Estriol: The Nurturing Protective Estrogen

By John Sherman, N.D., Consulting Physician, Meridian Valley Lab

Estriol, one of the three primary human estrogen metabolites, has been getting negative publicity lately as a weak and worthless estrogen, despite it being prescribed safely and effectively by many bioidentical hormone practitioners for decades. The debate on whether estriol supplementation is worthwhile or advantageous has come under scrutiny, even from some integrative hormone practitioners, and it’s time to differentiate truth from fiction.

Estriol is one of the primary endogenous estrogens, along with estradiol and estrone, and all three are considered bioidentical. Discovered in 1930, estriol's clinical use was introduced in 1938. Estriol is normally produced by the placenta during gestation, and becomes the dominant estrogen during this critical time, especially just before delivery. Levels of estriol increase up to 1000-fold during pregnancy and make up about 90% of the estrogen in a full-term pregnant woman's urine. This late pregnancy surge in estriol occurs about 2-4 weeks prior to delivery (2). The fetus also makes quite a bit of estriol, originating from DHEA-S in its adrenal glands, which transforms eventually into estriol in the placenta. Estriol is necessary for uterine growth, labor and delivery, and in breastfeeding (1), and at its peak helps initiate labor as the dominant pregnancy hormone just prior to delivery. Animal studies have proven that rising cortisol and estriol in the fetus causes the initiation of labor, with these hormones specifically increasing production of 'contraction-associated proteins' (2). Women with low levels of estriol at term may fail to go into labor spontaneously and require labor-induction procedures instead (1).

Estriol comprises only a fraction of a woman's pre-menopausal estrogen potency since it has much weaker influence on a woman’s physiology than estradiol and estrone (6). Estradiol and estrone are essentially chemically interchangeable and a post-menopausal woman can readily make estradiol out of her extra estrone as she ages. Estrone is the predominant metabolite during peri- and post-menopause, and tends to be associated with age, and elevated fat tissue. Estriol predominates during pregnancy, whereas estradiol predominates during the menstrual/ovulatory years. Estriol is chemically downstream from both estrone and estradiol and has a strong affinity for binding to estrogen receptors throughout the body. Estriol is hard to detect in the bloodstream due to its short half-life (20-30 minutes). Estradiol's halflife is much longer at 14 to 17 hours, potentiating some of its potency. Estriol is cleared from the non-pregnant woman's liver and kidneys very quickly, and

this is why circulating serum levels are low and hard to measure accurately. Despite its fleeting concentration, total levels of estriol in the urine are relatively high over a 24-hour time period. This makes urine perhaps the best method of measuring estriol levels accurately, especially in the non-pregnant female.

So, why consider estriol applications in menopause? Why bother with it if it's so weak and short-lived in the blood stream? Estriol's strength is in its weakness. Estriol is considered the “safe” estrogen and can be gently supportive in many ways without oversupplying excessive force on estrogen receptors. Estriol is commonly combined with estradiol in topical hormone creams to prevent symptoms of menopause. Both metabolites help improve many menopausal symptoms including hot flushes, vaginal dryness, thinning skin, urinary tract infections, and hair thickness. The difference is that estriol can alleviate symptoms with less risk. Estradiol improves bone density more effectively than estriol, but estriol does not increase breast density like estradiol can, and estriol has little effect on endometrial proliferation, compared to estradiol. Estradiol also is more potent in cholesterol metabolism, raising HDL cholesterol to higher levels than estriol. Estrone appears to help improve bone density the most, but because it can activate pro-inflammatory genes, and increase weight gain, it is avoided by most practitioners. A “Bi-Est” (estradiol + estriol) combination tends to be preferred over “Tri-Est” (estradiol + estriol + estrone) for these reasons. Estriol has also been shown to help with anxiety and insomnia, and appears to have a calming effect, which can be advantageous during labor, as well as menopause.

