Norepinephrine Amplifies Human Chorionic Gonadotropin-Stimulated Androgen Biosynthesis by Ovarian Theca-Interstitial Cells*

Abstract

Ovarian theca-interstitial cells, when cultured in serum-free medium, secreted androgens in response to hCG stimulation. This production was dependent on time (maximum production attained after 96 h) and dose (half-maximal effective dose of hCG, 9 ng/ml). When the sympathomimetics norepinephrine, epinephrine, and isoproterenol were added to the medium, androgen production in response to hCG was enhanced by 100-300%. The ability of the catecholamines to stimulate androgen production was dependent on the continuous presence of hCG. Treatment with catecholamines alone did not induce theca-interstitial cells to produce androgens. Catecholamine stimulation of steroid hormone metabolism was selective for intermediates in the delta 4-pathway, with greatest increases occurring in the production of androstenedione and testosterone. It was found that the effect of the catecholamines on androgen production was dependent on both beta 1-and beta 2-adrenergic receptors. The acquisition of catecholamine responsiveness was specific to hCG; if theca-interstitial cells were induced to differentiate with either prostaglandin E2 or cholera toxin, then isoproterenol did not enhance androgen synthesis. The catecholamine-induced increases in androgen production were not due to a granulosa cell contribution of steroid. The interstitial cells are the only steroid-producing cells in the ovary that are directly innervated by norepinephrine-containing fibers of the sympathetic nervous system. Our finding of catecholamine-augmented androgen production provides a direct link between the autonomic nervous system and regulation of ovarian steroid synthesis.

Effects of peripheral sympathetic denervation induced by guanethidine administration on the mechanisms regulating puberty in the female guinea pig

“…Studies in vitro using ovarian thecal interstitial cells showed that the addition of norepinephrine, epinephrine or isoproterenol to the medium enhanced androgen production in response to human chorionic gonadotrophin (hCG) (Dyer & Erickson 1985). This sympathetic alteration in ovarian innervation induced by guanethidine treatment would result in the accumulation of progesterone, while an active aromatase would convert any androgens which are present to oestrogen, resulting in the normal serum levels observed.…”

“…There is evidence that (1) norepinephrine acts synergistically with LH/hCG on the stimulation of androgen secretion (Dyer & Erickson 1985), (2) in the peripubertal stage of the rat, the number of 2-adrenergic receptors is very high and their stimulation results in an increase in testosterone output (Aguado et al 1982), (3) ovarian denervation produced a decrease in the 5-3 -hydroxysteroid dehydrogenase activity in the rat ovary during pregnancy (Burden & Lawrence 1977), and (4) in accordance with Greenwald and Roy (1994), the steroid profiles in atretic follicles demonstrate a fall in oestrogen secretion, attributable to a shutdown in thecal androgen secretion. Therefore, the increase in the number of atretic follicles in the ovaries of guanethidine-denervated guinea pigs reflects the modification of other mechanisms regulating the atresia of the follicles related, perhaps, to thecal vascularity (Greenwald 1993).…”

Establishment of heterogeneity among blood vessels: Hormone‐influenced appearance of hepatic lipase in specific subsets of the ovarian microvasculature

“…Thin-walled blood vessels in ovaries of nonhormonetreated immature rats bore little immunoreactive hepatic lipase, while those in all steroidogenic compartments of animals receiving PMSG or PMSG-hCG displayed abundant enzyme. It is also pertinent that the parenchymal cells of all compartments possessing blood vessels strongly positive for hepatic lipase are known to be regulated by, or bear binding sites for, luteinizing hormone, a pituitary gonadotropin (Bortolussi et al, 1979;Azhar and Menon, 1979;Dyer and Erickson, 1985;Petrusz, 1973).…”

Ovarian Nerve Extracts Influence Androgen Production by Cultured Ovarian Thecal Cells

“…The porcine theca cell culture system provides a model for the in vitro study of the influence of ovarian nerves and neurotransmitters on steroidogenesis in theca cells, without effects on blood flow which confound the interpretation of in vivo studies. Moreover, the present studies were done using theca cells which are known to be innervated (5,27,28], where as previous reports of the effects of putative neurotransmitters on ovarian steroidogenesis have used granulosa or luteal cells [7,10], neither of which are innervated.…”

“…Histochemical studies have shown the pre sence of noradrenergic [15, 19, 27[ and cholinergic [4, 15] [ or luteal cells [7] increase their production of progesterone and that cultured rat interstitial cells increase their production of androgen [ 10] in response to catecholamines. Also, stimulation of specific brain areas in hypophysectomiz.ed, adrenalectomiz.ed rats has been shown to cause changes in ovarian venous estrogen and proges terone concentrations without causing changes in ovarian blood flow [16].…”