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A Publication of The Endocrine Society

JULY 2010



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Puzzling Out Menopausal Hormone Therapy

PLUS Added Sugars & Dyslipidemia Femur Breaks from Bisphosphonates? Endocrinology Fun Facts

RegisteR now & sAve moRe thAn 15% At Ceu 2010 the enDocrine society’s CliniCal EndoCrinology UpdatE los angeles, caliFornia | sePteMber 30 – october 2, 2010

stay aheaD in the FielD oF enDocrinology. Make reservations to interact with the brightest minds in endocrinology and discover the most current standards of care at CEU. For three days, you’ll learn from nationally-recognized faculty through panel discussions, lectures and Meet-the-Professor case-based sessions. Along with a small group of peers, you’ll investigate critical issues in endocrinology and work to advance excellence in the field. RegisteR befoRe August 27 And sAve moRe thAn 15%. For early registration and full program details, visit or call Society Services at 1-888-363-6762 or 301-941-0210.

Ceu 2010 PRogRAm highlights 2010 endocrine board Review Course September 28 –29 thyroid moC self Assessment module September 29, 7:00 – 9:00 pm Practice management workshop September 30, 7:00 – 8:30 pm thyroid ultrasound hands-on workshop October 1, 5:30 – 9:30 pm

the endocrine society is accredited by the accreditation council for continuing Medical education to provide continuing medical education for physicians. the endocrine society has achieved accreditation with commendation. the endocrine society designates this educational activity for a maximum of 25 aMa Pra category 1 credits.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.

contents News & Insights for the Endocrine Community



pg. 12

Menopausal Hormone Therapy Statement

To undergo hormone therapy or not—that is the question many menopausal women have. This latest Scientific Statement pieces together recent findings to provide answers.


Bisphosphonates Behind Breaks?

Once rare, atypical femur fractures are on the rise. Two experts debate whether bisphosphonates are causing them.


pg. 18

The Skinny on Added Sugars

Ingesting lots of extra sugars not only threatens your teeth and promotes diabetes—it can also harm your heart.


Society on the Hill

The Society looks back on its past year’s advocacy successes on behalf of endocrinologists.


Busy Times at the FDA

A new contraceptive pill approved, an infusion pump recalled; this U.S. regulatory agency has been active on the endocrinology front.

pg. 20

Vol. 35



02.................................. Viewpoint 03............................. Editor’s Page 04....................... Trends & Insights 11.............................. Smart Moves 22.......................... Research Briefs 23...................... Spotlight on Policy 24......................Practice Resources 28............................Trainee Corner 29........................CME Connections 30........................... Society Update 31....................................Calendar 32................................. Classifieds 34............................. Puzzler Page


Ask Yourself...

From hypothyroidism in athletes to bones in space, these trivia questions will test your endocrinology knowledge. The statements and opinions expressed in Endocrine News are those of individual authors and do not necessarily reflect the views of The Endocrine Society. Advertising appearing in this publication does not constitute endorsement of its content by Endocrine News or The Endocrine Society.


JULY 2010



Introducing the New President: Kelly E. Mayo, Ph.D. By Cathy Kristiansen, Editor


The Endocrine Society welcomes Kelly E. Mayo, Ph.D., as President for 2010–2011. Dr. Mayo assumed this position on June 22, after serving for a year as President-Elect. A basic researcher, he follows clinician Robert A. Vigersky, M.D., in Kelly E. Mayo, Ph.D. accordance with the Society’s rotation of presidents representing its primary constituencies: basic researchers, clinical researchers, and clinical practitioners. He is professor and chair in the Department of Biochemistry, Molecular Biology and Cell Biology at Northwestern University, in Evanston, Ill., where he also directs the Center for Reproductive Sciences. He has written some 100 research papers and has contributed to dozens of books. His current research focuses on the hormonal regulation of follicle formation and maturation, as well as the transcriptional regulation of gene expression within the ovary; greater understanding in these areas should help combat fertility disorders. Dr. Mayo’s involvement with the Society dates back to a 1986 ENDO presentation, after which he became a member and served on many different committees, including those for research affairs, awards, governance, and strategic planning. He has also been on the boards of three Society journals, Endocrinology, Molecular Endocrinology, and Endocrine Reviews, and has served as an associate editor of Molecular Endocrinology. In 1994, he received the Society’s Ernst Oppenheimer Award.


When Dr. Mayo set off for college to study biochemistry, he envisioned a career involving animals, but something a bit larger than mice. He had grown up on a dairy farm, enjoyed the outdoors, and expected to continue working with domestic animals or wildlife. In his third year at the University of Wisconsin, he was fortunate to cross paths with the renowned late endocrinologist Jack Gorski, Ph.D., who permitted him to take a graduate course in regulatory mechanisms and spend a year in his lab completing a senior thesis. Dr. Mayo never looked back. “The lab was really an eye-opening experience and got me started in research,” he said. “It was Jack Gorski I went to for career advice. He started me thinking about graduate education and suggested some schools and research areas.”

You learn to be a jackof-all-trades—something that comes in handy in academic research. Dr. Mayo understood hard work from his rural upbringing—training that has served him well in his academic career. “We were up early, working before and after school and on weekends; there wasn’t a lot of free time. But it was a good lifestyle, too,” he said. “You learn to be a jack-of-all-trades—something that comes in handy in academic research.” Dr. Mayo’s interest in science was evident in his teens, but he zeroed in on biochemistry in an unusual way. “In eighth grade, I came across a book in the library on biochemistry, a field which I had never heard of, and by the time I read the last page, I had decided it would be my major in college!” He attended the University of Washington in Seattle for his graduate studies with Richard Palmiter, Ph.D., earning a Ph.D. in biochemistry in 1982, and then performed postdoctoral research with Ronald Evans, Ph.D. at the Salk Institute in San Diego. He now lives in Wilmette, Ill., with his wife and the youngest of their three sons, who is still in school. The eldest is in the army at Fort Polk, La., and the second is at the University of Washington. Dr. Mayo maintains ties to Wisconsin, where he owns a small cottage near his childhood town of Oconto and spends tranquil hours fly fishing. “I do like the outdoors, and although I very much enjoy fishing with good friends, I mostly fish alone. It’s important to just be able to think and get away from everything that happens in the average day.” The presidential year ahead may allow little solitude, but Dr. Mayo has no qualms. “It’s really a pretty amazing honor,” he reflected. “This is special because it’s an election by your peers. It’s a fair amount of responsibility, but it’s also pleasing and satisfying to be elected to this position. The Endocrine Society is very special to me, and has wonderful members, volunteers, and staff. So I look forward to the coming year and to meeting the challenges and opportunities ahead.” ■

F rom


E ditor

Endocrine News™ is a trademark owned by The Endocrine Society.

Dear Readers, Menopause hormone therapy continues to be a puzzling and controversial topic, with the data still unclear on a range of intertwined aspects such as benefits, risks, and dosage. To help put the research pieces together, The Endocrine Society recently released a Scientific Statement on the topic, described in the cover feature of this July issue (page 12). Bisphosphonates have helped preserve the lifestyles and even lives of many people by increasing their bone density and strength, but some unusual femur fractures have shown up in patients on these drugs, leading to theories about a link. A lively ENDO 2010 debate on the topic weighed the evidence, and the audience verdict might surprise you (page 18). Sobering recent research has added dyslipidemia and heart disease to the

list of damage that can come from eating too much in the way of added sugars. In many countries, adolescents are most prone to consuming excess sugars in items such as carbonized drinks, cereals, and baked goods, but nearly everyone ingests too much (page 20). In the newly launched Puzzler Page, you’ll find a series of trivia questions on endocrinology-linked facts—obscure, interesting, or just plain testing your endocrine textbook me mo r y. We ho p e yo u ’ l l e n joy answering them (page 34). ■ Sincerely,

Kelly Mayo, Ph.D.

President Janet E. Hall, M.D.

President-Elect John C. Marshall, M.D., Ph.D.

Secretary-Treasurer Robert A. Vigersky, M.D.

Past-President Scott Hunt

Executive Director & CEO Rebecca D. Rinehart

Senior Director & Publisher Cathy Kristiansen

Cathy Kristiansen Editor Endocrine News

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News, Notes, & Insights

Micronutrient Dearth Linked to Brain Defects ➤➤ If carbohydrates, fats, and proteins are the building blocks of the food pyramid, then micronutrients such as iodine, iron, and copper are its mortar—small, but no less important. Dietary micronutrient deficiencies are a global health problem, contributing to numerous cognitive and growth impairments. Iodine insufficiency leads to conditions such as cretinisim and goiter, and iron or copper inadequacies bring anemias that contribute to growth retardation, impaired immune ➤ ➤ ➤ ➤ ➤

responses, and poor temperature regulation. Previous studies in adult rodents and humans indicated that copper and iron deficiencies affect the hypothalamic-pituitarythyroid axis, leading to altered thyroid hormone (TH) levels. However, how insufficient levels of these metals might influence the developing fetus is unclear. Filling in this knowledge gap, Grant W. Anderson, Ph.D., at the University of Minnesota Duluth, and his colleagues measured the serum thyroxine (T4), triiodothyronine (T3), and brain T3 levels of postnatal day-12 rat pups born to mothers rendered copper, iron, or TH deficient via their diets. The results will appear soon in Endocrinology.* Copper-deficient pups displayed a 48% reduction in serum T3, 21% in T4, and 10% in whole-brain T3. Similarly, iron-deficient pups showed reductions of 43%,


Metabolic Syndrome Finding May Thwart Kidney Donation


➤➤ The number of kidney disease patients who need transplants exceeds the supply of donor kidneys throughout the world. In the United States alone, 83,000 people wait on the official kidney-transplant list; around 16,500 people received a kidney transplant in 2009. In Mexico 5,000 people were on the transplant list in 2001 and only 1,481 received a kidney. A key reason for this shortage is too few donors. Now a new finding threatens to shrink the supply further: People with metabolic syndrome (MetS) may have to be excluded from giv-

ing a kidney, according to a study described in an oral and poster presentation at ENDO 2010.* Daniel Cuevas-Ramos, M.D., at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico, and his colleagues evaluated how the presence of MetS in donors undermines their renal function before nephrectomy and at follow-up. They examined data regarding MetS criteria and renal function from 140 kidney donors (28 with MetS and 112 without). The glomerular filtration rate (GFR) in subjects with MetS declined

67%, and 25%. Furthermore, pups lacking these micronutrients experienced alterations in several THresponsive genes, such as type II diodinase (Dio2), parvalbumin (Pvalb), myelin basic protein (Mbp), myelin-associated oligodendrocyte basic protein (Mobp), and brain-derived neurotropic factor isoform IV (Bdnf IV), suggesting that reduced TH levels were sensed by the iron- and copper-deficient brain. The authors say that “at least some of the brain defects associated with neonatal [iron and copper] deficiencies are mediated through reductions in circulating and brain TH levels.” They stress the importance of eliminating “all possible threats to normal thyroid function during all stages of development.” ■ * Bastian TW, Prohaska JR, Georgieff MK, Anderson GW. Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology, in press.

significantly more (i.e., indicating reduced kidney function) than in those without the syndrome—27.5% vs. 21.4%. Furthermore, MetS donors had a GFR < 70 ml/min sooner after surgery (5.6 years) than apparently healthy donors (12.8 years). “This finding suggests that the presence of MetS before donation can negatively impact donors’ renal function outcome,” conclude the authors in their prepared abstract. ■ * Cuevas-Ramos D, Almeda-Valdes P, Alberu J, et al. Metabolic syndrome in kidney donors and long-term renal function outcome. OR15-2 and Abstract #148 at ENDO 2010.

➤➤ Talk about pressure: Surgeons operating on medullary thyroid carcinoma (MTC) in first-time patients know it is vital to remove all tumor cells or risk a poor prognosis. A patient might undergo a total thyroidectomy and central lymph node dissection, and, to be on the safe side, also have a lateral lymph node dissection. Looking for a marker to help guide surgeons and reduce unnecessary lymph node surgery, a team of researchers investigated whether serum calcitonin measures—already important in the diagnosis and followup of this cancer of the calcitoninproducing parafollicular cells—might also indicate whether the surgery has succeeded in removing all the MTC. Antongiulio Faggiano, M.D., Ph.D., at IRCCS Fondazione SDN, Napoli,

Cholesterol and Endogenous Estrogen Levels Synchronize ➤➤ Measure cholesterol levels on two different days of a woman’s menstrual cycle and the readings could raise a red flag … or not, depending on whether the test coincides with cyclically

Italy, and his colleagues investigated 20 patients (9 male, 11 female, age range 25-70 years) who had thyroid nodules revealed by ultrasound (8 had 1 nodule, 12 had ≥ 2) associated with abnormally high calcitonin levels consistent with a diagnosis of MTC. None preoperatively showed lymph nodes by ultrasound. Histological analysis showed positive MTC in 10 of these patients and C-cell hyperplasia in the other half. While the 20 patients underwent total thyroidectomy and central lymph node dissection, the team measured their serum calcitonin levels 4 times: at anesthesia (pre-incision), during manipulation, and at 10 and 30 minutes after excision. Post-surgery monitoring included calcitonin mea-

high or low estrogen levels, according to a new study. Following up on research showing that estrogen therapy influences a woman’s lipid profile, Sunni L. Mumford, Ph.D., and Enrique F. Schisterman, Ph.D., of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md., and their colleagues tested whether endogenous estrogen does the same thing. In a study of 259

sures every 3 months for the first year, then every 6 months. The researchers found that compared with calcitonin levels before thyroid excision, a calcitonin drop of > 50% at 30 minutes post-surgery indicated a cure, with 100% sensitivity and specificity; conversely, a calcitonin decline of < 50% indicated that some tumor cells remained. Readings at 10 minutes were unreliable. In an upcoming article in The Journal of Clinical Endocrinology & Metabolism,* the authors write, “Intraoperative calcitonin monitoring may be a useful tool to predict the completeness of surgery in patients with MTC.” ■ * Faggiano A, Milone F, Ramundo V, et al. A decrease of calcitonin serum concentrations less than 50% 30 minutes after thyroid surgery suggests incomplete C-cell tumor tissue removal. J Clin Endocrinol Metab, in press.

healthy, regularly menstruating women aged 18–44 years, the investigators measured serum levels of triglycerides and total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterols, up to 8 times per cycle for 1–2 cycles. Total and LDL cholesterol were lower during the low-estrogen luteal phase than in the follicular phase, varying overall by 5%–8%; the changes more often led to undesirably high cholesterol (LDL ≥ 130 mg/dl or total cholesterol ≥ 200 mg/dl) when measured during the follicular phase. HDL was highest around ovulation and varied by about 7% during the menstrual cycle.

