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PubMed1975

Subcellular distribution and properties of progesterone (delta4-steroid) 5alpha-reductase in rat medial basal hypothalamus.

The subcellular distribution and properties of rat hypothalamic progesterone 5 alpha-reductase, which accelerates the conversion of progesterone to 5 alpha-pregnane-3,20-dione, have been investigated by utilizing 3H-labeled substrate and a reverse isotopic dilution assay system. The enxymic activity was associated primarily with a cell debris-membranes fraction deribed from the 100 x g pellet. This fraction contained mainly membrane-like particulates and was free of nuclei. Little or no activity was associated with the purified nuclei. The hypothalamic 5 alpha-reductase was stimulated by NADPH but not by NADH. The reaction proceeded optimally over a pH range of 6.0 to 7.2 and at a temperaturhe substrate specificity of the enzyme for other delta 4-3-ketosteroids and the ability of these steroids to inhibit the 5 alpha reduction of [1,2-3H]progesterone as well as the effect of 17 beta-estradiol were also studied. 20 alpha-hydroxypregn-4-en-3-one was more reactive that progesterone, while testosterone was the least reactive. The estimated Km for 20 alpha-hydroxypregn-4-en-3-one was 8.6 +/- 1.9 x 10(-7) M, and for testosterone, 1.6 +/- 1.4 x 10(-5) M. The inhibition studies indicate that 20 alpha-hydroxypregn-4-en-3-one and 17 beta-estradiol are competitive and noncompetitive inhibitors, respectively, of the 5 alpha reduction of progesterone with Ki of 6.0 +/- 3.0 x 10(-8) M for 20 alpha-hydroxypregn-4-en-3-one and Kii (intercept inhibition constant) of 2.6 +/- 0.7 x 10(-5) M and Kis (slope inhibition constant) of 3.6 +/- 0.6 x 10(-5) M for 17 beta-estradiol. Testosterone is a poor competitive inhibitor of the reaction.

20-alpha-Dihydroprogesterone↗
PubMed1990

Expression of steroid metabolizing enzymes by aggregating fetal brain cells in culture: a model for developmental regulation of the progesterone 5 alpha-reductase pathway.

In this study, we established an in vitro model system for the study of developmental regulation of steroid enzyme expression in the perinatal brain. Single cell suspensions were prepared from the hypothalamic-olfactory tubercle region of 18-day-old rat fetuses, and aggregates were formed by incubation under constant rotation. On day 0, 3, 6, or 12 of culture, aggregates were incubated for 4 or 20 h with 3H-progesterone (P4) and the profile of 3H-steroids in the medium analyzed. Five major metabolites were formed from 3H-P4: 5 alpha-pregnan-3, 20-dione (DHP), 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP), 3 beta-hydroxy-5 alpha-pregnan-20-one (3 beta-OH-DHP), and two unidentified polar substances designated A and B. Progressively with aggregate-age in culture, there was a decrease in the relative amounts of 3H-P4 recovered in the medium and a sequential increase in DHP, 3 beta-OH-DHP, 3 alpha-OH-DHP, A and B. Aggregates maintained in a chemically defined, serum-free medium metabolized P4 at an accelerated rate compared to those maintained in serum. An inhibitor of the enzyme 5 alpha-reductase completely inhibited P4 metabolism, indicating that 5 alpha-reduction is the primary step in this pathway. Thus, the aggregates express three key enzymes in P4 metabolism: 5 alpha-reductase, 3 alpha- and 3 beta-hydroxysteroid oxidoreductases and the operation of this pathway is proposed: P4----DHP----3 alpha-OH-DHP + 3 beta-OH-DHP; A and B are derived from one or more of the latter three. Hence, this culture system can serve as a model to study regulatory processes in the developing steroidogenic brain.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Uterine glutathione reductase activity: modulation by estrogens and progesterone.