Estriol Physiology:

The physiological effects of estriol are similar to estradiol, but with much lower potency (1). Estriol is about 8% the potency of estradiol (x 0.125). Estriol's half-life is only 20 to 30 minutes, with 95% being quickly cleared into the urine. Both appear to help control menopausal symptoms effectively. Estrone is more prominent in post-menopausal women but can readily transform into estradiol when needed. Estrone is produced from fatty tissue, so estrone can predominate in obese women, and due to increased inflammatory cytokine production, estrone is linked to increased breast cancer risk.

Both estradiol and estrone eventually get converted to estriol as they get metabolized. Interestingly, estriol does not convert back to either estradiol or estrone and supplementing estriol does not increase levels of estradiol or

estrone. Studies of metabolism of estrogen by MCF-7 cells (breast cancer cell line) show no conversion of estriol to either estrone or estradiol (7). Estriol is not directly produced by the ovaries, and primarily generated by the placenta, and the attached fetal adrenals in pregnancy. During perimenopause and menopause, estriol appears directly downstream from estradiol and estrone metabolism.

Estriol Derivation:

The US patent office typically only allows patent applications for molecules not found in nature and estriol is found naturally in various plants containing isoflavones, a primary phytoestrogen (6). Being a naturally derived sex steroid, estriol can be sourced from phytoestrogenic plants, including foods such as soybeans, cruciferous vegetables, beans, and other foods (6). One of the predominant sources of almost all synthesized bio-identical hormones is from the vegetable, Mexican yam (Dioscorea spp.), also called 'wild yam'. The Mexican yam is grown for its diosgenin content, which was first isolated in 1940 to use to synthesize corticosteroids and sex hormones. Dioscorea villosa has one of the highest diosgenin content and can be purchased in standardized form. There are over 600 species of Dioscorea and the diosgenin content can vary significantly (8). Phytoestrogens can produce estrogenic activity in the body but are considered much weaker, perhaps 500 to 1000 times weaker than estradiol (6).

Safety & Efficacy:

Estriol is considered very safe and because it is considered a weaker estrogen, it provides many protective benefits without the risks attributed to stronger estrogens (3). When present continuously at adequate concentrations, estriol provides full estrogenic effects similar to estradiol (13). Estriol is well-tolerated and produces few side effects, especially when applied vaginally (12). In a systematic literature review, studies confirmed estriol's efficacy for vulvovaginal atrophy with few adverse reactions reported (12). It was concluded that estriol preparations appear to be safe for women at risk with factors related to systemic estrogen therapy (12).

Estriol controls many of the symptoms of menopause without the common side effects associated with the use of estradiol (3). In particular, estriol does not increase the risk of endometrial hyperplasia during typical hormone replacement therapy. However, it does not appear to prevent bone loss and prevent cardiovascular events as well as estradiol. Due to its safety record, estriol is approved as a treatment of osteoporosis under

the Japanese medical insurance provisions, where it is the preferred prescription for menopausal women (14).

In one 5-year study of 2007 treatment years involving 911 women using estriol, the incidence of HRT complications were not increased, and were found to be “lower than expected” (15). Endometrial and ovarian cancers were not observed, and although two breast cancers occurred during the study period, these were deemed “unrelated to treatment”(15).

“Bio-Identical” Dosing:

Correct physiologic proportional dosing is an important goal of bio-identical practitioners. To quote Dr. Jonathan Wright, the “grandfather” of bioidentical hormone replacement, “it's always best to copy nature”. This motto was something he followed throughout his practice, with almost all of his therapies. To copy nature's normal hormone levels, he tested multitudes of premenopausal healthy women, at their peak luteal phase (around day 20) of their cycles. This was primarily to find the peak progesterone level, but he also knew there were high estrogen levels at this time to help thicken the uterine lining, to help the fertilized egg attach to the uterine wall. He felt this would be a good approximation for post-menopausal hormone replacement levels.

