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National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

2015 Annual Report of the Division of Intramural Research

Disorders of the Hypothalamic-Pituitary-Ovarian Axis in Women

Alan DeCherney
  • Alan H. DeCherney, MD, Head, Section on Implantation and Oocyte Physiology
  • Lawrence M. Nelson, MD, Staff Scientist
  • Sharon N. Covington, LCSW-C, Associate Investigator
  • Sunday Rivers, PhD, MBA, Special Volunteer
  • E. Keith Zachman, MS, Senior Research Assistant

There are major gaps in knowledge regarding the etiologic mechanisms, psychosocial effects, natural history, and medical and psychosocial management of disorders of the hypothalamic-pituitary-ovarian axis in women. An international research consortium and disease registry formed under the guidance of an umbrella organization would provide a pathway to comprehensively increase basic and clinical knowledge about these conditions. Such a consortium and patient registry also would provide clinical samples and clinical data with a goal toward defining the specific pathogenic mechanisms. An international collaborative approach that combines the structure of a patient registry with the principles of integrative care and community-based participatory research is needed to advance the field of primary ovarian insufficiency. The program is in the early phases of organizing such an international effort using primary ovarian insufficiency as the focus.

Spontaneous POI affects 1 in 100 women by the age of 40. With no apparent cause, the ovaries of affected women do not function normally. They stop regularly releasing eggs and produce low levels of reproductive hormones, including estradiol (a type of estrogen) and testosterone (a predominantly male hormone that is also produced by women but in smaller amounts than by men). Women with POI have hot flashes, fertility problems, and irregular or no menstrual cycles. They also have reduced bone mineral density, which can lead to osteoporosis and bone fractures. Hormone replacement therapy (HRT) regimens have been well studied and optimized to improve bone health in postmenopausal women. But there has been limited research on the effects of these therapies in younger women. We found that HRT restores bone mineral density to normal in young women with primary ovarian insufficiency (POI). The findings provide important treatment information for women with POI and their physicians.

Normalization of bone density by HRT in women with POI

A team led by Vaishali B. Popat and Lawrence M. Nelson tested the effects of HRT on bone health in young women with POI. The trial was carried out at the NIH Clinical Center in Bethesda, Maryland. The team enrolled 145 women with POI between the ages of 18 and 42. The women were randomly assigned to two groups. One received an estradiol patch, progestin pills, and a testosterone patch. The other received an estradiol patch, progestin pills, and an inactive placebo patch. The researchers used bone density scans of the hip and lower spine to measure the effects of the regimens. For comparison, the scientists also measured bone mineral density in an untreated group of 70 women with normal ovarian function.

Both hormone treatment regimens led to increases in bone mineral density at three years. When the study began, women with POI had significantly lower hip and spine bone mineral density levels than those in the control group. By the study's end, bone density measures in both treatment groups had increased to the same level as in the women without POI. The group receiving a testosterone patch did not gain further benefits over those with a placebo patch. Studies with a greater number of women would be needed to learn whether testosterone replacement might benefit women with POI, the researchers noted. The study showed that not only could hormone treatment reduce the rate at which women with POI lose bone mineral density, but it could actually restore bone density to normal levels.

Lack of effect of testosterone treatment on mood disorders in POI

Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to the mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI. One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests.

No differences in baseline characteristics, including serum hormone levels, were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively. After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher than in the placebo group. Baseline testosterone levels were not associated with either adverse or beneficial clinical effects.

We conclude that a 150-microgram testosterone patch achieves physiologic hormone levels in women with POI. However, our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder.


  1. Popat VB, Calis KA, Kalantaridou SN, Vanderhoof VH, Koziol D, Troendle JF, Reynolds JC, Nelson LM. Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab 2014; 99(9):3418-3426.
  2. Guerrieri GM, Martinez PE, Klug SP, Haq NA, Vanderhoof VH, Koziol DE, Popat VB, Kalantaridou SN, Calis KA, Rubinow DR, Schmidt PJ, Nelson LM. Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency. Menopause 2014; 21:952-961.
  3. Falorni A, Minarelli V, Eads CM, Joachim CM, Persani L, Rossetti R, Yurttas Beim P, Pellegrini VA, Schnatz PF, Rafique S, Kissell K, Calis KA, Popat V, Nelson LM. A clinical research integration special program (CRISP) for young women with primary ovarian insufficiency. Panminerva Med 2014; 56:245-261.
  4. Joachim CM, Eads CM, Persani L, Yurttas Beim P, Nelson LM. An open letter to the primary ovarian insufficiency community. Minerva Ginecol 2014; 66:519-520.
  5. Gordon CM, Kanaoka T, Nelson LM. Update on primary ovarian insufficiency in adolescents. Curr Opin Pediatr 2015; 26:511-519.


  • Kerri A. Kissell, MD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
  • Maya B. Lodish, MD, MHSc, Program in Developmental Endocrinology and Genetics, NICHD, Bethesda, MD
  • Germaine M. Louis, RN, PhD, Division of Epidemiology, Statistics and Prevention Research, NICHD, Bethesda, MD
  • Vaishali B. Popat, MD, MPH, Reproductive Endocrinology and Infertility Fellowship Program, NICHD, Bethesda, MD
  • Margarita J. Raygada, PhD, CGC, Section on Clinical Genomics, NICHD, Bethesda, MD
  • James F. Troendle, PhD, Office of Biostatistics Research, NHLBI, Bethesda, MD
  • Erin F. Wolff, MD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD


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