The aim of this study was to determine whether glutathione reductase activity in uterine tissue is regulated by sex hormones. In spayed rats uterine glutathione reductase was significantly increased by exogenous estrogen (P< 0.01), progesterone (P< 0.01) or estrogen plus progesterone (P<0.01). When enzyme activity is expressed per mg protein, daily administration of estrogen or progesterone induces a progressive increase of this enzyme between 24 to 48 h or 24 to 72 h of treatment, respectively. Whereas the combination of both steroids causes an earlier and higher increase in glutathione reductase activity at 24 h of treatment. Estradiol singly or in combination with progesterone induced the highest protein concentration in the uterus. Whereas uterine DNA concentration is only significantly affected by estradiol. Our results suggest that uterine glutathione reductase is regulated by estradiol and progesterone and may be involved in maintaining levels of reduced glutathione in the uterus. This compound may be required for control of the redox state of thiol groups and in detoxification reactions involving H2O2 and electrophylic substances. The antioxidant action of estrogens is partially due to the stimulation of glutathione reductase.

Animals↗
PubMed1995

Progesterone stimulation of HMG-CoA reductase activity in cultured cells.

In a previous study we showed that progesterone (PG) stimulated HMG-CoA reductase (HMGR) activity in rat intestinal epithelial cells (IEC-6) incubated in the presence or absence of low-density lipoprotein (LDL) [1,2]. In the present study we examined further the mechanism of this stimulation. We observed that the stimulation of HMGR activity by PG was completely prevented by cycloheximide. Turnover studies utilizing immunoprecipitation of HMGR-labeled with [35S]methionine revealed that PG increased reductase activity by inhibiting HMGR degradation without affecting the synthesis of HMGR. The stimulation of HMGR activity by progesterone could be accounted for by a continuous synthesis of HMGR while its degradation was retarded. In the presence of LDL, the activity of HMGR in IEC-6 cells was effectively inhibited, however PG was able to stimulate HMGR in the presence of LDL. This effect was not due to an interference of normal cellular metabolism of LDL, since PG had no effect on the cellular uptake and lysosomal degradation of 125I-LDL. PG did not affect of the rate of lysosomal hydrolysis of [3H]cholesteryl linoleate-LDL. The free [3H]cholesterol derived from [3H]cholesteryl linoleate-LDL moved to the cell membrane and effluxed to HDL3 in the medium at the same rate in the presence or absence of PG. Although PG did not affect LDL metabolism, pre-treatment of cells with LDL delayed the onset of HMGR stimulation by PG. In IEC-6 cells deprived of LDL for 24 h, the HMGR activity was stimulated immediately following PG addition. In cells pre-treated with LDL for 24 h, the stimulation was delayed by 4 h. Treatment of cells with 25-hydroxycholesterol completely prevented PG stimulation of HMGR activity. We propose that the stimulation of HMGR activity in the presence or absence of LDL is related to the ability of PG to attenuate the formation and/or action of intracellular HMGR repressor molecules which accelerate the degradation of HMGR.

Animals↗
PubMed2005

Synthesis and pharmacological evaluation of new progesterone esters as 5alpha-reductase inhibitors.

