A review of the pathophysiology of functional hypothalamic amenorrhoea in women subject to psychological stress, disordered eating, excessive exercise or a combination of these factors

Clin Endocrinol (Oxf). 2021 Aug;95(2):229-238. doi: 10.1111/cen.14399. Epub 2021 Jan 11.


Introduction: Functional hypothalamic amenorrhoea (FHA) is a common form of secondary amenorrhoea without an identifiable structural cause. Suppression of gonadotrophin-releasing hormone (GnRH) pulsatility results in reduced luteinizing hormone (LH) levels, with subsequent reduction in oestradiol, anovulation and cessation of menstruation. GnRH pulsatility suppression is a recognized complication of psychological stress, disordered eating, low body weight, excessive exercise or a combination of these factors.

Pathophysiology of fha: Individuals with FHA demonstrate low energy availability (EA), body fat percentage and energy expenditure. Documented adipocytokine changes notably, raised adiponectin, ghrelin, PYY, and decreased leptin, are associated with GnRH suppression. Other endocrine responses seen in this low EA state include low insulin levels, low total T3, increased basal cortisol levels and a reduced response to corticotrophin-releasing hormone (CRH) administration. FHA is associated with raised growth hormone (GH) and low insulin-like growth factor (IGF-1), suggesting relative GH resistance. Kisspeptins are a group of polypeptides, recently discovered to play a major role in the regulation of the reproductive axis through influencing GnRH release. KNDy (kisspeptin/neurokinin B/dynorphin) act on GnRH neurons and a multitude of factors result in their release.

Implications for future treatment: Management of FHA is imperative to prevent adverse outcomes in bone density, cardiovascular risk profile, psychological well-being and fertility. Outwith modification of nutritional intake and exercise, limited therapeutic strategies are currently available for women with FHA. Advancements in the understanding of the pathophysiological basis of this under-recognized and under-treated clinical entity will aid management and may result in the development of novel therapeutic approaches.

Keywords: anorexia nervosa; conditions; female infertility; gonadotropin-releasing hormone; hormones/related; hypothalamus; kisspeptin; obesity/lipids/nutrition; ovary.

Publication types

  • Review

MeSH terms

  • Amenorrhea*
  • Feeding and Eating Disorders*
  • Female
  • Gonadotropin-Releasing Hormone
  • Humans
  • Kisspeptins
  • Luteinizing Hormone
  • Stress, Psychological


  • Kisspeptins
  • Gonadotropin-Releasing Hormone
  • Luteinizing Hormone