweden when working with Prof. Carl Gemzell, MD,2 widely credited with having been the first to extract human gonadotropins from the pituitary,3 a very important step in establishing later gonadotropin therapy as a fertility treatment. Friberg and Gemzell also reported pioneering work on donor inseminations.4 When Gemzell moved to NYC, the Friberg family moved with him and Jan as well as Inger completed their residencies and fellowships at Downstate Medical Center in Brooklyn, where Jan later also joined the full-time faculty.

Jan Friberg’s connection to the CHR

When in 1981 the CHR’s Norbert Gleicher, MD., was recruited from New York’s Mount Sinai Medical Center to Chicago’s Mount Sinai Hospital into the position of Chairman of the OB/GYN Department and Professor at Rush Medical College, he, in turn, recruited Jan Friberg as Head of the department’s REI division, which Inga also joined. Since the CHR later arose out of the department’s faculty practice, Jan Friberg must be considered a co-founder of the original CHR in Chicago.

Together, Gleicher and Friberg established Chicago’s and the Midwest’s first IVF center (the CHR) and developed a highly successful research program in REI, leading to such breakthroughs as ambulatory transvaginal tubal catheterization5 and the first transvaginal egg retrieval6 in the world - a development that radically changed how IVF was practiced. Friberg between 1983 and 1989 also served as Associate Editor of the Journal of In Vitro Fertilization and Embryo Transfer, of which Dr. Gleicher was the founding editor-in-chief, later renamed the Journal of Assisted Reproduction and Genetics (JARG) – and the subject of an article in this issue of the VOICE. Friberg in those years was also well known for his work on anti-sperm antibodies. Consequently, during those years he was also a member of the editorial board of the American Journal for Reproductive Immunology (AJRI), of which Gleicher, was also the founding editor-in-chief for about 20 years.

In 1989, Jan and Inga Friberg decided to establish their own infertility center in Chicago, which ended the decade-long, very successful collaboration between Gleicher and Friberg and Friberg’s association with the CHR. The Fribergs became very successful in building their fertility clinic into a large ambulatory surgery center and, according to the ASRM announcement, Jan Friberg continued to treat patients in his private practice until his passing.

The CHR expresses the deepest condolences of the CHR family to all of Jan Friberg’s surviving family members.

REFERENCES 1. ASRM. https://www.asrm.org/membership/in-remembrance/romaine-bayless2/#:~:text=It%20is%20with%20a%20heavy,Uppsala%2C%20Sweden%20in%20the%201960s.

2. Friberg J, Gemzell C. Int J Fertil 1972;17():178-182 3. Gemzell et al., J Clin Endocrinol Metab 1958;18(12):1333-1348 4. Fribert J, Gemzell C. Int J Fertil 1977;22(3):148-154 5. Confino E, Friberg J, Gleicher N. Am J Obstet Gynecol 1988;159(2):370-375 6. Gleicher N, Friberg J, et al., Lancet 1981;2(8251):878-879

31 | THE VOICE

ANNOUNCEMENT Plan ahead to the always unique 2024

FOUNDATION FOR REPRODUCTIVE MEDICINE CONFERENCE (FRMC) on

Translational Reproductive Biology and

Clinical Reproductive Endocrinology in New York City, December 6-8, 2024 VENUE: CONVENE Conference Center: 237 Park Avenue, between 45th and

46th Street, accessible from Park and Lexington Avenues

A lecture hall at the conference venue, CONVENE

The break and exhibition space at the conference venue

There is no better time in NYC than pre-Christmas!

New York’s famous Christmas tree at Rockefeller Center – just a few blocks away from the conference venue.

THE THE VOICE VOICE || 32 32

Welcome to the FRMC – 2024 Building on the success of the 2023 conference, the FRMC over 3 conference days will once again present a unique program in reproductive medicine, connecting in a single lecture hall between basic science and clinical practice, facilitating translational connections between bench and clinic in the process. As in preceding years, the principal purpose is demonstrating to clinicians what is possible and to scientists what is needed. The intent is not to dream about the future but to demonstrate what can already be achieved.

“To think differently” has been the principal motto of the FRMC since the beginning and will remain that, as questioning mainstream thinking has been at the core of the conference’s success since its beginning. The FRMC, in addition, also frequently premieres new treatment paradigms.

As new findings are reported in basic science and clinical journals, the conference content evolves over the preceding year. Since the embryo genetically contains universal information about almost everything in human biology - life, death, regeneration, immune tolerance, etc. - the earliest stages of embryo development never fall out of fashion and Photo credit: David F. Albertini, PhD. Follicles in the ovary have always occupied an important place in the program of the FRMC. While several big themes, such as reproductive genetics, the aging of infertile patient populations, “add-ons” to IVF practice, difficulties in IVF cycle outcome reporting, the relevance of the female immune system to fertility, and others that have been addressed before will return with hopefully new data, brand-new subjects can also be expected. For example, obesity is a rapidly growing worldwide health problem also adversely affecting female and male fertility as well as fertility treatment success. Very successful, newly-to-market anti-obesity drugs, therefore, must be integrated into routine infertility care of obese patients. Another big theme in the 2024 FRMC conference will be the ethics of infertility practice because the rapidly expanding takeover of infertility practice by outside financial interests is a subject gaining urgency by the day.

The FMRC can proudly point out to have affected the engrained ineffective and, at times, harmful daily practice patterns in IVF long before other conferences even noticed. This included preimplantation genetic testing for aneuploidy (PGT-A), and more recently, the long-standing concept of embryo selection in general, single embryo transfer for everybody, and blastocyst culture for everybody. Worldwide declines in IVF live birth rates since 2010-2013 have still not attracted the attention they deserve. Never bashful in addressing controversies, FRMC 2024, therefore, will stay the course in attempting to define the underlying causes for this observation.

The publication crisis in medicine will, of course, also have to be addressed, considering the constantly increasing number of paper retractions, even in very prominent journals involving very prominent individuals. Also related is the recognition that what is considered evidence-based medicine must be accompanied in parallel by “real world data” studies, as carefully planned prospectively randomized studies can never fully reflect what happened in “real-world” applications of treatments.

In short, following the annual lightening of New York City’s famous Christmas tree at Rockefeller Center that formally opens the city’s Christmas season by only several days, the 2024 FRMC will not only offer what, likely, is the most interesting professional conference in reproductive medicine anywhere in the world but also a unique time to visit New York City in one of the city’s most beautiful periods. There is simply no better time to visit NYC than in the weeks before Christmas!

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ARE YOU TRYING TO CONCEIVE AND ARE SEARCHING FOR ANSWERS? Here are questions from and answers for patients

I am 44 years old and have tried IVF with my own eggs more times than you want to know. I am ready for donor- eggs but my husband does not agree!

You may be surprised to hear this, but we encounter this “complaint” from many of our female patients.

Though on first impulse, it may be difficult to understand and even seemingly counter-intuitive, – after all the male partner, still, would contribute his semen to the procedure and, therefore would maintain genetic paternity – there is also a certain logic behind such objections from male partners and, in many ways, you should view your partner’s reaction as a compliment and as a reaffirmation of his love and admiration for you.

To understand men possibly better when they appear resistant to an egg donor or to egg donation in general, we need to diverge a bit to the question, - why do men enter into marriage or other serious long-term commitments?

There, of course, are multiple reasons that motivate men, with the literature suggesting that “love” in most cases is the most important one. A survey quite some years ago by the Pew Research Center, indeed, suggested that “love” is an important reason for men in a whopping 93% of cases.1 But surveys have also demonstrated that “establishing a family” is an almost equally important consideration and within that context, we must address the fact that there is considerable (though at times also contradictory) evidence that THE VOICE | 34

when we choose a partner, we actually choose his/her genes.2 It, indeed, appears that we “sniff out” partners based on certain immunity genes.3 If we assume this to be true, it will suddenly become apparent why men are often more ready to give up on their own genetic paternity than that of their wives.

They, simply, will put what they perceive as their wife’s potential genetic contribution to their future children ahead of their own contribution because the features your husband loves most in you – often why he chose you as a partner for life – are exactly what he, consciously or unconsciously, wants to see in his children.

So don’t be too harsh on him when he gives you a hard time in selecting an egg donor. Try to find somebody who looks like you and has a very similar background; and also, if possible, try to match in your donor as many personal characteristics of yours. So, for example, if you are an “artsy” person, find a donor who loves art; if you like to cook, find a donor who does, too; etc.

You may also want to talk to him about “epigenetics.”

This is a field of genetics that deals with how our genes work and what influences them. Here is why that may help: If you use an egg donor, her genes will, of course, make up (a little over) 50% of her genetic inheritance (the reason why women contribute a smidgen more

Continued on page 36 than men is that so-called mitochondrial DNA is only inherited from the mother). What this means is that roughly half of your child’s genes will come from the donor. But genes work like thermostats; they can be set on high or low function, or they can even be completely shut off. What determines how genes are set are environmental influences, and no period in our existence is more important for how our genes are set than the nine months we spend in our mothers’ wombs. In other words, using an egg donor means dealing with her genes; but how these genes work, you will significantly influence if you carry and deliver the pregnancy. And how you influence those genes can also be inherited, then, into the next generation.

Finally, and likely only as a last resort, if you cannot convince your husband and still want to give it yet another try with your own eggs, you may at age 44 still have a chance at the CHR. Women who have previously failed many IVF cycles – often at several IVF clinics – are our daily bread and butter, and age 44 in 2023 was the mean age of the CHR’s patients undergoing IVF. This means that over half of our female patients were over age 44 and only 16% of our patients were, indeed, under age 40. We, therefore, have to know how to treat older women with the use of their own eggs!

REFERENCES 1. https://www.marriage.com/advice/love/benefits-of-marriage-for-a-man/#:~:text=Men%20choose%20to%20get%20married%20 for%20a%20variety%20of%20reasons,important%20reason%20to%20 get%20married.

2. University of Colorado, Bolder. Science Daily. https://www.sciencedaily.com/releases/2014/05/140519160716.htm 3. Sample I. The Guardian.. May 24, 2009. https://www.theguardian.com/ science/2009/may/24/genes-human-attraction

I am 41 years old and single and want to freeze my eggs. Two fertility clinics refused me and told me I was too old. What are my options?

We are not surprised that you were refused, but we are unhappy that you were not given a choice. Taking choice away from patients is not how the CHR practices medicine and, simply, is not how we, here at the CHR, deal with our patients. As we have often stated in these pages, we do not feel qualified to tell our patients how to live their lives. We, however, feel very well qualified to explain to our patients what their options are and what the different options offer in risks and benefits. Which of the options a patient or a couple then chooses, is then her/his/the couple’s decision, and we will do our best to make her/him/them successful, whatever the decision.

This principle also applies to what some call social egg-freezing (SEF) and for which other colleagues prefer the term non-medical egg-freezing. Whatever you call egg-freezing, when the reason is not outright medical (as, for example, when a young woman has to receive medication that may wipe out the follicles and eggs in her ovaries), the purpose is to offer women the potential of pregnancy at older ages when, otherwise, she no longer may have eggs that can lead to pregnancy. And it is true that this kind of SEF is not recommended after age 38 and, preferably, should be done between approximately age 25-35 years.

The reason for this recommendation is basically twofold: (i) Younger eggs give better pregnancy and live birth rates than older eggs. This means that an egg from a 25-year-old will have better pregnancy chances than an egg from a 35-year-old woman and much better chances than an egg from a 42-year-old. (ii) Because chances per egg decline with age, more frozen eggs are needed to maintain cumulative pregnancy chances from whatever number of eggs a woman has frozen. But as women get older, the number of eggs a woman produces in a given cycle declines. As a consequence, as women get older the number of required cycles to get a to a desirable number of eggs frozen to have a desirable cumulative pregnancy and live birth chance increases.

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Continued from page 35 This, however, does not mean that a 41-year-old woman like you should be automatically refused SEF. If you were our patient, our recommendations would be the following: (i) If you can get pregnant now, do it! (ii) If for social or other reasons, getting pregnant now is not an option for you, then SEF should still remain an option, for as long as you understand how many cycles of egg-freezing you may have to undergo to get a large enough number of frozen eggs with reasonable certainty to still give you a decent pregnancy chance at more advanced ages.

Many IVF clinics (the CHR included) offer discounted multiple-cycle packages for egg-freezing cycles. Indeed, no IVF clinic in NYC, to the best of our knowledge, offers lower pricing for these multiple-cycle packages than the CHR because no other clinic has as many women of advanced age as the CHR, who of course need more cycles than younger women, and we want to keep egg-freezing affordable for them.

Here is a final word: Don’t let anybody trick you by claiming that a single egg-freezing cycle will be enough. That is almost never the case, not even at very young ages and especially not if you are considering having more than one child. It is an old “trick” to get you committed for at least one cycle, under the assumption that you will do more cycles, once you recognize that you don’t have enough eggs frozen. We strongly suggest that before you commit to egg-freezing, sit down with your physician, and ask just a few very simple questions: (i) Considering my age and ovarian reserve, what is the approximate number of freezable eggs I can expect from a single retrieval cycle? (ii) Again, considering my age and ovarian reserve, what is the average number of eggs I may need to have an approximately 80% chance (or other percentage if you so desire) of pregnancy? The answers to these two questions will then allow you to calculate how many retrievals you may need. Good Luck!

I am 32 years old and have stage IV endometriosis. My FSH is 16.8mIU/mL and my AMH is 0.562 ng/mL. I was told I no longer have any chance of pregnancy with my own eggs and should use donor eggs.

We, of course, do not know very much about you and assume you had surgery, considering your endomeTHE VOICE | 36

triosis diagnosis and since you know the stage of your disease; but we don’t know how radical your surgery was and whether you had endometriosis removed from your ovaries (which could be the reason for your low ovarian reserve based on FSH and AMH).

But even though we do not know enough about you, the one thing we can tell you for certain is that, as of this point, you do not need donor eggs; you are not even close to donor eggs! How can we be so certain?

The answer is simple: We are that certain based on your age and your ovarian reserve, which is low, but not horribly low; and, as we will explain below, we can probably improve it. Moreover, you are still very young and, therefore, even if we get only 1 or 2 eggs from you (and we would hope to get more), we can still offer you very good pregnancy chances.

As a first step at our center, you would undergo some additional testing in order to determine whether your low ovarian reserve is due to surgery on your ovaries, infiltration of endometriosis into your ovaries, or an independent development of premature ovarian aging from endometriosis. Whatever the cause, you still have excellent chances with your own eggs if you get the right treatments.

This means quite a lot of different things because the CHR treats women with low ovarian reserve very differently from most other IVF clinics. Differentiating between the three possibilities noted above as the principal cause for your low ovarian reserve is, therefore, of great importance because it allows us to choose the right treatment protocol for your specific IVF cycle. The CHR does not use identical protocols for everybody, unlike most other fertility clinics. Rather, we significantly individualize the treatment of every patient, which often includes the advanced preparation of ovaries for several weeks even before IVF cycle start.

Further testing is also important because endometriosis is associated with increased miscarriage risk, which is even higher if you demonstrate evidence of a hyperactive immune system. If that is the case, you will also need an additional treatment layer during your IVF cycle to prevent a miscarriage. The last thing we would like you to experience once you conceive is a preventable miscarriage.

On a side note: the following Case Report of The Month is actually much in common with your history.

You, therefore, may want to just go on reading!

Continued on page 38

FERTILITY TREATMENT AFTER SEVERAL SURGERIES FOR ENDOMETRIOSIS AND AFTER 5 FAILED IVF CYCLES BRIEFING

• Attempting to offer a teachable moment, we on a monthly basis present in this section of the VOICE an anonymized case report from the files of the CHR. • This case involves a 36-year-old G0 woman who presented with a principal diagnosis of stage III endometriosis, with this diagnosis reached based on 3 laparoscopies between ages 18 and 35 (one diagnostic and two operative), primarily for removal of bilateral endometriomas.

• We are presenting this case to point out some of the difficulties that can arise in the management of advanced endometriosis in infertile women.

Case-presentation: A 36-year-old G0 consulted with the CHR with a history of endometriosis since age 18, when she was diagnosed with stage I disease in a diagnostic laparoscopy and was started on oral contraceptives. She got married at age 28 and by age 31 stopped the contraceptives to attempt pregnancy. After six months of failed attempts, because of her endometriosis history, her gynecologist astutely referred her to a local fertility clinic.

There, a vaginal ultrasound revealed a left endometrioma of approximately 2cm diameter and suspicion of a left hydrosalpinx. A hysterosalpingogram confirmed a left hydrosalpinx and delayed fill but supposedly normal spill of the right tube. The patient underwent an operative laparoscopy that involved left salpingectomy and resection of endometrioma from the left ovary, as well as right tubal catheterization with free passage of blue contrast die following the procedure.

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Continued from Page 37 The operative report noted only mild and very sporadic endometriosis aside from the left-sided endometrioma.

The medical record unfortunately did not reveal either pre- or post-op FSH or AMH levels.