In this study we report the synthesis and pharmacological evaluation of four new progesterone derivatives; 17alpha-hydroxy-16beta-methylpregna-4,6-diene-3,20-dione 12, 17alpha-cyclopropylcarbonyloxy-16beta-methylpregna-4,6-diene-3,20-dione 13, 17alpha-cyclobutylcarbonyloxy-16beta-methylpregna-4,6-diene-3,20-dione 14, 17alpha-acetoxy-16beta-methylpregna-4,6-diene-3,20-dione 15 and the pregnatriene compound 17alpha-cyclobutylcarbonyloxy-16beta-methylpregna-1,4,6-triene-3,20-dione 16. The pharmacological effect of these compounds was determined in vivo as well as in vitro. The evaluation in vivo was carried out on gonadectomized male hamsters that were injected subcutaneously daily with testosterone (T) and/or finasteride, or with the novel compounds. At the end of the treatments the animals were sacrificed and the prostates were weighed. It was observed that when testosterone (T) and finasteride or compounds 12-16 were injected together, the weight of the prostate decreased significantly as compared to that of the testosterone-treated animals. The 5alpha-reductase inhibitory activity was evaluated in vitro using human prostate homogenates. These experiments showed the following IC50 values: compound 12 (alcohol at C-17) 1.2 x 10(-6) M, 13 (cyclopropyl substituent at C-17) 7.9 x 10(-10) M, 14 (cyclobutyl substituent) 3.2 x 10(-8) M, 15 (acetoxy substituent) 6.3 x 10(-11) M and 16 (cyclobutyl substituent) 3.9 x 10(-6) M. It is evident from these data that when the size of the substituent at C-17 is decreased, the 5alpha-reductase inhibitory activity increases. Apparently, in this biological model, the 5alpha-reductase inhibitory activity depends upon the steric effect of the substituent at C-17. However, the free alcohol 12 showed much lower 5alpha-reductase inhibitory activity.

5-alpha Reductase Inhibitors↗
PubMed1998

Effects of testosterone and progesterone on brain 5alpha-reductase and aromatase in Long-Evans males and comparison of aromatase in Long-Evans vs. Sprague-Dawley rats.

We investigated medial basal hypothalamic-preoptic area (MBH-POA) 5alpha-reductase and aromatase enzyme activities in gonadally intact and castrated adult Long-Evans (L-E) male rats treated with testosterone (T), progesterone (P), and a combination of T+P. MBH-POA 5alpha-reductase and aromatase activities did not differ significantly among the groups. The lack of a difference in MBH-POA aromatase between control and castrated L-E animals was unexpected. In two further experiments, MBH-POA aromatase was examined in intact and castrated L-E and Sprague-Dawley (S-D) rats, using direct and indirect assays. The activity in castrated S-D (but again, not in L-E) rats significantly decreased compared to control values. These data suggest that the absence of gonads does not decrease MBH-POA aromatase in adult L-E rats.

Animals↗
PubMed2005

Neurosteroids and female reproduction: estrogen increases 3beta-HSD mRNA and activity in rat hypothalamus.

A central event in mammalian reproduction is the LH surge that induces ovulation and corpus luteum formation. Typically, the LH surge is initiated in ovariectomized rats by sequential treatment with estrogen and progesterone (PROG). The traditional explanation for this paradigm is that estrogen induces PROG receptors (PR) that are activated by exogenous PROG. Recent evidence suggests that whereas exogenous estrogen is necessary, exogenous PROG is not. In ovariectomized-adrenalectomized rats, estrogen treatment increases hypothalamic PROG levels before an LH surge. This estrogen-induced LH surge was blocked by an inhibitor of 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD), the proximal enzyme for PROG synthesis. These data indicate that estrogen induces de novo synthesis of PROG from cholesterol in the hypothalamus, which initiates the LH surge. The mechanism(s) by which estrogen up-regulates neuro-PROG is unknown. We investigated whether estrogen increases 1) mRNA levels for several proteins involved in PROG synthesis and/or 2) activity of 3beta-HSD in the hypothalamus. In ovariectomized-adrenalectomized rats, estrogen treatment increased 3beta-HSD mRNA in the hypothalamus, as measured by relative quantitative RT-PCR. The mRNAs for other proteins involved in steroid synthesis (sterol carrier protein 2, steroidogenic acute regulatory protein, and P450 side chain cleavage) were detectable in hypothalamus but not affected by estrogen. In a biochemical assay, estrogen treatment also increased 3beta-HSD activity. These data support the hypothesis that PROG is a neurosteroid, produced locally in the hypothalamus from cholesterol, which functions in the estrogen positive-feedback mechanism driving the LH surge.

Animals↗
PubMed1976

Histochemical studies of delta5-3beta-, 20lapha- and 20beta-hydroxysteroid dehydrogenases and possible progestagen production in hamster eggs.

