Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline

Catherine M. Gordon; Kathryn E. Ackerman; Sarah L. Berga; Jay R. Kaplan; George Mastorakos; Madhusmita Misra; M. Hassan Murad; Nanette F. Santoro; Michelle P. Warren


J Clin Endocrinol Metab. 2017;102(5):1413-1439. 

In This Article

Future Directions

It is possible that prolonged exercise-induced amenorrhea has adverse cardiovascular consequences.[245] In a study of 68 women athletes, 24 with amenorrhea and 44 with regular cycles, the women with amenorrhea had significantly higher serum concentrations of total cholesterol [210 vs 186 mg/dL (5.47 vs 4.84 mmol/L)], triglycerides [68 vs 55 mg/dL (0.75 vs 0.61 mmol/L)], low-density lipoprotein cholesterol [121 vs 108 mg/dL (3.2 vs 2.8 mmol/L)], and high-density lipoprotein cholesterol [75 vs 66 mg/dL (1.95 vs 1.73 mmol/L)].

Studies have also noted impaired endothelial function and increased vascular resistance.[246–248] Whether the cardiovascular consequences of these differences are clinically important or whether the increased serum high-density lipoprotein cholesterol concentration is protective is not known. There is also evidence of increased visceral fat (a known risk factor for cardiovascular disease) in women nutritionally rehabilitated from anorexia nervosa[249] and evidence that estrogen levels are inversely related to abdominal fat. Women with FHA had more central fat than did healthy controls.[250] Preclinical primate evidence suggests that stress-associated hypoestrogenism causes a precocious acceleration of coronary artery atherosclerosis. Studies found a similar effect across all individuals following oophorectomy, which eliminates the "protection" typically observed in non-stressed animals.[40,251,252]

Other evidence that FHA may be associated with adverse cardiovascular consequences comes from the Women's Ischemia Syndrome Evaluation, an angiographic study in premenopausal women. Those with angiographic evidence of coronary disease were more likely to have a serum E2 of <50 pg/mL and low gonadotropins of LH <10 IU/L and FSH <10 IU/L when compared with women with normal coronaries. The diagnosis of FHA by this definition remains an independent predictor of coronary disease, even after adjustment for other risk factors such as diabetes. However, this criterion for FHA is broad, with no recognition given to menstrual history, and we often see E2 levels<50 pg/mL in normal women during the follicular phase of the cycle.[253]

In women with hypothalamic hypogonadism, clinicians can get an estimation of ovarian reserve using AMH measurements, because gonadotropins will be falsely low.[140] An antral follicle count can also provide a reliable estimate. In a patient with primary ovarian insufficiency, the diagnosis could be delayed because of FHAattenuated gonadotropin secretion.

It should be recognized that adolescents and young women with type 1 diabetes mellitus represent a group at high risk for the development of disordered eating behaviors and purging (e.g., vomiting, hyperexercise, and insulin omission).[254,255] Future studies should identify strategies that lead to the prevention of energy deficit situations in this population. Data indicate that HPO dysfunction is also common in these patients, although the underlying mechanisms beyond hypothalamic disturbances are not entirely clear.[256]

Research has yet to determine the acute and chronic consequences of ovulation induction and pregnancy in the face of elevated cortisol, low T3 and T4, and the other neuroendocrine concomitants associated with FHA, but available data suggest reason for concern,[257] and the risks include preterm labor and neurodevelopmental disorders, such as autism spectrum disorder and cardiovascular disease.

Another area of concern is the impact of prolonged hypogonadism on cognitive status and anxiety and mood symptoms. However, implications of FHA in these areas are currently unclear. Recent studies have reported that physiologic estrogen administration improves anxiety outcomes in adolescents with anorexia nervosa.[258]

We need more research into the treatment of amenorrhea and low BMD in FHA, with careful consideration of the effects on weight and body composition and the need for appropriate dosing adjustments, and we need more research regarding the impact of FHA on other body systems and neural function. Risk factors for the development and persistence of FHA include conditions that chronically activate the HPA axis. These risk factors include: greater energy expenditure than intake, as with excessive exercise and/or nutritional restriction; unrealistic expectations of self and others; and attitudes that increase reactivity to common and uncommon stressors, including perfectionism, high need for social approval, and conditional love.[19–21] Exercise per se can be considered as a stress situation,[259] and stressors are likely synergistic rather than additive.[22]