Now at age 32, the patient received three months of depo-leuprolide therapy before initiation of an IVF cycle under an antagonist protocol. This first IVF attempt was cancelled for lack of response, at which time, (and apparently for the first time) FSH (9.9 mIU/mL) and AMH (1.2 ng/mL) values were obtained. The patient then underwent two more consecutive retrievals at the same IVF clinic, in which, 5 and 6 oocytes were obtained that produced 2 and 3 blastocysts, respectively, that were tested by PGT-A. Following each cycle, only 1 embryo was reported as “euploid” and, unsuccessfully, transferred in a frozen-thawed cycle. Allegedly “aneuploid” embryos were discarded and the patient did not know what the abnormalities had been.

The couple at this point was recommended to resume depo-leuprolide suppression of the endometriosis for three months before resuming IVF. They, however, decided to get a second opinion, which resulted in a switch to another fertility clinic (the female now at age 33). In a renewed diagnostic work-up at the new clinic, an ultrasound was again suspicious of an endometrioma of approximately 1.5 cm diameter, this time in the right ovary. The patients, therefore, underwent a third, this time robotic, laparoscopy.

The operative report described a small endometrioma in the patient’s right ovary and diffuse superficial endometriosis on the surface of both ovaries. Moreover, the report also described small endometriotic lesions throughout the pelvis and on the bowel, with significant adhesions encasing the left ovary that previously had been operated on. Adhesions were lysed and endometriotic lesions were ablated “where possible.”

Following the surgery, the patient’s FSH was reported as 14.8 mIU /mL and her AMH as 0.82 ng/mL and she, once again, was placed on depo-leuprolide, but this time for six months. Upon completion of this treatment, she again was started in an IVF cycle with antagonist protocol, though the daily gonadotropin dosage was increased from 225 IU and 375 IU of FSH, respectively, in the two earlier cycles at the prior clinic, to 300 IU of FSH and 150 IU of hMG daily. She, likely, prematurely ovulated in her first IVF cycle at the new clinic because 2 out of 3 follicles had disappeared by the time of retrieval. One oocyte produced one embryo that arrested between day 3 and the blastocyst stage. In her second cycle at this clinic, she produced 2 blastocysts, which both by PGT-A were classified as “aneuploid.” She, therefore, never reached embryo transfer at that clinic. The two “abnormal” embryos were again discarded, with the couple not knowing the alleged embryo abnormalities based on PGT-A. At that point, the couple was advised that their only chance of pregnancy was in third-party egg donation, an option the couple was not willing to entertain.

They, therefore, sought out second opinions from two other clinics, which both concurred with the recommendation. The couple decided to remain childless or, at least, to take a break from fertility treatments. In a social gathering on her 36th birthday, an acquaintance who had been a CHR patient recommended a consultation with the CHR.

THE THE VOICE VOICE || 38 38

Continued on page 40

CHR diagnoses and conclusions

third infusion four weeks later after which APAs started The patient presented for her intake consultation about to decline. From this point, immune suppression was two months later. She underwent the CHR’s routine maintained with just prednisone until 12 weeks, when initial diagnostic work-up (internally called the “check- prednisone started to be tapered off. To prevent an inlist”), which at several different levels turned out to be creased preeclampsia risk because of her positive APAs, revealing. It demonstrated that the female’s ovarian re- she remained on bASA until 36 weeks, and uneventfulserve had continued to deteriorate: her FSH was 17.0 ly delivered a healthy female offspring vaginally at 39 mIU/mL and her AMH was down to 0.32 ng/mL. We, weeks. however, also noted several additional important findings which, before, had not even been tested for. Those CONFLICT STATEMENT included low androgens and high sex hormone binding The CHR and some of its staff members own shares in a globulin (SHBG), a finding almost typical for a diagno- company (Fertility Nutraceuticals, LLC, doing business sis of premature ovarian aging (POA).1 Endometriosis under the name Ovaterra), which produces a DHEA is widely considered an inflammatory condition and product. Since this case report, among other subjects, often also associated with autoimmunity3 and, there- addresses androgen supplementation with DHEA, fore, with a hyperactive immune system.Hyperactive readers are advised that expressed opinions in this paraimmune systems – whatever the cause - are, however, graph, therefore, may be accordingly biased. closely associated with increased miscarriage risk (and, possibly, also with poor implantation rates).4 So affected patients at the CHR, therefore, receive, if possible, an additional layer of immune-suppressive treatment during IVF cycles to prevent miscarriages.

Unsurprisingly, the patient demonstrated several immune system abnormalities, among those being inflammatory markers in the form of an elevated ESR, CRP, a positive ANA (speckled), and anti-phospholipid antibodies (APAs) in IgM isotype.

Also suspected because of her low ovarian reserve,5 she demonstrated low androgens and elevated SHBG and, therefore, received androgen supplementation with DHEA (25mg TID for six weeks prior to IVF start) – please note CONFLICT STATEMENT below –and was started on the anti-inflammatory hydroxychloroquine (Plaquenil, 200mg BID).6 Moreover, with IVF cycle start, she was started on daily bASA and immune suppression with 10 mg of Prednisone, which after retrieval was increased to 20mg. Several days before retrieval she also received 40g of intravenous gamma-globulin (IVIg) by slow infusion.

Ovarian stimulation involved 225 IU of FSH and 150 IU of an hMG product in a micro-dose agonist cycle.

She was triggered at lead follicle size 17.5mm, and had a day 3 embryo transfer of two 8-cell embryos. Three additional embryos were cryopreserved on day 3. She conceived in her first IVF cycle at the CHR. Because her APAs were still positive at the time of positive hCG, she received a second 40g IV-Ig infusion, and followed by a 39 | THE VOICE

Continued from page 39

Conclusions • Endometriosis can be a highly complex disease, causing infertility in a variety of ways. To maximize treatment outcomes, all aspects in which endometriosis can affect fertility, as well as fertility treatments, must be considered at the same time and appropriately treated.

• Though a recent study again confirmed that endometriosis, per se, does not adversely affect IVF outcomes,6 the fact that endometriosis is highly associated with POA – whatever the cause mandates individualized IVF protocols for these patients.

• In practical terms this means: (i) preparation of ovaries if indicated); (ii) no further ovarian suppression if ovarian function is already low (i.e., no oral contraceptives, no antagonists); (iii) timely (i.e., usually earlier) retrievals at smaller than usual lead follicle sizes.

• Careful consideration of the patient’s immune status and appropriate medical treatments - in this case an anti-inflammatory (Plaquenil), a glucocorticoid (prednisone), and bASA. Based on a recent study, we have stopped using Lovenox or heparin, unless there exist hematologic indications.

• Young endometriosis patients, even with relatively low ovarian reserve, still have excellent chances with the use of their own eggs REFERENCES 1. Gleicher et al., Hum Reprod 2013;28(4):1084-1091 2. Donnez J, Cacciottola L. Int J Mol Sci 2022;23(3):1518 3. Gleicher et al., Obstet Gynecol 1987;70(1):115-122 4. Mekinian et al., Am J Reprod Immunol 2016;76(1):8-28 5. Shohat-Tal et al., Nat Rev Endocrinol 2015;11(7):429-441 6. Fox RI. Semin Arthritis Rheum 1993;23(2 Suppl 1):82-91 7. Homer HA. ANZJOG 2023;63(1):3-5

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A Piece of My Mind

Continued on page 42

Norbert Gleicher, MD

Medical Director and Chief Scientist The CHR

Sometimes how other fertility clinics treat patients becomes personal: Prematurely pushing patients toward third-party egg donation is one such issue!

BRIEFING

• Though minimally increased in recent years from even lower numbers, women above age 42 to 43 undergoing autologous IVF cycles (i.e., cycles with the use of their own eggs) are still a rarity in the U.S. and elsewhere.

• IVF clinics generally still consider third-party egg donations as the treatment of choice in practically all women above age 42-43, even though most, of course, greatly prefer use of their own eggs.

• Advanced female age or on rarer occasions premature ovarian aging (POA), are the primary reason for the utilization of donor eggs, though the absence of “transferrable” embryos after PGT-A is quickly catching up as an additional major indication.

• Seeing no significant changes in how women for these indications are prematurely directed toward donor eggs for over almost two decades, I have started taking this issue very personally, which is the reason why this became this month the topic of my column.

What are the numbers?

In 2004 only 5% of all U.S. IVF cycles were performed in women above age 42, a large majority before age 43. IVF cycles above age 42 were a true rarity.1 According to most recently available 2021 CDC data, that number has increased to only 10.1%,2 with, again, most cycles performed before age 43 (the median age for all autologous cycles was, at 36.2%, practically unchanged from prior years). IVF cycles above age 43, therefore, have remained a rarity and, most of those performed (and reported to CDC) are, likely, what we consider to be so-called “alibi” cycles performed by clinics only to demonstrate to their patients that their advice to advance into donor egg cycles because of their own “too old” eggs had been correct. How do we know that? Simple, because these patients usually undergo IVF cycles under exactly the same treatment protocols as younger patients and that, of course, makes little sense.

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Continued from page 41 And then there is the second major reason why women are directed prematurely into third-party egg donation, - the explosive growth of IVF cycles with the use of PGT-A. A very recent study in an unselected patient population reported that among patients who had fully utilized their embryos after PGT-A utilization, the live birth rate was only 2.8% per oocyte (from 11.3% at age <35 to 1.2% at > age 42). Only between ages 35 and 40 were live birth rates per oocyte marginally higher with PGT-A (P<0.05).3 These dismally low numbers, of course, confirm that PGT-A in general populations does not improve IVF outcomes and under age 35, as well as over age 42, actually decrease the effectiveness of IVF. In practical terms, this means that in these two age groups, the chance of being told to advance into third-party egg donation is increased by PGT-A. Such patients, especially after repeated failed IVF cycles, even if relatively young, are then easy fodder for the (mostly false) argument from colleagues that they no longer produce “good-enough” eggs to make viable embryos.

This is not the place to repeat the CHR’s many longstanding complaints about the widespread use of PGT-A in routine IVF. I, however, have in the here-presented context to go on the record once more by noting that the CHR strongly opposes the steadily increasing routine utilization of PGT-A in IVF cycles (in many IVF clinics PGT-A has, indeed, become mandatory). This practice not only fails to improve IVF outcomes, but also adversely affects outcomes in quite large subpopulations of patients (including young women under age 38 and women with few eggs and embryos), while significantly increasing already excessively high IVF cycle costs.

But fitting the theme of this column, and almost completely overlooked in the literature, increasing PGT-A utilization unquestionably also leads to quickly increasing numbers of patients being prematurely directed into egg donation under the (false) allegation that they no longer produce good enough quality embryos with use of their own eggs. Moreover, the median age of U.S. women undergoing IVF cycles with their own eggs has not significantly changed in years, further confirming that the field is not significantly changing practice patterns in response to increasing evidence that PGT-A is not an effective “add-on” to IVF. That giving up one’s genetic maternity in the IVF proTHE THE VOICE VOICE || 42 42

cess likely represents the most consequential choice a female patient can be asked to make, cannot be disputed. To give incorrect medical advice in such a circumstance, in the CHR’s opinion, therefore, is not only inappropriate but, to be frank, unethical.

How are patients currently incorrectly advised on the use of their own eggs?

As already outlined above, patient age (and, of course related, low functional ovarian reserve, LFOR) and absence of “euploid” embryos after PGT-A are unquestionably the main reasons why so many colleagues direct so many patients prematurely toward donor eggs.

Our colleagues’ ultimate argument, however, is that by doing so, they are protecting their patients from ineffective IVF cycle attempts - ineffective in two ways: (i) based on risk-benefit, and (ii) based on cost-benefit.

If clinical IVF practice, indeed, was based on these two considerations, we would oppose PGT-A utilization less since assessments of risk-benefit and cost-benefit considerations are, indeed, the correct ethical basis of all informed consents. Over half of the CHR’s new patients, however, reach out to the CHR because they were directed toward third-party egg donation in a much more declaratory way by being very clearly told that “their only realistic chance of pregnancy was through the use of young donor eggs.” The contrast between these two alleged forms of informed consent is, of course, substantial: If based on risk-benefit, the patient is given her right of self-determination by reaching a personal judgment as to what risk-benefit and cost-benefit is appropriate for her (and where applicable her partner). Once told by her physician (an obviously authoritative source) that egg donation is her only chance, this right to self-determination is unethically withheld from the patient. The CHR, therefore, continues to offer PGT-A to patients who, after appropriate informed consent, still wish to utilize the process even though we, on principal grounds, oppose the utilization of PGT-A in almost all patients.

So, let us, therefore, examine risk-benefits and cost-benefits. Nobody, of course, can argue that pregnancy and live birth chances in older women, younger women with LFOR, and women with few and/or no “transferrable” embryos can match those achieved in donor-recipient cycles or can even come close.

But what are they?

Continued on page 44 The truth is that we really don’t know for sure, and there are several reasons for that: (i) Since, as already noted above, only very few IVF clinics even allow their patients above ages 42-43 to go through autologous IVF cycles, and many of these IVF cycles are what we consider to be “alibi cycles,” their outcome data cannot be considered reflective of overall chances of an unselected patient population. Consequently, ridiculous numbers are circulated, like live birth rates of 2.9% in women above age 423 and less than 1% above age 45.4. (ii) Age alone does not determine outcome chances. Almost equally important and, indeed, increasing in importance with advancing female age, is the number of transferrable embryos an IVF cycle produces. Reasons are obvious: As single embryos produce ever-declining pregnancy and live birth chances with advancing female age, IVF practice compensates at least partially with larger embryo numbers being transferred – though obviously only if available because embryo numbers unfortunately also decline with advancing female age.

A 45-year-old with 1 or 4 transferrable embryos will, therefore, have very different pregnancy and live birth chances. To judge a patient’s chances simply based on age demonstrates how poorly the IVF field in general understands the management of patient with very poor prognoses.

The VOICE in its last issue published the CHR’s preliminary outcome data for all autologous IVF cycles (where women used their own eggs) for the year 2023.

We here republish the age distribution of the CHR’s IVF patients in 2023 (live birth data will only be available much later in the year) to make several important points regarding the debate offered here, including the remarkable age of our center’s patients. Their median age for the CHR’s 2023 patients for the first time reached 44 years (vs. the national average age of 36.2 years in 2021; see the figure below). This means that over half of our patients undergoing autologous cycles were over age 44. It also means that only approximately 16% of our patients were under age 40, and even these women in a great majority had LFOR for their ages.

No other IVF clinic in the U.S. (and, likely, in the world) demonstrates this kind of age distribution

The CHR’s 2023 age distribution of patients who underwent IVF with autologous oocytes. The population’s median age was 44 years, meaning that over half of all patients were over age 44.

among autologous IVF cycles. And yet, if they had at least 1 embryo for transfer, our clinical pregnancy rate in this patient population was exactly 10.0%.

I am again reemphasizing that this is only a clinical pregnancy rate (pregnancy with fetal heart on ultrasound), as of this point; but even assuming a 50% miscarriage rate, which is a possibility considering how adversely selected in age and other patient characteristics this patient population was, this would still mean a 5% live birth rate. And who are we to tell patients that in their risk-benefit and cost-benefit assessments whether to try with autologous or third-party donor eggs, the choice of genetic maternity should not prevail?

What should IVF practice really look like in poor prognosis patients?

This brings me to the central issue of this opinion piece - my longstanding belief that IVF practice for much too long has been driving infertile women prematurely into third-party egg donation. Having made this point now for almost 20 years,1 I unfortunately have seen little change in all of those years, except, maybe, in only a handful of IVF clinics worldwide. Old enough to remember in early IVF days that we refused patients over age 38 access to IVF because we simply could not achieve pregnancies in women above age 38, I often wonder how IVF would look-like today if we then had remained similarly passive in wanting to drive the field forward.

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Continued from page 43 Would we then still to this day refuse women above age 38 IVF cycles with autologous oocytes, as we do today routinely to women at ages 42 to 43? How do we expect to progress in our knowledge if we don’t even attempt to make progress?

Despite many nay-sayers, we here at the CHR, have chosen to pursue alternatives when, for several reasons (repeatedly discussed in the pages of the VOICE before), now almost two decades ago, we identified the “aging ovary” as, likely, the most central problem in IVF practice. Consequently, basic research, as well as clinical trials, have ever since asked the question (disproportionally to many other important research areas pursued at the CHR), how can we improve outcomes in very poor prognosis patients in whom almost universally very low ovarian reserve represents a major problem?

Almost two decades and many sequential small steps of improvements later – all in very much detail published in the medical literature but so far mostly not picked up by colleagues – IVF practice at the CHR varies radically from practice at other IVF clinics in the U.S. and, likely, the world. The reasons are quite obvious: As the CHR’s expertise with poor prognosis patients improved, the word got out and more of those patients chose the CHR as their fertility service provider. This, in turn, changed the center’s patient population over almost 20 years to the above-described extremes which, in turn, mandated further changes, etc., and the evolution of the CHR’s practice continues.

We were delighted last month when we saw the above-noted 10% clinical pregnancy rate for 2023 because in prior years it had solidified at around 7-8%. Reaching 10%, therefore, strongly suggests that recent progress has been substantial, and this is, after all, the principal reward we here at the CHR are hoping for.

These numbers, however, go beyond just the obvious because they also allow us to improve our ability to offer patients progressively better-informed consent. Returning to the above-discussed informed consent for patients, who because of very poor prognosis, must decide between use of autologous and third-party donor eggs, we now can go beyond age in advising them what their chances likely will be, depending on the number of available embryos for transfer (we mostly transfer these women at cleavage stag on day 3 post-fertilization). But in the end, it always should be the patient who, after receiving proper informed consent, decides on their own vs. donor eggs because we, here at the CHR, do not feel qualified to tell our patients how to live their lives. Neither, however, should our colleagues who unfortunately, still too often, believe to know better!