Estrogen appeared to boost HDL levels within a day, whereas its impact in raising total cholesterol and LDL took 3–5 days. The authors, writing in an upcoming issue of The Journal of Clinical Endocrinology & Metabolism,* say that “cyclical variations in lipoprotein levels may need to be considered in the design and interpretation of studies in reproductive-age women.” For clinical management of a woman’s cholesterol, “standardizing the timing of lipid measurements may improve the interpretability of results and consequently reduce the overall number of tests,” they say. ■ * Mumford SL, Schisterman EF, Siega-Riz AM, et al. A longitudinal study of serum lipoproteins in relation to endogenous reproductive hormones during the menstrual cycle: Findings from the BioCycle study. J Clin Endocrinol Metab, in press.


Calcitonin Marker for Medullary Thyroid Cancer Surgery


Rehabbing Rimonabant in Obesity Battle? ➤➤ Obesity affects not only the body; it is also a state of mind. Researchers have linked this disorder to the hypothalamic-pituitaryadrenal (HPA) axis and are actively searching for ways to control its pathways. They are even revisiting mechanisms that have previously seemed unfruitful, such as the endocannabinoid system. Rimonabant, a cannabinoid receptor agonist once used as an appetite suppressor in Europe, was pulled because patients taking it ran the risk of severe depression and suicidal thoughts. It could be this drug was misunderstood. Hoping to rehabilitate the drug, Helen Atkinson, Ph.D., at the University of Western

Being Hot with Diabetes


➤➤ Some like it hot, but high temperatures hold particular challenges for people with diabetes, such as for their glucose level


Australia, and the team led by Stafford Lightman at the University of Bristol studied in rats the circadian effects of two cannabinoid receptor type 1 (CB1) receptor antagonists— AM251 and AM281—on the HPA axis. Endocannabinoids suppress the axis. The investigators collected blood and measured corticosterone levels at varying times throughout the day. They report their results in an upcoming article of Endocrinology.* Male rats displayed a more distinct diurnal impact from AM251, with greater activation of the HPA axis in the morning than in the evening; their circulating cortisol concentrations were elevated for about 4 hours after drug administration. Females

measurements and insulin storage. A poster presented at ENDO 2010* revealed that people with diabetes have varying degrees of knowledge about bracing against the heat. Adrienne Nassar, M.D., and Curtiss Cook, M.D., along with colleagues from the Mayo Clinic Arizona in Scottsdate, the National Oceanographic and Atmospheric Administration, and the Phoenix branch of the National Weather Service analyzed 152 surveys of diabetes patients, gauging their personal heat protective measures, knowledge of safe temperatures and exposure times, and weather data sources.

had higher levels only in the morning, for about 2 hours. In further experiments on the males, the researchers found that adrenocorticotropic hormone mediates AM251’s effects on corticosterone; the same was true with AM281. The authors postulate that depressed individuals frequently have higher basal HPA activity, which may have been the reason for rimonabant’s apparent failure. They caution that because rodent sex differences in HPA axis function are not as distinct, these findings may not be easily applied to humans. ■ * Atkinson HC, Leggett JD, Wood SA, Castrique ES, Kershaw YM, Lightman SL. Regulation of the hypothalamic-pituitary-adrenal axis circadian rhythm by endocannabinoids is sexually diergic. Endocrinology, in press.

Most respondants took steps to protect themselves and their diabetes equipment and medication, but they would often wait until temperatures were quite high (above 101°F) before doing so. Moreover, 37% simply left medications or supplies at home rather than risk exposing them to heat when out, and thus were vulnerable in managing their diabetes at these times. Although 73% of the respondents said they had received information about heat effects on insulin, the ➤ percentages were lower when it came to other medicines and equipment; 39% knew about the effect of heat on oral medications, 41% on glucose monitors, and 38% on glucose monitoring strips. While 82% of patients could correctly define humidity, only 55% could define “heat index”—an important measure of how

hot it really feels and how their body will react. Furthermore, only a minority of patients (38%) indicated that the weather forecast affected the way they managed their diabetes. Television was the primary source for weather information (89%), followed by radio (35%), Internet (34%), and newspaper (26%). Finally, cross-sectional analysis showed that 44% of patients had an HbA1C ≥ 8.0% during July to September, potentially placing them at risk for dehydration. “Increased public awareness of this important topic is needed, and diabetes education programs should include information about the heat where regionally appropriate,” the authors conclude. ■ * Nassar AA, Childs RD, Boyle ME, et al. Diabetes in the desert: What do patients know about the heat? Abstract #142 at ENDO 2010.

➤➤ Kisspeptin (KP), named after Hershey’s chocolate kisses,® may offer sweet relief for women suffering from hypothalamic amenorrhea who

hope to become pregnant. Accounting for 30% of amenorrhea cases in women of reproductive age, hypothalamic amenorrhea usually occurs when production of gonadotropinreleasing hormone (GnRH) stops. Previous research showed that KP treatment initiates GnRH secretion, but only with a single daily injection; twice-daily KP dampened the secretion or triggered tachyphylaxis. Seeking to determine a time course of desensitization to twicedaily KP injections, a research group led by Waljit Dhillo, M.D., at Imperial College London, United Kingdom, placed patients with

hypothalamic amenorrhea on either twice-daily KP injections for 2 weeks or twice-weekly KP injections for 56 days; controls received saline injections. The group then collected blood samples for luteinizing hormone (LH) and follicle-stimulating hormone (FSH) 4 hours post-injection over a variety of days. They reported their findings in poster and oral presentations at ENDO 2010.* In patients receiving the twice-daily injections, LH gradually diminished; following KP on the second, third, fourth, and fourteenth injection days, LH release was 40%, 75%, 88%, and 91% lower than on the first injection day. FSH release on the second injection day was 84% lower. For patients on the

Androgen Protects Against Doxorubicin-Induced Cardiotoxicity ➤➤ Doxorubicin (Dox) is a powerful anticancer agent, but a wide range of patients cannot tolerate it because of its dose-dependent cardiac toxicity, which can lead to congestive heart failure. This toxicity is believed to stem from increased oxidative stress, resulting in mitochondrial dysfunction and cardiomyocyte apoptosis. Ken-ichi Aihara, M.D., Ph.D., at the University of Tokushima Graduate School in Tokushima, Japan, and his co-workers have shown that the androgen-androgen receptor (AR) system is key in cardiac growth and also protects against pathological angiotensin (AngII)– induced cardiovascular remodeling. Could androgen’s potency as an antioxidant also defend against Dox's cardiac toxicity?

To find out, the researchers injected male AR knockout (ARKO) and wild-type male mice with Dox and discovered that ARKO mice had a lower survival rate and less left ventricular function than controls. The myocardial mitochondria of Dox-treated ARKO mice had vacuole formation more prominent than that in controls—evidence of accelerated mitochondrial damage—although small mitochondrial vacuoles in the myocardium of vehicle-treated ARKO mice implied that they had a basal level of mitochondrial dysfunction. Dox treatment spurred cardiac tissue oxidative stress and cardiomyocyte apoptosis, and decreased cardiac mitochondria transcription factor A (Tfam) expression and Akt phosphorylation more in ARKO mice than in controls. In cardiac myoblast

twice-weekly injection regimen, KP responsiveness was better on day 1 than on day 14, yet no further significant drop in KP responsiveness occurred beyond day 14; on the last (56th) day, KP injection raised LH by 16-fold compared with saline controls. The authors conclude that “twice-weekly KP administration stimulates reproductive hormone over a 2-month period,” thus making this hormone a possible therapy for reproductive disorders such as hypothalamic amenorrhea. ■ * Jayasena CN, Nijher GMK, Abbara A, et al. Twice-weekly administration of kisspeptin-54 for eight weeks stimulates reproductive hormone release in women with hypothalamic amenorrhea. OR39-1 and Abstract #1840 at ENDO 2010.

cells, testosterone up-regulated Akt phosphorylation and Tfam expression through an AR- and PI3Kdependent pathway, and alleviated Dox-induced cardiac toxicity. This study will be published soon in Molecular Endocrinology.* The researchers conclude that without a functioning androgenAR system, Dox’s cardiac toxicity is aggravated due to exacerbated mitochondrial damage and superoxide generation, leading to enhanced cardiomyocyte apoptosis. They propose that the androgen-AR system counteracts Dox-induced cardiac toxicity partly through Akt activation and Tfam up-regulation, protecting cardiomyocytes from mitochondrial damage and apoptosis. ■ * Ikeda Y, Aihara KI, Akaike M, et al. Androgen receptor counteracts doxorubicininduced cardiotoxicity in male mice. Mol Endocrinol, in press.


Kisspeptin Relieves Hypothalamic Amenorrhea


Surgery for All Acromegaly Patients? ➤➤ Surgery just might be the best medicine not just for some but for all patients with acromegaly, according to an upcoming article in The Journal of Clinical Endocrinology & Metabolism.* In more than 95% of cases, a growth hormone (GH)secreting pituitary adenoma is the underlying cause. This tumor is usually detected with conventional magnetic resonance imaging (MRI)

U.S. men > 65 years of age are


1.5 times


and excised via surgery. However, this technology fails to detect tumors in a small subset of patients. Two non-surgical treatment options exist, but they are not as successful; medical therapy is usually lifelong and typically does not reduce the GH-secreting pituitary adenoma, and radiation therapy brings biomedical remission in only 50% of patients. To understand how often MRI misses tumors and to define the optimal treatment for these patients, a research team led by Russell R. Lonser, M.D., at the National Institute of Neurological Disorders and Stroke, in Bethesda, Md., reviewed the records of 190 acromegaly patients who underwent surgery for suspected GH-secreting adenomas. Six had no evidence of a pituitary adenoma on

aged 65 years older. The more likely to die from an uninten- and group archived tional fall than older U.S. women. the men's blood samples at baseline and colSource: Centers for Disease Control and Prevention, National Health Statistics Reports, Number 24, April 21, 2010. lected outcome information every 3 months for about 4 years, recording Testosterone Levels CHD events that included Linked to Coronary acute coronary syndromes Heart Disease and percutaneous or sur➤➤ The jury is still out on gical revascularization. Among study subjects, whether non-optimal tes100 (14%) suffered an tosterone levels in men— incident CHD event. Men high or low—contribute with baseline testosterone to coronary heart disease in the highest quartile (CHD). A recent presentation at ENDO 2010* offers (≥ 495 ng/dl) had a CHD evidence that higher levels risk 2.2 times higher than those in the lowest may be the culprit. quartile of total testosKristin Sueoka, M.D., terone (< 308 ng/dl). at the University of Results were similar for California-San Francisco, ➤ bioavailable testosterone, and her colleagues free testosterone, and sex gathered the evidence by hormone–binding globuexamining the sex horlin. Estrogen and estrone mone serum levels of 697 levels were not associated community-dwelling men

standard MRI. Three of these imagenegative patients underwent a postcontrast, volumetric, breath-hold examination (VIBE) MRI sequence, which revealed a 4-mm pituitary adenoma in 1 patient. The authors conclude that in some acromegaly cases, VIBE MRI can be more sensitive than conventional MRI in detecting a GH adenoma. Regardless of detection, they suggest that exploratory surgery should be performed on all acromegalic patients because the major morbidity (< 3.5%) and mortality (< 1%) rates associated with microadenoma resections are so low and the biochemical remission rates are so high (80%). ■ * Lonser RR, Kindzelski BA, Mehta GU, Jane Jr. JA, Oldfield EH. Acromegaly without imaging evidence of pituitary adenoma. J Clin Endocrinol Metab, in press.

with CHD. These results indicate that higher endogenous testosterone levels may be linked to increased CHD risk in older men, a finding that could have important implications for patients contemplating testosterone therapy. ■ * Sueoka KT, Ewing SK, Ensrud KE, et al. Higher endogenous testosterone levels associated with increased risk of coronary heart disease in elderly men: A prospective study. Abstract #1514 and OR17-1 at ENDO 2010.

developments in the endocrinology world

* Norman H. Ertel, M.D., M.A.C.P., was awarded the title Master of the American College of Physicians. Dr. Ertel is professor of medicine (emeritus) at the UMDNJUniversity Hospital, Newark. He was chief of medicine in the Department of Veterans Affairs New Jersey Health Care System for 31 years. * Susan Greenspan, M.D., joined the National Osteoporosis Foundation’s Board of Trustees. Dr. Greenspan is professor of medicine at the University of Pittsburgh. She is director of the Osteoporosis Prevention and Treatment Center, director of the Bone Health Program at MageeWomens Hospital, and program director of the community Clinical Translational Research Center. * David M. Harlan, M.D., was appointed by the University of Massachusetts Medical School (UMMS) and the university’s Mass Memorial Medical Center as director of the Diabetes Center of Excellence and division chief of diabetes. Dr. Harlan is also the associate director of the university’s Diabetes and Endocrinology Research Center. He was previously at the National Institute of Diabetes and Digestive and Kidney Diseases. * Omega C. Logan Silva, M.D., M.A.C.P., was awarded the Foremother Award of the National Research Center for Women and Families. Harold E. Varmus, M.D., was nominated to head the National Cancer Institute. A former director of the National Institutes of Health, Dr. Varmus shared the 1989 Nobel Prize in Physiology or Medicine for discovery of the cellular origin of retroviral oncogenes. Dr. Varmus recently received an honorary degree from the University of Massachusetts Medical School in recognition of his foundational contributions to biomedical research and his commitment to excellence in scientific inquiry and clinical care worldwide. * Johannes D. Veldhuis, M.D., received the 2010 Distinguished Alumnus Award, Pennsylvania State University’s highest award. He is professor of internal medicine, consultant, and clinical investigator at Mayo Clinic College of Medicine, Rochester, Minn. * Member of The Endocrine Society Share Your News If you or others you know change jobs, receive a promotion, are granted an award, or otherwise make endocrinology-related career news, please don’t hesitate to let us know at

➤➤ The gastrointestinal side effects of chemotherapy can be very difficult for patients, causing anorexia and undermining their option to continue treatment. Circulating ghrelin, which normally spurs appetite then declines after eating, stays high in patients with anorexia or cancerinduced cachexia, yet puzzlingly does not spur their appetite. A research team in Japan, led by Koji Yakabi, M.D., at Saitama Medical University hypothesized that lower ghrelin secretion specifically in the brain contributes to chemotherapy-induced anorexia. Ghrelin genes, expressed primarily in the stomach, are also weakly expressed in the hypothalamus and pituitary. Previous studies showed that rats receiving exogenous ghrelin into the cerebral ventricle ate more, but the mechanism was unclear. In this new study, the team tested 7-weekold male rats that fasted for 24 hours, ate freely, or received cisplatin treatment at the outset. In the cisplatin-treated animals, they also investigated the therapeutic value of serotonin receptor antagonists (5-HT2c) and of a traditional Japanese medicine comprising several herbs— rikkunshito (RKT). The researchers found that hypothalamic secretion of acyl ghrelin (the form tested) was higher in the fasted rats than in

those freely feeding, and was markedly lower in the cisplatin animals 24 and 48 hours after treatment than in control rats given saline. The cisplatin and saline groups had comparable plasma ghrelin levels. Further testing of the cisplatin animals showed that intracerebroventricular ghrelin renewed their appetites. And treatment with RKT or 5-HT2c reversed the drop in hypothalamic ghrelin secretion and spurred food intake. “Our findings support the use of RKT for treating cisplatin-induced delayed anorexia,” the authors write in their report, to be published soon in Endocrinology.* RKT is manufactured by Tsumura & Co., which has financial ties to some of the researchers in this study. ■ * Yakabi K, Sadakane C, Noguchi M, et al. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia. Endocrinology, in press.