Hamster eggs at various developmental stages were studied histochemically fro the presence of delta5-3beta-hydroxysteroid dehydrogenase (HSD) (pregnenolone as the substrate and NAD as the cofactor), 20alpha-HSD (20alpha-hydroxypregn-4-en-3-one and NADP) and 20 beta-HSD (20beta-hydroxypregn-4-en-3-one and NAD). All three enzymes were absent from ovarian eggs but were demonstrated in unfertilized and fertilized eggs up to the blastocyst stage. The activities varied only slightly.

Animals↗
PubMed1979

Immunohistochemical studies on electron transport proteins associated with cytochromes P-450 in steroidogenic tissues. II. Microsomal NADPH-cytochrome c reductase in the rat adrenal.

NADPH-cytochrome c reductase (NADPH : ferricytochrome oxido-reductase, EC 1.6.2.4), the flavoprotein which mediates the NADPH-dependent reduction of cytochromes P-450 in adrenocortical microsomes, has been localized immunohistochemically at the light microscopic level in rat adrenal glands. Localization was achieved through the use of sheep antiserum produced against purified, trypsin-solubilized rat hepatic microsomal NADPH-cytochrome c reductase in both an unlabeled antibody peroxidase-antiperoxidase technique and an indirect fluorescent antibody method. The sheep antibody to rat hepatic microsomal NADPH-cytochrome c reductase concomitantly inhibited the NADPH-cytochrome c reductase and progesterone 21-hydroxylase activities catalyzed by isolated rat adrenal microsomes. When sections of rat adrenal glands were exposed to the reductase antiserum in both immunohistochemical procedures, positive staining for NADPH-cytochrome c reductase was observed in parenchymal cells of the three cortical zones but not in medullary chromaffin cells. The intensity of staining, however, was found to differ among the three cortical zones, with the most intense staining being found in the zona fasciculata and the least in the zona glomerulosa. The intensity of staining was also found to differ among cells within the zona fasciculata. These immunohistochemical observations demonstrate that microsomal NADPH-cytochrome c reductase is not distributed uniformly throughout the rat adrenal cortex.

Adrenal Cortex↗
PubMed1987

Regulation of sterol biosynthesis and of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in cultured cells by progesterone.

Treatment of rat intestinal epithelial cells in culture (IEC-6) with progesterone (10 micrograms/ml) caused a strong inhibition of cholesterol biosynthesis as indicated by a decreased incorporation of radiolabel from [3H]acetate. This inhibition was accompanied by an accumulation of radioactivity in an intermediate which coeluted with authentic desmosterol upon high performance liquid chromatography (HPLC). In addition, treatment of cells with progesterone caused lesser accumulation of radiolabel in products with retention times (RT) of 7.9 and 13.5 min on reverse-phase HPLC. The RT-13.5 compound was tentatively identified as cholesta-5,7,24-trien-3 beta-ol based on its relative retention and on its conversion to cholesterol upon incubation with untreated cells. The RT-7.9 compound was identified as 24 (S),25-epoxycholesterol (S-EC) based on its coelution with authentic S-EC and by its conversion to 25-hydroxycholesterol upon reduction with LiAlH4. Incubation of IEC-6 cells with chemically prepared S-EC resulted in dose-dependent suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity within 6 h (I50 = 0.3 microM). Pretreatment of cells with progesterone prevented this suppressive effect. No suppression of reductase activity was observed in progesterone-treated cells in spite of obvious accumulation of S-EC in amounts sufficient to effect regulation; instead, a 2-3-fold increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity occurred within a 24-h period. Following the removal of progesterone from the culture medium, reductase activity declined rapidly over the next 6 h. However, IEC-6 cells could not metabolize S-EC, derived either endogenously or exogenously, during a similar time frame; nor did progesterone affect the uptake of exogenous S-EC by IEC-6 cells. These results show that although progesterone treatment of cultured cells promotes the synthesis of a natural oxysterol suppressor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, the continued presence of progesterone prevents the regulatory action of S-EC. The unique nature of this interference is high-lighted by the observation that progesterone could not prevent the suppression of reductase activity by either 25-hydroxycholesterol or mevalonolactone.

