Functional hypothalamic amenorrhea

Functional hypothalamic amenorrhea is anovulation that occurs due to dysfunctional GnRH secretion and the resulting decrease in FSH and LH (hypogonadotropic hypogonadism). It is typically caused by excessive exercise, nutritional deficits, and/or psychological stressors. In addition to amenorrhea, patients may present with other features of estrogen deficiency (e.g., vaginal dryness or thinning) or the underlying cause (e.g., low BMI, stress). Functional hypothalamic amenorrhea is a diagnosis of exclusion; diagnostics for amenorrhea should be performed to exclude other causes of amenorrhea. In patients with amenorrhea for ≥ 6 months, a DEXA scan is recommended to assess for low bone mineral density. Management is focused on addressing the underlying cause through lifestyle modifications, including nutritional counseling, reducing exercise intensity, and stress management as indicated. Pharmacological therapy may be indicated for patients with persistent amenorrhea and/or individuals desiring fertility.

Functional hypothalamic amenorrhea is typically caused by one or more of the following: ^[1]

• Reduced calorie intake: e.g., in eating disorders such as anorexia nervosa
• Excessive exercise: e.g., in competitive athletes (also called exercise-induced amenorrhea)
• Stress

Decreased leptin (low body fat) and/or increased cortisol (exercise/stress) → decreased pulsatile release of GnRH from the hypothalamus → decreased secretion of FSH and LH → decreased estrogen levels → anovulation and secondary amenorrhea → infertility ^[1]

• Features of estrogen deficiency ^[1]
  • Menstrual cycle abnormalities: cycles > 45 days or absent for ≥ 3 months ^[1]
  • Infertility
  • Stress fractures ^[1]
• Features of underlying cause ^[1]
  • Low BMI or fluctuations in BMI
  • Symptoms of eating disorders
  • Relative energy deficiency in sport, including the following findings traditionally associated with the female athlete triad syndrome in adolescent and young adult female athletes: ^[2][3]
    • Relative calorie deficit compared to energy needs, with or without an eating disorder
    • Menstrual dysfunction
    • Decreased bone density
  • Stress, anxiety, and/or perfectionism

Functional hypothalamic amenorrhea is a diagnosis of exclusion. ^[1]

• All patients
  • Exclude other causes: See “Clinical evaluation of amenorrhea” and “Diagnostics for amenorrhea.”
  • Consider hormone withdrawal testing. ^[1]
• Suspected underlying chronic disease: CBC, CMP, ESR and CRP
• ≥ 6 months of amenorrhea: DEXA scan to assess for reduced bone mineral density ^[1]

• Identify and treat the underlying cause. ^[1]
  • Improve nutritional status and evaluate suspected eating disorders.
  • Screen for psychological stressors and recommend stress reduction (e.g., through lifestyle changes, ; cognitive behavioral therapy).
  • Exercise reduction if indicated
• Refer patients with refractory amenorrhea to appropriate specialists (e.g., endocrinology, reproductive endocrinology). ^[1]
  • Short-term transdermal estradiol with cyclic oral progestin may be used. ^[1]
  • Individuals who want to conceive with a BMI > 18.5 kg/m²: ovulation-induction therapy, e.g., pulsatile GnRH, gonadotropins, clomiphene citrate ^[1]

Ongoing energy imbalances and resulting complications may be masked by the use of cyclical COCs in individuals with functional hypothalamic amenorrhea. ^[1]