REFERENCES 1. Gleicher et al., J. Assist Reprod Genet 2007;24(12):639-644 2. CDC. 2012 Assisted Reproductive Technology Fertility Clinic and National Summary Report. www.cdc.gov/art/artdata/index.html. p14 3. Sabbagh et al., Fertil Steril 2023;120(6):1210-1219 4. Forbes, https://www.forbes.com; September 18, 2023 5. Advanced Fertility Center of Chicago. https://advanced fertility.com; 9/16/2020

THE THE VOICE VOICE || 44 44

Non-traditional treatments to overcome the adverse impact of obesity on fertility BRIEFING: Obesity has become a major societal health problem. That obesity adversely affects female as well as male fertility and reduces treatment success in infertility is now well established, - yet has so far not found the deserving recognition in infertility practice. This section of the VOICE, therefore, is dedicated to filling this gap by offering relevant information about the role of nutrition, pharmacological interventions to fight obesity, and (where applicable) supplements, to a comprehensive treatment approach toward female as well as male infertility.

For the many long-distance patients of the CHR who often spend considerable time in NYC and, of course also for local patients who are interested in this information, we in this section also offer a listing of our favorite restaurants in the city. In at least some of them, letting them know that the CHR referred you, may even help with difficult-to-get reservations. As in other sections of the VOICE, we welcome comments and suggestions, which are to be sent to social@thechr.com.

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THINK DIFFERENTLY – A CHR OPINION

CONSIDERING OBESITY AS AN INFERTILITY DIAGNOSIS BRIEFING: Infertility in women and men is widely recognized as a multifactorial condition. Obesity is not only associated with increased infertility in both sexes but also with poorer outcomes of infertility treatments. Though these associations have been known for decades, most remedies attempting to integrate weight loss into infertility practice have failed for two reasons: (i)Weight loss programs, per se, failed to achieve weight loss goals, and/ or (ii) patients (mostly because of age) did not have the time to pursue weight loss programs to effectiveness over prolonged time periods. A new family of weight loss drugs, classified as Glucagon-Like Peptide-1 (GLP-1) receptor agonists has, however, now radically changed the picture, virtually guaranteeing significant weight loss within as little as three months. This opinion article argues that the time has come to consider obesity in both sexes as an infertility diagnosis and include pharmacologic weight loss in obese patients in infertility treatment protocols.

THE ASSOCIATION OF BMI WITH FERTILITY It is probably not accidental that the medical literature – not only the fertility literature – recently appears increasingly interested in how weight loss in women and men can improve fertility. For example, the International Journal of Molecular Sciences recently published a review article on exactly this subject,1 concluding that even modest weight loss can have positive effects on fertility, though larger weight loss following longer treatment duration, of course, increases these effects. Improvements in female fertility can be observed based on improved hormone profiles, menstrual cyclicity, ovulation rates as well as pregnancy rates. Similarly, men will demonstrate improved hormone profiles, semen analyses, and sexual function.

A series of recent articles in Fertility and Sterility also reemphasized the connection between obesity and fertility as well as fertility treatment outcomes, though a well-written accompanying opinion article made the correct point that it would be a mistake to use this information to in any way restrict infertility care to obese patients who need treatment.2

Female infertility: After transfers of 56,564 “euploid” blastocysts, colleagues from Northwestern University in Chicago reported that frozen embryo transfer outcomes declined with increasing female body mass index (BMI).3 Trying to understand why that is, a European group of investigators from a large number of different clinics investigated the effects of BMI in THE VOICE | 46

oocyte donors and recipients on IVF cycle outcomes and demonstrated that the donors’ BMI apparently did not matter, while recipients’ obesity affected pregnancy rates adversely in a linear way until BMI 25 kg/m2 when the decline sharply increased up to BMI 35 kg/ m2. These findings suggest that obesity likely affects the establishment of pregnancy through the implantation process, which means that the likely target organ is the uterus.

This study interestingly also looked at the association between BMI and miscarriage risks and, here, donor as well as recipient BMI was positively related to increasing miscarriage risk.4 Though donor BMI did not appear to affect pregnancy chances, the authors – correctly, in our opinion –recommended against using oocyte donors with abnormally high BMI. These data, unsurprisingly and in contrast to the above-noted pregnancy outcomes, suggest that uterine as well as oocyte influences affect miscarriage risk.

Finally, a group of U.S. investigators used national SART data to investigate the effects of BMI in frozen embryo transfer cycles after PGT-A and reported that a BMI of 23-25 kg/m2 was associated with the highest probability of clinical pregnancy and live birth in autologous as well as donor-recipient cycles. BMIs outside that range were associated with poorer IVF outcomes.5

Continued on page 48

Male infertility: A recent narrative review in

Medicina reviewed the use of GLP-1 receptor agonists (for further information, see below). Pointing out that, as already noted above, male obesity can affect fertility in several different ways, including disruption of fertility hormones, poor semen quality, and even technical difficulties during intercourse. Obesity, of course, also has well-known associations with erectile dysfunction.6 The authors suggested that a main effect may lie in excessive adipose tissue aromatization of testosterone into estradiol; obesity in males, therefore, affects their androgenic hormonal axis by reducing testosterone, thereby indirectly also affecting spermatogenesis.

A recent study, moreover, suggested that weight loss from the GLP-1 analog Liraglutide (Ozempic®) beneficially affected obese men (BMI 30-40 kg/m2) with metabolic hypogonadism and severe erectile dysfunction.7 Whether observed effects were the consequence of weight loss, direct drug effects, or both remains to be established. Because testes (at least in mice) demonstrate GLP-1 receptors on Sertoli and Leydig cells, a direct effect of the medication appears possible. Based on a mouse study, the GLP-1 agonist Exenatide was demonstrated to modulate the brain leptin JAK2/ STAT3/SOCS3 pathway in a fat diet-induced obesity and insulin resistance mouse model,8 improving sperm motility, DNA integrity, and leading to lower expression of pro-inflammatory cytokines.

Whether this new family of weight loss drugs affects medical conditions directly, through weight loss only, or through both, has become a point of discussion in several medical subspecialties since these medications are revealed to have additional medical benefits almost daily, ranging from taming inflammation,9 at least in a rodent model improving hyperandrogenism and ovarian function (a potentially promising observation especially for hyperandrogenic obese PCOS patients),10 preventing cardiovascular events,11,12 and improving cardiometabolic parameters.13 They have even been reported to have “mind-body benefits,”14 and cut the craving for opiates.15

GLP-1 AGONISTS (and ANTAGONISTS), THE NEW FAMILY OF WEIGHT-LOSS DRUGS So, what about these new wonder drugs? The first GLP-1 receptor agonist approved by the FDA in June of 2021 was semaglutide.16 Consequently, new anti-obesity drugs like Wegovy,® Ozempic,® and Rybelsus are all semaglutide products. Semaglutide acts as an agonist to the so-called glucagon-like peptide-1 (GLP1) receptor and it, thus, pretends to be the GLP1 hormone which makes us less hungry by sending signals of feeling full to the brain.

Mounjaro®, a second-generation product, is, however, a little more complicated because it is made up of two effective substances that induce weight loss - once again a GLP-1 receptor agonist but, now added to it, a so-called glucose-dependent insulinotropic polypeptide (GIP). This drug combination, thus, mimics the GLP-1 as well as the GIP hormone in their activities on their respective receptors. Like GLP-1, GIP triggers a feeling of fullness.

These compounds, however, likely also affect the brain’s control of food intake and this function has been associated with anti-addictive behavior, a reason why these drugs now are also investigated for their potential effectiveness in drug and other addictive behaviors.

Other medications, alleged to be even more effective in inducing weight loss, appear on the way to market. All are destined to change medicine by offering virtually guaranteed weight loss at highly significant proportions to everybody who starts injecting these medications. Remarkably, these medications have relatively few and usually easy-to-overcome side effects.

CNBC recently reported that Amgen is working hard on “getting in on the booming weight loss drug market,” though with a different approach that works differently from currently available drugs and will require injections, at most, only once a month (in comparison to currently available drugs which require either daily or weekly injections).17 The company is also working on an oral weight loss medication. According to this report, Goldman Sachs projected that between 10 and 70 million Americans will be on these weight loss drugs by 2028.

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Continued from page 47 Similar to the already available drugs activating the GLP-1 and GIP receptor, the new Amgen drug allegedly blocks the receptors. The drug was apparently quite successful in a small early-stage phase-one trial, at the highest dosage (420mg once a month) diminishing body weight by 14.5% in just 12 weeks.18 Though, as with earlier weight loss drugs in this family, the exact reasons why these drugs work so well is still only poorly understood.

There is reason to believe that blockage of the receptors may have additional advantages over earlier drugs beyond fewer required injections by maintaining weight loss longer.

The following is a summary from the recent MSNBC article of currently known approved and still experimental weight loss drugs: • Wegovy from Novo Nordisk: Approved weekly injection that activates GLP-1 • Zepbound from Eli Lilly: Approved weekly injection that activates GLP-1 and GIP • Saxenda from Novo Nordisk: Approved weekly injection that activates GLP-1 • MariTide from Amgen: Experimental monthly injection that activates GLP-1 and blocks GIP • Danuglipron from Pfizer: Experimental once-daily pill that activates GLP-1 • VK2735 from Viking Therapeutics: Experimental weekly injection that activates GLP-1 and GIP • Pemvidutide from Altimmune: Experimental weekly injection that activates GLP-1 and another gut hormone called glucagon • GSBR-1290 from Structure Therapeutics: Experimental weekly pill that activates GLP-1 • Survodutide from Zealand Pharma, Boehringer Ingelheim: Experimental weekly injection that activates GLP-1 and glucagon

ARE GPL-1 DRUGS SAFE?

Since these kinds of medications have already been on the market for the treatment of diabetes for several years, their longer-term profile of side effects is already quite well known. The most common side effects are nausea, diarrhea, decreased appetite (if this can be considered a side effect), vomiting, indigestion, and abdominal pain. In a similar pattern to Metformin, these gastrointestinal symptoms, however, usually quickly disappear with use and these medications are ultimately usually very well tolerated. They, however, should not be used if family members had medullary thyroid carcinoma, Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), or when allergic to individual ingredients in the medicine.

Because some animal models suggested potential abnormalities in newborns as well as small-for- gestational-age offspring, GLP-1 agonists are currently not recommended for use in pregnancy. Nothing is, however, currently known about the human experience with these drugs in pregnancy. Companies producing them have, indeed, announced the establishment of registries for women who unknowingly conceived while exposed to GLP-1 agonists. These registries should offer “real life data” very quickly, allowing for determination of their safety profile in pregnancy. Companies producing these drugs are, therefore, THE VOICE | 48

indeed actively looking for patients who have been taking these medications during pregnancy.

The CHR has started to integrate these medications into cycle preparation protocols for patients with BMI over 30kg/m2 and is maintaining its own registry of patients on these medications. We, however, instruct patients to discontinue the medication at least one month before the IVF cycle starts. Since these drugs induce slowing of gastric emptying, unsurprisingly, there have been reports of aspirations of gastric contents during anesthesia in individuals on these drugs, yet another reason why -at least until clinical data become available - these medications should be discontinued at least one month before IVF cycle starts.

How these drugs should be stopped – and whether they can ever be stopped without gaining much of the lost weight back – is still unclear. Women, however, of course expect to gain weight during pregnancy.

Whether this weight gain will differ after discontinuation of GLP-agonists is also still unknown.

USING THESE DRUGS IN INFERTILITY It has been known for decades that even minor weight loss (by some reports as little as 15 pounds, and by other reports, weight loss of only as little as about 5% of body weight) already positively affects fertility and improves outcomes of fertility treatments. Those goals in the past were, however, only rarely met either because of patient non-compliance with diets and/or exercise routines or because patients simply did not have the time to delay their infertility treatments for as long as it may have taken to lose the desired weight before treatment start. These new drugs, however, virtually guarantee significant weight loss within 3 months, but certainly within 6 months; a time period of delay almost all obese infertility patients can afford.

This does not mean that every female or male infertility patient who is a little overweight should now immediately be treated with these new weight loss drugs. That is most definitely not the case because in milder cases of obesity, it does not appear that the potential loss in pregnancy chances and/or increases in miscarriage risks warrant the delay of treatment, effort, and (still considerable) cost of these drugs (insurance companies are currently not very forthcoming in covering the significant costs of these medications). But for patients with BMI over 3035kg/m2, benefits of weight loss appear worth these negatives. For morbidly obese patients, pretreatment, whether medical or surgical (for example through gastric sleeve surgery) really should be a precondition for fertility treatments, also because of the potential morbidity of such severe obesity during pregnancy.

Readers who have further questions or comments, please write to social@thechr.com.

ADVERTISEMENT REFERENCES 1. Pavli et al., Int J Molec Sci 2024;25:1909 2. Bollig KJ, Dolinko AV. Fertil Steril 2024;121(2):248-251 3. Bakkensen et al., Fertil Steril 2024;121(2):271-279 4. Fabozzi et al., Fertil Steril 2024;121(2):281—289 5. Peterson et al., Fertil Steril 2024;121(2):291297 6. Varnum et al., Medicina (Kaunas) 2023;60(1):50 7. La Vignera et al., J Clin Med 2023;12(2):672 8. Tawfir et al., Arch med Sci 2023;19(5):1508-1519 9. Lenharo M. Nature 2024;626:346 10. Wu et al., Peptides. 2021;145:170624 11. Michos ED. Healio. March 8, 2024. https://www.healio. com/news/cardiology/20240308/semaglutide-24-mg-approvedto-prevent-cv-events-in-patients-with- overweight-obesity.

12. Hansen et al., J Am Col Cardiol 2024;83(9):956-958 13. Ruseva et al., Obesity Sci Practice 2024;e737 14. O’Mary L., WebMD Health News. https://www.medscape.com/s/viewarticle/study0suggests-mind-body...0_daily_240209_MSCPEDIT_etid6300414&uac=223637CN&impID=6300414 15. Science. 2024;383(6658):801 16. Golovaty I, Hagan S. N Engl J Med 2024;390(8):677-679 17. Constantino AK. CNBC. March 24, 2024. https://www. cnbc.com/2024/03/24/amgen-aims-to-enter-weight-loss-drugmarket-with-a-new-approach.html 18. Véniant et al., Nat Metab 2024;6:290-303

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THE VOICE | 50

Continued on page 52

The CHR’s favorite NYC restaurants

All listed restaurants are in Manhattan unless otherwise noted. Like all opinions about restaurants, ours are subjective and are to be understood as such. If you visit one of them, let us know whether you agree with our ratings.

We value your feedback.

SYMBOLS WE USE IN OUR RATINGS _______________________________________________________ PRICES $ .………… $$ ………… $$$ ………… $$$$. …………

Inexpensive Moderately expensive Expensive Special event expensive

FOOD QUALITY - Not worth the trip * Good ** Very good *** Excellent **** Uniquely delicious

SPECIAL COMMENTS + Overall favorite of the CHR v Special vibe M Michelin starred V vegetarian/vegan dishes on the menu

____________________________________________

ADDRESS TELEPHONE COMMENTS AUSTRIAN Koloman +/•••/$$/v

16 W 29th Street (212) 790-8970 V; Excellent desserts Wallsé +/•••/$$/v/* 344 W 11th (212) 352-2300 V; Excellent desserts CHINESE Hwa Yuan Szechuan +/•••/$$/v 42 East Broadway (212) 966-6002 V; Authentic Szechuan Mr. Chow Downtown +/••/$$$/v 121 Hudson St., Tribeca (212) 965 9500 V Uptown 324E, 57th Street (212) 751 9030 V CONTINENTAL 425 ***/$$$/v 425 Park Avenue (212) 751-6921 V; Gorgeous restaurant FRENCH Le Gratin ••/$$ 5 Beekman St. (212) 597-9020 V; Try the gratin potatoes Le Charlot +/•• /SS 19 E 69th St. (212) 794-6419 V; Best steak au poivre and Thai mussels; great desserts Le Bernadine +/••••/$$$$/ MMM 155 W 51st (212) 554-1119 V; Mostly seafood. Likely

the best NYC restaurant ITALIAN Cipriani Downtown +/••/$$/v

376 West Broadway (212) 343 0999 Great food, beautiful people Uptown 781 5th Avenue (212) 753-5566 Great food and high society Elio’s +/•••/$$/v 1621 2nd Ave. (212) 772-2242 Best Italian home cooking and where everybody meets Principe ••/$$/v 50 West Broadway (212) 335-0509 V; mostly seafood but one

of the best chicken dishes Sistina •••/$$$ 24 E 81st St. (212) 861-7660 V; Amazing wine list FRENCH-ITALIAN Café Carmellini •••/$$$$/v 250 Fifth Avenue (212) 231 9200 V; Gorgeous place, top

service; sophisticated and

adventurous food JAPANESE SUSHI Sushi Ann +/••• /$$$$ 8 E 51st St. (212) 755-1780 V; Best quality fish; make reservation at the bar Sakagura +/•••/$$ 211 E 43rd St. (212) 953-7253 V; Amazing food; Best sake selection 51 | THE VOICE

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JAPANESE GENERAL Sakagura +/•••/$$ 211 E 43rd St. (212) 953-7253 V; Amazing food; Best sake selection Yakitori Torishin +/+++/$$$/M 362 West 53rd Street (212) 757-0108 Unique and amazing skewer restaurant KOREAN Jungsik •••/$$$$/ MM 2 Harrison St. (212) 219-0900 Where NYC’s Korean restaurant revolution was born …

Oiji Mi +/•••/$$/v / M 17 W. 19th St. (212) 256-1259 … and has continued GREEK Elias Corner (Queens) ••/$ 24-02 31st St. (718) 932-1510 Mostly seafood HAMBURGERS Jackson Hole Burgers (the “original”) +/••/$ 232 E 64th St. (212) 371-7187 Not a place for vegetarians MIDDLE EASTERN-ISRAELI Dagon ••/$$ 2454 Broadway (212) 873 2466 Best hummus in NYC NEW YORK JEWISH DELI P. J. Bernstein’s Deli •/$ 1215 3rd Avenue (212) 879-0914 All the great classics;

pastrami, chicken soup PERUVIAN Mission Ceviche •••/$$ 1400 2nd Avenue (212) 650-0014 If you like Peruvian – the best PIZZA San Matteo Pizzeria e Cuccina ••/$ 1559 2nd Avenue (212) 861-2434 True Napoli POLISH Karczma (Brooklyn) +/•/$ 136 Greenpoint Avenue (718) 349-1744 Great authentic Polish

food – and dirt-cheap UKRAINIAN/RUSSIAN Caviar Russe +/••••/$$$$/ M 538 Madison Avenue (212) 980-5908 V; Most underrated

restaurant in NYC Russian Samovar •/$/v 256 West 56th St. (212) 757 0168 Great Russian/

Ukrainian food and music Any suggestions and/or comments, please write to social@thechr.com.

