Neuroendocrine control of reproduction and its therapeutic manipulation with GnRH and its analogs.

ABSTRACT

The hypothalamus mediates the neuroendocrine control of reproduction in both males and females through pulsatile secretion of GnRH. The anterior pituitary gland, in turn, appears to require this episodic GnRH stimulation in order to secrete the gonadotropins LH and FSH in a physiologic fashion. Deficiency of GnRH manifests as a failure to attain puberty in both sexes, and in females it may also produce amenorrhea and/or anovulation. Replacement regimens of GnRH which employ an episodic pattern of delivery correct the deficiency of endogenous GnRH secretion and stimulate gonadotropin secretion, gonadal steroidogenesis and gametogenesis. However, continuous occupancy of the GnRH receptor by native GnRH and/or its long-acting analogs paradoxically inhibits pituitary gonadotropin secretion. GnRH analogs have been synthesized which exhibit greater affinity and prolonged occupancy on the GnRH receptor and can produce pituitary desensitization of gonadotropin secretion. Chronic administration of these GnRH analogs is capable of producting a selective "medical castration." Thus, by altering the frequency of episodic GnRH administration or by utilizing long-acting GnRH analogs it is possible to stimulate or suppress the neuroendocrine control of reproduction. The use of GnRH or its long-acting analogs has demonstrated a profound clinical impact in restoring or inhibiting fertility.