Founded by Dr. Wright in 1976, the Meridian Valley Laboratory (www.meridianvalleylab.com) has been evaluating 24-hour urine hormone levels for both women and men for many decades, continually updating and refining their reference ranges. Interestingly, their results have been consistently stable, and relatively the same since Dr. Wright's original research.

Serum testing of estriol has been difficult through the years, perhaps due to estriol's very short half-life within the bloodstream. The majority of studies do not show any change in serum estriol levels after vaginal estriol applications, the preferred delivery route (16). Also, post-estriol applications show no increase in serum estrone, estradiol, testosterone, progesterone or sex hormone binding globulin (16). Saliva testing also has limitations, since many external factors such as time of day tested, diet, and smoking can all cause variable measurements. There are differences in hormone saliva excretion rates among women, especially after starting therapy. Spotchecking saliva samples need to correspond directly with when and how the hormones were applied and represent only a single point in time. Neither serum nor saliva testing allow for measurement of various hormone

downstream metabolites, which provide insights into cancer risk and osteoporosis tendency.

24-hour urine collections have stood the test of time and offered many advantages over other forms of monitoring hormones. According to many clinics, including the Cleveland Clinic, a 24-hour urine test is the most accurate way to measure estriol levels (1). Estriol is sometimes checked in the 15th to 20th week of pregnancy to help screen for birth defects (1). It is typically combined with three other tests at the same time, namely HCG (human chorionic gonadotropin), alpha-fetoprotein, and inhibin-A proteins. This screening is usually performed when the mother is over 35, diabetic, or has a family history of birth defects (1).

Rather than taking a 'snapshot' in time (saliva or blood specimens) of hormone levels, a full day's total hormone excretion and how they are metabolized, provide the practitioner with the most accurate tool to fine tune therapy for their patients. Most laboratories agree that 24-hour urine hormone testing provides the highest level of sensitivity to assess even very low levels of hormones by direct measurement of the amount produced over an entire circadian cycle (24 hours).

Despite estriol being a “pregnancy” metabolite, luteal testing of premenopausal women shows higher than expected levels of estriol compared to estradiol. (So much for estriol being “unimportant”.) Mid-luteal reference range (day 20 of 28) for estriol is 7 mcg/24 hr to 29.7 mcg/24 hr (median 18.3). Estradiol reference range for the same mid-luteal period is 2 mcg/24 hr to 7.8 mcg/24 hr (median is 4.9). So, despite conventional wisdom espousing that estriol is only a minor player for the pre-menopausal woman, the estriol/estradiol mid-luteal ratio is close to 4 and has remained close to 4 for many decades of monitoring women. This is why the grandfather of bioidentical hormone replacement (Jonathan Wright, MD) has always recommended an estrogen cream dose close to 80% estriol and 20% estradiol, similar to what is produced naturally. Actual ratio is 78.9% estriol and 21.1% estradiol, but an 80/20 cream is a close approximation to copy nature for prescriptive use. Estrone is rarely or never used in therapy, since it tends to be pro-inflammatory and is associated with weight gain. As stated, prior, estrone and estradiol become interchangeable biochemically at different rates unique to each woman.

Estriol is the great balancer. For the practitioner treating menopausal vasomotor and other complaints, using a blend of mostly estriol, with smaller amounts of estradiol, is easier to accurately dose and adjust than using

estradiol alone. It is much easier to dispense excessive amounts of estradiol than it is estriol, since estradiol is much stronger, and associated with breast tenderness, breast glandular proliferation, weight gain and uterine bleeding. The safety margin for estradiol is very thin and can be easily over prescribed. The 'sweet spot' dosage for each woman is more easily obtained using predominantly estriol, while using estradiol judiciously in combination with estriol.

Estriol is very well tolerated with few side effects, but at higher doses has the rare potential to cause similar adverse effects as estradiol, including breast tenderness, and post-menopausal bleeding. However, typical dosing of vaginally applied estriol does not cause endometrial proliferation, and the need for opposing progesterone in combination with estriol is less critical (5) although still recommended. Estriol also has poor affinity to SHBG (sex hormone binding globulin) in vivo, with more 'free' estriol available throughout the circulation compared to estradiol.

