Psychosocial stress in women with functional hypothalamic amenorrhea and potential implications for cardiovascular disease risk

Functional hypothalamic amenorrhea (FHA) is a form of hypogonadotropic hypogonadism that accounts for approximately 30-35% of secondary amenorrhea in women of reproductive age. This condition is characterized by anovulation due to a reduced gonadotropin-releasing hormone (GnRH) drive, activation of the hypothalamic‒pituitary‒adrenal (HPA) axis and sick euthyroid syndrome, resulting in nonorganic hypoestrogenemia, hypercortisolemia, and hypothyroidism. The stressors contributing to FHA include psychological factors such as perfectionism and mood disorders; psychosocial factors such as adverse life events and relationship conflicts; and metabolic factors such as excessive exercise and undernutrition. Stress-induced behaviors and energy deficiency may then result in the neuroendocrine triad of HPA activation, hypothalamic-pituitary-thyroid suppression, and hypothalamic-pituitary-gonadal suppression. FHA has been associated with endothelial dysfunction, a preclinical form of cardiovascular disease (CVD) characterized by physiological yet asymptomatic changes in the blood vessels that can progress to CVD. Research suggests that hypoestrogenism alone does not explain the risk for preclinical CVD in women with FHA. The combined neuroendocrine and metabolic alterations in women with FHA may predispose them to endothelial dysfunction and increase long-term CVD risk. Hypercortisolemia may be a key mediator in linking stress physiology with both reproductive suppression and cardiometabolic risk in women with FHA. This narrative review explores the psychological, psychosocial, and metabolic factors contributing to stress in young women with FHA and their potential impact on cardiovascular health.