Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progesterone has been shown to decrease occupied pituitary and uterine nuclear estradiol receptor (E2R) binding in mature and immature estrogen-primed rats. Progesterone has also been shown to stimulate pituitary but not uterine 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) in the rat. The conversion of estradiol to its less active metabolite estrone by 17 beta-HSD and activation of phosphatase are among mechanisms considered to be involved in the reduction of E2R. To determine if 17 beta-HSD stimulation was a mechanism by which progesterone induced nuclear E2R decrease, the synthetic estrogen ethinylestradiol, which is not oxidized by 17 beta-HSD, was used instead of estradiol to prime adult ovariectomized rats. When ethinylestradiol-primed rats received 0.8, 2.0 or 4.0 mg/kg body wt of progesterone 2 h before sacrifice, the total and occupied nuclear E2R accumulation in the anterior pituitary by a subsequent ethinylestradiol injection 1 h later did not show any decrease. This response was different from that observed previously in estradiol-primed animals in which progesterone showed a multiphasic decrease of occupied form of nuclear E2R. However, in the uterus of ethinylestradiol-primed rats, a partial decrease of total and occupied nuclear E2R accumulation was observed in the presence of the three doses of progesterone used. The decrease of uterine nuclear E2R with the three progesterone doses was different from the dose-dependent effect of progesterone observed in the uterus of estradiol-primed rats. Affinity constants of the interaction between [3H]estradiol and the nuclear E2R were similar among groups treated with ethinylestradiol, estradiol and progesterone. These results demonstrate the involvement of 17 beta-HSD in the reduction of anterior pituitary gland E2R by progesterone in the estradiol-treated animals. Furthermore, the mechanism of decrease of E2R by progesterone in the uterus appears to be different from the pituitary gland.
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PMID:Role of 17 beta-hydroxysteroid dehydrogenase in the modulation of nuclear estradiol receptor binding by progesterone in the rat anterior pituitary gland and the uterus. 217 25

Ovine luteal cells were collected and plated 36 h (Day 2) after injection of human chorionic gonadotropin (Day 0) to induce ovulation. Cells were maintained (Days 2-12) in Medium 199 containing 5% calf serum, which was replaced daily. Progesterone secretion was not stimulated (p greater than 0.05) by luteinizing hormone (LH, 10 ng/ml or 100 ng/ml) at any time during culture. However, it was enhanced (p less than 0.05) with a 24-h pulse of dibutyryl adenosine 3', 5'-monophosphate (dbcAMP) during early (2.2-fold stimulation over basal; Days 5,6) or mid- (1.7-fold stimulation over basal: Days 8,9) culture if the pulsing medium contained serum, but not if serum had been withdrawn for 24 h. Continuous exposure of cultures to dbcAMP (2 mM, Days 3-12) resulted in continuously stimulated (p less than 0.05) progesterone secretion (range 1.8- to 4.1-fold stimulation). An increased (p less than 0.05) percentage of cells staining positive for 3 beta-hydroxy-delta 5-steroid dehydrogenase-delta 5, delta 4-isomerase (3 beta HSD) activity were recovered on Day 12 in cultures incubated (Days 3-12) with dbcAMP. Incubation of cultures continuously with prostaglandin F2 alpha (PGF2 alpha) produced dose-dependent inhibition (p less than 0.05) of progesterone secretion. Reduced numbers of 3 beta HSD-positive cells were recovered from these incubations. These experiments demonstrate luteotropic (dbcAMP) as well as luteolytic (PGF2 alpha) effects on ovine luteal cells in long-term culture. This study provides evidence that these cultures will be useful for investigating the development of hormonal regulation of luteal function.
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PMID:Luteotropic and luteolytic responsiveness of ovine luteal cells in long-term culture. 255 79

We measured concentrations of cytosol and nuclear estrogen, as well as progestin receptors and activities of 17 beta-hydroxysteroid dehydrogenase (17-HSD), and examined histopathology and ultrastructure of endometrial carcinoma specimens taken before and after one-week danazol (200 mg, 3 times daily) or medroxyprogesterone acetate (MPA, 100 mg daily) treatments in 14 and 16 patients, respectively. A typical progestin effect, a significant increase in the activity of 17-HSD, was observed after both treatments. The post-therapy 17-HSD activities correlated significantly with the pretreatment cytosol progestin receptor concentrations in both treatment groups. Both MPA and danazol decreased the proliferative activity and increased the secretory activity of the malignant epithelial endometrial cells. These biochemical and morphological results support the concept that danazol has progestin-like actions on the human endometrium, and might therefore be an alternative for hormonal treatment of endometrial carcinoma.
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PMID:Short-term effects of danazol and medroxyprogesterone acetate on cytosol and nuclear estrogen and progestin receptors, 17 beta-hydroxysteroid dehydrogenase activity, histopathology, and ultrastructure of human endometrial adenocarcinoma. 315 97