One of the easiest and most effective way of calculating a woman's hormonal balance point was theorized by Dr. David Rosensweet, a well-known integrative endocrinologist who has been working with menopausal women for decades. He is the author of The Target Method: A Woman's Guide to Navigating Menopause. Dr. Rosensweet is a firm believer in the accuracy and clinical monitoring of 24-hour urinary hormone tests to measure the three human estrogen metabolites accurately. He theorized that since estriol is about 1/8th the strength of estradiol, he could multiply a woman's 24-hour urinary estriol result by 0.125, while assigning estradiol the “estradiol equivalent” potency of 1. According to Mayo Clinic Labs, estrone has 0.2 to 0.75 the potency of estradiol, yielding an average potency of about 0.5 the estradiol equivalency.

Estrogen Metabolite Reference Ranges: 24-hour mid-luteal pre-menopausal ranges:

E1 (estrone): 4.7 – 27.6, average 16.15 ug/24hr

E2 (estradiol): 2.0 – 7.8, average 4.9 ug/24hr 21.1%

E3 (estriol): 7.0 – 29.7, average 18.35 ug/24hr 78.9%

These totals confirm the importance of maintaining an 80/20% potency of E3/E2 prescription creams to copy nature's levels throughout the postmenopausal years. Since these are also premenopausal averages, the transition to menopausal replacement becomes seamless and with minimal, if any, side effects when applied in these proportions.

Urinary estrogen potency calculation: (an example)

24-hour excretion total: Equivalency factor: E potency equivalent total:

(estrone): 16 ug

(estradiol): 4.9ug 1.0

E3 (estriol): 18 0.125

Total potency: 15.2 (optimal: 10-24)

Estrogen potency calculations provide the practitioner with a safe and effective template for therapy, while ensuring each woman is provided an optimal and protective amount of both E2 and E3.

Of course, every woman is unique in her absorption and excretion rate of these metabolites, but by calculating potencies of the key metabolites, an optimal estimation can be made for each woman's metabolic needs. By making sure estrogen potency is in the optimal range (10-24), the provider can be confident it will provide all the expected protection against common menopausal symptoms, bone loss, cardiovascular disease, and other disorders of aging.

Other Benefits of Estriol

Estriol can be just as effective as estradiol in alleviating menopausal symptoms, including hot flushes, sleep disturbance, vaginal dryness, painful sex, and urinary tract infections (3).

Some of estriol's other attributes include improving cognitive function, menstrual migraines, improving age-related wrinkles, and post-partum depression (1). Estriol seems to also have an affinity for the human nervous system, helping to improve multiple sclerosis, and acute disseminated encephalomyelitis (1). This may be due to all the beta estrogen receptor sites within the brain and central nervous system, which estriol has the strongest affinity compared to estradiol and estrone.

It is well documented that pregnancy has an immunosuppressive effect on many autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, autoimmune thyroiditis, and psoriasis (9). This is largely attributable to estriol's elevated levels during pregnancy. The immune modulatory effects of estriol is a vital component of therapy to reduce proinflammatory cytokines in neurodegenerative and chronic autoimmune illnesses. Due to its very mild side effects, it may even be considered for treatment in men with MS and other autoimmune diseases (9).

Estriol improves healthy vaginal flora, to prevent vaginal thinning and urinary tract infections. In one study of 93 women (18), the incidence of

urinary tract infection in the women given estriol had significantly fewer UTIs (0.5 vs 5.9 episodes per patient year in the placebo group). The estriol group improved vaginal pH and also Lactobacillus appeared in 61% of the estriol group within one month, while no Lactobacillus appeared in the placebo recipients (18).

Stress urinary incontinence also improved after just 12 weeks of vaginal estriol cream applications (19). This study of 46 postmenopausal women with an average age of 62.1 had significantly improved stress urinary incontinence and improved vaginal pH. 42% of the estriol users were dry on the cough stress test (19).

