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At least 253 records · Page 14Linked to original sources
PubMed1990

Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene-isomerase activity.

Human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene isomerase (3 beta-HSD) purified from human placenta transforms C-21 (pregnenolone and 17 alpha-hydroxy pregnenolone) as well as C-19 (dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol) steroids into the corresponding 3-keto-4-ene-steroids and is thus involved in the biosynthesis of all classes of hormonal steroids. Trilostane, epostane and cyanoketone are potent inhibitors of 3 beta-HSD with Ki values of approximately 50 nM. 4-MA, a well known 5 alpha-reductase inhibitor, is also a potent inhibitor of 3 beta-HSD with a Ki value of 56 nM. Synthetic progestin compounds such as promegestone and RU2323 show relatively strong inhibitory effects with Ki values of 110 and 190 nM, respectively. Cyproterone acetate, a progestin used in the treatment of hirsutism, acne and prostate cancer as well as norgestrel and norethindrone that are widely used as oral contraceptives also inhibit 3 beta-HSD activity at Ki values of 1.5, 1.7 and 2.5 microM, respectively.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

The clinical development of a 5 alpha-reductase inhibitor, finasteride.

Finasteride, a 4-aza steroid compound, is an orally active inhibitor of the 5 alpha-reductase enzyme. 5 alpha-Reductase is necessary for the metabolism of testosterone (T) to dihydrotestosterone (DHT) and is found in high levels only in certain tissues such as the prostate. Finasteride has been shown to markedly suppress serum DHT levels in man without lowering testosterone levels. In patients with benign prostate hyperplasia (BPH), finasteride was found to decrease prostate volume by a mean of 28% over a period of 6 months, without causing clinically significant adverse effects. DHT appears to be the primary androgen for prostatic growth. Selective inhibition of 5 alpha-reductase by finasteride may provide a novel approach to BPH therapy by reducing prostate size without affecting T-dependent processes such as fertility, muscle strength, and libido. The clinical development of finasteride for the treatment of benign prostate hyperplasia is reviewed.

5-alpha Reductase Inhibitors↗
PubMed1991

Differential inhibition of dehydrogenase and 5-ene----4-ene isomerase activities of purified 3 beta-hydroxysteroid dehydrogenase. Evidence for two distinct sites.

The success in synthesis of [3H]5-androstene-3,17-dione, the intermediate product in the transformation of DHEA to 4-androstenedione by 3 beta-hydroxysteroid dehydrogenase/5-ene----4-ene isomerase (3 beta-HSD) offers the opportunity to determine whether or not the two activities reside in one active site or in two closely related active sites. The finding that N,N-dimethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) inhibits competitively and specifically the dehydrogenase activity whereas a non-competitive inhibition type with a Ki value 1000 fold higher was observed for the isomerase activity, indicated that dehydrogenase and isomerase activities belong to separate sites. Using 5 alpha-dihydro-testosterone and 5 alpha-androstane-3 beta, 17 beta-diol, exclusive substrates for dehydrogenase activity, it was shown that dehydrogenase is reversible and strongly inhibited by 4-MA and that thus the irreversible step in the transformation of DHEA to 4-androstenedione is due to the isomerase activity.

3-Hydroxysteroid Dehydrogenases↗
PubMed1992

Role of 5 alpha-reduction in progesterone's ability to release FSH in estrogen-primed ovariectomized rats.

In ovariectomized estrogen-primed rats, progesterone as well as 5 alpha-dihydroprogesterone (5 alpha-DHP) are capable of inducing the release of gonadotropins. This study examined the need of 5 alpha-reduction as a prerequisite for the action of progesterone. The 5 alpha-reductase inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide was injected at a 1 or 2 mg dose/rat 2 h prior to an injection of 0.4 or 0.8 mg progesterone/kg body weight at 0900 h to immature ovariectomized, estrogen-primed rats and serum was analyzed for LH and FSH at 1500 h. Pituitary and hypothalamic 5 alpha-reductase activity was measured at the time of progesterone administration and at the time of the surge by incubating tissue homogenates with [3H]progesterone. Substrate, ([3H]progesterone) and product ([3H]5 alpha-DHP), were separated by reverse phase HPLC. The pituitary 5 alpha-reductase activity was not blocked at 1500 h. However, both pituitary and hypothalamic 5 alpha-reductase was blocked at the time of progesterone administration. No effect was seen by acute administration of the 5 alpha-reductase inhibitor upon either the 0.4 or 0.8 mg progesterone/kg-induced release of LH and FSH. There was, however, a specific, significant inhibition of progesterone-induced FSH but not LH release when the 5 alpha-reductase inhibition was sustained throughout the afternoon of the gonadotropin surge. These results indicate a biologically significant role for the irreversible 5 alpha-reduction of progesterone in the modulation of the release of FSH.

Androgen Antagonists↗
PubMed1992

Stimulatory and inhibitory effects of progesterone on FSH secretion by the anterior pituitary.