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RESTAURANT NEWS

Continued on page 54

NEW RESTAURANT REVIEW: Café Carmellini ***/$$$$/v Fancy restaurants offering expensive food in all forms of tasting menus suddenly appear again to be in vogue. This is the third relatively new restaurant after 425 (on our favorite restaurant list) and Café Boulud (definitely not on our favorite restaurant list) we recently reviewed. This one took a little longer to review because it was so much more difficult to get a reservation in a reasonable time slot and – to be fair – we, therefore, visited only twice so far.

Pete Wells described the restaurant in his New York Times reviews as “the most opulent” new opening in the city in recent years and that may indeed come close to the truth.” It after all has (fake) lifesize trees growing in its at least two-stories-high dining room at The post-modern Art-Nuveau bar the Fifth Avenue Hotel in NoMad (see photo); but Sakagura (very much on our most favorite list) also used to have fake trees before it remodeled after COVID and could never have been suspected of being “opulent” either before or after the remodeling. The restaurant’s opulence, therefore, comes from other impressions.

What gives the appearance of opulence is a new post-modern architectural style context we first noticed at Le Coucou (which used to be on our favorite restaurant list, but no longer is) and later at Verõnika which was an absolute favorite on our list under chef Wofgang Ban, but then started serving really disappointing food under his successor and ended up being removed. What all of these restaurants have in common is an opulence characterized by high ceilings which offer an opportunity for oversized modern chandeliers, very comfortable seating exuding comfort, a backlit bar, at the same time French-traditional and modern, and an overall projection of over-the-top luxury and wealth. To call this restaurant a café, therefore, is misleading. Based on its opulent decor (and price), it most certainly is not a café but a complex restaurant highly rewarding to all senses and with truly superb service from entry into the space until departure.

Though the (expensive) menu offers five courses, Raw and Cured, First, Second, Entrées, and Desserts, one – in contrast to many other recent upscale new restaurant openings - somewhat surprisingly, can order a-la-carte, an opportunity that allowed us in even only two visits to taste several dishes. Why we were not surprised about the food’s originality and sophistication mandates a quick diversion to the background of chef-owner Andrew Carmellini, who we have known for over 20 years from the good old days of Café Boulud in its heydays when we still loved the place. Now as a partner in the NoHo Hospitality group, which also owns sevThe grandiose dining room with trees eral other restaurants in the city and elsewhere, we are delighted to learn that he is fully dedicating his time these days to this new flagship restaurant of the restaurant group. We know his creativity from his chef days at Café Boulud and, therefore, were not surprised to find this creativity confirmed in the French-Italian menu the restaurant offers. But the restaurant does more than that: it is trying to surprise and does so successfully.

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Continued from page 53 If we had to choose – and not an easy choice - our favorite dish so far would likely be the Veal Tongue Castellucio (see photo), a good example of why the restaurant often surprises and, at times, appears somewhat adventurous. With so many excellent French as well as Italian restaurants in the city, the last thing one wants to see in a new restaurant is more of the same dishes. Carmellini makes sure that this does not happen!

Not everything works, however, equally well: While Pete Wells in his review liked the Oysters á la Pomme (see photo), we were less impressed. Small balls of apple sorbet on the oysters, which of course instantly melt in the mouth, in our opinion dominate the overall flavor of the dish in a somewhat boring way. It is likely the numbing experience of sudden cold on the pallet (rather than the mildly tart apple taste) that seems responsible for this perception. The consequence is the absence of a defining new taste for this oyster appetizer, as chefs Markus Glockner at Koloman and Abram Bissel at Principe do offer with their oyster appetizers which exude distinctive flavors. Interestingly, Carmellini brilliantly achieves such distinctive flavors in a competing seafood appetizer on the menu, the so-called Red Snapper ‘Meuniére.’

Our favorite entrée so far was the Scallops Cardoz, a dish offering four perfectly cooked giant scallops in a heavily Thai-influenced coconut foam. We are very much looking forward to a broader entrée experience in future visits. We also loved the Petit Fours at the very end of the meal, not only because of their delicious sweetness but also because of their presentation in a commercially available “art piece” we previously only saw at the museum store of the Fotograsiska Museam on Park Avenue (see photo).

The efforts this restaurant makes are obvious and warrant its expense. Especially during peak hours, it is likely one of the most difficult reservations to obtain currently. We are planning on going back (assuming we can get reservations) and, knowing Carmellini, we expect the place to only get better. It so far made our best restaurant list (see above) and we fully expect it also to make our overall most favored list of NYC restaurants which always takes a few more visits, however.

Oysters á la Pomme

Veal Tongue Castellucio

THE VOICE | 54

Petit Fours within an artisan sculpture

TWO RESTAURANTS WE HAD TO SCRATCH OFF OUR MOST FAVORITE LIST That restaurants change in their overall performance is almost expected. Changes, unfortunately, are only rarely to the better; most of the time they go the other way. Here are two recent examples which - for different reasons resulted in removal from our favorite restaurant list.

Avena on East 66th Street in Manhattan, because of its sophisticated and original Italian cuisine was definite-

ly one of our favorite Italian restaurants in the city, - until something really crazy and rare happened: The wine we ordered during a visit was corked. Not interested in an argument with the sommelier of the day (their usual person in this position was off), we offered to pay for the bottle but wanted a different bottle to start the dinner.

It was served and was perfectly delicious. The evening, otherwise, progressed uneventfully, with food as excellent as always. As, at the end, we were not charged for the corked bottle of wine, we left an extra-large tip.

Roughly a week later, we called to make another reservation for an even larger group of people. The reservation was accepted and immediately confirmed electronically; but ca. 10 minutes later, we received an electronic message that the reservation had been cancelled (no explanation given, even though we called). We apparently no longer are welcome at the restaurant and, therefore, can no longer judge its continuous performance. So don’t even taste wines at Avena because you, too, may become a persona non-grata if you have the bad luck of getting a corked bottle.

The reasons for removal of Le B in the West Village were very different: We felt abused: As a big table of seven we ordered in bulk with many dishes shared (the restaurant offers two separate appetizer courses). We then with obvious intent were over-served but not only in food. It was even more obvious in how wine glasses were constantly filled to the rim (who likes to drink from wine glasses filled to the rim?). And to make it even more obvious, the same also happened to bottled water. Abusive, is the only word that comes to mind in describing the staff ’s behavior.

Chef-owner Angie Mar is in her kitchen, obviously, an extremely talented chef. As owner of the restaurant, her performance, however, leaves much to be desired. According to media reports, she closed the precursor restaurant to Le B (in the same location) to “scale down” its pricing structure. If over-serving is part of this restructuring effort, she will fail again - even if the food she serves - more often than not - is delicious because even the most loyal guests don’t like to feel abused.

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NUTRITIONAL NEWS Changes in diet rewire the immune system within 2 weeks A recent paper in the highly prestigious medical journal Nature Medicine reported that a change in diet very quickly rewires the immune system. As 29 study participants sequentially consumed vegan or ketogenic diets for 2 weeks, they were investigated regarding their immune function as well as macrobiotics using a multiomics approach including multidimensional flow cytometry, transcriptomic, proteomic, metabolomic and metagenomic datasets. The findings were remarkable: the ketogenic diet was associated with a significant upregulation of pathways and enrichment in cells associated with the adaptive immune system, while a vegan diet had a significant impact on the innate immune system, including upregulation of pathways associated with antiviral immunity.

Both diets also affected microbiomes and amino-acid metabolism differently: a ketogenic diet strongly downregulated most microbial pathways in comparison to a vegan diet and baseline diets. In short, diet changes affect the immune system within a short 2 weeks, - an observation which could be used for nutritional interventions.

REFERENCE 1. Link et al., Nat Med 2024;30:560-572

Report of a meeting on the relationship between food, nutrition, and fertility The American Journal of Clinical Nutrition – with some delay – just published a summary report of a November 2022 meeting in Boston and Tufts University Friedman School of Nutrition Science and Policy and the school’s Food and Nutrition Innovation Institute which exclusively addressed the relationship between food, nutrition, and fertility. Because this is to the best of our knowledge – at least within recent memory – the only such meeting held anywhere, we quote from the summary:2 MALE FERTILITY: A positive association exists with a healthy dietary pattern, with high-quality evidence for semen quality and lower quality evidence for clinical outcomes. Folic acid and zinc supplementation have been found to not impact male fertility.

FEMALE FERTILITY: body weight status and other nutrition-related factors are linked to nearly half of all ovulation disorders. Females with obesity have worse fertility treatment-, pregnancy-related, and birth-related outcomes. Environmental contaminants found in food, water, or its packaging, including lead, perfluorinated alkyl substances, phthalates, and phenols, adversely impact female reproductive outcomes.

Epigenetic research has found that maternal and paternal dietary-related factors can impact outcomes for future generations. Priority evidence gaps identified by meeting participants relate to the effects of nutrition and dietary patterns on fertility, gaps in communication regarding fertility optimization through changes in nutritional and environmental exposures, and interventions impacting germ cell mechanisms through dietary effects. Workshop findings can serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and fertility.

REFERENCE 1. Link et al., Nat Med 2024;30:560-572 2. Maitin-Shepard et al., Am J Clin Nutr 2024;119(2)578-589

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Continued on page 58

BRIEFING: In this section of the newsletter, The VOICE offers commentaries on a broad survey of recent articles in the English literature, which the CHR found of interest, even if at times not immediately applicable to daily clinical practice. Articles are mostly chosen for their translational value to clinical medicine, often helping in determining where clinical practice will likely go.

Translational research is, since its founding in 1981, one of the CHR’s principal goals and has produced some milestone discoveries and a good number of U.S. patents over the years. Such research has also propelled the CHR into its current status as a worldwide center of last resort for infertile patients who have failed treatments elsewhere. This section of the VOICE, demonstrates and makes public the process through which the CHR for decades has been following and interpreting the published literature, a process always at the very core of how research and clinical practice have evolved at the CHR. Primarily directed at physicians and basic scientists, this section of THE VOICE to our surprise has also attracted many of the CHR’s patients, from which we assume that it also has found a readership among the broader public. The VOICE, therefore, strives through its writing style, to make this section also accessible and understandable for a general audience.

Recent medical literature relevant to

Reproductive Medicine

Artificial intelligence (AI) AI in Endometriosis

AI has become such a frequent topic in the medical literature that we concluded a general AI section was warranted in our literature review, and here it is. Two papers that reported on A.I. applications in association with endometriosis caught our attention. To explain the first, we have to explain the term “cuproptosis.” Only relatively recently discovered, it is a copper-dependent non-apoptotic form of cell death mode that regulates mitochondrial respiration and is distinctively different from other known cell death models such as apoptosis, necrosis, pyroptosis, and ferroptosis.1 Why is this relevant? Because immunologically dependent infiltration is significantly involved in the infiltration of endometriosis into tissues. Investigators, therefore, wondered whether cuproptosis- related genes (CRGs) may be involved in the invasiveness of endometriosis.2 Using machine learning algorithms, the first reviewed publication identified three such genes: GLS, NFE2L2, and PDHA1. These genes were upregulated in women with moderate and severe endometriosis but downregulated in women with only infertility. Genomic enrichment revealed that these genes also closely correlated with autoimmune diseases like lupus (SLE). They furthermore also correlated with immune cells, including eosinophils, NK cells, and macrophages. The authors, therefore, concluded that profiling endometriosis patients based on these three genes helped in judging endometriosis progression. The authors also validated mRNA and protein expression levels for the three genes in endometriosis patients by qRT-PCR and Western blotting, concluding that CRGs may play an important role in the occurrence and progression of endometriosis.

57 | THE VOICE

Continued from page 57 We found most interesting the close association of the noted CRGs with other autoimmune conditions, as the CHR’s investigators already in 1987 pointed out the association of endometriosis with autoimmunity and suggested that endometriosis itself may be an autoimmune condition.3

adversely affected by poor embryology management and/or poor clinical judgments. Any potential advantage from A.I., therefore, can at best only positively affect time to pregnancy by a better embryo being chosen first (and even that appears to be the case only in good-prognosis patients).

To a related degree, U.S. investigators from Utah took an AI approach to investigate multifactorial pain-related features of endometriosis.4 Using a Bayesian network analysis rather than more traditional statistical techniques, they clustered 155 anatomical sites of pain into 15 specific pain locations which, after pruning, left them with a final Bayesian network of 18 nodes. What they expectedly found was that any single pain-related feature increased the relative risk of having endometriosis significantly (P<0.001). The most profound risk was associated with the presence of chronic pelvic pain, subfertility, and dyspareunia. In other words, exactly what our textbooks told us already decades ago.

REFERENCES 1. Wang et al., Biomed Pharmacotherapy 2023;163:114830 2. Wang et al., Sci Rep 2023;13:21603 3. Gleicher et al., Obstet Gynecol 1987;70(1):115-122 4. Kiser et al., PLoS One 2024;19(2): e0297998

What did surprise us, were some of the locations of these 18 nodes, as some of them were located on the arms and the upper chest. Particularly, nodes at the upper arms are difficult to explain based on endometriosis, unless one considers once more the association of endometriosis with autoimmunity and rheumatologic diseases.

AI in association with time-lapse

Finally, one cannot address A.I. without at least taking a quick peek at its utilization in association with closed incubation systems with time-lapse capabilities.

We have lost count of how many start-ups by now are claiming outcome advantages from their A.I. programs on embryo selection.5 A recent paper in JARG attempted to review those, and with great likelihood, is already outdated in that additional studies have been published and new start-ups have been founded.

The paper, of course unsurprisingly, suggested that A.I. in this application minimizes variability in interand intra-subjectivity of embryologists and thereby improves embryo quality assessments, and with it, IVF outcomes. As repeatedly noted in these pages, we of course strongly disagree with these assumptions because it appears obvious that once an egg cohort is retrieved, assuming everything else in its future management is constant, cumulative pregnancy and live birth chances are fixed to the upside and can only be THE VOICE | 58

5. Luong T-M-T, Le N-Q-K. J Assist Reprod Genet 2024;41:239-252

Infertility

General aspects of fertility/infertility MALE FERTILITY: Though it may sound crazy, males may derive an evolutionary health benefit from being afflicted by inflammatory joint disease (arthritis). A recent Norwegian study of 10,865 males in the country’s Arthritis Registry found that males affected by arthritis were significantly less likely than controls to have remained childless.1 The mean number of children per man among arthritis patients was 1.80 vs. 1.68 in controls (P<0.001) and 21% vs. 27% were childless, respectively (P<0.001). This difference was most pronounced when men were diagnosed between ages 30-39 (20% vs. 32%; P<0.001).

This previously unreported finding in a well-powered study raises interesting questions and, of course, is hypothesis-generating. Likely, the principal question is: How can biological (or other) factors related to the existence of arthritis positively affect male fertility?

One potential answer may lie not in the disease itself but in the treatments these men are receiving for their arthritis. Alternatively, one cannot exclude the possibility that systemic inflammation induces immune responses that have positive effects on male fertility. One thing is clear, however: not only is the female immune system, as so often discussed in these pages, closely interconnected with fertility but the same applies to the male immune system. As the paper suggests, the associations between fertility, autoimmune, and other inflammatory disease as well as immune-modulating medications must be further investigated in both sexes.

