Pregnenolone

About: Pregnenolone is a research topic. Over the lifetime, 3539 publications have been published within this topic receiving 126444 citations. The topic is also known as: (3b)-3-hydroxy-Pregn-5-en-20-one & 3-Hydroxypregn-5-en-20-one.

Bipotential Actions of Estrogen on Progesterone Biosynthesis by Ovarian Cells. I. Relation of Estradiol's Inhibitory Actions to Cholesterol and Progestin Metabolism in Cultured Swine Granulosa Cells*

Abstract: In short term, serum-free cultures of granulosa cells, estradiol inhibited basal progesterone production by more than 84% in a time- and dose-dependent fashion. Half-maximal inhibition (ID50) was observed at a mean estradiol concentration of 70 ng/ml. The acute inhibitory effects of estradiol were independent of cell density or maturational status of the parent follicle (small, medium, or large follicles). Estrogen decreased total progesterone biosynthesis, rather than merely progesterone secretion by granulosa cells. In addition, the production of progesterone and its 20 alpha-reduced metabolite were suppressed in parallel over a 30-fold range of inhibitory effects. Moreover, estradiol inhibited progesterone production from both endogenous and exogenous (25-hydroxycholesterol) substrate. In contrast to its inhibition of progesterone production, estradiol acutely enhanced pregnenolone accumulation and led to a 14- to 20-fold increase in the ratio of pregnenolone to progesterone. Inhibition of 3 beta-hydroxysteroid dehydrogenase activity was confirmed by demonstrating estrogen's ability to antagonize the conversion of exogenously supplied pregnenolone to progesterone in intact granulosa cells (ID50, 74 ng/ml) and to directly inhibit enzymic activity in ovarian homogenates (ID50, 79 ng/ml). On the other hand, estradiol did not alter the incorporation of [14C]acetate into cholesterol and specific progestins or influence the time-dependent hydrolysis of prelabeled cholesteryl ester stores in granulosa cells. In summary, in short term cultures of swine granulosa cells, estradiol significantly inhibits basal progesterone biosynthesis in a time- and dose-dependent fashion, encompassing estradiol concentrations attainable in vivo. Estrogen's inhibition is accomplished by mechanisms that are independent of cytotoxicity, cell density, and maturational stage of the parent follicle. The predominant locus of estrogen action is blockade of pregnenolone's conversion to progesterone, rather than accelerated metabolism of progesterone to its 20 alpha-reduced metabolite. Moreover, estradiol simultaneously enhances functional cholesterol side-chain cleavage activity without suppressing de novo cholesterol biosynthesis or impairing the mobilization of cellular cholesteryl ester stores. Thus, we infer that increasing concentrations of estradiol attained in antral follicular fluid during the later stages of follicle maturation could effectively limit the premature secretion of large quantities of progesterone before ovulation without impairing the cell's capacity for de novo cholesterol biosynthesis or cholesteryl ester hydrolysis.

Steroid Production in “Nonfunctioning” Adrenal Cortical Tumor

Abstract: The urinary steroids in 3 patients with metastatic “nonfunctioning” adrenal tumor have been studied. There was no excessive production of hydrocortisone or adrenal androgen metabolites. However, the isolation of rather large amounts of Δ5-pregnene-3β,20α-diol and pregnane-3α,20α-diol from 2 patients indicates that the metastases were at least capable of the first step in corticosteroid biosynthesis—cholesterol to pregnenolone. There was further evidence of a relative inability to oxidize the C-3 hydroxyl group and to rearrange the 5,6-double bond. Δ5-Pregnene-3α,16α,20α-triol was isolated from the urine of one of these patients. There was an absence of abnormal steroids in the third patient studied.

Inhibition of 3‐beta‐hydroxy steroid dehydrogenase activity in first trimester human pregnancy with trilostane and win 32729

Abstract: The effects of equivalent doses of 2 inhibitors of the 3-beta-hdyroxy steroid dehydrogenase enzyme system--WIN 24540 (trilostane) and WIN 32729--on the secretion of progesterone in early human pregnancy are described. Patients and controls less than 12 weeks pregnant were given a single dose of either drug and the resultant hormonal changes monitored for 7 1/2 hours. A consistent fall in plasma progesterone concentrations occurred at all dose levels and at the highest dose they fell to less than 50% of pretreatment levels. However while with trilostane the associated increase in plasma concentrations of pregnenolone was always accompanied by a rise in plasma DHA concentrations with WIN 32729 there appeared to be adrenal effect at the lower dosage levels. These data demonstrate inhibition of progesterone secretion in human pregnancy using nonhormonally active steroids. The pattern of steroid precursors indicates that while both drugs inhibit 3-beta-hydroxy steroid dehyrogenase activity WIN 32729 is more selective and only interferes with adrenal steroid biosynthesis at high doses. (authors)