Endocrine Abstracts

The proximate cause of functional hypothalamic amenorrhea (FHA) is reversible suppression of GnRH drive that results in chronic anovulation and low estradiol levels that preclude endometrial growth and shedding. Clinical management of FHA requires not only understanding the neuromodulation of GnRH drive, but also how cognitive and behavioral concomitants suppress GnRH drive. FHA results in a constellation of neuroendocrine concomitants that include activation of the hypothalamic-pituitary adrenal (HPA) axis and suppression of the HP-thyroidal (HPT) axis in addition to insufficient GnRH drive to support folliculogenesis. Hypercortisolism is the hallmark of stress and may elicit undernutrition and overnutrition depending on fuel availability, genotype, and individual factors. In monkeys and women, energy deficiency elicited by undernutrition combined with increased energy expenditure synergized with social stress to compromise ovulatory function. In monkeys, when high-fat, high-sugar food was plentiful, stressed (subordinated) female monkeys ate more than unstressed (dominant) ones and overeating was reversed by CRH antagonism. Our monkey model of stress-induced overeating may explain why obesity tracks with social stress in humans. While thin women with FHA reported attitudes such as perfectionism and high drive for thinness, attitudes associated with stress-induced overeating remain to be better characterized. The clinical management of FHA requires identifying and remediating behaviors that elicit the above constellation of neuroendocrine adaptations. Our monkey model focused on understanding the role of CRH as a modulator of GABAergic function and disordered eating. In women, we identified some of the mechanisms by which cognitive variables associated with FHA and utilized these insights to pioneer the use of cognitive behavior therapy to reverse FHA and its neuroendocrine concomitants. The neuroendocrine constellation of FHA results in antagonism of estrogen and insulin action and results in health consequences beyond reproduction compromise due to anovulation. Treatment guidelines should recognize the potential impact of FHA on pregnancy and offspring and acute and chronic compromise of cardiovascular, brain, bone, and metabolic health.