Continued on page 60 PENILE ERECTIONS: To continue the subject of male fertility, though on a more basic science level and in a mouse model, a recent study offers interesting insights with possible relevance for the human experience as well by demonstrating that perivascular fibroblasts expressing the high-affinity amino acid transporter SLC1A3 (for solute carrier family 1, member 3) are essential (at least in mice) for penile erection.2 Extent and duration of erection is always determined by the balance between vasodilators (acetylcholine and nitric oxide) and vasoconstriction (norepinephrine) on the supplying arteries. It now appears (at least in mice) that SLC1A3 reduces nitric acid availability, thereby promoting the dilatation of corpora cavernosa. Perivascular fibroblasts that were SLC1A3+, however, decreased with advancing male age. These observations offer new treatment possibilities for erectile dysfunction by positively affecting norepinephrine uptake by these fibroblasts. Alternatively, decreasing notch signaling in those fibroblasts could have the same effects.3

PRP.5 That the repeated needling of ovaries can lead to (fortunately rare) infectious complications has, of course, been known for decades from the egg-retrieval experience in IVF cycles. That it also can happen after PRP injections into the ovaries, therefore, should not surprise, but at the same time can be seen as a reminder that every intervention in medicine can have risks. Interventions therefore should always be done cautiously and only if expected benefits outweigh possible risk.

Such risk-benefit assessments are especially necessary when the expected benefits are small a-priori.

INTRAOVARIAN INJECTION OF PRP: Often under the (in our opinion, inappropriate) term “ovarian rejuvenation,” increasing numbers of IVF clinics are routinely injecting autologous platelet-rich plasma (PRP) into ovaries claiming that PRP “rejuvenates” ovaries leading to improved oocyte numbers and better oocyte quality. What nobody is talking about, however, is the fact that these alleged benefits of intraovarian PRP (ioPRP) are anything but established. As repeatedly noted in the VOICE, the CHR, initiated three registered clinical trials, of which the first (in women with primary ovarian insufficiency) just closed patient recruitment and will be reported in the near future. A preliminary report on a still ongoing trial of women above age 45 was already published and demonstrated only marginal benefits at best.4

THE RELEVANCE OF TIME: To bring philosophical thought into the discussion of science is rare and not always easy to execute well. Probably nobody in our field, however, does this better than David F. Albertini, PhD, the long-term Editor-in-Chief of the JARG, past director of the Division of Laboratories at the CHR, currently still a Visiting Senior Scientist at our center who almost monthly returns to NYC from his home outside of Boston for a week of valuable research time at the CHR. With his widely acclaimed research images in “Dr. Albertini’s Photo Gallery,” he, of course, is also a regular contributor to the VOICE (in this issue as well).

Because of his brilliant writing style in a monthly introductory “Commentary” to the JARG – a truly remarkable feat for an editor-in-chief of a major journal, only shouldered by very few in this position – these commentaries in themselves have established a real following. Once in a while, however, they go even beyond the usual and, by integrating philosophical thoughts into the discussion, become true “literature.”

The February 2024 issue of JARG offered an example, when under the heading, “Searching for answers to the problem of TIME in human ARTs,” he did exactly that.1 We are featuring this brief article here particularly for our younger colleagues, so they can appreciate and learn how medical writing really should be done. Here is an opportunity to learn from a master!

We therefore believe to have good reasons for disliking the term “ovarian rejuvenation” because it simply appears to promise too much. Considering how little is known about intraovarian PRP injections as of this point, we strongly believe that this procedure should not yet be performed outside of well-controlled clinical research settings with patients fully informed about the experimental nature of intraovarian PRP. That the procedure, moreover, also is not as “innocent” as often presented, was recently documented in a case report by Canadian and Irish colleagues who reported a 1st case of bacteremia and bilateral abscess formation following

REFERENCES 1. Sigmo GD, et al., Ann Rheum Dis 2024;83:457-463 2. Ma HY, et al., J Mater Sci Technol 2024;183:32 3. Ryu J-K, Koh GY. Science 2024;383(6683):588-589 4. Barad et al., Hum Reprod Open 2022;2023(3):hoac072 5. Mejia-Gomez J, et al., Gynecol Reprod Endocrinol Metab 2023;4(23):97-101.

In vitro fertilization (IV)

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Continued from page 59 PROGESTIN-PRIMED vs. GnRH-ANTAGONIST PROTOCOLS: With progestin-priming of IVF cycles quickly gaining popularity, a recent study by Chinese investigators attracted our attention. Studying first IVF cycles in infertile women with normal ovarian reserve (174 patients in each group) in a prospectively randomized study, they found no outcome differences in IVF cycles whatsoever. According to a pre-study power analysis, 167 patients in each group were required to reach significance at P=0.05 level. Major patient characteristics also allegedly did not differ significantly, even though some numbers seemed somewhat suspicious. For example, the duration of infertility was reported as exactly identical in both groups, yet the P-value was reported as 0.095.

Considering recent reports of highly significant irregularities, especially in Chinese contributions, to the literature,3 one such very obvious inconsistency in data presentation automatically raises serious questions about a publication as a whole. Several, however, are real warning signs. Stages at which embryos were transferred significantly varied (P=0.032), yet no statistical adjustments were apparently made. Why this difference exists, if everything else was the same between the two groups, therefore raises further questions Finally, 17.2% of patients in each group failed to reach ET, basically bringing the study size to below a minimal power range. In short, it was not a great study and, certainly not a definite word on this subject.

ICSI YES or NO IN MALE INFERTILITY? Another paper by Chinese investigators, this time in the prestigious medical journal The Lancet, offered somewhat surprising findings about the use of intracytoplasmic sperm injection (ICSI) in couples with infertility where the male demonstrated mildly to moderately abnormal semen analyses.4 The study was well-powered, with 2,387 couples from 10 fertility clinics in China, and randomized to IVF with or without use of ICSI in an attempt to discover at least a 7% improvement in IVF outcomes through utilization of ICSI. Outcomes, however, did not differ (33.8% vs. 36.6% in favor of nonuse (P=0.16)). Moreover, ICSI produced fewer day-3 embryos (4 vs 5, P=0.0009) and mildly lower implantation rates for embryos (34.3% vs. 37.7%; RR 0.91 [95% CI 0.83-1.0]).

This paper should not be read without concomitantly also reading the accompanying Commentary by SanTHE VOICE | 60

dro C. Esteves and Peter Humaidan,5 which outlines the strengths and weaknesses of this paper extremely well. This study very clearly supports the increasing belief in the field that ICSI is overutilized. What the study, however, unfortunately, does not tell is in whom ICSI should or should not be used. As the study was performed in men with only mild to moderate semen abnormalities (only defined by one semen analysis), it does not address severe semen abnormalities and/ or proven poor prior fertilization results. Most importantly, and not even raised in the Commentary, the study did not address the relevance of the female in reaching a decision to use or not use ICSI. In short, a good and important study in support of rethinking the utilization of ICSI, but likely not a study that will change practice in the short term.

THE PERIVITELLINE SPACE (PVS) IN OOCYTES: That the presence of an unusually wide PVS, suggesting post-maturity, prognostically represents a poor sign for an M2 oocyte, has been known for some time.

That a narrow PVS, however also has the adverse consequence of poor fertilization, embryo development, and pregnancy potential was, however, news to us, leading us to note here a recent paper by Japanese colleagues that offered these results.6 The analysis included 634 oocytes from 278 IVF cycles with narrow PVS and 12,121 oocytes with normal PVS from 1698 cycles. Unfortunately, the paper has several significant weaknesses. Not necessarily in order of importance, the criticism starts with the retrograde assessment of results and the varying treatment protocols patients received in their IVF cycles. As no adjustments – or at least sub-group analyses - were made for patient characteristics and treatment variabilities, it is difficult to accept reported differences in results as final. The authors must, however, be given credit for noting some of the limitations of their study in the discussion of their paper.

Continued on page 62 USING MODELLING IN IVF: As readers of the VOICE probably know by now, the CHR is not a fan of modeling studies, - though some may at times offer useful information. We here present two studies which, once again, demonstrate well why we have reservations. In a first, colleagues from the Stanford University program in California7 offered a decision analytic model based on age cutoffs with model inputs for probabilities of successful IVF (clinical pregnancy, live birth) and costs for IVF with pre-implantation genetic testing for aneuploidy (PGT-A), embryo transfer, live birth, amniocentesis, and dilatation and curettage. The principal purpose was to compare the performance of an additional IVF cycle with PGT-A, to transfer of frozen embryos by PGT-A-reported as “mosaic” (the quotation marks in this context are routine practice in the VOICE because what the PGT-A industry reports as “mosaicism” does not fulfill the widely accepted biological definition of mosaicism). Consequently, current PGT-A practice underestimates the frequency of mosaicism and overestimates the the presence of outright aneuploidy.

Quoting the paper, the results were as follows: Under age 43, one additional IVF+PGT-A cycle produced an on average 14.5% higher relative live birth rate (the difference ranged from +20% under age 35 to +6% between ages 40-42) but did so with an additional average cost of $16,633. At ages 43-44, the additional rate was +5%. The study, therefore, concluded that the transfer of “mosaic” embryos above age 42 was the superior alternative in comparison to another IVF+PGT-A cycle.

Here is why we have a problem with this paper: Does anybody really believe that the data this modeling study claims to have produced has any major relevance for a patient’s decision? We don’t think so!

It does not take a fancy modeling study to understand that patients will make their decision based on clearly predictable facts: (i) Where are the best chances for a healthy live birth? (ii) What is the cost comparison for the respective cycle? (iii) Where is the psychological and physical exposure the smallest? And, maybe most importantly, (iv) how many additional children are still hoped for? (If only 1, it obviously makes all the sense in the world to use embryos that the patient already

has first). In other words, this modeling study has not added much to our understanding of what algorithms are the best. According to the CHR’s view of the IVF world, priorities should be clear: (i) Don’t use PGT-A in the first place. (ii) If you have already PGT-A-tested embryos, use first those reported as “normal-euploid” (the quotation marks again reflect the CHR’s understanding that a majority of “normal-euploid”-reported embryos in reality will be truly mosaic embryos). (iii) Use selectively as “mosaic” or “aneuploid” PGT-A-reported embryos.

A second modeling study came again out of China8 and presented a predictive model of recurrent implantation failure in the form of a retrospective cohort study comparing 462 women with alleged repeated implantation failure (RIF) and 4750 patients as controls.

A diagnosis required at least 3 fresh or frozen embryo transfer cycles with at least 4 good-quality embryos.

The purpose of the study was to find out whether recurrent implantation failure was predictable based on clinical data and what the authors considered a routine laboratory evaluation. The following parameters were found predictive with increased RIF risk: increased duration of infertility, uterine cavity abnormalities, low AMH, insulin resistance, positive ANA, and positive beta-2 glycoprotein antibody (an anti-phospholipid antibody). Combining all of these factors, the area under the curve for a logistic regression model was highly significant (0.900) for the training cohort and for the testing cohort (0.895).

Advanced age was a risk factor that came into play with no live birth in subsequent IVF cycles after a first failed cycle. Blastocyst-stage embryo transfer increased the probability of live birth in subsequent cycles in RIF patients, with the area under the curve of the logistic regression model being 0.673 (95% CI, 0.597-0.748).

The remaining question regarding this paper, however, is once again – so what? What exactly has this study taught us that was not already known?

DID ANTI-COVID VACCINES AFFECT LIVE BIRTH RATES AFTER IVF? Here, we are pointing out a retrospective single IVF clinic study from the University of Pennsylvania faculty program, including practically all of their IVF cycles. Even though the results of this study on first impression appear interesting (in that it did not demonstrate effects of vaccines on fresh IVF cycle but suggested actually mild 61 | THE VOICE

Continued from page 61 outcome-enhancing effects on frozen-thawed cycles9), upon more detailed review, it becomes abundantly clear that not too much can be read into this paper’s reported results. Aside from the usual shortcomings of retrospective studies, the fact that all kinds of different IVF cycles were included (even egg-freezing cycles) and only 28.9% of unvaccinated and 17.1% of vaccinated women reached embryo transfer, really makes this study uninterpretable and practically defines this paper as a complete waste of time. How it made it through peer review at Fertility & Sterility is truly amazing, but maybe the fact that the editor-in-chief is housed in the same Penn State fertility unit as the authors has something to do with it. Clearly, it is a paper deserving of this issue’s “worst paper award.”

REFERENCES 1. Albertini DF. J Assiste Reprod Genet 2024;41:237-23 2. Ye et al., Hum Fert 2024;27:1 3. Mallapaty S. Nature 2024;626:700-701 4. Wang et al., Lancet 2024;403:924-934.

5. Esteves S, Humaidan P. Lancet 2024;403:880-881 6. Shioya et al., J Assist Reprod Genet 2024; doi: 10.1007/s10815-02403084-y. Online ahead of print.

7. Khorshid et al., J Assist Reprod Genet 20024;41:635-641 8. Fang et al., Reprod Biol Endocrinol 2024;22:32 9. Applebaum et al., Fertil Steril 2024;121(3):452-458 [“WORST PAPER AWARD RECIPIENT”]

milder (stages I and II) and more severe disease (stages III and IV). Interestingly, the study revealed a trend for an association between NLR and chronic pelvic pain in these patients which, however, did not reach significance, though the association got stronger in not previously treated endometriosis patients.

Even though the data demonstrated absolutely no difference between women below and above the NLR cutoff, the authors in the discussion treated the observed minimal trend as if it was a positive statistically highly significant finding (once again one must wonder about the peer review process at this Springer-Nature journal, a publisher from whom one would expect more).

We can only hope that the authors’ readiness to pay for “open access” publication did not play a role in the acceptance of this paper, an obvious additional contender for the “worst paper award” of this issue. This of course does not mean that investigating the NLR in endometriosis may not make sense, but such an investigation would have to proceed in very different ways.

In a much better paper, Chinese investigators looked at CD8+ T cells in an endometriosis study.2 They collected endometriosis tissue from ovarian endometriosis in 3 patients and defined the cellular landscape by singe-cell RNA sequencing (scRNA-seq), identifyEndometriosis and adenomyosis MORE ON ENDOMETRIOSIS AND IMMUNOLO- ing 5 cell clusters. Endometrial cells were the biggest GY: That endometriosis is an inflammatory condition, component, and among those, the most prevalent were mesenchymal cells, characterized by inflammaclosely associated with autoimmunity has been nottion and estrogen production within endometriosis. ed in the VOICE on many earlier occasions (see also above). Here we report on two recent studies that claim Biopsied lesions showed decreases in proportions of T cells (mostly CD8+ T cells) while CD4+ cells were to bring new information to the subject. In the first, Italian investigators reported in Scientific Reports that in normal range and cytotoxicity and cytokine levels in ectopic T cells were depressed. The authors also the so-called neutrophil-to-lymphocyte ratio (NLR), which in various autoimmune diseases has been found reported that CD8+ cells depressed the proliferation to be a marker of systemic inflammation, was informa- of embryonic stem cells (ESCs) through the inhibition of the CDK1/CCNB1 pathway, arresting the cell cycle, tive for the clinical management of endometriosis. In and triggering inflammation through the activation of the title of the paper, the claim was even more specific the STAT1 pathway. in stating that their study specifically referred to deep 1 infiltrating endometriosis.

Co-culture with ESCs resulted in dysfunction of CD8+ cells through upregulation by STAT1/PDCD1 and glyUnfortunately, this was one more study that, in the colysis-promoted reprogramming of the metabolism. end, did not come even close to delivering what the In nude mouse models, endometriotic lesions grew to title promised. For study purposes, the cut-off NLR larger sizes than in normal mouse models and lesion was defined at +/- 2.62. The study population was unfortunately again representing retrospectively analyzed sizes increased in mouse models if T cells were inhibited via CD90.2 or CD8A antibody. In contrast, supdata of 199 premenopausal women between 2013 and plementation of T cells to nude mouse models reduced 2020 (an obviously huge timespan) diagnosed with lesion sizes. endometriosis. The authors differentiated between THE VOICE | 62

Continued on page 64 It, thus, appears that endometriotic stromal cells can trigger CD8+ T cells to become dysfunctional, thereby promoting immunologic survival of endometriosis.

Correction of T cell function, therefore, could offer therapeutic benefits to symptomatic patients with endometriosis.

