Novel concepts about normal sexual differentiation of reproductive neuroendocrine function and the developmental origins of female reproductive dysfunction: the sheep model.

The neuroendocrine regulation of GnRH secretion plays a central role in timing gamete release in both sexes. This regulation is more complex in the female because the discontinuous release of ova is more complex than the continuous release of spermatozoa. This review provides an evolving understanding of the sex differences in reproductive neuroendocrine controls and how these differences arise. The rules for sexual differentiation of steroid feedback control of GnRH secretion conceptually parallel the well-established principles that underlie the sexual differentiation of the internal and external genitalia. In the context of the neuroendocrine regulation of the ovarian cycle, and using the sheep as a model, four steroid feedback controls for GnRH secretion are inherent (default). They require no ovarian developmental input to function appropriately during adulthood. Two steroid feedback controls regulate the preovulatory surge mode of GnRH secretion, and two regulate the pulsatile mode. If the individual is a male, three steroid feedback controls of GnRH secretion become unnecessary or irrelevant, and these are abolished or become functionally inoperative through programmed reductions in hypothalamic sensitivity. This central programming occurs through exposure of presynaptic GnRH neurons in the developing male brain to the androgenic and estrogenic actions of testicular steroids. In precocial species such as ruminants, this programming begins well before birth. Understanding how GnRH secretion normally becomes sexually differentiated is of practical importance to determining how inappropriate hormonal environments during development can variously malprogram the neuroendocrine system to produce a variety of reproductive dysfunctions relating to patterning of gonadotropin secretion.