Little is known about the dopamine system in the ovary. The present study has been undertaken to investigate the effect of dopamine (DA) on the ovarian steroidogenic enzymes of pregnant mare serum gonadotropin (PMSG)-treated immature rats. Ovarian cells from PMSG-treated rats were cultured for 1-5 hours with or without DA, D1 agonists or bulbocapnine (Bul)(D1 antagonist). Progesterone (P) and estradiol (E2) in the media were assayed by specific RIAs. The enzyme activities were assayed by adding radioactive substrates in the media before incubation. DA and D1 agonists increased P in the media which was caused by the increment of 3 beta -hydroxysteroid dehydrogenase (3 beta -HSD) activity because cholesterol side chain cleavage enzyme (CSCC) activity showed no significant change. The stimulating effects of DA and DA agonists on P and 3 beta -HSD activity were inhibited by Bul. DA showed no effect on 17 alpha-hydroxylase activity. DA decreased 17.20 lyase activity, but this decrement was probably a non specific effect. DA alone did not affect the E2 level in the media and aromatase activity. The present results suggest that DA mainly stimulated 3 beta -HSD activity of the PMSG-treated rat ovary which regulated P synthesis.
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PMID:[Dopamine increases the ovarian progesterone synthesis of PMSG-treated rats by regulating 3 beta-HSD activity]. 795 94

Colocalization of progesterone receptors and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), a key enzyme in progesterone biosynthesis, in macaque luteal cells suggest that progesterone has an autocrine role in the regulation of primate luteal function. To test this hypothesis, we administered trilostane, a 3 beta HSD inhibitor, to rhesus macaques at the midluteal phase of spontaneous menstrual cycles to rapidly and reversibly reduce progesterone production. Animals received trilostane (600 mg/dose; treated group; n = 5) or vehicle (control group; n = 4) orally on days 6-7 of the luteal phase. Trilostane significantly (P < 0.05) elevated pregnenolone levels within 1 h of treatment compared to those in vehicle-treated animals; after 1 day of treatment, the mean pregnenolone level (173 nmol/L) was 86-fold greater than the control value. Pregnenolone levels dropped after cessation of drug administration and became indistinguishable from control levels by day 13. Trilostane significantly reduced serum progesterone levels within 3 h of initial administration (P < 0.01), and levels remained near baseline (1.0 nmol/L) throughout the 2 days of treatment. Progesterone levels also remained low after cessation of trilostane treatment in four of five monkeys, and trilostane-treated animals experienced a shorter luteal phase than vehicle-treated animals (7.8 +/- 0.2 vs. 16 +/- 1 days; P < 0.01). Histological analysis (n = 3/group) revealed indexes of premature structural luteolysis by 4 days after the onset of trilostane administration. Exposure to trilostane had no effect on the percentage of luteal cells expressing progesterone receptors, as determined by immunocytochemistry. Serum LH levels were not different between treatment and control groups throughout the experimental period. As trilostane dramatically reduced serum progesterone and induced premature menses without major concurrent alteration in serum cortisol, we conclude that trilostane ios an effective, rapidly acting inhibitor of 3 beta HSD in the macaque corpus luteum during the midluteal phase of the menstrual cycle. Progesterone production did not typically resume after cessation of trilostane treatment despite continuing gonadotropin support luteolysis. Thus, progesterone or a related metabolite may be required to maintain the function and structural integrity of the primate corpus luteum during the normal menstrual cycle.
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PMID:Acute administration of a 3 beta-hydroxysteroid dehydrogenase inhibitor to rhesus monkeys at the midluteal phase of the menstrual cycle: evidence for possible autocrine regulation of the primate corpus luteum by progesterone. 798 60