DOES ADENOMYOSIS AFFECT IVF OUTCOMES? If there is anybody who reliably can point out what adenomyosis really does to IVF outcomes, may she or he please step forward! Despite increasing study numbers and published meta-analyses, the truth is nobody really knows the answer! A recently published observational study in Fertility and Sterility did not change the picture when reporting no difference to controls in implantation, pregnancy, and live birth rates. The study, however, did reveal significantly higher miscarriage rates (35.4% vs. 18.1%).3 Interestingly, however, neither authors (whose principal conclusion was paradoxically only that patients with adenomyosis should be better followed with vaginal ultrasounds) nor Jacques Donnez and Marie-Madeleine Dolmans in a quite informative accompanying commentary 4 noted what we here at the CHR took away as the most important conclusion of this study’s findings: adenomyosis on an immunological level is perceived by a woman’s immune system exactly like endometriosis, which for decades been associated with immunologically-mediated miscarriages.5 That the same miscarriage risk affects endometriosis and adenomyosis was recently reconfirmed in the same journal.6 Recognition of adenomyosis on ultrasound and classification by location, therefore, will not reduce the observed miscarriage risk. That will only be achieved, if indicated by laboratory findings, by appropriate immune monitoring, and appropriate immunosuppression in early pregnancy. CHR investigators already in 1988 pointed out that the drug of choice in such circumstances may not be the now routinely utilized GnRH-agonists but rather good old-fashioned Danazol, which because of its androgenic effects not only suppresses endometriosis/adenomyosis but also autoantibodies (which GnRH-agonists do not do).7

5. Gleicher et al., Autoimmunity 1993;16(2):115-140 6. Vercellini et al., Fertil Steril 2023;119(5):727-740 7. El-Roeiy et al., Fertil Steril 1988;50(6):864-871

Polycystic Ovary Syndrome (PCOS) A persistent argument at the CHR for at least a decade has been that unless PCOS studies are in outcomes stratified by Rotterdam criteria phenotypes, it does not make any sense to select patient populations for such studies by phenotypes. Now comes a study (interestingly out of India) that has studied this issue.1 As expected, phenotype A was the most prevalent among patients (37%), followed by C (26%), D (24%), and B (13%). Because the study population was very young (average age 28 years), it also was no surprise that phenotype D patients produced the highest pregnancy rates (57.7%), as they were still at normo-androgenic range (between approximately age 25 and 35) before. Then, after age 35, women with D phenotype start becoming hypo-androgenic and often demonstrating evidence of a hyperactive immune system.

They, therefore, become treatment resistant to IVF unless pre-supplemented with androgens.2 As repeatedly noted in the VOICE before, the CHR is not the only interested party in the PCOS arena that no longer believes PCOS is made up of four phenotypes, as the Rotterdam Criteria have suggested for decades.

The CHR, indeed, has argued for a good number of years that PCOS should be understood more as a condition of two, and likely genomic distinct, entities which we called “metabolic” and “immunologic.” As recently discussed in these pages, Andrea Dunaif’s group at NYC’s Mount Sinai, also came to similar conclusions following a phenotypic clustering analysis, calling the two phenotypes “metabolic” and “Infertility-related.”3

REFERENCES 1. Dominoni et al., Sci Reports 2024;14:7575 [[“WORST PAPER AWARD RECIPIENT”] 2. Huang et al., Immunology 2024; doi: 10.1111/imm.13786. Online ahead of print.

3. Cozzolino et al., Fertil Steril 2024;121(3):480-488 4. Donnez J, Dolmans M-M. fertile Sterile 2024;121(3):442-443

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Continued from page 63 Now a group of Boston investigators defined specific pathways in PCOS patients through clustering of genetic loci. They identified 4 such clusters: (i) Obesity/ insulin resistance (gene: FTO; clinical trait: increased BMI, increased type 2 DM ); (ii)hormonal/menstrual cycle changes (gene: FSHB; clinical trait: increased age at menarche); (iii) blood markers/inflammation (genes: ATXN2/SH2B3; clinical trait: multiple decreased blood markers, including mean platelet volume); (iv) metabolic changes (genes: MAF, SLC38A11; clinical trait: increased alkaline phosphatase). Based on genomics, we are clearly cruising toward a better understanding of the heterogeneity that constitutes what is currently called PCOS. Investigating normal BMI PCOS patients (i.e., under Rotterdam criteria mostly phenotype-D patients), Chinese investigators offered information on the association of embryo quality in IVF with intra-ovarian inflammatory states via proteomic analysis.5 They reported that suppression of substance metabolism and steroid biosynthesis resulted in anti-inflammatory and more general immune response in granulosa cells (GCs) that involve cytokines in this patient population.

Luminex analysis further demonstrated that follicular fluid (FF) macrophage inflammatory protein-1 beta (MIP-1beta) and stromal cell-derived factor-1 alpha (SDF-1a) were greatly increased in comparison to controls. (P=0.0005 and P=0.035, respectively). Moreover, FF MIP-1beta correlated inversely with the number of good d-3 embryos and blastocysts (P=0.006 and P=0.003, respectively).

These interesting data suggest that phenotype-D PCOS patients experience local ovarian inflammation which affects follicular development. Follicular MIP-1beta, moreover, may be a biomarker for embryo quality in these patients. However, what the paper left unmentioned is that this PCOS phenotype, as reported by the CHR’s investigators in approximately 85% of patients, is associated with evidence of a hyper-active immune system.2 REFERENCES 1. Patel et al., J Hum Reprod Sci 2023;16(4):340-345 2. Gleicher et al., Biomedicines 2022;10:1505 3. Dapas et al., PLoS Med 2020;17(6):e1003132 4. Stamou et al., J Clin Endocrinol Metab 2024;109:968-977 5. Shang et al., Reprod Biol Endocrinol 2024;22:11

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Endocrinology ADRENAL INSUFFICIENCY IN INFERTILITY AND PREGNANCY: Likely the most overlooked endocrine organs with relevance to fertility are the adrenal glands, and there are at least two good reasons for this statement. First, adrenals and ovaries share a primordium during embryologic development. In other words, they share a developmental history. Within this context, it is also important to note that among all hormones both glands produce, only androgens are shared, with the exception of DHEA that is approximately half-and-half produced by ovaries and adrenals.

DHEA-S is the only androgen almost exclusively produced only by adrenals and, therefore, serves as a “marker” of androgen abnormalities when one must determine the origin of too low or too high testosterone levels.

The second reason for the above-made statement lies in the fact that the adrenal glands, after the ovaries, demonstrate the second-highest density of AMH receptors. Yet, adrenals have so far not been shown to demonstrate any AMH-related activity. As the presence of hormone receptors can usually be assumed to represent such activity (especially if as dense as reported for AMH receptors in adrenals), it is surprising that nobody has so far demonstrated interest in finding out what such a likely AMH-controlled function of the adrenals might be.

Within this context it should also not be surprising that adrenal function, in association with fertility and during pregnancy, has found unusually limited attention in the endocrine literature. Making this point, colleagues from Ireland therefore recently published a review article on adrenal insufficiency as a contributing factor to infertility and in pregnancy.1 One reason why we immediately liked this review is that the authors defined primary adrenal insufficiency as a condition that affects the normal structure as well as its glucocorticoid, mineralocorticoid, and adrenal androgen production. While the CHR fully concurs with this definition, the widely utilized definition of adrenal insufficiency includes only insufficiency of glucocorticoid and mineralocorticoid hormones, mistakenly leaving out androgen production, as the CHR’s investigators already pointed out several years ago.2

Continued on page 66 Because, as repeatedly discussed in these pages of the VOICE, androgen levels exert significant effects on ovarian function, the adrenals control ovarian function in certain ways (please note conflict statement below), which in practical terms means that what is widely described as a hypothalamic-pituitary-adrenal axis really should have added the ovaries as a fourth affected station of the HPA axis.

CONFLICT STATEMENT The CHR and some of its staff members own shares in a company (Fertility Nutraceuticals, LLC, doing business under the name Ovaterra), which produces a DHEA product. Since this literature review marginally addresses androgen supplementation, readers are advised that, despite a commitment to unbiased reporting of facts, expressed opinions in this paragraph could be biased.

Secondary adrenal insufficiency is then defined as insufficient ACTH stimulation of the adrenal cortex resulting in cortisol and androgen deficiency, while tertiary adrenal insufficiency is the consequence of suppression of the HPA axis due to exogenous glucocorticoid administration (or opioid use). We recommend this article because it covers a rarely discussed subject in the medical literature, even though we found the section regarding the importance of androgens for female fertility lacking in detail.

DOES “ADRENAL FATIGUE” REALLY EXIST? There exists a consensus that “adrenal fatigue” is not a formal diagnosis3 but a loosely applied terminology to describe the presence of non-specific symptoms, such as unusual fatigue, physical weakness, sleep disturbances, and cravings for sugar and salt. The diagnosis is often also attached to obviously depressed individuals. The consensus arose after a systematic review published in 2016 which summarized this diagnosis as a “myth.”4 MD edge/Endocrinology recently brought the subject to attention again,5 and we thought it was worthwhile bringing it also again to the attention of our readers because we see an increasing number of women who have this diagnosis. According to the article, the Endocrine Society relates the term to long-term mental, emotional and/or physical stress.

Though the CHR has not formally studied patients with this alleged diagnosis, we have found a significant group among them to be hypo-androgenic (though the association may be accidental and/or age-related) and have found androgen-supplementation to often be helpful in improving symptoms (please note again the conflict statement above).

REFERENCES 1. Green et al., Encocrine Connections 2024;13:e230088 2. Gleicher et al., J Clin Endocriol Metab 2017;102(9):3569-3570 3. Keams A. Mayo Clinic. April 10, 2024. https://www.mayoclinic.org/ diseases-conditions/addisons-disease/expert-answers/adrenal-fatigue/ faq20057906#:~:text=Adrenal%20fatigue%20isn’t%20an,cravings%20 for%20suga r% 20 and %20salt.

4. Cadegiani FA, Kater CE. BMC Encocr Disord 2016;16(1):48 5. McCall B. MD edge/Endocrinology. March 6, 2024; https://www. mdedge.com/endocrinology/article/268116/pituitary-thyr...I-fatigue-real-condition?channel=39313&ecd=WNL_ENDO_240309_mdedge

Genetics

General aspects

It was not long too ago that everybody believed every gene had only one function, and once we figured out what that function was, we would be able to control our biology. The extreme degree of this oversimplification has by now, of course, been well-recognized and has been to significant degrees corrected. But as the review of a book by Philip Ball (How Life Works.

Pan Macmillan, 2024) by Denis Noble, an emeritus professor of physiology and biology at the University of Oxford, UK, brilliantly notes, the view of biology is still often oversimplified and out of date.1 The next big illusion occurred in 2001 after the human genome was sequenced for the first time, with much of the world again believing that this would provide an “instruction manual” for life as Noble described it.

However, by now we understand that most genes do not have a pre-set function that can be learned from their DNA sequence. Instead, external (epigenetic) factors determine gene function to significant degrees, while each trait is influenced by many genes together.

As an example, he offers schizophrenia which has been associated with mutations in almost 300 genes. Genes, indeed, create repeated redundancies so that even mutations in seemingly essential genes can be compensated. Here, he offers as an example the HCN4 gene which encodes a protein that acts as the heart’s primary pacemaker, yet the heart stays beating, even when the gene is mutated.

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Continued from page 65 A similar principle applies to proteins that, on purpose, do not have to bind perfectly to their target. A degree of imprecision, indeed, appears essential for having the opportunity of redundancy.

lifetime. In the figure, the average risk in the population is 12.5% (1/8) over a person’s lifetime, but that risk may vary and be differently distributed over the age of the person.

We recommend the book and the original writings of the reviewer, as both call for a radical rethinking of “how life works.”

Related to the subject of epigenetics Italian investigators recently published in Nature magazine a new method to silence genes durably and efficiently in mice in vivo by so-called hit-and-run epigenomic editing.2 it would exceed the current framework of discussion to go into the technical details, but it is important to understand that this kind of work established the foundation for the development of potentially useful in vivo therapeutics capable of epigenetic silencing of genes.

REFERENCES 1. Noble D. Nature 2024;626:254-255 2. Cappelluti MA, et al., Nature 2024;627:416-423

Polygenic risk scoring (PRS) BASICS: The CDC defines polygenic risk scoring (PRS) as the evaluation of a combination of an individual’s different versions of many genes that are related to a specific disease (see Figure 1 below). Each circle in the figure represents an individual. Higher scores (red) suggest more disease risk than lower scores (yellow).

Figure 1. Polygenic risk scoring: Source, CDC

But other considerations also play important roles.

Genes are not the only determining factor of risk to develop a disease. Considering also an individual’s behavior and environment will further add detail to the risk assessment. As a consequence, as Figure 2 demonstrates, personal risks may deviate from general risk in a population which in addition may determine when a certain disease will manifest itself during the THE VOICE | 66

Figure 2. Personal risk vs. average risk in a population. Source, CDC.

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Continued on page 68 PRS IS STILL AN EXPERIMENTAL TOOL: PRS is still widely considered an experimental tool. The CDC notes that “important issues need to be considered before polygenic risk scores can be routinely used in health care and public health. Studies are looking at how useful polygenic risk scores are in real-life clinical practice. Information on how each gene change affects disease risk comes from population-level genetic studies, such as a genome wide association studies (GWAS). Addressing diversity in development of polygenic risk scores is important because polygenic risk scores developed from studies in one population might not work as well for other populations. Also, how each gene change affects the polygenic score varies from study to study.”

How important these considerations are for the clinical implementation of PRS in diverse populations was recently pointed out in an editorial in Nature Medicine.2 In the same journal, investigators from several U.S. institutions then presented the selection, optimization, and validations of ten chronic disease PRSs for clinical implementation in diverse populations.3 Things, therefore, appear to be moving toward clinical utilization in adults at an accelerated pace.

PRS ON HUMAN EMBRYOS: Paradoxically, PRS is already being offered by several genetic laboratories and IVF clinics for use in association with PGT-A in IVF cycles. Above-noted difficulties with adult use of PRS will, of course, demonstrate rather obviously how much more difficult PRS upon embryos must be.

Unsurprisingly – as repeatedly noted in these pages previously – a European society of geneticists, as well as ESHRE, have come out publicly against concurrent use of PRS in association with IVF, declaring such use not only premature (since unvalidated) but also “unethical.”

(ii) Based on the evidence provided here, the clinical utility of PGT-P to reduce disease burden remains “unproven” and must be established through further research and longitudinal studies before the test can be responsibly offered. In many clinical scenarios in which PGT-P might be implemented, the risks outweigh the benefits, leading to concern for individual harm to either the prospective parent or the future child. Even in the best scenarios, there remains the risk of harm in the form of false assurance and monetary loss for unclear gain. (iii) At this time, there is insufficient evidence for the clinical utility of PRS testing for embryo selection. It should not be offered as a clinical service. The establishment and institution of technical standards across all types of PRS testing, and longitudinal clinical research on the clinical validity of PGT-P are required. Genome databases must continue to be expanded across populations. (iv) We reaffirm the recent statement by the ACMG Board of Directors on a related topic that “prenatal testing for disorders that exhibit multigenic or polygenic inheritance is not yet appropriate for clinical use and should not be offered as direct-to-consumer testing.”5 One can only wonder why we have not yet heard from ASRM/SART, ACOG and/or PGDIS? REFERENCES 1. https://www.cdc.gov/genomics/disease/polygenic.htm 2. Editorial. Nat Med 2024;30:354-355 3. Lennon NJ et al., Nat Med 2024;30:480-487 4. Grebe et al., Genet Med 2024; 26(4):101052 5. ACMG Board of Directors. Genet Med 2021;23:2027-2028

The American College of Medical Genetics and Genomics (ACMG) offered a very detailed analysis of the subject for which the college used the acronym PGT-P (Preimplantation Genetic Testing for Polygenic Disorders) and concluded: (i) “As the community of genetics professionals, we must proceed carefully to discern the clinical utility of new testing methodologies and how implementation may help or harm our patients, to thereby provide informed guidelines for care.

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Continued from page 67

Preimplantation chromosomal testing of human embryos

As if there was a need for more proof that chromosomal abnormalities were extremely common at human blastocyst-stage, a recent study in The Journal of Clinical Investigation again confirmed it.1 This time, Dutch investigators did the work, utilizing single-cell analysis (single-cell whole genome analysis) after separating the inner cell mass (representing the embryonic cell lineage) and the trophectoderm (extraembryonic cell lineage). They discovered mosaicism involving numerical or structural chromosomal abnormalities in 82% of embryos, with most abnormalities affecting less than 20% of all cells of the embryos.

Structural abnormalities were observed in 69% of embryos. In short, the authors discovered mosaicism at high prevalence in embryos, with current PGT-A widely reported as “euploid.”

These results were practically identical to a study CHR’s investigators reported already in 2021 in collaboration with colleagues at Rockefeller University.2 An accompanying commentary to their paper by Australian colleagues correctly concluded, and we are quoting: “The application and benefit of this technology (i.e., PGT-A) is controversial, and the findings provide more cause for caution on its use.”3 One, however, remains wondering when somebody will finally come out with a less polite statement saying that PGT-A is basically a worthless, and in some patients even hurtful test that should no longer be performed without clear and specific indications.

REFERENCES 1. Chavil EA, et al., J Clin Invest 2024;134(6):e174483 2. Yang et al., Nat ell Biol 2021;23(4);314-321 3. Robertson SA, Richards RI. J Clin Invest 2024;134(6):e179134

Non-invasive prenatal chromosomal testing in pregnancy

A recent paper by a large international consortium of researchers in Nature Medicine documented the progress made with non-invasive prenatal testing (NIPT) of early pregnancies for chromosomal as well as single-gene abnormalities.1 Using prenatal cell-free DNA (cfDNA) screening based on coordinative allele-aware target enrichment sequencing, they were able to detect aneuploidies, microdeletions, and monogenic variants.

Results were then compared to 1090 invasive prenatal or postnatal diagnostic test results.

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cfDNA detected a genetic abnormality in 135 pregnancies with 98.5% sensitivity and 99.3% specificity.

