Perspective: The Importance of Genetic Defects in Humans in Elucidating the Complexities of the Hypothalamic-Pituitary-Gonadal Axis

Extract

Demonstrating marked variability across the life cycle, yet exquisitely regulated, the hypothalamic secretion of GnRH in the human triggers a cascade of events leading to gonadal sex steroid secretion, folliculogenesis, and spermatogenesis. Animal studies have demonstrated a remarkable concordance between GnRH pulses in hypothalamic portal blood and LH pulses in the periphery (1), establishing that LH pulsatility is a reflection of antecedent, intermittent discharges of GnRH. Not only is pulsatile GnRH secretion necessary for the maintenance of normal gonadotropin secretion, but continuous, as opposed to pulsatile, administration of GnRH actually desensitizes gonadotropin release (2). In GnRH-deficient animals and humans, administration of pulsatile GnRH reestablishes normal hormone responses, and in patients with congenital hypogonadotropic hypogonadism, pulsatile GnRH can recapitulate normal pubertal development (2–5).

Although these principles of GnRH secretion have been established for over two decades, the regulation of GnRH secretion via sex steroid and nonsteroidal factors in normal reproduction (i.e. the menstrual cycle), different stages of the life cycle (i.e. gonadotropin amplification during puberty) and pathophysiologic states (i.e. polycystic ovary syndrome) is a complicated and incompletely understood phenomenon. Patients with single gene mutations within the hypothalamic-pituitary-gonadal axis have provided unique avenues to increase our understanding of reproductive neuroendocrinology. Genetically engineered animal models have further elucidated the roles of specific hormones in reproductive function, by confirming and extending human findings, establishing species-specific phenotypes, or predicting phenotypes when no human model exists.