A 22-year-old athlete with intense training has secondary amenorrhea for 8 months. Serum FSH 3 IU/L, LH 2 IU/L, estradiol 18 pg/mL, prolactin and thyroid function normal. This hormonal profile is consistent with hypogonadotropic hypogonadism. The pathophysiology involves which primary neuroendocrine mechanism?

• A Elevated cortisol from exercise stress suppresses GnRH pulsatility at the hypothalamic level
• B Low energy availability suppresses kisspeptin/NKB/dynorphin (KNDy) neurons, reducing GnRH pulse frequency and amplitude ✓
• C Energy deficiency activates kisspeptin neurons in the arcuate nucleus, increasing GnRH pulse frequency
• D Elevated leptin from adipose stores directly inhibits pituitary FSH/LH secretion

Explanation

Exercise-associated amenorrhea (part of the Female Athlete Triad/RED-S) results from low energy availability (LEA) suppressing hypothalamic GnRH pulsatility. The KNDy neurons (Kisspeptin/Neurokinin B/Dynorphin neurons) in the arcuate nucleus serve as the GnRH pulse generator. LEA reduces circulating kisspeptin signaling, decreasing GnRH pulse frequency, leading to low LH/FSH and hypo-estrogenemia. Elevated cortisol and reduced leptin (not elevated) from fat mass loss also suppress GnRH. The primary mechanism in LEA is reduced kisspeptin drive to GnRH neurons.

Reference: Shaw's Textbook of Gynaecology, 17th ed.

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