Smart Moves

Enhancing Ghrelin to Battle Chemotherapy’s Anorexia





g n i l z z u P t u O

Menopausal Hormone Therapy D i ffe re n t E ffe c t s o n Yo u n g e r v s . O l d e r Wo m e n

By Eric Seaborg*

Latest Puzzle Piece The WHI did not distinguish among ages in its conclusions. It enrolled more than 16,000 women between ages 50 and 79 years, but the vast majority were long-gap. “The average age of participants was 63 and only 3.5% of the women were aged 50–54 years, a time when women usually make a decision regarding the initiation of MHT,” the statement notes. The study investigated mainly long-gap patients.

“Hence the WHI clinical trial was originally designed to determine whether hormone therapy reduced the risk of heart disease, the commonest cause of death in women,” Dr. Santen said. “The idea was that if you lacked hormones, you should have the hormones replaced. We do that for thyroid, we do that for the pituitary, and we do it for testes and adrenals when they are not working. The ovary stops working at age 50, therefore every woman ought to be on estrogen. This was the hypothesis tested by the WHI.” When the study results were published in 2002, hormone therapy’s overall effects appeared to be negative. A closer look at the evidence now indicates that the concept of “overall effects” can be misleading. For one thing, the WHI did not look at the major reason menopausal women take hormones—the relief of symptoms such as hot flashes, night sweats, and urogenital problems. For another thing, the more closely one looks at the data, the clearer is the need to take an individual approach to the therapy according to a woman’s specific history and risk factors. “Women who have a high risk of breast cancer because of family history should probably not take hormones unless their symptoms are very severe. But if somebody is at low risk for breast cancer and has a lot of symptoms, then she should consider hormones,” Dr. Santen explained.

Straightening Out the Pieces It may not be appropriate to give MHT scattershot, but it can be effective for certain problems or to achieve certain objectives. Despite the impression of danger from MHT in the original study, the scientific statement notes that such therapy is associated with a significant reduction in mortality among women aged 50–59. “MHT was associated with a 40% reduction in mortality in women in trials in which participants had a mean age less than 60 years or were within 10 years of menopause onset,” the statement indicates. This amounts to 5 fewer deaths per 1,000 women per 5 years of therapy. The risks for both breast cancer and cardiovascular disease reported in the initial WHI publication required clarification later. “The breast cancer risk, as first described in the original publication, was not formally statistically significant and the increase in cardiovascular risk, initially stated to apply across age strata, was subsequently reported as occurring only in the participants [above] age 70 years,” the statement notes. Among the short-gap patients receiving estrogen alone, MHT actually leads to a decrease in cardiovascular events. The statement also concluded, based on top quality evidence, that estrogen reduces the symptoms of hot flashes and night sweats, as well as of overactive bladder and vaginal



rescriptions for hormone therapy dropped substantially after results from the milestone Women’s Health Initiative (WHI) hit the headlines in 2002, but a new document from The Endocrine Society suggests that women just entering menopause and their doctors should take a fresh look at the latest data. Menopausal hormone therapy (MHT) research has many puzzling elements. “Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement,” released in June at the Society’s ENDO 2010: The 92nd Annual Meeting & Expo and published in the July issue of The Journal of Clinical Endocrinology & Metabolism (JCEM),1 puts many pieces in place and contains some new surprises according to its lead author, Richard J. Santen, M.D. The Society’s scientific statements give an overview of basic and clinical science on topics of emerging importance. Perhaps the most significant new aspect in this document, produced by experts in the field2 who reappraised the WHI data in light of subsequent studies, is the need to consider how long after menopause a woman starts receiving therapy. “The effect of menopausal hormonal therapy is really different in women who are just starting the menopause, as opposed to those who are 10 or more years after the menopause,” Dr. Santen, professor of internal medicine at the University of Virginia in Charlottesville, said in an interview with Endocrine News. The scientific statement refers to patients as “short gap” or “long gap,” depending on the time between the onset of menopause and the start of therapy. Dr. Santen said the most noteworthy surprises highlighted by the new statement are some little-known benefits of hormonal therapy: a 30%–40% decrease in overall mortality in the short-gap cohort; a decrease in overactive bladder and urinary tract infections in both the short-gap and long-gap groups; less diabetes risk in both groups; and reduced mortality in women experiencing premature menopause, such as from removal of their ovaries. Women who took estrogen plus a progestogen (progestogens include progestins and progesterone) also showed a lowered risk for colon cancer.


COVER STORY dryness causing painful sex. Vaginal estrogen is more effective than systemic estrogen in countering recurring urinary tract infections. Dr. Santen said that those women with symptoms are going to benefit most from hormone replacement. Improvements in specific urinary tract benefits—overactive bladder and recurrent infections—are little appreciated among women and physicians. Other little-noticed benefits include the decreased risk of colon cancer associated with estrogen plus a progestogen and the reduced risk of diabetes with either estrogen alone or estrogen plus progesterone.

A New Piece: Premature Menopause An additional takeaway point from the scientific statement concerns premature menopause, particularly occurring after surgical removal of the ovaries before age 45. This surgery brings a higher risk of negative health outcomes in the cardiovascular system, bone, cognition, mood, and sexuality. “If you give estrogen to those women, then you get a decrease in mortality and a decrease in heart disease. You reverse some of [the risk]. We don’t tend to think about that; we tend to think of the premature menopause women as similar to the others,” Dr Santen said.


Breast Cancer Risk Revisited


The statement not only re-evaluates MHT's benefits, but also brings some risks into sharper focus. For example, if a short-gap woman receives estrogen plus a progestogen, she may have an even greater risk of breast cancer than the long-gap patients. MHT’s effects on breast cancer risk are complex, and even contradictory. Estrogens can increase the risk of breast cancer after more than 5 years of use, particularly in the short-gap women. The duration of exposure needed to exert this effect is not clear, and the extra risk dissipates within 5 years of stopping therapy. Taking combined estrogen and progestogen increases the risk of invasive breast cancer by about 7 cases per 1,000 women over 5 years. The risk continues to rise progressively beyond that. However, the use of estrogen alone for less than 5 years may reduce the risk of breast cancer in patients who start therapy many years after menopause onset. The statement cited recent findings on breast cancer indicating that some forms appear to share certain indolent characteristics with prostate cancer. Autopsies show that 7% of women aged 50–80 years have undiagnosed breast cancer. Lower level evidence indicates that only 30% of undiagnosed breast cancers grow to a detectable size over a period of 7 years. The effects of MHT in increasing breast cancer risk are possibly related to the hormones stimulating growth of preexisting, undiagnosed tumors.

Full Circle The statement also confirms some previously well-understood aspects of MHT, including that taking it orally increases the risk of venous thromboembolism and stroke. Also confirmed are that hormone treatment prevents bone loss, reduces fractures, relieves hot-flash symptoms, counters vaginal atrophy, and generally improves the quality of life in symptomatic patients.

Some Critical Actions Needed (from the statement's executive summary) • Disseminate literature to practitioners and postmenopausal women regarding the benefitrisk ratio associated with MHT as prescribed in currently used doses, in women close to menopause and for periods of < 3–5 years. • Continue research on lowest doses, optimal administration routes, and optimal products. • Conduct research to identify women who may specifically benefit or be at risk from MHT. • Develop new approaches to maximize benefit and minimize risk. • Conduct randomized trials to examine the rates of cardiovascular events, stroke, breast cancer, and carbohydrate intolerance as primary end points in women starting MHT for the first time between the ages of 50–55 years.

Dr. Santen compared the process of creating the statement to that of writing a textbook. Each section was written by an expert in the assigned field, then subjected to a peer reviewer. The writers followed the GRADE system in rating the evidence quality so the evaluations would be consistent and evidence-based. Then, as with Endocrine Society clinical practice guidelines, the Scientific Statement was posted for review by Society members, reviewed by the Endocrine Society Council, and peer-reviewed at JCEM. The authors responded to the critiques, and journal reviewers and the Council scrutinized those responses. “Clinicians are clearly very confused about menopausal hormone therapy. Part of the reason is that new studies come out about every 6 months and it is very hard to keep up,” Dr. Santen said. This therapy has many different aspects and effects, so the scientific statement’s executive summary is organized according to the quality level of the evidence and the area of concern. “If you want to know, does hormone therapy increase stroke, you just go to that section and look at it,” he said. “It should be a pretty good resource for people.” ■ * Eric Seaborg is an award-winning writer based in Charlottesville, Va. Footnotes: 1. Postmenopausal hormone therapy: An Endocrine Society scientific statement. J Clin Endocrinol Metab, 2010;95(Suppl):S1–S66. It can be purchased separately via, by emailing societyservices@, or by calling 888-363–6762. Or you can review it at www. This statement is the second to be published by the Society. Also available is “Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement.” 2. The panel of experts comprised Richard J. Santen, D. Craig Allred, Stacy P. Ardoin, David F. Archer, Norman Boyd, Glenn D Braunstein, Henry G. Burger, Graham A. Colditz, Susan R. Davis, Marco Gambacciani, Barbara A. Gower, Victor W. Henderson, Wael N. Jarjour, Richard H. Karas, Michael Kleerekoper, Roger A. Lobo, JoAnn E. Manson, Jo Marsden, Kathryn A. Martin, Lisa Martin, JoAnn V. Pinkerton, David R. Rubinow, Helena Teede, Diane M. Thiboutot, and Wulf H. Utian.

Once-daily Victoza® : Can provide the additional benefit of weight loss Safety and tolerability were studied in clinical trials that included nearly 4000 patients

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Victoza® is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials.

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Indications and usage Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied.

Important safety information Liraglutide causes dose-dependent and treatment-durationdependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed. When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza ® or any other antidiabetic drug. The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients. Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment. Please see brief summary of Prescribing Information on adjacent page. *Victoza® was evaluated in a 52-week monotherapy trial and in four 26-week, add-on combination trials.

Victoza® is a registered trademark of Novo Nordisk A/S. © 2010 Novo Nordisk A/S


May 2010

Victoza® (liraglutide [rDNA origin] injection) Rx only BRIEF SUMMARY. Please consult package insert for full prescribing information. WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications and Warnings and Precautions]. INDICATIONS AND USAGE: Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied. CONTRAINDICATIONS: Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning, Contraindications]. In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza®-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza® clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza®treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza® 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza® 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza®. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza® 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza® 1.2 mg, placebo and active control, respectively. Otherwise, Victoza® did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza®-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza®-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza®. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza®-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown. Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza®, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. Pancreatitis: In clinical

trials of Victoza®, there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. In one case in a Victoza®-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pancreatitis has subsequently been reported in a Victoza®-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis with Victoza® treatment. After initiation of Victoza®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza® and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza® should not be restarted. Use with caution in patients with a history of pancreatitis. Use with Medications Known to Cause Hypoglycemia: Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients and in no comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues [see Adverse Reactions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Victoza® was evaluated in a 52-week monotherapy trial and in four 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza® 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza® 1.2 mg, Victoza® 1.8 mg or placebo. Withdrawals: The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Tables 1 and 2 summarize the adverse events reported in ≥5% of Victoza®-treated patients in the five controlled trials of 26 weeks duration or longer. Table 1: Adverse events reported in ≥ 5% of Victoza®-treated patients or ≥5% of glimepiride-treated patients: 52-week monotherapy trial All Victoza® N = 497 Glimepiride N = 248 (%) (%) Adverse Event Term Nausea 28.4 8.5 Diarrhea 17.1 8.9 Vomiting 10.9 3.6 Constipation 9.9 4.8 Upper Respiratory Tract Infection 9.5 5.6 Headache 9.1 9.3 Influenza 7.4 3.6 Urinary Tract Infection 6.0 4.0 Dizziness 5.8 5.2 Sinusitis 5.6 6.0 Nasopharyngitis 5.2 5.2 Back Pain 5.0 4.4 Hypertension 3.0 6.0 Table 2: Adverse events reported in ≥ 5% of Victoza®-treated patients and occurring more frequently with Victoza® compared to placebo: 26-week combination therapy trials