Estriol also helps lower blood pressure and improves serum lipid levels (20). In a comparative study of Japanese women using either CEE (conjugated equine estrogens) or E3 (estriol), both benefited with improved lipid panels along with significant improvements in bone metabolism. The E3 group had better triglyceride numbers (lower), and it appeared that elevated triglycerides are a side effect of CEE use (20). Both HDL (“good” cholesterol) and LDL (“bad” cholesterol) improved with hormone replacement in general.

Estriol's effectiveness in osteoporosis and osteopenia remains controversial, due to its weaker effect on bone metabolism (15). It should be noted that the Japanese national medical society has approved estriol for use in osteoporosis, and is preferred over CEE (conjugated equine estrogens) due to estriol initiating fewer side effects than CEE, including uterine bleeding and elevated triglycerides (15)

Estriol and Autoimmunity

Pregnancy is known to have an immunosuppressive effect on autoimmune disorders such as multiple sclerosis, psoriasis, thyroiditis (Hashimoto's), uveitis, and rheumatoid arthritis (9). More evidence is emerging that estriol has potent immune modulating effects for many inflammatory autoimmune diseases, including those of neurodegenerative origin (9).

Estriol has great potential in the treatment of numerous autoimmune and chronic inflammatory conditions. It appears estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity (11). In this mouse study, estriol treatment protected against pro-inflammatory challenges, and it was concluded it has “potential applications in the treatment of numerous autoimmune and chronic inflammatory disease.” (11)

Estriol and Multiple sclerosis

It's been observed that women with multiple sclerosis who become pregnant notice improvement in symptoms, and a significant reduction in relapses, with a shift in autoimmune response. When non-pregnant women with MS were treated with estriol, delayed hypersensitivity responses were decreased, and when the estriol was stopped, MS lesions increased to pretreatment levels. When estriol treatment was restarted, the lesions significantly decreased again. Using estriol treatment in pregnancy doses may also help other autoimmune disorders that have been shown to improve during pregnancy. Since estriol is a weak estrogen with few side effects, it may be beneficial and well-tolerated even for men with MS (9).

Serum neurofilament light chain is a biomarker for nerve degeneration in multiple sclerosis, aging, and other neurodegenerative diseases. A midpregnancy oral dose of estriol (8 mg) daily has shown to decrease neurofilament light chain levels in estriol-treated multiple sclerosis (19).

Rheumatoid arthritis/Lupus

Estriol has shown effectiveness in Th-1 mediated autoimmune diseases, which include rheumatoid arthritis, and multiple sclerosis (15), but this category of autoimmune disease also includes type 1 diabetes, sarcoidosis, and Crohn's disease. Some studies show that lower estrogen levels in the menopause transition increase inflammatory proteins known to contribute to RA (21). The American College of Rheumatology guidelines now recommend HRT for those with lupus (SLE) who don't have anti-phospholipid antibodies (21), although there is no preferred recommendation for estriol over other estrogen therapy.

Neurodegenerative disorders

Estriol offers substantial benefit for postmenopausal women who are at risk while using conventional hormone therapies (9). Estriol has potential for immunomodulatory benefits for many autoimmune and neurodegenerative conditions (9).

Estriol and Breast Cancer:

According to Dr. Henry Lemon, MD, an early pioneer in estriol research, estriol is minimally altered after absorption, does not bind to SHBG (sex hormone binding globulin), and has an-anti estradiol action which results in

reduced proliferative changes in target organs of cancer-prone women (22). In this study, estriol treatment demonstrated the most significant antimammary carcinogenic activity of 22 tested compounds (22). Dr. Lemon's investigations found that women who developed breast cancer had significantly lower levels of estriol than women who did not (15). From other research studies, he also discovered that the EQ [(estrogen quotient = Estriol/(Estrone + Estradiol)] was higher in populations with lower incidence of breast cancer (15). Dr. Lemon developed this mathematical equation to evaluate a woman's risk for reproductive proliferative response in both breast and uterine tissue (15). He suggested that by keeping the EQ elevated >1.5 during post-menopausal therapy with estriol as the predominant metabolite, a woman would be protected against breast cancer developing. Thus, estriol in quantities greater than estradiol and estrone combined, is protective against proliferative disease.

