By Robert W. Rebar, MD
Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo
Dr. Rebar reports no financial relationships relevant to this field of study.
SYNOPSIS: Functional hypothalamic amenorrhea is a common but often overlooked cause of menstrual dysfunction that remains a diagnosis of exclusion.
SOURCE: Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2017;102:1413-1439. doi: 10.1210/jc.2017-00131.
Using a taskforce of experts, the Endocrine Society, cosponsored by the American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society, developed a Practice Guideline based on the best available evidence from other published systematic reviews and individual studies. Functional hypothalamic amenorrhea (FHA) is defined as a form of chronic anovulation that has no identifiable organic causes and that typically is associated with stress, weight loss, or exercise, or a combination of those factors. The guideline emphasizes that the diagnosis remains one of exclusion. Consequently, investigation of possibly affected individuals should include assessment of systemic and endocrinologic etiologies. Significant medical problems resulting from FHA can include, among others, bone loss and infertility. The authors of the guideline suggested that the best approach to therapy is multidisciplinary and includes medical, dietary, and psychological support.
COMMENTARY
This is a brief summary of a long and complex guideline. The best feature of the guideline is the thoroughness of the literature review. But why choose to discuss a clinical practice guideline rather than a novel research study? Because I am seeing a failure to make the diagnosis because of advances in the treatment of infertile couples combined with the explosion in the number of women presenting with polycystic ovary syndrome (PCOS) as a result of the increasing obesity in our population. Virtually all cases of amenorrhea or oligomenorrhea are deemed to be PCOS now, even if that may not always be true. Oral contraceptives commonly are prescribed to prevent endometrial hyperplasia until fertility is desired. If ovulation induction with clomiphene or letrozole is not successful, these women commonly advance to in vitro fertilization.
Yet, obesity itself need not exclude FHA or another etiology, and apparent FHA may have a more serious etiology. So just how should women with amenorrhea be evaluated? All of us learned that the initial evaluation of amenorrheic women should include basal measurements of follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and prolactin. Luteinizing hormone (LH) can be measured as well and is most helpful in women with FHA. Androgens, typically total testosterone and dehydroepiandrosterone (DHEA) sulfate, should be measured if there is any clinical evidence of androgen excess and/or if PCOS is suspected. Assessment of 17-alpha-hydroxyprogesterone is warranted if any form of congenital adrenal hyperplasia is suspected, and cortisol should be measured if Cushing syndrome is considered in the differential diagnosis.
Many texts discuss the evaluation of amenorrheic women in far more detail than I can outline here. Women with FHA typically have normal basal values of all these hormones; in fact, FSH and LH levels typically are in the lower part of the normal range. There should be no need to measure estradiol because estrogen can be assessed clinically during the pelvic examination by inspection of the vaginal mucosa and cervix. Estrogen levels also tend to be normal or low in women with FHA. When LH and FSH are relatively low, then imaging of the sella turcica is warranted to rule out a hypothalamic or pituitary neoplasm. How extensive the imaging should be depends on the clinician’s index of suspicion, as well as on the insurance status of the patient, as imaging can be quite expensive.
The term FHA was coined by Klinefelter et al in 1943 when they used the term “hypothalamic hypoestrinism” in noting that “nervous pathways” might fail to stimulate release of LH from the anterior pituitary gland.1 That women with FHA have this defect was documented by Yen et al,2 who reported in 1973 that women with apparent FHA failed to secrete LH in a pulsatile manner but responded normally to exogenous gonadotropin-releasing hormone (GnRH) with vigorous release of LH and FSH. Since then it has become clear that women with FHA invariably have elevated mean levels of cortisol compared to normally menstruating control women (but not outside the normal range)3 and a relative caloric “energy deficit.”4
Several other subtle hormonal disturbances have been characterized as well.4,5 The Endocrine Society’s guideline correctly notes that the underlying cause of FHA can be a woman’s overzealous approach to “healthy” behavior, but that is not always the case. Our group noted that FHA can follow any traumatic psychological event, including sexual assault, death of a beloved one, or the trauma associated with war.2 In any event, changing the habits of restricting caloric intake, excessive exercise, and/or weight restriction can be just as challenging as dealing with psychological problems.
Pulsatile administration of GnRH can induce ovulation in virtually all women with FHA,6 but this agent is no longer available in the United States. That the etiology of FHA is multifactorial is made clear by several studies of other different approaches to treatment that depend on indirectly stimulating release of GnRH. In one small randomized trial of cognitive behavioral therapy (CBT), only six out of eight women in the CBT group actually resumed ovulation over the 20-week study period.7 Recombinant human leptin led to ovulation in three and preovulatory follicular development and withdrawal bleeding in an additional two women out of eight with FHA in another small study.8 In other studies, kisspeptin was shown to increase LH pulsatility and stimulate release of LH and FSH in women with FHA,9,10 and studies of the usefulness of kisspeptin in inducing ovulation are ongoing. The variability of responsiveness in these studies attests to the diverse etiology of FHA, which results in all cases in failure of GnRH to stimulate release of FSH and LH.
For now, the focus should remain on confirming the diagnosis and then providing therapy to prevent the consequences. Generally, that means providing some form of exogenous estrogen with at least periodic progestin if a uterus is present. Because ovulation can begin before ovulation and menses, it is important to provide contraception to women who are sexually active and do not wish a pregnancy. Moreover, it is important to inform women with FHA that they likely will be anovulatory after discontinuing estrogen. Still, pregnancy is likely, even if in vitro fertilization will be required. That should be the hopeful message provided to all women with FHA.
REFERENCES
- Klinefelter HF Jr, Albright F, Griswold GC. Experience with a quantitative test for normal or decreased amounts of follicle stimulating hormone in the urine in endocrinological diagnosis. J Clin Endocrinol 1943;3:529-544.
- Yen SSC, Rebar R, VandenBerg G, Judd H. Hypothalamic amenorrhea and hypogonadotropinism: Responses to synthetic LRF. J Clin Endocrinol Metab 1973;36:811-816.
- Villanueva AL, Schlosser C, Hopper B, et al. Increased cortisol production in women runners. J Clin Endocrinol Metab 1986;63:133-136.
- Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2017;102:1-27 doi:10.1210/jc.2017-00131.
- Berga SL, Mortola JF, Girton L, et al. Neuroedocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1989;68:301-308.
- Miller DS, Reid RR, Cetel NS, et al. Pulsatile administration of low-dose gonadotropin-releasing hormone. Ovulation and pregnancy in women with hypothalamic amenorrhea. J Am Med Soc 1983:250:2937-2941.
- Berga SL, Marcus MD, Loucks TL, et al. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavioral therapy. Fertil Steril 2003;80:976-981.
- Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci USA 2011;108:6585-6590.
- Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987-997.
- Jayasena CN, Nijher GM, Abbara A, et al. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin Pharmacol Ther 2010;88:840-847.
Functional hypothalamic amenorrhea is a common but often overlooked cause of menstrual dysfunction that remains a diagnosis of exclusion.
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