Adverse Event Term Nausea Diarrhea Headache Vomiting

Adverse Event Term Nausea Diarrhea Constipation Dyspepsia

Add-on to Metformin Trial Glimepiride + Placebo + All Victoza® + Metformin Metformin Metformin N = 242 N = 121 N = 724 (%) (%) (%) 15.2 4.1 3.3 10.9 4.1 3.7 9.0 6.6 9.5 6.5 0.8 0.4 Add-on to Glimepiride Trial All Victoza® + Placebo + Glimepiride Rosiglitazone + Glimepiride N = 695 N = 114 Glimepiride N = 231 (%) (%) (%) 7.5 1.8 2.6 7.2 1.8 2.2 5.3 0.9 1.7 5.2 0.9 2.6

Add-on to Metformin + Glimepiride Placebo + Metformin Glargine + Metformin Victoza® 1.8 + Metformin + + Glimepiride + Glimepiride Glimepiride N =114 N =232 N =230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 Diarrhea 10.0 5.3 1.3 Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 Vomiting 6.5 3.5 0.4 Add-on to Metformin + Rosiglitazone Placebo + Metformin All Victoza® + Metformin + Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 Vomiting 12.4 2.9 Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 Headache 8.2 4.6 Constipation 5.1 1.1 Fatigue 5.1 1.7 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in no comparator-treated patients. Six of these 7 patients treated

with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 3). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake). Table 3: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator Glimepiride None Monotherapy Victoza® (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — Not classified 1.2 (0.03) 2.4 (0.04) — Glimepiride + Placebo + Add-on to Victoza® + Metformin Metformin Metformin Metformin (N = 724) (N = 242) (N = 121) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) Rosiglitazone + Placebo + Add-on to Glimepiride Victoza® + Glimepiride Glimepiride Glimepiride (N = 695) (N = 231) (N = 114) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Placebo + Add-on to Victoza® + Metformin + None Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 355) (N = 175) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Insulin glargine Placebo + Add-on to Victoza® + Metformin + + Metformin + Metformin + Metformin + Glimepiride Glimepiride Glimepiride Glimepiride (N = 230) (N = 232) (N = 114) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparatortreated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. More detailed information is available on request. For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: January 2010 Version: 1 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2010 Novo Nordisk A/S 140586-R1 4/2010


Mysterious Bone Breaks:

By Cathy Kristiansen, Editor


id the lively ENDO 2010 Endocrine Debate settle the question of whether bisphosphonates are guilty of causing unusual femoral fractures? Not exactly! The audience did, however, vote at the start and end of the debate, as you will see. Below is a summary of the arguments. In the interests of space, “bisphosphonate” is shortened to “BP,” even in quoted speech.




Already braced after learning of a link between BPs and osteonecrosis of the jaw, many endocrinologists and orthopedists were jolted recently by reports of a possible association between BPs and atypical subtrochanteric and femoral shaft fractures. Are BPs innocent or guilty? Most are waiting to decide. The U.S. Food and Drug Administration entered the foray, stating that the evidence does not show a link, but it will investigate further. This controversial topic was aired in a session at The Endocrine Society’s recent annual meeting, with two bone experts taking opposite positions and trying to win over the audience.* First to speak was Joseph M. Lane, M.D., chief, Metabolic Bone Disease Service, Hospital for Special Surgery, and also at New York Presbyterian Hospital, then came Juliet E. Compston, M.D., F.R.C.P., professor of bone medicine at Addenbrookes Hospital, University of Cambridge, United Kingdom.

The Prosecution Dr. Lane said that some ominous signs are appearing among long-term BP users. “BPs definitely decrease fracture risk overall, but the question is, do they interfere with healing? In patients on BP, the remodeling is dramatically down and the healing is delayed by every parameter you can measure. It is hard to recognize clinically—the callus is very large, so that compensates and gives you a better mechanical feel. Anabolic agents [parathyroid hormone], in contrast to the BPs, stimulate healing … So, in the setting of a fracture, there are some problems with the BPs.”

Not the Quantity, but the Quality Investigating the puzzlingly large calluses at break sites, Dr. Lane and colleagues found that they comprised 90% old bone, rather than the normal 20%. “Every time you’re walking around downtown San Diego, you’re getting probably a thousand micro-fractures a day. No problem—you fix them. And you don’t break the bone, because the bone can accommodate and absorb energy. But in patients with old bone, the energy is not absorbed and the bone cracks. You lose toughness with glycation of the collagen.”

How Long on BPs? Dr. Lane said short-term BP use does not seem problematic. However, “the longer the BP therapy, the rarer the presentation of a femoral neck or an intertrochanteric fracture, but

at e s n o h p s Bispho the greater the risk of the subtrochanteric fracture, particularly after 4 years.” This and other factors have prompted him to consider a “drug holiday” for patients on long-term BP therapy, especially at 5 years, which is when old bone tends to accumulate.

Bottom Line “So, yes there are fractures with BPs, and yes there are fractures without. But certainly before the year 2000, not a single of my 90 colleagues at the hospital ever saw this fracture. So I do believe that BPs are associated: In old bone, they encourage glycation and stress fractures—especially in people who are relatively active.” “Okay, I’m ready to be killed by my partner here!”

The Defense Dr. Compston came out brandishing studies that she said prove BPs are innocent of the charge. From the get-go, she stressed they’re not cure-alls, but they reduce fracture risk. “We will continue to see many fractures in patients who are receiving effective treatment, and those fractures are far more likely to be attributable to the disease itself rather than to the treatment.” “Now in seeking proof of causality between BPs and socalled atypical femoral fractures, there are several relevant issues. The first is, do we see these fractures in patients who have never had BP therapy? Secondly, if these fractures are due to BP, then we would expect to see a different epidemiology from that of classical osteoporotic fractures. And thirdly, with causality, we would expect a relationship between dose and duration of therapy. Finally, are there plausible pathophysiological mechanisms to implicate BPs in the pathogenesis of these fractures?” Dr. Compston cited studies showing that atypical fractures indeed occur in BP-naïve patients, sometimes more often than in treated patients. She also cited epidemiological evidence showing similar age-related increases in typical and atypical fractures. Turning to her third point, Dr. Compston said that although Dr. Lane had shown a slide suggesting an increase in the risk of fracture with duration of therapy, there are too few patients in that study to be definitive. She tackled the fourth point showing more graphs. “These histological studies do not support the concept of frozen bone and, crucially, there are no data to show that bone turnover is suppressed more in patients with atypical fractures than in other patients receiving BP who do not have these fractures.” She countered Dr. Lane’s argument about micro-damage, saying that although BPs increase micro-damage in animal bone, even when the animals received industrial amounts of

or y t l Gui


BPs, causing a large amount of micro-damage accumulation, “never has it been shown that this has adverse effects on bone strength. It’s likely that any adverse effects caused by micro-damage and maybe changes in crystallinity and collagen cross-linking are outweighed by the beneficial effects on bone volume, bone micro-architecture, and bone mineralization.”

Jury Participation The audience stirred things up even more, posing questions about whether the atypical fractures might have been present before, but just not recognized; whether the number of such fractures might be up because women abandoned hormone therapy in droves after the WHI study; and who should have a drug holiday. The two speakers answered and gave wrap-up summaries, hoping to win a few more votes.

Speaker Summaries Citing human fallibility, Dr. Compston said: “It’s a kneejerk reaction to attribute any unusual events that occur during treatment to the treatment itself rather than to the disease. Here, reduction of bone turnover, suppression of bone turnover, in the context of a high bone turnover state where bone loss is occurring, where micro-architecture is deteriorating, is a good thing, not a bad thing. It strengthens bone and is the mechanism by which antiresorptives are so effective in reducing fractures. So nothing you have heard today can have convinced you that BPs are causally linked to so-called atypical femoral fractures … Thank you.” Sticking to his guns, Dr. Lane said he sees what he sees: “As orthopedists who see these patients, when 1 out of every 50 fractures that come into our hospital looks like this, we get concerned. So I don’t know the cause, I don’t know the etiology, but I do know that there’s a high association. And that means I’m hoping smarter people like Juliet will explain to me why this is occurring. But for now, when somebody comes in and tells me they’ve got thigh pain and they’ve been on BPs for 5 years, boy, I get an MRI of that thigh, because I know it’s inclined to break. And I look at the other leg. Thank you very much.”

Audience Gives the Final Verdict The audience now turned to their hand-held electronic ballots or cell phones, answering: Do BPs cause these atypical fractures? Here are their votes, with pre-debate responses in parentheses: Yes = 35% (35%). No = 50% (45%). Don't know = 15% (20%). ■ * Find a transcription of the debate at (click “ENDO 2010 Bisphosphonate Debate”). To view the debate (subscription required), visit and click “Session Library.” – X-ray photos: Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab, 2010;95(4):1555–1565.





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More Dysli pidem i a?

By Jennifer Grant Lee, Ph.D.*


ow cholesterol, low salt, and now … low sugar? It’s hard for patients to keep up with everything they shouldn’t eat. Nonetheless, recent research suggests that holding back on added sugars should definitely be part of the recipe for a heart-healthy diet. Coming on the heels of some elegant mechanistic work (see side box) showing that sugars—in particular fructose—induce metabolic changes that encourage fat storage, a large-scale epidemiological survey published in JAMA shows that Americans eat way too much sugar for the sake of not only healthy teeth, but also a healthy heart.1


Not-So-Sweet Findings In the survey, whose participants represented a crosssection of the adult U.S. population, researchers measured blood lipid levels and estimated dietary “added sugar,” defined as caloric sweeteners used in processed or prepared foods, not just white table sugar. They found that on average, 15.8% of total calories came from added sugars—the young, nonHispanic blacks, and subjects with low-incomes were more likely to consume the most.

“Generally, the higher the consumption, the more unfavorable the lipid levels,” said lead author Jean A. Welsh, M.P.H., R.N., at Emory University in Atlanta, Ga. As added sugar consumption data surged from < 5% to ≥ 25% of total calories, adjusted mean high-density lipoprotein cholesterol (HDL) levels significantly dropped from 58.7 to 47.7 mg/dl and geometric mean triglyceride (TG) increased from 105 to 114 mg/dl. Mean low-density lipoprotein cholesterol (LDL) levels among women slightly increased with greater sugar consumption, ranging from 116 to 123 mg/ml, but the study found no significant LDL trend among men. The National Institutes of Health's Adult Treatment Panel-III (ATP-III) guidelines define abnormal lipid levels as HDL < 40 mg/dl for men and < 50 mg/dl for women, LDL ≥ 130 mg/dl, and TG ≥ 150 mg/dl. The higher sugar consumers (≥ 10%) were 50% more likely to have low HDL than the reference group (< 5%), whereas those in the highest group (≥ 25%) were three times as likely to have low HDL. If high LDL were the only focus in treating dyslipidemia, this study would indicate that carbohydrate consumption was not a concern. However, “That’s not the way medicine is go-

• U.S. Institute of Medicine: < 25% total energy. • World Health Organization: < 10% total energy. • American Heart Association: < 100 kcal/d women, < 150 kcal/d men (about 5% total energy). Examples of calories from added sugar, from the USDA MyFoodapedia and the USDA's database for food added sugar content: 12 oz can cola:130 kcal (9% added sugar) ¾ cup chocolate puffed corn cereal: 51 kcal (47%) 1 chocolate chip cookie:16 kcal (34%) 1 tsp granulated sugar: 16 kcal (100%)

ing. As obesity has gone up in the United States (and that's connected with diabetes), triglycerides and HDL, have come to be more significant players in terms of treatment for dyslipidemia. The ATP-III guidelines have changed, and now triglyceride is in the metabolic syndrome definition,” said Elizabeth J. Parks, Ph.D., who works in both clinical nutrition and internal medicine at the University of Texas Southwestern Medical Center in Dallas. “This is an interesting study, potentially highlighting some adverse metabolic effects of ingestion of large quantities of added sugars,” wrote Karin Harnden, research dietician, and Keith N. Frayn, Ph.D., Sc.D., at the University of Oxford in the United Kingdom, in an email to Endocrine News. In 2008-2009, added sugar intake in the U.K. was estimated at 12.5% for the general population and 15.7% for adolescents—the highest consuming group, “so by U.K. standards, the highest-consuming group in this [U.S.] study was consuming very large amounts,” they added. The 6,113 participants were drawn from the National Health and Nutrition Survey (NHANES), conducted in 19992006. The researchers estimated daily added sugar intake from participants’ 24-hour dietary recalls and U.S. Department of Agriculture food composition databases. They placed respondents in 5 groups, ranging from those in whom added sugars were < 5% of total caloric intake to those with intake ≥ 25%. In their regression models, the researchers controlled for possible confounding factors that can co-vary with sugar intake, including body mass index (BMI), waist circumference, and dieting history, as well as other known risk factors for cardiovascular disease such as history of hypertension, smoking, exercise, and dietary covariates (including consumption of other carbohydrates, fats, and cholesterol).

Diet Minus Extra Sugar = Fat Loss? As in the U.K., U.S. adolescents consume the most added sugar. In preliminary results, Ms. Welsh and the research team at Emory University found that adolescents’ added sugar intake and lipid levels are likewise linked. The next step in understanding these effects is to follow blood lipid levels as high sugar consumers reduce their individual intake. The group

is also tracing the sources of added sugar, using the NHANES data—research that could help in efforts to improve dietary behavior. Sweetened beverages, estimated to contribute up to 40% of ingested sweetener calories, are one leading suspect, but eliminating soft drinks would not be enough to make the average U.S. diet healthy. “We have to look at our whole diet. I don’t want people to get the message that it’s [only] added sugar now … Unfortunately people get bounced from one end to the other on what is the right thing to do,” said Ms. Welsh. Eating less processed food and more fruits and vegetables is “one of the best and simplest things we can do, and we don’t have to worry about, do we know how to read a label or not,” she said. ■ * Jennifer Grant Lee is a free-lance writer based in Silver Spring, Md. Reference: 1. Welsh JA, Sharma A, Abramson JL, Vaccarino V, Gillespie C, Vos MB. Caloric sweetener consumption and dyslipidemia among U.S. adults. JAMA, 2010;303(15):1490-1497.