Receptors alpha and beta

:

Alpha estrogen receptors tend to promote breast cell growth to create more density, whereas beta receptors inhibit breast cell growth. Estriol binds more to the beta receptors and when applied as a cream, helps reduce breast cell growth and density. Due to its beta-attachments, estriol is neuroprotective, and can improve cognition and memory due to the brain's beta receptors protecting the brain from atrophy of aging and brain fog. Remember, alpha receptors are more prevalent in uterine endometrial and breast tissue. This is why estriol is safer, not because it is necessarily weaker, but that it tends to not promote endometrial or breast tissue proliferation.

Summary:

Despite being the weaker 3rd sister of the estrogen metabolites, estriol can play a major role in the protection and treatment of post-menopausal vasomotor dysfunction, auto-immune disorders, vulvo-vaginal atrophy, chronic UTIs of aging, and even in breast cancer prevention. Estriol has clinically been used by skilled integrative endocrinologists and gynecologists safely and with confidence for many decades. Its time the FDA approved estriol as a viable, safe and effective therapy for women all over the United States.

Conflict of Interest

:

Dr. Sherman has been using the services of Meridian Valley Laboratory for over 15 years, and in 2024 was hired to act as MVL's consulting physician to other practitioners interested in accurately monitoring endocrine imbalance using 24-hour urine testing. Meridian Valley Lab offers free interpretative

consultations for 24-hour urine testing and other laboratory panels to account providers.

References:

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5. Review of the endometrial safety during intravaginal treatment with estriol. Eur Jr Obstet Gynecol Reprod Biol. 1995 Sep;62(1):101-6

6. Stay Young & Sexy with Bio-Identical Hormone Replacement, The Science Explained by Jonathan V. Wright, MD and Lane Lenard, PhD, Smart Publications, 2010

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10. Menopause & Andropause: Optimizing Hormones for Better Health, Training Intensive Workshop with Dr. Jonathan Wright & Dr. David Rosensweet, April 26-28, 2013

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12. The efficacy and safety of estriol to treat vulvovaginal atrophy in postmenopausal women: a systematic literature review. Climacteric, Vol 20, 2017 PMID: 28622049

13. The agonistic and antagonistic actions of estriol. Jr Steroid Biochem, 20 (4B): 1005-1013 PMID: 6202959

14. Beneficial aspect of oral estriol as hormone replacement therapy: consideration on bone and lipid metabolism. Tokai J Exp Clin Med. 2009;34:92-8

15. Estriol: The 'Good' Estrogen Advances and Updates in its Clinical Uses. Jr of Restorative Medicine 2013;2:46-52

16. Impact of vaginal estriol on serum hormone levels: a systematic review. Climacteric Volume 27, 2024 Issue 2

17. Mayo Clinic Laboratories: https://endocrinology.testcatalog.org/show/ESTF

18. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. NEJM, 1993 Sep 9;329(11):753-6

19. Decreased neurofilament light chain levels in estriol-treated multiple sclerosis. Ann Clin Transl Neurol. 2022 Aug;9(8):1316-1320PMID: 35770318

20. Beneficial aspect of oral estriol as hormone replacement therapy: consideration on bone and lipid metabolism. Tokai J Exp Clin Med. 2009 Sep 20;34(3):92-8

21. The Arthritis Foundation (https://www.arthritis.org/healthwellness/healthy-living/family-relationships/family-planning/menopausewith-a-rheumatic-disease)

22. Pathophysiologic considerations in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma Acta Endocrinol Suppl (Copenh) 1980;233:17-27