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Review
. 2012 Jan 1;302(1):E4-E18.
doi: 10.1152/ajpendo.00488.2011. Epub 2011 Oct 25.

Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective

Virendra B Mahesh  1
Affiliations
Review

Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective

Virendra B Mahesh. Am J Physiol Endocrinol Metab. .

Abstract

This career retrospective describes how the initial work on the mechanism of hormone action provided the tools for the study of hirsutism, virilism, and polycystic ovarian disease. After excessive ovarian and or adrenal androgen secretion in polycystic ovarian disease had been established, the question whether the disease was genetic or acquired, methods to manage hirsutism and methods for the induction of ovulation were addressed. Recognizing that steroid gonadotropin feedback was an important regulatory factor, initial studies were done on the secretion of LH and FSH in the ovulatory cycle. This was followed by the study of basic mechanisms of steroid-gonadotropin feedback system, using castration and steroid replacement and the events surrounding the natural onset of puberty. Studies in ovariectomized rats showed that progesterone was a pivotal enhancer of estrogen-induced gonadotropin release, thus accounting for the preovulatory gonadotropin surge. The effects of progesterone were manifested by depletion of the occupied estrogen receptors of the anterior pituitary, release of hypothalamic LHRH, and inhibition of enzymes that degrade LHRH. Progesterone also promoted the synthesis of FSH in the pituitary. The 3α,5α-reduced metabolite of progesterone brought about selective LH release and acted using the GABA(A) receptor system. The 5α-reduced metabolite of progesterone brought about selective FSH release; the ability of progesterone to bring about FSH release was dependent on its 5α-reduction. The GnRH neuron does not have steroid receptors; the steroid effect was shown to be mediated through the excitatory amino acid glutamate, which in turn stimulated nitric oxide. These observations led to the replacement of the long-accepted belief that ovarian steroids acted directly on the GnRH neuron by the novel concept that the steroid feedback effect was exerted at the glutamatergic neuron, which in turn regulated the GnRH neuron. The neuroprotective effects of estrogens on brain neurons are of considerable interest.

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Figures

Fig. 1.
Fig. 1.
Stimulatory effects of progesterone on the hypothalamus in the release of LHRH and stimulation of 17β-hydroxysteroid dehydrogenase activity in the pituitary. It also had direct action on the pituitary in increasing the sensitivity of the pituitary to LHRH in release of LH and synthesis of new LH and FSH. Progesterone also inhibited peptidase activity in the hypothalamus and pituitary, slowing degradation of LHRH and increasing greater availability of LHRH for LH secretion. Enhanced 17β-hydroxysteroid dehydrogenase activity brings about increased conversion of estradiol to estrone in the pituitary, resulting in decreased nuclear occupancy of the estrogen receptor. Progesterone thus decreased the inhibitory action of estrogens on the pituitary on LH release and decreased progesterone receptor synthesis. Decreased progesterone receptors prevent the stimulatory effect of progesterone on LH secretion. Stimulatory pathways are shown in green, inhibitory pathways in red.
Fig. 2.
Fig. 2.
Progesterone is converted into two major metabolites, 5α-dihydroprogesterone and 3α,5α-tetrahydroprogesterone. The former uses the progesterone receptor and brings about selective release of FSH; the latter uses the GABAA receptor and brings about selective release of LH. Administration of a 5α-reductase inhibitor in vivo or in vitro reduced FSH release without affecting LH release. Stimulatory pathways are shown in green; inhibitory pathways in red.
Fig. 3.
Fig. 3.
Progesterone inhibition of glutamic acid dehydrogenase-67 (GAD67) permits more glutamate release and less GABA release, thus permitting an LH surge. Stimulatory events are shown in green, inhibitory events in red.
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References

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