Impact of Fructose vs. Glucose Nearly all sweet foods contain fructose or glucose—or both. Their physiological impacts differ. Glucose metabolism needs insulin, unlike fructose. Fructose, especially highfructose corn syrup, costs less and tastes sweeter. Hepatic breakdown of fructose boosts appetite, raising ghrelin and decreasing insulin and leptin, combining to spur weight gain. Other sweetener alternatives include maple syrup, honey, agave, and stevia. Fructose vs. Glucose—Acute Effects1, 2 • Muted insulin and glycemic response. • Increased lipogenesis. • Enhanced fatty acid esterification. • Increased liver TG synthesis and secretion. • Higher postprandial plasma TG. • Elevated risk of impaired postprandial plasma TG removal. Fructose vs. Glucose—Chronic Effects3, 4 • Increased risk of visceral fat. • Lowered insulin sensitivity. • Reduced HDL. • Elevated plasma-TG and remnant lipoproteins. • Elevated small dense LDL. References: 1. Chong MF, Fielding BA, Frayn KN. Mechanisms for the acute effect of fructose on postprandial lipemia. Am J Clin Nutr, 2007;85:1511–1520. 2. Parks EJ, Skokan LE, Timlin MT, Dingfelder CS. Dietary sugars stimulate fatty acid synthesis in adults. J Nutr, 2008;138:1039–1046. 3. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructosesweetened, not glucose sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/ obese humans. J Clin Invest, 2009;119(5):1322–1334. 4. Bantle JP, Raatz SK, Thomas W, Georgopoulos A. Effects of dietary fructose on plasma lipids in healthy subjects. Am J Clin Nutr, 2000;72:1128–1134.


Sugar Consumption Guidelines


RESEARCH BRIEFS ➤ The studies below will be published in Endocrine Society journals. Before print, they are edited and posted online free at For journal subscriptions, email Studies Coming in The Journal of Clinical Endocrinology & Metabolism ➤ Obesity is not linked to aggressive differentiated thyroid cancer or to a higher risk of persistence/ recurrence. Paes JE, Hua K, Nagy R, Kloos RT, Jarjoura D, Ringel MD. The relationship between body mass index and thyroid cancer pathology features and outcomes: A clinicopathologic cohort study. ➤ These particular DAX1 mutations lead to a rare adrenal gland development disorder. Li N, Liu R, Zhang H, et al. Seven novel DAX1 mutations with loss of function identified in Chinese patients with congenital adrenal hypoplasia.


➤ In the first trimester, serum TSH should be no higher than 2.5 mIU/L. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5–5.0 in the first trimester of pregnancy.


➤ Exercise and fasting stimulate myocellular GH signaling, then STAT5b phosphorylation and/or IGF-I gene expression. Vendelbo MH, Jørgensen JO, Pedersen SB, et al. Exercise and fasting activate growth hormone–dependent myocellular STAT5b phosphorylation and IGF-I mRNA expression in humans. ➤ In some patients with rickets, a CYP27B1 mutation significantly reduces 1α-hydroxylase activity.

Alzahrani AS, Zou M, Baitei EY, et al. A novel G102E mutation of CYP27B1 in a large family with vitamin Ddependent rickets type 1. Studies Coming in Endocrinology ➤ Disparate cognitive effects result when conjugated equine estrogen is given to surgically or transitionally menopausal rats. Acosta JI, Mayer LP, Braden BB, Nonnenmacher S, Mennenga S, Bimonte-Nelson HA. The cognitive effects of CEE depend on whether menopause etiology is transitional or surgical. ➤ Dehydroepiandrosterone and Δ5-androstenediol are metabolized by 3βHSD to activate the androgen receptor in this prostate cancer. Evaul K, Li R, Papari-Zareei M, Auchus RJ, Sharifi N. 3β-hydroxysteroid dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate cancer. ➤ Null mouse studies reveal a role for CNP in energy metabolism. Inuzuka M, Tamura N, Yamada N, et al. C-type natriuretic peptide as a new regulator of food intake and energy expenditure. ➤ Satiety signaling by VAN occurs when CCK and leptin jointly regulate activation and synthesis of EGR1. de Lartigue G, Lur G, Dimaline R, Varro A, Raybould H, Dockray GJ. EGR1 is a target for co-operative interactions between cholecystokinin and leptin, and inhibition by ghrelin, in vagal afferent neurons. ➤ ActRIIB-mFc treatment in castrated mice restores muscle mass, adiposity, and bone quality. Koncarevic A, Cornwall-Brady M, Pullen A, et al. A soluble activin receptor type IIb prevents the effects

of androgen deprivation on body composition and bone health. ➤ Cross communication between α and β cells contributes to tumorigenesis in the absence of the tumor suppressor gene Men1. Shen H-CJ, Ylaya K, Pechhold K, et al. Multiple endocrine neoplasia type 1 deletion in pancreatic α cells leads to development of insulinomas in mice. Studies Coming in Molecular Endocrinology ➤ These granulosa cell–specific receptors promote pre-antral follicle growth and stop follicular atresia. Sen A, Hammes SR. Granulosa cellspecific androgen receptors are critical regulators of ovarian development and function. ➤ During pregnancy, transcription factor MiTF-CX suppresses IL-8 to maintain cervical competency. Li X-H, Kishore AH, Dao D, Zheng W, Roman CA, Word RA. A novel isoform of microphthalmia associated transcription factor inhibits interleukin-8 gene expression in human cervical stromal cells. ➤ Transcription factors Foxa1 and Foxa2 are critical for the development and maintenance of β cell– specific secretory and metabolic pathways. Gao N, Lay JL, Qin W, et al. Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature β cell. ➤ Interactions of the WNT/ CTNNB1 pathway and G protein– coupled gonadotropin receptors are critical in female fertility. Fan H-Y, O’Connor A, Shitanaka M, Shimada M, Liu Z, Richards JS. Betacatenin (CTNNB1) promotes preovulatory follicular development but represses luteinizing hormone-mediated ovulation and luteinization. ■

S potlight


P olicy


t’s a broad yet important list: biomedical research funding, diabetes prevention and research funding, regulation of endocrinedisrupting chemicals, Medicare physician payment cuts, and endocrinologist workforce shortages. These weighty topics were the focus of the latest Capitol Hill meetings between members of The Endocrine Society’s Advocacy and Public Outreach Core Committee (APOCC) and key staff in House and Senate offices.

Society Members Advocate on Capitol Hill By Stephanie Kutler*

Backing Research Funding

APOCC members present Sen. Arlen Specter with the Congressional Leadership Award.

tion and research. APOCC members discussed these concerns with staff from the offices of Rep. DeGette and Sen. Byron Dorgan (D-ND), specifically asking that they support providing $5 billion of the recently authorized Prevention and Public Health Fund to diabetes prevention, and thanking them for their role in the reauthorization of the Type 1 Diabetes Strategic Plan Fund. The Society has served as a resource to a number of offices on Capitol Hill that have introduced legislation on endocrine-disrupting chemicals. Committee members used these Hill visits to broaden awareness of this topic among other members of Congress. Society representatives asked that Reps. Shimkus and Matheson support greater regulation of these chemicals. Members of Rep. Frank Pallone’s (D-NJ) staff were also involved in discussing this topic during the visit.

Workforce and Payments Endocrinologist workforce shortages and physician payments are top Society concerns, and committee members discussed them with Sen. Nelson and Reps. DeGette, Shimkus, Burgess, Matheson, Bill Pascrell (D-NJ), Carolyn McCarthy (D-NY), and the staffs of Reps. Pallone and Pete Stark (D-NJ). Committee members emphasized the need to find a permanent solution to the flawed Sustainable Growth Rate formula, which results in annual Medicare payment cuts, and for policy solutions to the shortage of endocrinologists in the country. To read more about these and other advocacy initiatives, visit Endocrine Insider at www.endo-society. org/advocacy/insider/index.cfm. ■ * Stephanie Kutler is director, government affairs, The Endocrine Society.


During the visit, APOCC members presented a 2009 Endocrine Society Congressional Leadership Award to Sen. Arlen Specter (D-PA), for his strong support of biomedical research funding. Sen. Tom Harkin (D-IA) and Rep. Diana DeGette (DCO) were also given a 2009 award for their support of biomedical research and diabetes prevention and research. To see additional information on the winners, visit index.cfm and look under April 29. Society members discussed the need for increased biomedical research funding with Sen. Ben Nelson (D-NE); Reps. John Shimkus (R-IL), Michael Burgess (R-TX), and Jim Matheson (D-UT); and staff from Rep. Brian Bilbray’s (R-CA) office. The Society recognizes the commitment of President Obama and members of Congress to biomedical research, as illustrated by the $10 billion allocated to the National Institutes of Health (NIH) in the 2009 American Recovery and Reinvestment Act, but remains concerned about the future of that research without sustained support from the federal government. The Society recommends that NIH receive at least $37 billion in FY 2011 to prepare for the post-stimulus era and to promote the steady and sustainable growth necessary to continue building on scientists’ advances during the past decade. The Society has been actively working to ensure that federal funds are also allocated to diabetes preven-


P ractice R esources PressAnnouncements/ucm211176.htm.

Busy Times at the FDA By Jacqueline Ruttimann, Ph.D., Staff Writer An estimated 40 million people worldwide have taken some form of this drug. See NewEvents/Newsroom/ PressAnnouncements/ ucm213470.htm.




Proton Pump Inhibitors

A new type of osteoporosis drug for postmenopausal women at high risk for fractures—the first new class of medicine introduced in nearly a decade for this disorder—was recently approved by the U.S. Food and Drug Administration (FDA) and the European Commission. Prolia (denosumab), developed by Amgen, is a fully human monoclonal antibody designed to target RANKL, an osteoclast maturation factor. The drug mimics osteoprotegerin, a naturally occurring protein produced by osteoblasts; it acts as a decoy receptor for RANKL and helps keep the balance of osteoblasts to osteclasts in check. The drug is delivered subcutaneously every 6 months. For more information, see PressAnnouncements/ucm214150.htm.

Patients on proton pump inhibitors or stomach acid–reducing medicines for longer than 1 year or at high doses face the possibility of increased fracture of the hip, wrist, and spine. The FDA ordered manufacturers of these drugs [e.g., Nexium (esomeprazole), Dexilant (dexlansoprazole), Prilosec (omeprazole), Prevacid (lansoprazole), Protonix (pantoprazole), Aciphex (rabeprazole)] to reflect this risk in their products’ labeling. Joyce Korvick, M.D., deputy director for safety in the FDA's Division of Gastroenterology Products suggested that “health care professionals should consider whether a lower dose or a shorter duration of therapy would adequately treat the patient's condition.” Learn more at NewsEvents/Newsroom/Press Announcements/ucm213377.htm.



Those who opt to use the weightloss medication orlistat (marketed as the prescription drug Xenical and over the counter as Alli) may have to consider a potential risk for the drug: severe liver injury. Receiving reports of 13 severe liver injury cases involving Alli—1 from the United States and 12 from outside the country—the FDA recently advised consumers and health care professionals about this risk and has been working with the manufacturers to revise their drug labels to reflect this rare occurrence.

The birth control pill has a new sibling. The FDA has approved Natazia (estradiol valerate and estradiol valerate/dienogest) tablets for use as an oral contraceptive. Manufactured by Bayer HealthCare Pharmaceuticals, Natazia differs from previous marketed combination oral contraceptives in that it contains estradiol valerate rather than ethinyl estradiol and is the first to supply four different doses of progestin and estrogen throughout the 28-day treatment. For more information, see

New Ovarian Cancer Test A wider net has been cast for ovarian cancer detection with the FDA’s recent approval of a new diagnostic test. Manufactured by Abbott Laboratories, ARCHITECT HE4 (human epididymis protein 4) is a blood test that looks for a biomarker usually secreted by ovarian cancer patients. Its use in conjunction with the current blood test to monitor ovarian cancer, CA125, is anticipated to detect more of these cancers; 80% of ovarian cancers are detected with CA125, yet 20% are missed because of tumors that do not express CA125. Early detection is key in these patients­—the 5-year survival rate is 46%, according to the American Cancer Society. This rate soars to 93% when the disease is diagnosed and treated before the cancer has metastasized, but less than 20% of ovarian cancer is found at this early stage. See com/global/url/pressRelease/en_US/ 60.5:5/Press_Release_0870.htm.

Thyrogen Hoping to avoid shortages of Thyrogen (recombinant thyroidstimulating hormone [TSH]), a drug used in the treatment and follow-up diagnosis of thyroid cancer, the FDA developed criteria to help physicians and other health care providers identify patients for whom the drug is medically necessary. Genzyme Corp., Thyrogen’s manufacturer, recently entered into a consent decree agreeing to correct manufacturing quality violations at its Allston, Mass., facility and to move operations from this plant to other facilities. According to the FDA, these critical patients include those undergoing initial radioiodine ablation of thyroid tissue remnants, those who have had a thyroidectomy, those deemed to be at significantly increased risk of side effects/complications from undergoing thyroid hormone withdrawal, and those considered


Klinefelter Syndrome PLEASE TEAR HERE

What is Klinefelter syndrome?

or after conception. Klinefelter syndrome is the most common sex-chromosome abnormality, affecting about one in every 500 to 700 men.

What are the signs and symptoms of Klinefelter syndrome? Signs and symptoms can vary. Some males have no symptoms but a doctor will be able to see subtle physical signs of the syndrome. Many males are not diagnosed until puberty or adulthood. As many as two-thirds of men with the syndrome may never be diagnosed.

How is Klinefelter syndrome diagnosed? Diagnosis is based on a physical examination, history of social or learning problems, hormone testing, and chromosome analysis. The syndrome can also be diagnosed before birth but testing is not routinely done at that time.

What causes Klinefelter syndrome?

What is the treatment for Klinefelter syndrome?

