Sex Differentiation of Cyclic Gonadotropin Secretion

ABSTRACT Early studies from this laboratory demonstrated that the exposure of the central nervous system of female rats and mice to androgen or estrogen at a critical period in development permanently alters the cyclic secretion of LH and FSH. We originally suggested that prepubertal exposure of female rats to androgen deleteriously affected preoptico-suprachiasmatic (POA-Sch.N.) function so that preovulatory surges of IH and FSH were abolished. We proposed that this area (POA-Sc.N.) was responsible for cyclic (preovulatory) gonadotropin discharge, whereas the release of tonic amounts of LH/FSH (regulated by the arcuate-median eminence region) could occur independent of this higher level of control. Since these original observations, considerable information has been gathered on the dosage and age limits for the production of aberrant reproductive endocrine and behavioral effects in rats, mice, guinea pigs, hamsters, sheep and primates. Administration of low dosages of androgen during the “critical period” in CNS development produces the delayed androgen syndrome in which, at puberty, such animals exhibit normal cyclic and ovulatory behavior but at a variable time interval thereafter become anovulatory. The syndrome produced by androgen treatment of prepubertal female rats is characterized by ovaries which are polyfollicular but which lack corpora lutea. The vaginae are persistently comified, preovulatory LH and FSH surges are absent, plasma estradiol levels are low and plasma prolactin concentrations are elevated to varying degrees depending upon the sterilizing dose of androgen administered. The pituitary glands of androgenized rats respond to LHRH in a manner similar to normal cyclic rats, although ovarian ovulatory thresholds to LH are elevated 5-10 fold above those of normal proestrous rats. While in earlier studies it was proposed that testosterone “masculinized” the preopticohypothalamic system, more recent work suggests that the preoptic and limbic regions aromatize androgens to estrogens and that it is these latter steroids which alter normal preoptic brain function. Yet, neuronal receptors to testosterone have been identified and testosterone is reduced by 5γ-reductase to dihydrotestosterone within the hypothalamus. At least abnormal sex behavior seems attributable to the CNS effects of androgen. Administration of estrogen to prepubertal female rats also results in anovulatory sterility. Electrochemical stimulation of the preoptic brain in normal proestrous and in androgen and estrogen-sterilized rats (ASR-ESR) results in peak plasma LH and FSH concentrations in ESR which are greater than those in ASR or control rats. In all steroid-sterilized rats, the preoptico-hypophysiotropic system seems competent to respond to extrinsic activation. This suggests that the failure of such animals to display spontaneous preovulatory gonadotropin discharges is not due either to loss of hypothalamic axonal responsiveness or loss of the synthesis and release of endogenous LHRH. Rather, the critical malfunction may reside in the inability of estrogen (and progesterone) to exert a positive feedback action on neurons involved in the cyclic release of LH and FSH. Neither estrogen alone nor estrogen in combination with progesterone will precipitate the spontaneous release of LH or FSH in ESR or ASR. Studies by others suggest a decrease in neuronal cytoplasmic estrogen receptors in sterile rats. The reduced ability of estrogen to be translocated to the neuronal nucleus, where it would affect function of the genome, may be a prime cause for the absence of preovulatory LH and FSH surges in steroid-treated rats.