Animals↗
PubMed1982

In vitro metabolism of progesterone and 17 alpha-hydroxyprogesterone in the testis of the rainbow trout, Salmo gairdneri Rich., at different stages of spermatogenesis.

Rainbow trout testicular fragments were incubated at 8 different stages of the spermatogenetic cycle in the presence of tritiated progesterone or 17 alpha-hydroxyprogesterone. This paper describes the potential enzymatic activities involved in the delta 4 route leading to the production of "major" derivatives. 1) A 5-reductase converted progesterone into 5 alpha (beta)-pregnane-3,20-dione. 2) A 20 beta-oxydoreductase converted 17 alpha-hydroxyprogesterone into 17 alpha-hydroxy-20 beta-dihydroprogesterone. At some stages this synthesis reached or exceeded androgen production. 3) 20 beta-oxydoreductase, 17-20 desmolase and 17 beta-oxydoreductase are proposed as putative enzymatic steps in the regulation and modulation of steroidogenic metabolism in the trout testis. 4) The physiological role of the different major steroids synthesized by the testis in vitro is discussed, and the hypothesis of the involvement of 17 alpha-hydroxy-20 beta-dihydroprogesterone in the control of germ cell mitotic activity and/or feedback on the hypothalamo-pituitary system is examined.

17-alpha-Hydroxyprogesterone↗
PubMed1999

Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice.

Progesterone is an effective anticonvulsant against pentylenetetrazol (PTZ) seizures. This action is hypothesized to require the metabolic conversion of progesterone to the gamma-aminobutyric acidA receptor potentiating neuroactive steroid allopregnanolone by 5alpha-reductase isoenzymes followed by 3alpha-hydroxy oxidoreduction. We evaluated this possibility using the competitive 5alpha-reductase inhibitor finasteride. Progesterone (50-200 mg/kg, i.p.) protected mice against PTZ-induced seizures in a dose-dependent manner (ED50, 94 mg/kg). Pretreatment with finasteride (50-300 mg/kg, i.p.) produced a dose-dependent (ED50, 146 mg/kg) reversal of the protective effects of progesterone (2 x ED50 dose = 188 mg/kg). In contrast, finasteride (up to 300 mg/kg) failed to affect the anticonvulsant activity of allopregnanolone (10-30 mg/kg, i.p.; ED50, 12 mg/kg). Finasteride (up to 300 mg/kg) did not block the protective effect of high doses of progesterone (250-350 mg/kg) on tonic hindlimb extension in the maximal electroshock seizure test (progesterone ED50, 235 mg/kg). The anticonvulsant activity of progesterone against PTZ-induced seizures can be blocked by 5alpha-reductase inhibition, providing strong evidence that the anticonvulsant effect of the steroid in this model is mediated by its active metabolite allopregnanolone.

Animals↗
PubMedDate not supplied

QSARs for 6-azasteroids as inhibitors of human type 1 5alpha-reductase: prediction of binding affinity and selectivity relative to 3-BHSD.