The addition of extra chromosomes seems to occur by chance. The syndrome is not inherited from the parents. The addition occurs in the sperm, the egg,

Treatment can help males overcome many of the physical, social, and learning problems associated with the syndrome. Males with Klinefelter syndrome should

Signs and Symptoms by Age Group Infants and young boys may have:

Adolescents may ALSO have:

Adults may ALSO have:

• Problems at birth, such as testicles that haven’t dropped into the scrotum or a hernia* • A small penis • Weak muscles • Speech and language problems, such as delayed speech • Problems with learning and reading • Problems fitting in socially • Mood and behavioral problems

• Small, firm testicles • Enlarged breasts, called gynecomastia • Long legs but a short trunk • Above-average height • Reduced muscle bulk • Sparse facial and body hair • Delayed puberty • Low energy levels

• Low testosterone (male hormone) levels • Infertility from a lack of sperm • Decreased sex drive • Problems getting or keeping an erection • Other difficulties, such as being unable to make plans or solve problems

* when an internal organ bulges through a body cavity wall

EDITORS: Adrian Dobs, MD, MHS Alvin M. Matsumoto, MD December 2009

Health Problems Associated with Klinefelter Syndrome Klinefelter syndrome can lead to weak bones (osteoporosis), varicose veins, and autoimmune diseases (when the immune system acts against the body), such as lupus or rheumatoid arthritis. XXY males have an increased risk for breast cancer and cancers that affect blood, bone marrow, or lymph nodes, such as leukemia. They also tend to have excess fat around the abdomen (which raises the risk of health problems), heart and blood vessel disease, and type 2 diabetes. be seen by a team of health care providers. The team may include endocrinologists, general practitioners, pediatricians, speech therapists, genetic counselors, and psychologists. Surgery may be needed to reduce breast size. With treatment, men can lead very normal lives. Experts recommend testosterone replacement, starting during puberty, for proper development of muscles, bones, male sex characteristics such as facial hair, and sexual function. Continued treatment throughout life helps prevent long-term health problems. Testosterone replacement does not cure infertility, however. Infertility treatments require specialized—and costly—techniques, but some men with Klinefelter syndrome have been able to father children.

Resources Find-an-Endocrinologist: or call 1-800-HORMONE (1-800-467-6663) National Institute of Child Health and Human Development Information Resource Center, National Institutes of Health (NIH): topics/klinefelter_syndrome.cfm or call 1-800-370-2943 Genetics Home Reference website, National Library of Medicine, NIH: www.ghr.nlm.

For more information on how to find an endocrinologist, download free publications, translate this fact sheet into other languages, or make a contribution to The Hormone Foundation, visit or call 1-800-HORMONE (1-800-467-6663). The Hormone Foundation, the public education affiliate of The Endocrine Society (, serves as a resource for the public by promoting the prevention, treatment, and cure of hormone-related conditions. This page may be reproduced non-commercially by health care professionals and health educators to share with patients and students. © The Hormone Foundation 2009


Klinefelter syndrome is a group of conditions affecting the health of males who are born with at least one extra X chromosome. Chromosomes, found in all body cells, contain genes. Genes provide specific instructions for body characteristics and functions. For example, some genes determine height and hair color. Other genes influence language skills and reproductive functions. Each person typically has 23 pairs of chromosomes. One of these pairs (sex chromosomes) determines a person’s sex. A baby with two X chromosomes (XX) is female. A baby with one X chromosome and one Y chromosome (XY) is male. Most males with Klinefelter syndrome, also called XXY males, have two X chromosomes instead of one. The extra X usually occurs in all body cells. Sometimes the extra X only occurs in some cells, resulting in a less severe form of the syndrome. Rarely, a more severe form occurs when there are two or more extra X chromosomes.



Síndrome de Klinefelter ¿Qué es el síndrome de Klinefelter? El síndrome de Klinefelter es un grupo de aflicciones que afectan la salud de los varones que nacen con por lo menos un cromosoma X adicional. Los cromosomas se encuentran en todas las células del cuerpo y contienen genes. Los genes dan instrucciones específicas para las características y funciones del cuerpo. Por ejemplo, algunos genes determinan la estatura y el color del cabello. Otros genes influyen en las aptitudes lingüísticas y funciones reproductivas. Generalmente, cada persona tiene 23 pares de cromosomas. Uno de estos pares (los cromosomas sexuales) determina el género de una persona. Los bebés con dos cromosomas X (XX) son de sexo femenino. Los bebés con un cromosoma X y un cromosoma Y (XY) son de sexo masculino. La mayoría de los varones con el síndrome de Klinefelter, también llamados varones XXY, tienen dos cromosomas X en vez de uno. El cromosoma X adicional usualmente está presente en todas las células del cuerpo. A veces, sólo está presente en algunas células, lo que resulta en casos menos severos del síndrome. En ocasiones, se presentan casos más severos y poco comunes en los que hay dos o más cromosomas X adicionales. ¿Qué causa el síndrome de Klinefelter? La presencia de cromosomas adicionales parece ocurrir por casualidad. El síndrome

no se hereda de los padres. El cromosoma adicional parece surgir en el esperma, el óvulo o después de la concepción. El síndrome de Klinefelter es la anormalidad más común de los cromosomas sexuales y afecta a uno de cada 500 a 700 hombres. ¿Cuáles son los indicios y síntomas del síndrome de Klinefelter? Los indicios y síntomas pueden variar. Algunos varones no tienen síntomas, pero un médico puede notar indicios físicos sutiles del síndrome. Muchos varones no reciben un diagnóstico hasta que alcanzan la pubertad o edad adulta. Hasta dos tercios de los hombres con el síndrome nunca recibirán un diagnóstico al respecto. ¿Cómo se diagnostica el síndrome de Klinefelter? El diagnóstico se basa en un examen físico, una historia de problemas sociales o de aprendizaje y un análisis de cromosomas. El síndrome también se puede diagnosticar antes del nacimiento, pero en la actualidad no se hace la prueba de manera rutinaria. ¿Cuál es el tratamiento del síndrome de Klinefelter? El tratamiento puede ayudar a los varones a superar muchos de los problemas físicos, sociales y de aprendizaje relacionados con

Indicios y síntomas por edad Los bebés y niños pueden tener: • Problemas al nacer, como testículos que no descienden al escroto o una hernia* • Un pene pequeño • Músculos débiles • Problemas de dicción y lenguaje, como retraso para hablar • Problemas de lectura y aprendizaje • Problemas sociales • Problemas anímicos y de conducta

Los adolescentes TAMBIÉN pueden tener: • Testículos pequeños y duros • Pechos desarrollados, denominados ginecomastia • Piernas largas pero tórax corto • Estatura superior a la promedio • Menor musculatura • Escasa vellosidad facial y corporal • Retraso en la pubertad • Poca energía

Los adultos TAMBIÉN pueden tener: • Nivel bajo de testosterona (hormona masculina) • Infertilidad debido a ausencia de esperma • Disminución del libido • Problemas para tener o mantener erecciones • Otras dificultades, como no poder hacer planes o resolver problemas

* cuando un órgano interno se sale parcialmente por la pared de una cavidad

EDITORES: Adrian Dobs, MD, MHS Alvin M. Matsumoto, MD Diciembre del 2009

Problemas del corazón relacionados con el síndrome de Klinefelter El síndrome de Klinefelter puede resultar en debilidad ósea (osteoporosis), venas varicosas y enfermedades autoinmunes (cuando el sistema inmunológico ataca al cuerpo), como lupus o artritis reumatoide. Los varones XXY tienen un riesgo más elevado de cáncer de las mamas y de otros tipos que afectan la sangre, la médula espinal o los ganglios linfáticos, como leucemia. También tienden a tener exceso de grasa alrededor del abdomen (que eleva el riesgo de problemas de salud), enfermedades cardiovasculares y diabetes de tipo 2. el síndrome. Los hombres con el síndrome de Klinefelter deben recibir tratamiento de un equipo de proveedores de servicios de salud. El equipo puede incluir a endocrinólogos, médicos generales, pediatras, terapeutas de dicción, asesores genéticos y sicólogos. Es posible que sea necesaria una operación para reducir el tamaño de los pechos. Con tratamiento, los hombres pueden llevar una vida muy normal. Los expertos recomiendan terapia de testosterona sustitutiva a partir de la pubertad para el debido desarrollo de los músculos, huesos, características masculinas como vellos faciales y función sexual. El tratamiento continuo durante toda la vida ayuda a evitar problemas de salud a largo plazo. Sin embargo, la testosterona sustitutiva no cura la infertilidad. El tratamiento para la infertilidad requiere técnicas especializadas y costosas, pero algunos hombres con el síndrome de Klinefelter han podido tener hijos. Recursos Encuentre a un Endocrinólogo: o llame al 1-800-467-6663 Centro de Recursos del Instituto Nacional de Salud Infantil y Desarrollo Humano, Instituto Nacional de Salud (NIH por sus siglas en inglés): felter_syndrome.cfm o llame al 1-800-370-2943 Sitio de Internet para consultas sobre genética, Biblioteca Nacional de Medicina del NIH: syndrome

Para más información sobre cómo encontrar un endocrinólogo, obtener publicaciones gratis de la Internet, traducir esta página de datos a otros idiomas, o para hacer una contribución a la Fundación de Hormonas, visite a o llame al 1-800-HORMONE (1-800-467-6663). La Fundación de Hormonas, la filial de enseñanza pública de la Sociedad de Endocrinología (, sirve de recurso al público para promover la prevención, tratamiento y cura de condiciones hormonales. Esta página puede ser reproducida para fines no comerciales por los profesionales e instructores médicos que deseen compartirla con sus pacientes y estudiantes. © La Fundación de Hormonas 2009

P ractice R esources at high risk for thyroid cancer recurrence. For more information, see PressAnnuouncements/ucm213212.htm and DrugShortages/ucm213008.htm.

Benicar The manufacturer of the blood pressure medication Benicar (olmesartan medoxomil) is feeling the squeeze from the FDA after two recent studies (ROADMAP and ORIENT) found that patients taking the drug had a higher cardiovascular death rate than those taking a placebo. The agency is currently evaluating data from these trials and encourages physicians and other health care professionals to watch for adverse events. Meanwhile, the FDA holds that the drug’s benefits still outweigh the potential risks. Learn more at MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts.

For additional information about ROADMAP and ORIENT, see http://

See Newsroom/PressAnnouncements/ ucm210664.htm.

Colleague Infusion Pump Recall

GnRH Agonists

The FDA ordered Baxter Healthcare Corporation to recall and destroy all of its Colleague volumetric infusion pumps currently in use in the United States, due to the company’s “longstanding failure” to fix serious problems with it. Baxter will provide refunds to customers or replace pumps at no cost. The FDA believes there may be as many as 200,000 of these pumps in use, primarily in hospitals, but also in private homes. These pumps deliver fluids such as nutrients and medications into a patient’s body in a controlled manner. All models, including the Baxter Colleague, have been the source of persistent safety problems, with more than 56,000 adverse events reported to the agency over the past 5 years. Those events have included serious injuries and more than 500 deaths.

The jury is still out on whether gonadotropin-releasing hormone (GnRH) agonists, a class of medications primarily used to treat men with prostate cancer, are linked to an increased risk for diabetes, heart attack, stroke, and sudden death, according to a preliminary and ongoing analysis of several studies by the FDA. For now, the agency advises health care professionals to be aware of these potential risks when determining use of these drugs and to monitor patients for diabetes and cardiovascular disease. Medications in the GnRH class are marketed under the brand names Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex. Several generic products are also available. For more information, see Newsroom/PressAnnouncements/ ucm210549.htm. ■

The endocrine SocieTy’S

2010 EndocrinE Board rEviEw coursE Los angELEs, ca | sEptEmBEr 28 –29, 2010 Hyatt rEgEncy cEntury pLaza HotEL

the 2010 endocrine Board review course is an interactive workshop held two days prior to the clinical endocrinology update. Board Review provides an intensive review of key areas covered by the aBiM blueprint for the subspecialty exam in diabetes, endocrinology and Metabolism. the course includes: instant feedback from experts in their field a comprehensive review notebook containing all questions and answers up to 17.5 aMa PRa category 1 credits™ to register, visit or call society services at 1.888.363.6762 or 301.941.0210. early registration deadline: August 27, 2010


RegisteR Now foR Reduced Rates


TRAINEE CORNER Junior Faculty Development ➤➤ Dear Trainee, I recently made the transition from a 5-year postdoctoral research position at Baylor College of Medicine to an assistant professor position at the University of Texas-Pan American. The new position includes teaching, research, and professional service obligations. The university’s New Faculty Support Program was helpful in my transition. I hope this account of my personal experience will give insight into how critical the early days of a young investigator’s career are and emphasize the value of new/junior faculty development programs. *** The transition from postdoctoral training to faculty is not a step forward but a leap. The learning curve is steep and you may feel you are marooned on an island, alone. The decisions you make in your first few years, which can define your career, encompass not only your research goals but also teaching and service obligations (if required by your institution). Your training gives you the confidence and skills necessary for an independent research agenda, yet it frequently neglects to prepare you for the additional requirements placed on new faculty. Therefore, you must rely on institutional and mentor guidance to navigate the turbulent waters of academia. For me, adjusting from trainee to fac-

ulty has been challenging, not because of insufficient training (my confidence in my abilities as a researcher are high) but due to my lack of familiarity with the new additional requirements. Overnight, I went from working in an established laboratory to running my own lab, teaching classes, and serving on numerous institutional and external committees. I had to learn the institutional infrastructure, from purchasing to parking, and navigate through university politics. I am challenged daily with making choices that could lead to success or doom. A negative first tenure evaluation can have long-lasting consequences. The pressure to secure research funding, serve on committees, and prepare courses is daunting. One pitfall for me was committing to too many academic endeavors. Getting external funds to support your research is a priority; agreeing to serve on numerous university committees or teaching several classes is secondary and potentially distracting. It is imperative that you receive counsel when making such decisions; you may need to seek this from several different sources. Choosing a university with a new faculty or junior faculty development program greatly increases your chances of success. My university’s new faculty support program is intensive and covers the full academic year, beginning with a 2-day symposium, followed by bi-monthly workshops. Topics range from understanding university culture to informa-




ENDOCRINE Board Review Course • • Endocrine Board Review—September 28 and 29, Los Angeles, Calif. • Registration for Endocrine Board Review now open. • ABIM fall exam date—November 18

tion technology (IT) support. Specific workshops cover teaching effectiveness, grant writing/submission, funding sources, building research collaborations, the tenure process, and faculty expectations. The program also acts as a support group consisting of faculty from almost every academic department on campus—sharing experiences and ideas is invaluable. Universities that add numerous faculty members annually are more likely to have a structured faculty development program. These may not always be personalized; I found myself relying heavily on individual mentors. Finding appropriate mentors can be difficult, but extremely beneficial. For example, I have a teaching mentor who helps me with course load and institutional decisions. I also have several research mentors outside my resident campus who have provided guidance on research-related questions ranging from how to set up a lab to developing a multi-year research agenda. I am very grateful to all my mentors and give them a great deal of credit for my early successes. The Endocrine Society has also recently developed a mentorship program to help support its members at all stages of their career. This program is unique in that it draws on the vast expertise of active members to help others in the field. Whether you have a mentor or not, this program is available to all Society members who wish to seek guidance from successful teachers and researchers. The Mentor Exchange is a membersonly online portal where trainees and junior faculty can search for a mentor to help them with work/life balance, publishing, grant writing, and more. To learn more about finding a mentor or becoming one, contact Ciara Durkan, Membership Marketing Manager, or log on to the Society Web site at ■

Clinical Endocrinology Update • • September 30–October 2, Los Angeles, Calif.