It is clear that steroid hormones of placental and fetal adrenal origin have critically important roles in regulating key physiological events essential to the maintenance of pregnancy and development of the fetus for extrauterine life. Thus, progesterone has suppressive actions on lymphocyte proliferation and activity and on the immune system to prevent rejection of the developing fetus and placenta (see Fig. 9). Progesterone also suppresses the calcium-calmodulin-MLCK system and thus activity of uterine smooth muscle, thereby promoting myometrial quiescence to ensure the maintenance of pregnancy. Estrogen enhances uteroplacental blood flow and possibly placental neovascularization to provide optimal gas exchange and the nutrients required for the rapidly developing fetus and placenta. In turn, estrogen has specific stimulatory effects on the receptor-mediated uptake of LDL by, and P-450scc activity within, syncytiotrophoblasts, thus promoting the biosynthesis of progesterone. Moreover, there is an estrogen-dependent developmental regulation of expression of the LDL receptor and NAD-dependent 11 beta-HSD in the placenta, processes reflecting functional/biochemical differentiation of the trophoblast cells with advancing gestation. The increase in 11 beta-HSD causes a change in transplacental corticosteroid metabolism, which results in activation of the HPAA in the fetus. As a result of this cascade of events, there is an increase in expression of pituitary POMC/ACTH and key enzymes, e.g. 3 beta-HSD and P-450 17 alpha-hydroxylase, important for de novo cortisol formation by, and consequently maturation of, the fetal adrenal gland. In turn, cortisol has well defined actions on surfactant biosynthesis and consequently fetal lung maturation, as well as effects on placental CRH/POMC release, which may be important to the initiation of labor. At midgestation, estrogen also selectively feeds back on the fetal adrenal to suppress DHA and maintain physiologically normal levels of estrogen. Preparation of the breast for lactation and nourishment of the newborn appears to involve a multifactorial system of regulation that includes estrogen. It is apparent, therefore, that autocrine/paracrine, as well as endocrine, systems of regulation are operative within the fetoplacental unit during primate pregnancy. A major goal of this review has been to illustrate the critically close functional communication existing between the developing placenta and fetus in the biosynthesis and the actions of steroid hormones during primate pregnancy. The functional interaction of the human fetal adrenal and placenta with respect to the biosynthesis of estrogen was demonstrated many years ago. However, the recent studies presented in this review show that the endocrine interaction between the fetus and placenta is more extensive, involving complex physiological regulatory mechanisms. Thus, as illustrated in Fig. 9, estrogen, acting via its receptor within the placenta and other reproductive tissues, orchestrates the dynamic interchange between the placenta and fetus responsible for the developmental regulation of the biosynthesis of the various steroid and peptide hormones and their receptors necessary for the maintenance of pregnancy and development of a live newborn. It would appear, therefore, that the immediate and long range challenges in this area of reproductive endocrinology are to employ in vitro molecular and in vivo experimental approaches simultaneously to elucidate the nature of these complex interactions and define the cellular and molecular mechanisms underlying these important regulatory events.
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PMID:Actions of placental and fetal adrenal steroid hormones in primate pregnancy. 852 74

Progesterone 5-alpha-reductase activity and 3-alpha-hydroxysteroid dehydrogenase activity were determined in the cortex of male and female rats in vitro. Age effects were investigated. The age of the male rats was 3-23 months, and that of the female rats 4-23 months. On addition, we investigated the enzyme 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase in rat cortex in order to estimate the local synthesis of progesterone from pregnenolone. We found age-related increases in progesterone 5-alpha-reductase activity in the female rats (r = 0.64, p < 0.01, n = 6) and in the male rats (r = 0.5, p < 0.05, n = 18). 3-alpha-HSDH activity remained constant with age in female and male rats. The ratio of 3-alpha-hydroxysteroid dehydrogenase activity to 5-alpha-reductase activity tended to decrease with age (not significantly) in both male rats (r = -0.45, p = 0.06, n = 19) and the female rats (r = -0.36, p = 0.17, n = 16). We could not detect significant metabolism of pregnenolone to progesterone in rat cortex in vitro. The sensitivity of the assays of 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase was calculated from the mean of the blank values + 3SD; the sensitivity of the assay was calculated as 0.103 fmol/mg protein/min. No significant metabolism of pregnenolone could be detected in cortex pooled from several male rats. The mean metabolism of progesterone was 1,200 times higher than the detection threshold of the assay for 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase. We conclude that modifications of the inhibitory effects of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one via altered progesterone metabolism in rat cortex are possible with aging. A connection with the age-related increase in incidence of epileptic attacks, and with age-related changes in the effects of anticonvulsant and GABAA-active drugs, appears possible.
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PMID:Effect of age on synthesis of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one in rat cortex in vitro. 920 86