Quantitative structure-activity relationships (QSARs) are developed to describe the ability of 6-azasteroids to inhibit human type 1 5alpha-reductase. Models are generated using a set of 93 compounds with known binding affinities (K(i)) to 5alpha-reductase and 3beta-hydroxy-Delta(5)-steroid dehydrogenase/3-keto-Delta(5)-steroid isomerase (3-BHSD). QSARs are generated to predict K(i) values for inhibitors of 5alpha-reductase and to predict selectivity (S(i)) of compound binding to 3-BHSD relative to 5alpha-reductase. Log(K(i)) values range from -0.70 log units to 4.69 log units, and log(S(i)) values range from -3.00 log units to 3.84 log units. Topological, geometric, electronic, and polar surface descriptors are used to encode molecular structure. Information-rich subsets of descriptors are identified using evolutionary optimization procedures. Predictive models are generated using linear regression, computational neural networks (CNNs), principal components regression, and partial least squares. Compounds in an external prediction set are used for model validation. A 10-3-1 CNN is developed for prediction of binding affinity to 5alpha-reductase that produces root-mean-square error (RMSE) of 0.293 log units (R(2) = 0.97) for compounds in the external prediction set. Additionally, an 8-3-1 CNN is generated for prediction of inhibitor selectivity that produces RMSE = 0.513 log units (R(2) = 0.89) for the external prediction set. Models are further validated through Monte Carlo experiments in which models are generated after dependent variable values have been scrambled.

Azasteroids↗
PubMed1994

Enhanced stimulation of 5 alpha-reductase activity in cultured Leydig cell precursors by human chorionic gonadotropin.

Previous studies have demonstrated that the increase in number of Leydig cells during prepubertal maturation results, in part, from the differentiation of mesenchymal precursors between the second and fourth week of postnatal life. After conversion to immature Leydig cells, they actively synthesize testosterone, but this androgen does not accumulate because high 5 alpha-reductase activity rapidly converts testosterone to 5 alpha-reduced metabolites. The present studies examined whether the conversion of precursor cells to immature Leydig cells in vitro by human chorionic gonadotropin (hCG), as characterized by progressive increases in testosterone formation and 5-ene-3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD) activity, is associated similarly with an enhanced stimulation of 5 alpha-reductase activity. We also evaluated whether this conversion occurs following blockade of dihydrotestosterone (DHT) formation by the inclusion of a 5 alpha-reductase inhibitor during the entire treatment period. Precursor cells were isolated from immature rats using a multi-step procedure normally used to isolate highly purified Leydig cells from adult or immature rats. These cells localize in a region of lower density on Percoll gradients than Leydig cells. Although the acute (3h) response to hCG with respect to testosterone formation, and basal 3 beta-HSD and 5 alpha-reductase activities on day 1 of culture were much higher in purified Leydig cells than precursor cells from immature rats, the response of each parameter to chronic (6-day) treatment with hCG was much greater in precursor cells. Furthermore, the conversion of precursor cells to immature Leydig cells occurred in the presence of a 5 alpha-reductase inhibitor during the entire treatment period, suggesting that this conversion occurs in the absence of DHT. These results demonstrate for the first time that in addition to increased testosterone biosynthesis and 3 beta-HSD activity, the conversion of precursor cells to immature Leydig cells, in vitro, in response to chronic hCG treatment, involves enhanced 5 alpha-reductase activity.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2000

Current understanding of androgenetic alopecia. Part I: etiopathogenesis.

Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. This continuous process results in a type of alopecia that follows a definite pattern in those individuals who are genetically predisposed. At present the predisposing genes are unknown but the relatively strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait and a polygenic basis is therefore most likely. AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive HF. Today we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss in AGA. However, recent experimental and clinical advances enable us to explain some pathogenetic steps leading to androgenetic hair loss. Among other steroidogenic isoenzymes such as 17b- and 3b- hydroxysteroid dehydrogenases, the type 2 5a-reductase within the dermal papilla plays a central role by the intrafollicular conversion of T to DHT.

17-Hydroxysteroid Dehydrogenases↗
PubMed2000

Microsomal cytochrome P450 2C5: comparison to microbial P450s and unique features.

Although microsomal P450s represent the majority of P450s, only microbial P450s have been amenable to crystal structure solution. We have recently solved the first crystal structure of a microsomal P450, 2C5, a progesterone hydroxylase from rabbit. We discuss the features of the protein in common with existing structures of microbial P450s and limitations of homology modeling mammalian P450s based on the microbial structures. Unique features involving membrane, substrate and cytochrome P450 reductase interactions are also discussed.

Animals↗