CLINICAL INVESTIGATORS WORKSHOP • index.cfm • Nomination forms now available. • November 5–7, 2010, San Francisco, Calif.

Robert K. Dearth, Ph.D.➤ Assistant Professor University of Texas-Pan American, Edinburg

CME connections Endocrine Board Review Course

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Knowing Trivia Pays!


ENDO 2010: The 92nd Annual Meeting & Expo debuted the ENDO Trivia Cup Challenge, a series of exhibition rounds for trainees and a champi-


Reporter Wins Society Journalism Award

Find more information about the award at

The Endocrine Society presented its 2010 Award for Excellence in Science and Medical Journalism to Science News reporter Tina Hesman Saey for her winning article, “Dying to Sleep.” Then-President Robert A. Vigersky, M.D., presented the award to Ms. Saey at ENDO 2010. In her in-depth report, Ms. Saey examined how the body reacts to insufficient sleep. She explained how losing sleep, even for one night, can trigger a flood of changes, and she successfully communicated these complex physiological processes in terms of general understanding. The article appeared in the October 24, 2009, issue of Science News and is available online at www.sciencenews. org/view/feature/id/48146/title/ Dying_to_Sleep. The Award for Excellence in Science and Medical Journalism includes ENDO-related travel and accommodation, and a plaque. Established in 2008, this annual award recognizes outstanding reporting that enhances the public understanding of health issues pertaining to the field of endocrinology. The award is also intended to promote greater visibility of the Society among medical and science writers and to foster media relationships.

A Step Above the Rest The Hormone Foundation’s 3rd ENDO Step Challenge gave meeting attendees a great reason to explore sunny San Diego! Three thousand ENDO attendees competed with each other to see who could walk the most steps. In addition to the individual competition, the Step Challenge also included a team challenge, with corporate sponsors, exhibitors, academic institutions, trainees, and other organizations competing.

Fourteen ENDO attendees won prizes in the daily raffles. These included gift certificates to hotels and restaurants and a free lab coat for one lucky participant. The team winner this year was Caminito Tango 2: La Revancha from Argentina with a total of 52,302 steps walked during ENDO. Each member of Caminito Tango 2: La Revancha won gift certificates to the ENDO 2010 store. This year’s Step Challenge was sponsored by Novogyne and SanofiAventis U.S. Stay tuned for results from the individual competition!

onship event for all ENDO attendees. The ENDO Trivia Cup Challenge was moderated by Bradley Anawalt, M.D., of the University of Washington, and Jon Levine, Ph.D., of Northwestern University, who tapped their creativity to generate questions for this new event. The Trainee Challenges took place Saturday, Sunday, and Monday at the Showcase ENDO Stage. The daily winning trainee teams were ENDO1, Fat Killers, and Reproductive Endocrinologists; all their members won ENDO T-shirts. At the championship event, ENDO attendees enjoyed an evening of camaraderie, appetizers, and cocktails, while participating in the trivia challenge as teams. The winning team was Triviatoxicosis. Theirs is the first name to be engraved on the ENDO Trivia Cup, housed at the Society’s headquarters in Chevy Chase, Md. Members of the winning team each received $40 Visa gift cards. Winning the competition for “best team name” was Game Ovary; they earned a place in Society history! Look for an even bigger cup challenge at ENDO 2011 in Boston! In the meantime, you can try answering selections of questions you missed, which will appear periodically on the Puzzler Page of Endocrine News (see page 34 in this issue).

Member Discount on Epocrates Endocrine Society members are entitled to a 20% discount on all Epocrates mobile and online products, such as the #1 Epocrates© Essentials. Epocrates provides point-of-care access (via mobile devices and the Web) to information on drugs, diseases, and diagnostics. Learn more at epocrates.cfm.

Receive FDA Alerts Electronically The Society, in partnership with the Health Care Notification Network, gives physician members free electronic delivery of drug safety alerts from the U.S. Food and Drug Administration (FDA). Learn more about this useful service, at www.

Special Member Discount on Endocrinology Books The Society is offering members an exclusive 25% discount on endocrinology and metabolism titles from Springer, an international publisher of clinical and research books. Popular titles in the field of endocrinology include Cardiovascular Endocrinology: Shared Pathways and Clinical Crossroads; Insulin Resistance—Childhood Precursors and Adult Disease; and Acute Endocrinology: From Cause to Consequence. To learn more, visit ■

In Memoriam Nadir R. Farid, M.B.B.S., F.R.C.P., F.R.C.P. (C.), F.A.C.P. Watford, United Kingdom 1944-2010 Dorothy R. Hollingsworth, M.D. Nevis, West Indies 1922-2010

calendar SEP 12–16, 2010: TOKYO, JAPAN Sixth International Symposium on Hormonal Oncogenesis. See www. SEP 28–29, 2010: LOS ANGELES, CALIF. Board Review 2010. Please see SEP 29–OCT 2, 2010: DENVER, COLO. American Academy of Family Practitioners. See SEP 30–OCT 2, 2010: LOS ANGELES, CALIF. Clinical Endocrinology Update (CEU) 2010. See more at CEU/index.cfm. JUNE 4–7, 2011: BOSTON, MASS. ENDO 2011: The 93rd Annual Meeting & Expo of The Endocrine Society. Please see The above events are Endocrine Society– related. See more events at, on the Worldwide Endocrine Events Calendar.

Now Available


Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline Originally published in June 2006, the Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes guideline has been updated to reflect new recommendations in this field. As with the original version, this update is evidence-based and has been vetted through a multi-step peer review process. In addition, The Endocrine Society is offering CME with this guideline. Readers who study the content and complete the CME post test and evaluation may earn up to 2.0 AMA PRA Category 1 Credits.™ Visit the website below for more details. This updated Guideline includes: • Revised PSA Exclusion Criterion for Testosterone Therapy • Revised PSA Follow-up Guidelines • Refined Guidance for Treating Older Men with Testosterone Therapy

Endocrine Society Clinical Guidelines ALSO AVAILABLE • Treatment of Transsexual Persons • Adult Hypoglycemic Disorders • Pediatric Obesity • Cardiovascular Disease and Type 2 Diabetes in Patients at Metabolic Risk • Primary Aldosteronism • Cushing’s Syndrome • Hirsutism in Premenopausal Women • Thyroid Dysfunction during Pregnancy & Postpartum • Androgen Therapy in Women

To purchase the available guidelines visit: guidelines/Current-Clinical-Practice-Guidelines.cfm. To view patient guides (companion pieces to the clinical guidelines), visit The Hormone Foundation’s Web site at © 2010 The Endocrine Society®

• Adult Growth Hormone Deficiency

C lassifieds

If you are interested in submitting classified advertising to Endocrine News, please contact Christine Whorton at or 800-361-3906.

Eastern Virginia Medical School EVMS and its academic affiliate, the Hampton Veteran’s Administration Hospital (VA), seek an Endocrinologist at the assistant professor or associate professor rank. A well qualified individual could easily be assimilated in the department as a Clinical Educator or a Physician Scientist. For the research oriented candidate, an interest in the area of Cardiovascular Disease related to Diabetes or Metabolic Syndrome would fit nicely with the institu-

tions’ research goals. The position affords the opportunity to collaborate on research with the Department’s Strelitz Diabetes Center NIH funded faculty (Jerry Nadler, M.D., FAHA, Diabetes Center Director and Department Chair) and research faculty at the Hampton Veteran’s Hospital. EVMS will supply modern laboratory space and contribute significant additional research support. As a Clinical Educator, the candidate should possess documented teaching expertise, superior clinical skills

and have an interest in training students, residents and fellows. All candidates should be board certified or board eligible in Endocrinology. This full-time position is .8 FTE at EVMS and .2 FTE at the VA with salary, benefits, academic appointment and start up support commensurate with the candidates’ training and experience. EVMS is centrally located in a seven city metropolitan area of 1.6 million people and is 20 minutes from the ocean front in the historic port city of Norfolk, Virginia. The Veteran’s Hospital is located at the water’s edge in Hampton, Virginia, just across the port of Hampton Roads. Please send a letter of interest, including current curriculum vitae, to the Executive Search Committee by email at The Eastern Virginia Medical School is an Affirmative Action / Equal Opportunity Employer and DrugFree Workplace.

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Medical Director Pediatric Endocrinology — Children’s Hospital Central California in affiliation with Specialty Medical Group Central California, Inc. is seeking a Medical Director to lead and grow a well established, collegial group of 4 pediatric endocrinologists in a busy, rewarding clinical practice. Practice at a large, free standing, state-of-the-art tertiary, children’s hospital. Ancillary support is superb. The Diabetes Center is fully staffed with 4 full time CDEs, 1 CDE/NP, 1 full time RD/ CDE, and 1.5 FTE social workers and has been recognized by the ADA as a center of excellence for diabetes education. Enjoy a wonderful lifestyle in sunny California with affordable housing, abundant recreational opportunities, and excellent schools. Academic appointment is available through UCSF Fresno Medical Education Program. Compensation is very competitive with excellent benefits. Please forward CV or letter of interest to Lourdine Skillin at mdrecruitment@childrenscentralcal. org or call 559.353.8173 for more information.

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support staff in a recently remodeled facility opened in 2009. OSF Saint Francis Medical Center has a 131-year history of commitment and dedicated service as the major referral center to the 23-county region of north-central Illinois with a population greater than 2 million. Call or send CV to Rachel Reliford, OSF Recruitment. Ph: 309-683-8352 or 800-232-3129 (8). Email: rachel. Web: ■

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Pocono Medical Center Seeks Endocrinologist Pennsylvania’s Pocono Mountains Endocrinologist greatly needed in Monroe County, Pennsylvania, a friendly family-oriented community nestled in the heart of the Poconos yet in close proximity to NYC and Philadelphia. The second fastest growing county in PA., Monroe County currently has no full-time endocrinologist. PMC is a 231-bed community hospital transitioning to a regional medical center. A Level III Trauma Center, PMC will continue to expand over the next several years with focuses in Surgery, Women’s and Children’s Services, Primary Care, Oncology, Musculoskeletal Services, and Cardiac Wellness. The Pocono Mountains boast excellent schools and an abundance of recreational activities. Come join our rapidly growing community. Excellent salary and benefits. For more information please contact: Theresa Manuel Director, Physician Retention & Recruitment Pocono Health System 206 East Brown Street East Stroudsburg, PA 18301 Phone - 570.476.3533 Fax - 570.420.2433


C lassifieds C ont .


P uzzler P age

Ask Yourself …



here are many amazing and puzzling facts in the field of endocrinology and here are a few of them in quiz form.* Test your knowledge, then find the answers online immediately (www. index.cfm) or on Puzzler Page in the August issue of Endocrine News.


1. Laughing strengthens the immune system and lowers levels of stress hormones. Six-year-olds laugh an average of 300 times a day. How many average daily laughs do adults have? a. 3 b. 15 c. 50 d. 100 2. Which U.S. President’s election was helped by an endocrine disorder that enhanced his complexion? a. Abraham Lincoln b. John Kennedy c. Woodrow Wilson d. Calvin Coolidge

3. According to the 2004 Nature paper, a primitive Y chromosome was discovered in which species of fruit or vegetable? a. zucchini (courgette) b. plum c. asparagus d. papaya e. kumquat 4. In diabetes mellitus, the “mellitus” is from the Greek root for “honey.” What does “diabetes” mean? a. double water b. flow through a siphon c. running along the road d. drinking water 5. What was the first vitamin to be “discovered?” a. A b. B1 c. C d. D 6. One should never do what to a patient with pheochromocytoma? a. withhold fluids b. administer sodium c. allow them to sleep d. palpate their abdomen 7. Which animal typically has only one functioning ovary? a. bird b. frog c. rat d. snake 8. They say the more the merrier, but how many pairs of sex chromosome homologues does the duck-billed platypus have? a. 5 b. 3 c. 1 d. 10 e. None

9. Extended stays on the Soviet space station Mir caused bone mass loss of as much as: a. 20% b. 5% c. 14% d. 3% e. 35% 10. Which athlete was diagnosed with hypothyroidism shortly before the Olympics, received treatment, and competed? a. Sebastian Coe b. Voula Patoulidou c. Lance Armstrong d. Carl Lewis 11. A patient on prednisone should not suddenly stop taking it because: a. It can result in death b. It can weaken the immune system c. It could cause excessive inflammation d. It causes a surge in blood sugar 12. Which female sex hormone was recently found in certain plants, e.g., the English Walnut tree? a. estrogen b. progesterone c. follicle-stimulating hormone d. luteinizing hormone ■ * These questions were devised by Howard B.A. Baum, M.D., John C. Achermann, M.D., Jacqueline Ruttimann, Ph.D., and Cathy Kristiansen, Editor. If you enjoy these types of questions, you can enter the Trivia Cup Challenge at ENDO 2011 in Boston, Mass.

Crossword Answers: June 2010

To see the original, blank crossword and clues, see page 52 of the June issue either online or in your printed copy.