Human placenta and fetal membranes contain two types of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). 11Beta-HSD1 interconverts cortisol and cortisone and is the predominant isoform found in the fetal membranes. 11Beta-HSD2, which predominates in the placenta syncytiotrophoblast, converts cortisol to cortisone. It has been proposed that placental 11beta-HSD protects the fetus from high levels of maternal glucocorticoids. In this study, cultured term human placental and chorionic trophoblasts were used to examine the regulation of 11beta-HSD1 and 11beta-HSD2 activities and mRNA expression by progesterone, estrogen, and activators of adenylate cyclase (forskolin) and protein kinase C (phorbol 12-myristate 13-acetate, PMA). Placental trophoblast displayed mainly type 2 oxidase activities. 11Beta-HSD in the chorionic trophoblast was exclusively an 11beta-HSD1 reductase. Progesterone (0.001-1 microM) inhibited 11beta-HSD2 activity in a dose-dependent fashion. Inhibition of endogenous progesterone production with trilostane enhanced 11beta-HSD2 activity. The inhibitory effect of progesterone on 11beta-HSD2 activity was not reversed by the progesterone receptor antagonists RU-486 or onapristone. Progesterone (1 microM) also reduced levels of 11beta-HSD2 mRNA, an effect that was attenuated by both RU-486 and onapristone. Estradiol (1 microM) inhibited type 2 oxidase activity as well. Activation of adenylate cyclase by forskolin (100 microM) up-regulated both 11beta-HSD2 activity and mRNA expression; there was no effect of PMA (1 microM) on 11beta-HSD2. 11Beta-HSD1 reductase activity was unaffected by progesterone, estrogen, forskolin, or PMA in either the placental or chorionic trophoblasts. We conclude that both progesterone and estrogen are inhibitors of 11beta-HSD2 activity in term human placenta in vitro. Levels of 11beta-HSD2 activity and mRNA are increased by activation of the cAMP pathway. Progesterone also suppresses levels of 11beta-HSD2 mRNA.
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PMID:Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by progesterone, estrogen, and the cyclic adenosine 5'-monophosphate pathway in cultured human placental and chorionic trophoblasts. 962 96

Troglitazone (a thiazolidinedione that improves insulin resistance) lowers elevated androgen concentrations in women with polycystic ovarian syndrome. In this study, we assessed the direct effects of troglitazone on steroidogenesis in porcine granulosa cells. Troglitazone inhibited progesterone production in a dose- and time-dependent manner (earliest effects at 4 h, maximum at 24 h) without affecting cell viability. Progesterone production was also inhibited by troglitazone in the presence of 25-hydroxycholesterol, indicating that the drug does not affect intracellular cholesterol transport. Troglitazone also inhibited FSH- and forskolin-stimulated progesterone secretion. The reduced progesterone production was accompanied by marked elevations of pregnenolone concentrations, suggesting inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). The activity of 3beta-HSD in troglitazone-treated granulosa cells was decreased by more than 60%, compared with controls after 24 h. Troglitazone did not affect aromatase activity in porcine granulosa cells. In summary, troglitazone has direct effects on porcine granulosa cell steroidogenesis. The drug specifically inhibits 3beta-HSD activity, resulting in impaired progesterone production. The clinical relevance of this direct in vitro effect on steroidogenesis needs further investigation.
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PMID:Troglitazone inhibits progesterone production in porcine granulosa cells. 983 34

Recently, we have demonstrated, using biochemical and immunochemical methods, that the quail brain possesses the cholesterol side-chain cleavage enzyme (cytochrome P450scc) and produces pregnenolone and its sulfate ester. To clarify progesterone biosynthesis in the avian brain, therefore, we examined the expression of messenger RNA (mRNA) encoding for the enzyme 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase (3beta-HSD) and its enzymatic activity using the quail. RT-PCR analysis together with Southern hybridization indicated the expression of 3beta-HSD mRNA in the brain of sexually mature birds but with no clear-cut sex difference. Employing biochemical techniques combined with HPLC analysis, the conversion of pregnenolone to progesterone was found in brain slices of mature males. Progesterone biosynthesis was increased in a time dependent manner and completely abolished by trilostane, a specific inhibitor of 3beta-HSD. The enzymatic activity of 3beta-HSD was greatest in the cerebrum and lowest in the mesencephalon. A specific RIA indicated that progesterone concentrations in the different brain regions closely followed the level of 3beta-HSD activity. High levels of progesterone concentration were observed in the diencephalon and cerebrum with lowest values in the mesencephalon. Progesterone levels in the brain regions were significantly higher than those in the plasma. These results suggest that the avian brain possesses not only cytochrome P450scc but also 3beta-HSD and produces progesterone. It is also indicated that progesterone biosynthesis in the avian brain may be region-dependent.
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PMID:Expression and activity of 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase in different regions of the avian brain. 1008 43


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