Among 876 fetuses with structural abnormalities on ultrasound, cfDNA identified 55 (6.1%) aneuploidies, 6 (6.1%) microdeletions, and 37 (37.8%) single-gene pathologies. The addition of targeted monogenic conditions alongside chromosomal abnormalities increased the detection rate by 60.7% (from 61 to 98 cases). The authors rightly concluded that we likely are on the way toward the ability to detect both chromosomal and single gene mutations in early pregnancy and in non-invasive ways from blood.

REFERENCE 1. Lennon et al., Nat Med 2024;30:470-487

Immunology

General aspects

OFF-THE-SHELF T-CELL THERAPY: Highly individualized precision immunological treatments are improving medical treatments in several areas with gratifying speed. A recent phase 3 study of allogeneic T-cell therapy in refractory Epstein-Barr virus-positive post-transplant lymphoproliferative disease demonstrated a better than 50% response rate.1 Another quickly evolving approach involves natural killer (NK) cells, lymphocytes of the innate immune system that have the ability to recognize a wide range of tumor cells and/or cells infected with viruses and have both effector function against such cells in distress but also participate in various multicellular immune responses.

An excellent recent review article in Nature magazine recently summarized treatment strategies based on the roles of NK cells in cancer immunity through immune checkpoint inhibitors, NK cell engagers, and infusion of preactivated and/or genetically modified autologous as well as allogeneic NK cell products.2 It all started with CAR T-Cell therapy (targeting the CD19 antigen on B-cells) in cancer treatments (initially specifically in B-cell-derived lymphomas and leukemias), but this treatment approach has now also proven applicable to autoimmune diseases. Here, the concept is to reset the abnormal autoimmune response of patients in diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis, where long-term immune suppression has been standard treatment (with all of the wellknown side-effects) by depleting their B cells and, thus, obtaining remission without the use of drugs.

Continued on page 70 A recent article by German investigators in the New England Journal of Medicine involving only 15 patients with those three autoimmune diseases proved this point when CD19 CAR T-cell transfers proved not only to be feasible but also to be safe and efficacious.3 Such treatments, therefore, can be expected to revolutionize treatments of autoimmune diseases as they have revolutionized treatments in oncology for some time now.4 INFLAMMATION, AGING and LIFESPAN: There are several good reasons why we do not like inflammation in women who are trying to conceive (we will come back to this point). Now it also becomes increasingly clear why inflammation shortens the lifespan. A group of investigators from several European countries followed up on the fact that rapamycin (Sirolimus) - an mTOR inhibitor - ameliorated aging in diverse species; but why that seems to be the case has been unclear.

Using a Drosophila model, they demonstrated that TORCI-S6K-Syx13 signaling appears to regulate inflammation in hepatic tissues via the endolysosomal system, in the process alleviating immunosenescence and enhancing longevity.5 The study demonstrated that age-related inflammation was higher in females than in males and in males was not lowered by rapamycin treatment or by lowered S6K. Rapamycin treatment, however, also elevated Syntaxin 12/13 levels in mouse liver and prevented age-related increases in noncanonical NF-KB signaling, strongly suggesting that the effect of TORC1 on inflammation is conserved from flies to mammals.

This brings us to the relevance of this work for reproductive medicine. Already in 2017, Chinese investigators demonstrated that short-term rapamycin treatment increases ovarian lifespan in young and middle-aged female mice.6 In 2021, a review article very well described how organ aging may lead to a variety of diseases and therefore affects the lifespan, how rapamycin can prolong the lifespan of many species by inhibiting mTOR, and how rapamycin treatment could extend the lifespan also in humans.7 More recently, U.S. and Canadian investigators brought this concept into reproductive medicine by suggesting low-dose pulsed rapamycin to standard PRP (platelet-rich plasma) treatments in women with low functional ovarian reserve,8 while pointing out that among over 1,000 anti-aging trials using rapamycin, less than 10 are

addressing ovarian aging. One of these trials, indeed, is taking place here in NYC at Columbia University, led

by Yousin Suh and Zeev Williams.9 We are very much looking forward to the outcomes of these trials.

And since we are already talking about inflammation, another group of investigators from Columbia University recently published an interesting paper in Cell, in which they reported that maternal inflammation regulates fetal emergency myelopoiesis.10 More specifically, they demonstrated in a mouse model that fetal hematopoietic stem and progenitor cells (HSPCs) include only limited numbers of myeloid cells and fail to activate an emergency myelopoiesis program as adults usually do.

Though fetal HSPCs can respond to stimuli that induce such a program, the process is maternally restricted in utero by anti-inflammatory factors, especially IL-10.

Loss of IL-10 activates the response in fetal HSPCs but leads to fetal demise. In an evolutionary sense, this anti-inflammatory maternal response thus maintains pregnancy (yet another good reason why we do not like inflammation in women who are trying to conceive), thereby rendering the fetus unresponsive to emergency myelopoiesis and making the fetus susceptible to infections.

FOOD ALLERGIES: The significance of food allergies is often greatly underestimated. They cause significant morbidity, and currently, only one FDA-approved product against food allergies is on the market - an oral immunotherapy for peanut allergy. Investigators now, however, reported a successful trial of the monoclonal anti-IgE antibody, Omalizumab, as an effective and safe monotherapy in patients with multiple food allergies.11 In a placebo-controlled prospectively randomized trial of individuals between age 1 and 17 years, treatment with Omalizumab for 16 weeks was significantly superior to placebo in increasing the reaction threshold for peanut and other common food allergens. An accompanying commentary, however, suggested that additional data will be required before this anti-IgE monoclonal antibody can be considered a routine treatment option.12 REFERENCES 1. Mahadea KM, et al., Lancet Onc. 2024;25(3):376-387 2. Vivier E, et al., Nature 2024;626:727736 3. Müller F, et al., N Engl J Med 2024;390:687-700 4. Isaacs JD. N Engl J Med 2024;390;758759 5. Zhang et al., Nat Aging 2024; doi: 10.1038/s43587-024-00578-3. Online ahead of print.

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Continued from page 69 6. Dou et al., Aging Cell 2017;16:825-836 7. Zhang et al., Ageing Res Rev 2021;70:101376 8. Sills et al., J Pers Med 2023;13:1147 9. Tawfik D. Insider.com. https://community.gethealthspan.com/t.rapamycin-to-prolong-fertility-and-ovarian-health/316?gad_source=1&gclid=EAIaQobChMI9vKtw4PChQMVY1dHAR3AF...

10. Collins et al., Cell 2024;187:1402-1421 11. Wood et al., N Engl J Med 2024;390(1):889—899 12. Wong GWK. N Engl J Med 2024;390(1):946948

Autoimmunity

AUTOANTIBODIES: Self-reactive antibodies should in principle not exist in healthy individuals, yet they do exist in various forms and situations. So-called natural autoantibodies, indeed, often exist at low levels in everybody (take for example antiphospholipid antibodies) and become “pathological” only once they exceed certain threshold levels. A recent article in Science magazine attempted to review the subject, recognizing that the whole subject of self-reactive (auto-) antibodies represents a critical yet largely unexplored subject that has the potential of influencing human health and disease.1 We strongly recommend this relatively short paper.

The authors note that the primary function of antibodies is to offer adaptive immunity against pathogens, though some of the antibodies that arise in everybody also bind to self-antigens. It is now also already well understood that by doing so these antibodies can elicit a wide range of biological effects. Every person has what the authors call an “autoantibody reactome,” now believed to contribute to trait diversity, just as we now know genetic differences influence the phenotype.

Hearing the word “autoantibody,” everybody first thinks about systemic autoimmune diseases because they are known to play etiological roles in the pathophysiology of autoimmune diseases. They also can drive inflammation in almost any organ, including in glands, and can also be found associated with distinctive diseases (anti-acetylcholine antibody in myasthenia gravis, or the anti-thyrotropin receptor antibody in Grave’s disease). And then there are autoantibodies that reveal themselves only in situations of stress.

An important example the authors noted was type I interferon (IFN-1) neutralizing antibody which, in cases of COVID-19, was found to increase the risk of death 200-fold. Like so-called natural antibodies (as noted above always present in everybody at low levels), this antibody increases in prevalence with age and was associated with approximately 20% of all COVID-19 deaths. The importance of antibodies like this is, therefore, becoming increasingly obvious.

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The article, however, also points out that in some instances autoantibodies may also be protective. Indeed, even anti-IFN-1 antibodies can be protective as SLE demonstrates, which is a disease with elevated IFN-1 signaling in about 50% of cases. Yet, about 5% of SLE patients have an autoantibody that neutralizes IFN-1 signaling, thereby substantially lowering disease activity. Another example is the presence of tumor-associated antibodies in several cancers, generally considered a positive prognostic sign.

The authors foresee a time in the relatively near future when thousands of autoreactivities will be revealed across many different diseases (and controls), proposing the truly tantalizing possibility that, in analogy to the human genome that was sequenced to annotate mutation, the same methodology may be applied to the human proteome and autoantibodies. They further suggest that every protein may in some individuals have functional antibodies which, through “autoantibody-wise association studies,” could be identified and subsequently utilized for diagnostic as well as therapeutic purposes; a truly exiting prospect. However, we, first, still would like to know why we all have low levels of anti-phospholipid antibodies.

REFERENCE 1. Jaycox et al., Science 2024;383(6684):705-707

Bacteria and viruses COVID-19

Increasingly more evidence is being reported that COVID-19 infections are associated with more longterm autoimmune inflammatory rheumatic outcomes.

A recent study published in the Annals of Internal Medicine involving South Korean and Japanese study populations now, once again, confirmed the association: 10,027,506 Korean and 12,218,689 Japanese patients with mean age of 48.4 years (51.1% men), where 394,274 had a history of COVID-19 and 98,596 a history of influenza. After propensity score matching, beyond 30 days after infection, COVID-19 patients demonstrated a significantly increased risk for autoimmune/inflammatory/rheumatic diseases compared to patients without either infection in both patient groups, and in comparison, to patients with influenza. Moreover, the risk increased with the severity of COVID-19 and was maintained for up to 12 months, though was somewhat mitigated by vaccination.

Continued on page 72 “Long COVID” (LC), as discussed in the preceding issue of the VOICE, has remained a puzzle. Considered a fantasy by some, others have allegedly described distinct changes to the immune system in patients with LC. A recent article in Science magazine attempted to shed some light but did not succeed and, indeed, lined up even more potential explanations for even more different forms of the condition.2 Symptoms apparently can be cardiovascular, neurologic, and/or metabolic.

The pathophysiology may involve viral persistence, immune dysregulation, microbiome dysbiosis, endothelial inflammation, neuronal inflammation, and mitochondrial dysfunction. One wonders, whether anything is left?

A recent article in the New England Journal of Medicine attempted to describe “Long COVID” but found no evidence of more impaired cognition in “Long COVID” than in regular COVID, though both groups demonstrated mild impairment in comparison to no patients who did not have COVID (loss of 3 IQ points).3 An accompanying commentary was skeptical about the study’s results, and again extensively hypothesized how “COVD-19 could have affected patients with Long COVID.” The commentary had the same first author as the above-cited Science article but still had really no good explanation for the skepticism (even though the drawings this time were more interesting).

REFERENCES 1. Kim et al., Ann Int Med 2024;177(3). https://doi.org/10.7326/M231831 2. Al-Aly Z, Topol E.Science 2024;383:6685:830-832 3. Hampshire A et al., N Enl J Med 2024;390(9):806818 4. Al-Aly Z, Rosen CJ. N Engl J Med 2024;390(9):858818

Microbiomes

FALLOPIAN TUBE MICROBIOME AND OVARIAN CANCER? It has now become increasingly clear that what for many decades were considered ovarian cancers, in reality have been malignancies arising from mostly distal parts of the fallopian tubes. It, therefore, should not be a surprise that studies of tubal microbiota have started appearing in the literature which have been trying to find an association between bacterial colonization of fallopian tubes and ovarian-tubal cancer. Now researchers from Stanford University joined the discussion with a paper in eLife, in which they report (i) that women with ovarian cancer demonstrated a clear shift in tubal microbiota in comparison to women without cancer; and (ii) women with serous

carcinoma had a higher prevalence of almost all 84 fallopian tube bacterial species compared to other ovarian cancer subtypes.1 The authors concluded from their study – supported by the editors’ assessment – that these data warranted further exploration of a possible causal link between tubal microbiome and ovarian-tubal cancer. Though that, of course, cannot be ruled out, one can also imagine that the cancer secondarily affects the microbiome. One should never forget the old “chicken or egg” question!

INTESTINAL MICROBIOTA AND FIBROMYALGIA: A recent paper in the International Journal of Rheumatologic Diseases published an alleged systematic review of the importance of intestinal microbiota in the “ethio-pathogenesis” (a “word-salad” really use) of fibromyalgia.2 The problem with this paper already starts with the definition of fibromyalgia as a “chronic disease.” Fibromyalgia is, however, not a disease but a “disorder” which, like “adrenal fatigue” discussed elsewhere, must be correctly understood as a disorder with widespread musculoskeletal pain, accompanied by fatigue, sleep disturbances, memory, and mood issues.3 How one attempts a systematic review on a so poorly defined disorder is, therefore, difficult to understand.

We, therefore, approached this paper with a degree of skepticism, but were pleasantly surprised: It turned out to be a relatively quick educational read, mostly about the gut-brain axis, which in recent years has not only become a popular subject of discussion but, indeed, appears to affect significant portions of daily human function. One, therefore, cannot argue with the hypothesis that the intestinal microbiome may be connected to at least some symptoms closely associated with what is called fibromyalgia.

And if we already are talking about intestinal microbiota, how about a recent paper that claims that distinct intestinal microbial signatures are linked to accelerated systemic and intestinal biological aging? To understand the authors’ conclusion, it is important that the studies were performed in patients with HIV. They identified specific microbial compositions and microbiota-related metabolic pathways in those patients that were intertwined with intestinal as well as systemic biological aging.4 71 | THE VOICE

Continued from page 71 REFERENCE 1. Yu et al., eLife 2023;12:RP89830 2. Palma-Ordóñez et al., Int J Rheum Dis 2024;27:e15021 3. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/fibromyalgia/symptoms-causes/syc-20354780 4. Singh et al., Microbiome 2024;12:31

Pharmacology

Perimenopausal statin use in women on hormone replacement Here is for a change some good news for women on hormone replacement therapy. A recent study in JAMA Network Open concluded in a case-control study of 223,949 women at ages 50 through 64 that the 53 % higher risk of venous thromboembolism with hormone replacement therapy was reduced by more than half to 25% if patients were also on statins. The authors concluded that in women in this age group, hormone replacement therapy may, therefore no longer be contraindicated if they also are on statins.

REFERENCE 1. Davis et al., JAMA Netw Open 2023;6(12):e2348213

Pregnancy

Is pregnancy a disease?

This is the question asked in one of the most interesting articles we recently came across by two Finnish colleagues in the Journal of Medical Ethics.1 They concluded that there are normative as well as pragmatic reasons to consider pregnancy a disease – obviously a highly controversial conclusion – but surprisingly well supported by many of their arguments. Like a disease, (i) pregnancy affects the health of the affected person; (ii) can cause a range of symptoms from discomfort to death; (iii) can be treated (and we would add “is” treated) like a disease; (iv) pregnancy is caused by a “pathogen,” defined as an external organism invading the host’s body (i.e., the embryo); and (v) its occurrence risk can be reduced by prophylactic measures.

The authors, however, also recognize contrarian arguments such as, (i) the “normality” of pregnancy; (ii) it’s obvious necessity for human survival; and (iii) the obvious value society attached to its occurrence.

Coming away from reading this paper, one is confronted by contradictory emotions of outrage about how something as “natural” as procreation can be considered to be a disease, while on the other hand having to acknowledge the fact that how medicine treats THE VOICE | 72

pregnancy in modern societies is exactly how we treat diseases. But, as we all know, behaving in contradictory ways is, of course, nothing new in medicine.

REFERENCE 1. Smajdor A, Räsänen J. J Med Ethics 2024;0:1-8

General aspects of pregnancy

SINGLETON vs. TWIN PREGNANCIES AFTER ART: An international consortium of investigators recently reported in Human Reproduction Update a “monster” study on outcomes of twin pregnancies established through assisted reproductive technologies (ART).1 All cohort studies in all languages based on searches in MEDLINE and EMBASE between 1990 and 2023 were reviewed. Ultimately, the study included a systematic review and meta-analysis of 111 prior publications involving 802,462 pregnancies in an effort to compare maternal and neonatal outcomes between naturally and ART-conceived pregnancies, whether singleton or twin pregnancies.

What the study claimed to demonstrate was as follows: Regarding maternal outcomes, ART pregnancies had an increased risk for preterm birth, gestational diabetes, hypertensive disorders, and Cesarean delivery. Regarding perinatal/neonatal outcomes, ART cycles produced increased as well as decreased risks.

Increased risks were detected for respiratory distress syndrome, congenital malformations, NICU admissions, and birth weight discordance. ART, however, decreased risks for twin-twin transfusion syndrome, stillbirth, and small for gestational age diagnoses.

And what was the final conclusion of the 13 authors?

“Twin pregnancies conceived following ART have significantly higher adverse maternal and offspring outcomes than non-ART twin pregnancies, including GDM, hypertensive disorders in pregnancy, PTB, cesarean delivery, NICU admission, and congenital malformation. Therefore, ART twin pregnancies should be recognized and managed as a higher-risk group. Additionally, women seeking assisted reproduction should be counseled regarding the increased risks of ART twin pregnancies. However, obvious limitations of this study warrant an extremely cautious interpretation.