R E S M A T P R H M O 0 O T E B N E N T O S S I I N D H T E Y G O A S C R O G A T


Sandostatin LAR® Depot

(octreotide acetate for injectable suspension) Initial U.S. Approval: 1988

BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE Sandostatin LAR Depot 10 mg, 20 mg and 30 mg is indicated in patients in whom initial treatment with Sandostatin Injection has been shown to be effective and tolerated. 1.1 Acromegaly Long-term maintenance therapy in acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal [see Clinical Studies (14) and Dosage and Administration (2) in the full prescribing information]. 1.2 Carcinoid Tumors Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. 1.3 Vasoactive Intestinal Peptide Tumors (VIPomas) Long-term treatment of the profuse watery diarrhea associated with VIPsecreting tumors. 1.4 Important Limitations of Use In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth and development of metastases, has not been determined. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Cholelithiasis and Gallbladder Sludge Sandostatin may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Patients should be monitored periodically [see Adverse Reactions (6)]. 5.2 Hyperglycemia and Hypoglycemia Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Sandostatin LAR treatment is initiated, or when the dose is altered. Antidiabetic treatment should be adjusted accordingly [see Adverse Reactions (6)]. 5.3 Thyroid Function Abnormalities Octreotide suppresses the secretion of thyroid-stimulating hormone, which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic octreotide therapy [see Adverse Reactions (6)]. 5.4 Cardiac Function Abnormalities In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other EKG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of Sandostatin Injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge [see Adverse Reactions (6)]. 5.5 Nutrition Octreotide may alter absorption of dietary fats. Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot. Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels. 5.6 Monitoring: Laboratory Tests Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy [see Dosage and Administration (2.0) in the full prescribing information]. Acromegaly: Growth Hormone, IGF-1 (somatomedin C)

Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P VIPoma: VIP (plasma vasoactive intestinal peptide) baseline and periodic total and/or free T4 measurements should be performed during chronic therapy 5.7 Drug Interactions Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine [see Drug Interactions (7.2)]. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. 6.1.1 Acromegaly The safety of Sandostatin LAR in the treatment of acromegaly has been evaluated in three phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. Sandostatin LAR was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous Sandostatin Injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14-81 years old and 53% were female. Approximately 35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10-60 mg every 4 weeks. Table 1 below reflects adverse events from these studies regardless of presumed causality to study drug. Table 1. Adverse Events Occurring in ≥10% of Acromegalic Patients in the Phase 3 Studies WHO Preferred Term

Phase 3 Studies (Pooled) Number (%) of Subjects with AE’s 10 mg/20 mg/30 mg (n=261) n (%)

Diarrhea Abdominal Pain Flatulence Influenza-Like Symptoms Constipation Headache Anemia Injection Site Pain Cholelithiasis Hypertension Dizziness Fatigue

93 (35.6) 75 (28.7) 66 (25.3) 52 (19.9) 46 (17.6) 40 (15.3) 40 (15.3) 36 (13.8) 35 (13.4) 33 (12.6) 30 (11.5) 29 (11.1)

The safety of Sandostatin LAR in the treatment of acromegaly was also evaluated in a postmarketing randomized phase 4 study. 104 patients were randomized to either pituitary surgery or 20 mg of Sandostatin LAR. All the patients were treatment naïve (‘de novo’). Crossover was allowed according to treatment response and a total of 76 patients were exposed to Sandostatin LAR. Approximately half of the patients initially randomized to Sandostatin LAR were exposed to Sandostatin LAR up to 1 year. The population age range was between 20-76 years old and 45% were female, 93% were Caucasian, and 1% Black. The majority of these patients were exposed to 30 mg every 4 weeks. Table 2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug. Table 2. Adverse Events Occurring in ≥10% of Acromegalic Patients in Phase 4 Study WHO Preferred Term

Diarrhea Cholelithiasis Abdominal Pain Nausea Alopecia Injection Site Pain Abdominal Pain Upper Headache Epistaxis

Phase 4 Study SAS LAR N=76 n (%) 36 (47.4) 29 (38.2) 19 (25.0) 12 (15.8) 10 (13.2) 9 (11.8) 8 (10.5) 8 (10.5) 0

Phase 4 Study Surgery N=64 n (%) 2 (3.1) 3 (4.7) 2 (3.1) 5 (7.8) 5 (7.8) 0 0 6 (9.4) 7 (10.9)

Gallbladder Abnormalities Single doses of Sandostatin Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with Sandostatin Injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure. In clinical trials 52% of acromegalic patients, most of whom received Sandostatin LAR Depot for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones. Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin Injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide, 1% of patients developed acute symptoms requiring cholecystectomy. Glucose Metabolism – Hypoglycemia/Hyperglycemia In acromegaly patients treated with either Sandostatin Injection or Sandostatin LAR Depot, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients [see Warnings and Precautions (5)]. Hypothyroidism In acromegaly patients receiving Sandostatin Injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin Injection. In acromegalics treated with Sandostatin LAR Depot, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving Sandostatin LAR Depot required initiation of thyroid hormone replacement therapy [see Warnings and Precautions (5)]. Cardiac In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin Injection therapy. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5)]. Gastrointestinal The most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3. Table 3. Number (%) of Acromegalic Patients with Common G.I. Adverse Events Adverse Event

Diarrhea Abdominal Pain or Discomfort Nausea Flatulence Constipation Vomiting

Sandostatin Injection S.C. Three Times Daily n=114 n % 66 (57.9) 50 34 15 10 5

(43.9) (29.8) (13.2) (8.8) (4.4)

Sandostatin LAR Depot Every 28 Days n=261 n % 95 (36.4) 76 27 67 49 17

(29.1) (10.3) (25.7) (18.8) (6.5)

Only 2.6% of the patients on Sandostatin Injection in U.S. clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving Sandostatin LAR Depot discontinued therapy for a G.I. event. In patients receiving Sandostatin LAR Depot, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with Sandostatin LAR Depot. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity. In rare instances, gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding. Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4%-6% of patients. In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27%-38% and constipation or vomiting in 15%-21% of patients treated with Sandostatin LAR Depot. Diarrhea was reported as an adverse event in 14% of patients but since most of the patients had

diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related diarrhea. Pain at the Injection Site Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalics receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of Sandostatin LAR Depot. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20%-25% at a 10-mg dose and about 30%-50% at the 20-mg and 30-mg dose. Antibodies to Octreotide Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; however, in two acromegalic patients who received Sandostatin Injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether octreotide antibodies will also prolong the duration of GH suppression in patients being treated with Sandostatin LAR Depot. 6.1.2 Carcinoid and VIPomas The safety of Sandostatin LAR in the treatment of carcinoid tumors and VIPomas has been evaluated in one phase 3 study. Study 1 randomized 93 patients with carcinoid syndrome to Sandostatin LAR 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25-78 years old and 44% were female, 95% were Caucasian and 3% Black. All the patients had symptom control on their previous Sandostatin subcutaneous treatment. 80 patients finished the initial 24 weeks of Sandostatin exposure in Study 1. In Study 1, comparable numbers of patients were randomized to each dose. Table 4 below reflects the adverse events occurring in >15% of patients regardless of presumed causality to study drug. Table 4. Adverse Events Occurring in ≥15% of Carcinoid Tumor and VIPoma Patients in Study 1

WHO Preferred Term Abdominal Pain Arthropathy Back Pain Dizziness Fatigue Flatulence Generalized Pain Headache Musculoskeletal Pain Myalgia Nausea Pruritus Rash Sinusitis URTI Vomiting

Sc N=26 8 (30.8) 5 (19.2) 7 (26.9) 4 (15.4) 3 (11.5) 3 (11.5) 4 (15.4) 5 (19.2) 4 (15.4) 0 8 (30.8) 0 1 (3.8) 4 (15.4) 6 (23.1) 3 (11.5)

Number (%) of Subjects with AE’s (n=93) 10 mg 20 mg N=22 N=20 8 (35.4) 2 (10.0) 2 (9.1) 3 (15.0) 6 (27.3) 2 (10.0) 4 (18.2) 4 (20.0) 7 (31.8) 2 (10.0) 2 (9.1) 2 (10.0) 2 (9.1) 3 (15.0) 4 (18.2) 6 (30.0) 0 1 (5.0) 4 (18.2) 1 (5.0) 9 (40.9) 6 (30.0) 4 (18.2) 0 0 3 (15.0) 0 1 (5.0) 4 (18.2) 2 (10.0) 0 0

30 mg N=25 5 (20.0) 2 (8.0) 2 (8.0) 5 (20.0) 2 (8.0) 4 (16.0) 1 (4.0) 4 (16.0) 0 1 (4.0) 6 (24.0) 0 0 3 (12.0) 3 (12.0) 4 (16.0)

Gallbladder Abnormalities In clinical trials, 62% of malignant carcinoid patients who received Sandostatin LAR Depot for up to 18 months developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients. Glucose Metabolism – Hypoglycemia/Hyperglycemia In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with Sandostatin LAR Depot [see Warnings and Precautions (5)]. Hypothyroidism In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported [see Warnings and Precautions (5)]. Cardiac Electrocardiograms were performed only in carcinoid patients receiving Sandostatin LAR Depot. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5)]. Other Clinical Studies Adverse Events Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving Sandostatin LAR Depot were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia and pleural effusion.

6.2 Postmarketing Experience The following adverse reactions have been identified during the postapproval use of Sandostatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Myocardial infarction has been observed in the postmarketing setting, mainly in patients with cardiovascular risk factors. Hypoadrenalism has been reported in some reports in patients 18 months of age and under. Additional events reported in the postmarketing setting include anaphylactoid reactions, including anaphylactic shock, cardiac arrest, renal failure, renal insufficiency, convulsions, atrial fibrillation, aneurysm, hepatitis, increased liver enzymes, gastrointestinal hemorrhage, pancreatitis, pancytopenia, thrombocytopenia, arterial thrombosis of the arm, retinal vein thrombosis, intracranial hemorrhage, hemiparesis, paresis, deafness, visual field defect, aphasia, scotoma, status asthmaticus, pulmonary hypertension, diabetes mellitus, intestinal obstruction, peptic/gastric ulcer, appendicitis, creatinine increased, CK increased, arthritis, joint effusion, pituitary apoplexy, breast carcinoma, suicide attempt, paranoia, migraines, urticaria, facial edema, generalized edema, hematuria, orthostatic hypotension, Raynaud’s syndrome, glaucoma, pulmonary nodule, pneumothorax aggravated, cellulitis, Bell’s palsy, diabetes insipidus, gynecomastia, galactorrhea, gallbladder polyp, fatty liver, abdomen enlarged, libido decrease, and petechiae. 7 DRUG INTERACTIONS 7.1 Cyclosporine Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. 7.2 Insulin and Oral Hypoglycemic Drugs Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Sandostatin LAR treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly. 7.3 Bromocriptine Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. 7.4 Other Concomitant Drug Therapy Concomitant administration of bradycardia-inducing drugs (e.g., betablockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. 7.5 Drug Metabolism Interactions Limited published data indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose and have revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed [see Nonclinical Toxicology (13.2) in the full prescribing information]. 8.3 Nursing Mothers It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Sandostatin LAR Depot is administered to a nursing woman. 8.4 Pediatric Use Safety and efficacy of Sandostatin LAR Depot in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin LAR Depot in pediatric under 6 years of age. In post-marketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions.

The efficacy and safety of Sandostatin LAR Depot was examined in a single randomized, double-blind, placebo-controlled, six-month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR Depot administered by IM injection every four weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m2 in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adults indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Sandostatin LAR Depot was 10 to 30 mg once a month. 8.5 Geriatric Use Clinical studies of Sandostatin did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment In patients with renal failure requiring dialysis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. In patients with mild, moderate, or severe renal impairment there is no need to adjust the starting dose of Sandostatin. The maintenance dose should be adjusted thereafter based on clinical response and tolerability as in nonrenal patients [see Clinical Pharmacology (12) in the full prescribing information]. 8.7 Hepatic Impairment – Cirrhotic Patients In patients with established liver cirrhosis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. Once at a higher dose, patient should be maintained or dose adjusted based on response and tolerability as in any noncirrhotic patients [see Clinical Pharmacology (12) in the full prescribing information]. 10 OVERDOSAGE No frank overdose has occurred in any patient to date. Sandostatin Injection given in intravenous bolus doses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients. Doses of 2.5 mg (2500 mcg) of Sandostatin Injection subcutaneously have, however, caused hypoglycemia, flushing, dizziness, and nausea. Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®**. Mortality occurred in mice and rats given 72 mg/kg and 18 mg/kg intravenously, respectively, of octreotide. 16 STORAGE For prolonged storage, Sandostatin LAR Depot should be stored at refrigerated temperatures between 2°C-8°C (36°F-46°F) and protected from light until the time of use. Sandostatin LAR Depot drug product kit should remain at room temperature for 30-60 minutes prior to preparation of the drug suspension. However, after preparation the drug suspension must be administered immediately. **Trademark of Thomson Healthcare, Inc. T2010-23 Sandostatin LAR® Depot vials are manufactured by: Sandoz GmbH, Schaftenau, Austria (Subsidiary of Novartis Pharma AG, Basle, Switzerland) The diluent syringes are manufactured by: Solvay Pharmaceuticals B.V. Olst, The Netherlands Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

For the long-term treatment of acromegaly, Sandostatin® LAR Depot provides…


The only somatostatin analogue with proven long-term efficacy in acromegaly.1 ■ Backed by over 600,000 patient-years of experience with Sandostatin®*2 ■ 57%-68% of patients experienced both GH <2.5 ng/mL + IGF-1 normalization†1,3

Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term maintenance therapy in acromegalic patients who have had inadequate response to surgery and/or radiotherapy or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal. Important Safety Information: As with immediate release Sandostatin® Injection, the most frequently reported drug-related adverse events were biliary disorders (52%), gastrointestinal disorders (7% to 36%), and injection-site pain (2% to 11%). Hypoglycemia (2%), hyperglycemia (15%), hypothyroidism (2%), and goiter (2%) have been reported. While not measured in acromegalic patients receiving Sandostatin® LAR Depot, ECG changes have been reported in patients receiving immediate release Sandostatin® Injection; the degree to which these abnormalities are related to octreotide acetate is not clear, as many acromegalics have cardiovascular disease. Please see brief summary of Prescribing Information on adjacent page. References: 1. Sandostatin® LAR Depot [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 2. Data on file, Novartis Pharmaceuticals Corporation. 3. Cozzi R, Attanasio R, Montini M, et al. Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results? J Clin Endocrinol Metab. 2003;88:3090-3098. *Combined use of immediate-release Sandostatin® Injection and Sandostatin® LAR Depot from all approved indications. † Range reflects results derived from a pivotal trial and long-term, follow-up data.

STRONG. EVIDENCE. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2010 Novartis

Printed in USA on recycled paper




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