HYPOTHALAMIC CONTROL OF GONADOTROPIN-SECRETION BY LHRH, FSHRF, NO, CYTOKINES, AND LEPTIN

Gonadotropin secretion by the pituitary gland is under the control of luteinizing hormone-releasing hormone (LHRH) and the putative follicle stimulating hormone-releasing factor (FSHRF). Lamprey III LHRH is a p otent FSHRF in the rat and seems to be resident in the FSH controlling area of the rat hypothalamus. It is an analog of mammalian LHRH and m ay be the long sought FSHRF. Gonadal steroids feedback at hypothalamic and pituitary levels to either inhibit or stimulate the release of LH and FSH, which is also affected by inhibin and activin secreted by th e gonads. Important control is exercised by acetylcholine, norepinephr ine (NE), dopamine, serotonin, melatonin, and glutamic acid (GA). Furt hermore, LH and FSH also act at the hypothalamic level to alter secret ion of gonadotropins. More recently, growth factors have been shown to have an important role. Many peptides act to inhibit or increase rele ase of LH and the sign of their action is often reversed by estrogen. A number of cytokines act at the hypothalamic level to suppress acutel y the release of LH but not FSH. NE, GA, and oxytocin stimulate LHRH r elease by activation of neural nitric oxide synthase (nNOS). The pathw ay is as follows: oxytocin and/ or GA activate NE neurons in the media l basal hypothalamus (MBH) that activate NOergic neurons by alpha(1) ( alpha(1)) receptors. The NO released diffuses into LHRH terminals and induces LHRH release by activation of guanylate cyclase (GC) and cyclo oxygenase. NO not only controls release of LHRH bound for the pituitar y, but also that which induces mating by actions in the brain stem. An exciting recent development has been the discovery of the adipocyte h ormone, leptin, a cytokine related to tumor necrosis factor (TNF) alph a. In the male rat, leptin exhibits a high potency to stimulate FSH an d LH release from hemipituitaries incubated in vitro, and increases th e release of LHRH from MBH explants. LHRH and leptin release LH by act ivation of NOS in the gonadotropes. The NO released activates GC that releases cyclic GMP, which induces LH release. Leptin induces LH relea se in conscious, ovariectomized estrogen-primed female rats, presumabl y by stimulating LHRH release. At the effective dose of estrogen to ac tivate LH release, FSH release is inhibited. Leptin may play an import ant role in induction of puberty and control of LHRH release in the ad ult as well. (C) Elsevier Science Inc. 1998