Continued on page 74 In many ways this was just another of so many research efforts these days which have nothing new to contribute, leaving the reader wondering what new findings the authors expected? Even if it involved 11 publications and 802,462 pregnancies, while studies of undefined patient populations – so-called “real world data” – can produce important data, this, however, will not be the case when the underlying study hypothesis makes no sense. In this case this means, how can comparisons of outcomes between singleton and twin pregnancies make any sense if outcomes differ (1 vs. 2 offspring)? Outcomes, of course, must be equalized before outcome comparisons can be made (i.e., comparisons cannot be made between one singleton and 1 twin pregnancy but must be made between 2 consecutive singleton pregnancies and 1 twin pregnancy). In short, another study deserving of the “worst paper award” in this issue of the VOICE. PRETERM BIRTH and MATERNAL NATIVITY, ETHNICITY and RACE: Though considerable data exist on the association of preterm birth with race, ethnicity, and economic class, at least some of those data have remained controversial. Investigators from several U.S. universities now addressed the subject once more in a paper that just appeared in JAMA Network Open.2 The study involved 34,468,901 singleton live births of birthing people with a mean age of 28 years. All minorities, whether by nativity, ethnicity, or race had increased adjusted risks of preterm birth in comparison to Whites in the U.S.-born birthing people (except for non-U.S.-born Whites and Hispanics). Racial and ethnic minorities also had increased adjusted risk for extremely preterm births within each group (except for non-Hispanic Native Hawaiian and other Pacific islanders).

The authors noted that, “results suggested heterogeneity of preterm births across maternal nativity, ethnicity, and race as well as gestational age categories” and that “understanding these patterns could aid the design of targeted preterm birth interventions and policies, especially for birthing people, typically underrepresented in research.” Really?! Is that it?

HUMAN CHORIONIC GONDADOTROPIN (hCG) LEVELS AND ADVERSE PREGNANCY OUTCOMES: And since we by now are already well-known for bashing the onslaught of systematic reviews and meta-analyses that are flooding our medical journals

with often useless data and conclusions, here is one more. This time, it is an Australian group of investigators spending their seemingly not very valuable research time trying to find out what too low and too high hCG levels in early pregnancy really mean.3 As if we haven’t known the answer for decades!

Abnormal hCG levels in early pregnancy, of course, are associated with adverse pregnancy outcomes, mostly mediated by the placenta. At 66 pages, this is clearly one of the longest manuscripts ever published in our specialty with absolutely no important new information. (It may be time to introduce a new category of price paper: “the biggest paper waster.”) Imagine,“both high and low hCG in the first trimester can be early warning signs of adverse outcomes.” And then comes the really important final conclusion: “Further analysis of hCG subtypes and pregnancy outcomes is required to determine the diagnostic utility of these findings in reference to specific cutoff values.” And this after 66 manuscript pages; truly amazing!

REFERENCES 1. Marleen et al., Hum Reprod Update 2024;dmae002. [“WORST PAPER AWARD RECIPIENT”] 2. Barreto et al., JAMA Network Open 2024;7(3):e243194 3. Peris et al., Am J Obstet Gynecol 2024;230(2):118-184

Diseases in Pregnancy

One of the basic principles in the management of medical complications of pregnancy is that diseases can affect pregnancy and pregnancy can affect diseases. Here are a few examples in reference to recently published papers. A study by Chinese investigators in the JCEM, for example, reported on the association of maternal thyroid disease (TD) in early pregnancy and gestational diabetes (GD). Both of these subjects are, of course, very well described in the literature; but whether they interrelate and, if so, to what degree, is not.

Like most good Chinese studies, one of their characteristics is usually a large number of study subjects, which also applied to this paper. Among 26,742 pregnant women, 3,985 (14.9%) had GD. Women with GD were significantly older than normal women (33.3 vs.

31.5 years (P=0.001). After appropriate adjustments, TSH levels (P=0.012) and subclinical hypothyroidism (P=0.039), though not free thyroxine or TPO antibodies, were associated with GD. TSH and GD, moreover, apparently had a nonlinear relationship (<0.05): < TSH 1.24 mIU/L GD was elevated, > 1.44 mIU/L it was not.

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Continued from page 73 But once again, we cannot agree with the authors’ conclusion that “high TSH might be associated with risk of GD,” and the reasons seem obvious. Considering the substantial size of the study population, levels of significance of observed associations are really marginal. In addition, such an association currently lacks any physiological underpinnings.

cally a characteristic of all autoimmune inflammatory diseases, likely representing the early discontinuation of immunologic tolerance of the fetal-placental unit by the mother’s immune system.4 Women with those 12 diseases also had increased risk of small for gestational age infants (P<0.0001). Women with rheumatoid arthritis and IFBD, however, lost the association with preterm birth and low gestational weight after statistiInvestigators from Seattle in eClinical Medicine report- cal adjustments.

Now a word about mental health in pregnancy. It may ed, in contrast, very interesting data on maternal-fetal come as a surprise that mental illness contributes to pregnancy outcomes in women with immune-mematernal mortality up to twice as much as postpartum diated inflammatory diseases (IMIDs, see Table 1).2 IMIDs, are, of course, classical examples affected by hemorrhage. This is one important piece of informapregnancy (and into the postpartum period) and, in tion we gleaned from a recent article in JAMA Psychiaturn, affecting pregnancy, even though the broad spec- try.5 The goal of this article was to highlight the undertrum of disease, at least to a degree, must be viewed as recognized contribution of mental illness to maternal morbidity and mortality. potentially obfuscating possible findings.

Table 1. Immune-mediated inflammatory diseases included in this study Psoriasis Inflammatory bowel disease (IFBD) Rheumatoid arthritis Spondyloarthritis Multiple sclerosis Systemic lupus erythematosus Psoriatic arthritis Antiphospholipid antibody syndrome Sjögren’s syndrome Vasculitides Sarcoidosis Systemic sclerosis

In a retrospective cohort study (with all the usual limitations of such a study format) the authors, nevertheless, were able to reconfirm potentially important information. Among 5,784 women with IMID and 359,291 without who served as controls, pregnancies that reached at least 20 weeks of gestational age doubled over the last 10 years of the study (credit be given to where it is deserved). This finding alone demonstrates the progress made over the last decades with the treatment of inflammatory diseases in pregnancy.

Only a minority of affected patients (17%) had at least one immunomodulatory treatment during pregnancy, among them a majority (up to 70% depending on the drug) who just continued prior to pregnancy prescribed medications.

Patients with one of these 12 inflammatory diseases were uniformly at increased risk for preterm births (P=0.02) The CHR’s Norbert Gleicher, MD, already in 2010 reported that premature delivery was practiTHE VOICE | 74

Finally, a few words about a very important subject that unfortunately affects too many women: pregnancy after breast cancer. A recent paper reported important new data on the safety of pregnancy following BRCA mutation-associated breast cancer. With follow-up of almost 8 years in 4,732 patients who had 659 pregnancies with help from IVF, these authors found no effects of pregnancy on survival. A commentary in JAMA Surgery warns about generalizing these findings to all breast cancers7 and that is, of course, good advice.

REFERENCES 1. Huang et al., J Clin Endocrinol Metab 2024;109:e780-787 2. Hwang et al., eClinicalMedicine 2024;68:102435 3. Gleicher N. Clin Rev Allergy Immunol 2010; 39(3):194-206 4. Gleicher N. Clin Rev Allerg Immunol 2010;39(3):194-206 5. Wisner et al., JAPA Psychiatry 2024; doi: 10.1001/jamapsychiatry.2023.5648. Online ahead of print.

6. Lambertini et al., JAMA 2024;331(1):49-59 7. Newman et al., JAMA Surg 2024l doi: 10.1001/jamasurg.2024.0005.

Online ahead of print.

Testing for pre-eclampsia

By now, it seems everybody has their own, new diagnostic early pregnancy test for pre-eclampsia. Hardly a week goes by without yet another one being published. However, what almost never comes up in these reports is the purpose of the proposed test or -to be more specific – so what if one really assumes a test can predict and/or diagnose pre-eclampsia? Whether the test under such circumstances offers a benefit that will change/improve the clinical outcome then becomes the really decisive question.

Continued on page 76 This is why a recent study in The Lancet by U.K. investigators is worth mentioning because this study for the first time asked the right follow-up question: whether doing the testing is really worth it. And, like so many times in medicine, if this question is asked, the disappointing answer is a big no!1 Using repeat placental growth factor-based testing in women with suspected preterm pre-eclampsia in a multicenter, parallel-group, superiority randomized controlled trial, the authors concluded that “routine repeated testing in women with suspected pre-eclampsia was not associated with improved perinatal outcomes.”

Such testing, therefore, was not recommended, though the authors pointed out that their study was performed in a population of high income and, therefore, relatively low pre-eclampsia prevalence, leaving open the possibility that such routine testing may still demonstrate outcome benefits in a patient population with higher pre-eclampsia prevalence.

REFERENCE 1. Hurrell et al., Lancet 2024;403:619-631

Drugs in pregnancy

Diseases in pregnancy often require medical treatments, and medication use in pregnancy is almost always a tricky issue because almost every medication has to consider the fetus as a second patient. Within such a context, post-marketing constantly alleges adverse associations, which often are just anecdotal but, of course, also can be real. Differentiating between these two possibilities is not always easy. Here are three new reports.

First, in the BMJ, French investigators reported that prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningiomas.1 The levonorgestrel intrauterine system, oral, intravaginal, as well as transdermal progesterone in contrast were, however, found to be safe. Special concern was expressed about the widely used injectable medroxyprogesterone acetate.

A second study in The New England Journal of Medicine reported an increased risk of autism spectrum disorder in the offspring of women who received antiseizure medications in pregnancy. Drugs to be affected included topiramate, valproate, and lamotrigine.2 Most concern was expressed for valproate, while the effects

of the other two drugs were attenuated after indications and cofounders.

And, finally, a study in JAMA Newtwork Open reported in a case-control study a positive association between opioid dose dispensed and odds of preterm birth. The guidance given as a result was to minimize therapeutic opioid use in pregnancy in general and, when absolutely needed, restrict it to the lowest effective dosage.3 REFERENCES 1. Roland et al., BMJ 2024;384:e078078 2. Hernández-Diaz et al., N Engl J Med 2024;390(12):1069-1079 3. Boswort et al., JAMA Network Open 20347(2):e2355990

Basic research

A mouse model for the aging reproductive tract

Reproductive cycles in the female require extensive repeated remodeling. Using single-cell and spatial transcriptomics, mostly German investigators now in a very interesting paper in Cell systematically described changes morphology and gene expression in ovaries, fallopian tubes, uterus, uterine cervix, and vagina during the phases of the estrous cycle in the mouse during decidualization and into aging. What they discovered was a central role for fibroblasts in highly organ-specific ways involving extracellular matrix reorganization and inflammation. Yes, inflammation here is once more an essential component of reproductive function!

The authors concluded that – at least in the mouse – repeated reproductive tract remodeling over the reproductive lifespan drives the gradual development of fibrosis and chronic inflammation and was confirmed by the investigators by demonstrating that ablation of cycling reduced fibrotic accumulations during the aging process. That ovaries with advancing age undergo fibrosis has, of course, been known for decades.

Based on excellent IVF cycle outcomes in older women with donor eggs, the uterus, however, to this day has been assumed to remain mostly unaffected by aging.

Assuming that the mouse in this case is a model for the human experience (which it, of course, often is not), this would require a radical reassessment because this study suggested that not only in the uterus but also in fallopian tubes and vagina fibrosis accumulates.

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Continued from page 75 This has relevance not only for fertility but, as the authors noted, fibrosis and chronic inflammation promote diseases, likely including certain cancers. They pointed out that cycle suppression has, indeed, been demonstrated to reduce endometrial cancer risk. In summary, not only an interesting but also a potentially clinically very relevant study!

REFERENCE 1. Roland et al., BMJ 2024;384:e078078

Modeling implantation

Japanese colleagues never fail to amaze in their research capabilities in reproductive biology. A consortium of Japanese investigators from several universities again offered an important paper - in this case, a model for the implantation process which so far has mostly remained an impenetrable black box.1 The study involved the development of hormone-responsive endometrial organoids which emulate the in vivo architecture of the endometrium. The authors co-cultured those with stem-cell-derived blastoids, and in a three-dimensional “assembloid” system, recapitulated critical implantation stages, including apposition, adhesion, and invasion. The model tracked how endometrial epithelial cells were disrupted by syncytial cells which invade and fuse with endometrial stromal cells.

We are going to hear much more about this and, hopefully, several additional models. More insights into the implantation process are, indeed, urgently needed.

REFERENCE 1. Shibata et al., Sci Adv. 2024;10:eadi4819

Modeling human embryos

And if we are already talking about embryo models derived from stem cell lines, we have to point out a commentary in Nature Methods by one of the most formidable biologists in the world over the last decade, Magdalena Zernicka-Goetz, PhD., in which she described the evolution of mouse and human embryo models, both in which she played a quintessential role.1 It is no exaggeration to state that the development of human embryo models in recent years has made amazing progress which can be expected to continue. These models, of course, are at the very basis of all progress that can be expected to be made in the coming months and years in reproductive biology, and not only when it comes to implantation, as noted above. With obvious THE VOICE | 76

ethical restrictions and limited availability of human embryos for research, these models have quickly become irreplaceable.

What blocks polyspermy?

Following fertilization of an egg by a single sperm, other spermatozoa are prevented from penetrating the egg by the hardening of the zona pellucida, thereby in most cases preventing polyspermy. Now a group of investigators from around the world published a paper in Cell that finally explains this phenomenon. They suggested that oligomerization of the cleaved ZP2 N-terminal region of glycoprotein ZP2 (a major subunit of ZP filaments) extensively cross-links ZP filaments, rigidifying the zona and making it impenetrable to sperm.

REFERENCE 1. Nishio et al., Cell 2024;187:1440-1459

Statistics and study design

As repeatedly addressed over recent months in the VOICE, the safeguarding of research integrity has become a major theme not only in the medical and science literature but also in general media. The Lancet, indeed, recently published one of its rare unsigned editorials on the subject.1 Though pointing out the urgency for change from regrettable habits that have overtaken the publishing industry, the editorial offers nothing new that has not been discussed in detail in the pages of the VOICE over recent months. They concluded that “perverse incentives” have led to drive quantity over quality and to profiting from a system that is no longer rewarding and supportive of (honest) researchers’ merits.

Somewhat related, in a Letter to The Lancet, two Iranian statisticians offered a panel of 10 excellent recommendations for accurate reporting of statistics.2 Listing them all here would exceed the framework of this section, but we recommend this brief communication for everybody interested in the subject.

Finally, another subject dear to our heart and repeatedly discussed in the VOICE - the importance of patient selection in performing studies. A recent editorial in the New England Journal of Medicine makes this point very well; this time in association with discussing a onco-gynecological study.3 Whatever the clinical framework, one cannot often enough point out the essentiality of patient selection for any clinical study!

REFERENCE 1. Editorial. Lancet 2024;403:699 2. Mansournia MA, Nazemipour M.Lancet 2024;403:611-612 3. Ramirez PY. N Enl J Med 2924390(9):861-862

The business of medicine

Another subject frequently discussed in the VOICE and dear to our hearts is the increasing “practice of medicine” by medical insurance companies. They do this by denying care coverage and/or mandating certain predetermined treatment patterns. A good example in the fertility field is the mandate of some insurance companies that patients in most cases cannot be advanced into IVF unless they had three failed insemination cycles before.

The CHR has always been of the opinion that such treatment patterns represent “practice of medicine” and, therefore, are illegal because corporations, of course, are not licensed to practice medicine.

The subject is now suddenly attracting considerable attention in legislations and media. The New York Times, for example, recently called it in an article, “The Big Business of Denying Medical Care.”1 It finally also attracted the attention of the American Medical Association (AMA) which, in a recent posting by Kevin O’Reilly, described the resulting time-waste and delaying of care as the “bane of physicians’ existence.”

REFERENCE 1. Stockton A. The New York Times. March 14, 2024. https://www.nytimes.com/2024/03/14/opinion/health-insurance-prior-authorization.html 2. O’Reilly KB. AMA. April 15, 2024. https://www.ama-assn.org/practice-management/prior-authorization/5-positive-signs-road-fixing-prior-authorization

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NEWSLETTER INFORMATION

The CHR VOICE is the newsletter of The Center for Human Reproduction (CHR), an independent, academically affiliated infertility and research center located at 21 East 69th Street in Manhattan, New York, N.Y 10021. www.centerforhumanreprod.com. Telephone +212 994 4400.

The CHR VOICE attempts to inform and engage a global community of infertility patients, infertility service providers, and researchers in reproductive medicine, physiolo- gy, and biology. The mission of The CHR is clinical care, research, and education, all at highest standards, with empathy, honesty, integrity, and equity.The newsletter is published 10 times a year (except July and August). Copyright © 2023 by The CHR. All rights reserved. Print ISSN 2836-3086. Online ISSN 2836-3094. Copyright © 2023 by The CHR. All rights reserved.

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