The purpose of this study was to investigate whether progesterone exerted progesterone receptor mediated direct effects on the anterior pituitary in the secretion of FSH and whether such effects were mediated through the 5 alpha-reduction of progesterone. Treatment of anterior pituitary dispersed cells for 48 h with 0.5 nM estradiol reduced the ED50 for gonadotropin releasing hormone (GnRH)-stimulated FSH release from 0.58 to 0.36 ng/ml and the ED50 for GnRH-induced LH release from 0.54 to 0.19 ng/ml. When dispersed pituitary cells were treated with 0.5 nM estradiol and exposed to various doses of progesterone for 1 to 6 h, the most consistent rise in basal and GnRH-stimulated FSH release was observed with the 50 nM dose of progesterone with a 3-h exposure period. All three doses of progesterone elevated basal LH and GnRH-stimulated LH was increased by the 50 and 100 nM doses of progesterone during the 3-h period of treatment. Using the 50 nM dose of progesterone, basal and GnRH-stimulated LH was increased after 2, 3 and 6 h of progesterone treatment. When the period of exposure of progesterone was extended to 12, 36 or 48 h, there was a significant inhibition of GnRH-stimulated FSH release. GnRH-stimulated LH release was inhibited at 36 and 48 but not 12 h after progesterone treatment. These studies showed that the effect of progesterone administered for periods of 1 to 6 h enhanced the secretion of LH and FSH whereas progesterone administered for periods beyond 12 h inhibited FSH and LH release by dispersed pituitary cells in culture. These results are similar to those observed in vivo after progesterone treatment. Furthermore estrogen priming of the dispersed pituitary cells was necessary to observe the effects of progesterone. The progesterone antagonist RU486 prevented the progesterone-induced rise in GnRH-stimulated FSH release. Furthermore the 5 alpha-reductase inhibitor N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane- 17 beta-carboxamide also prevented the progesterone-induced rise in GnRH-stimulated FSH release in estrogen-treated dispersed pituitary cells. These results indicate that the anterior pituitary is a major site of action of progesterone in the release of FSH and that 5 alpha-reduction of progesterone plays an important role in FSH release.

5-alpha Reductase Inhibitors↗
PubMed1992

Selective inhibition of the 5 alpha-reductase of the rat epididymis.

The effect of several synthetic steroids belonging either to the 4-aza-3-oxo-steroid family or to androstene and androstane derivatives was investigated "in vitro" on the epididymal as well as prostatic 5 alpha-reductase activity. For this purpose rat caput epididymis and prostate were incubated with the different steroidal compounds at molar concentrations of 10(-7), 10(-6), and 10(-5) in the presence of labelled testosterone as substrate. The steroids 4-MA (17 beta, N,N-diethyl-carbamoyl-4-aza-5 alpha-androstan-3-one) and 4-OH-A (4-hydroxy-androstenedione), already known to be effective 5 alpha-reductase inhibitors at the level of the prostate, have been used as reference molecules. The 5 alpha-reductase activity was evaluated by measuring pg of dihydrotestosterone (DHT) formed in 2 h of incubation by mg of tissue. The steroids A, B, C, F, G and I inhibit the formation of DHT in the rat epididymis although to different extents; they are also equally effective on the formation of DHT in the rat prostate. The steroids D, E, H and L are devoid of any inhibitory property on the formation of DHT in both the rat epididymis and prostate. The most interesting results were obtained with compound M which exhibits a dose-dependent and significant inhibitory effect on the formation of DHT in the epididymis, but it is inactive at the level of the prostate. These findings suggest that it is possible (a) to selectively interfere with the 5 alpha-reductase of the epididymis without affecting that present in the prostate, and (b) consequently to envisage new ways to regulate male fertility.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1994

Inhibition of the activity of 'basic' 5 alpha-reductase (type 1) detected in DU 145 cells and expressed in insect cells.

The purpose of this study was 2-fold: (1) to identify the 5 alpha-reductase (5 alpha-R) isozyme(s) present in DU 145 cells, a human cell-line of low androgen sensitivity derived from a cerebral metastasis of an epithelial prostate cancer; and (2) to compare the inhibitory potencies of three compounds on the 'basic' 5 alpha-R isozyme expressed in a baculovirus-directed insect cell system. Conversion of testosterone (T) into 5 alpha-dihydrotestosterone (DHT) in DU 145 cells was measured by HPLC coupled to a Flo-one HP radioactivity detector. DU 145 cells exhibited 5 alpha-R activity (21 pmol DHT/min/mg protein) at pH 7.4 which disappeared at pH 5.5 suggesting that, of the two genomically distinct human isozymes identified so far, type 1 5 alpha-R is expressed in DU 145 cells. This was confirmed by at least two observations: first, 5 alpha-R activity in DU 145 cells was inhibited with much higher potency by 4-MA than by finasteride which is known to be a very poor competitor of the 'basic' enzyme (IC50s = 2.8 +/- 0.2 and 264 +/- 55 nM, respectively). Second, only the type 1 5 alpha-R cDNA and not type 2 5 alpha-R cDNA hybridized with DU 145 RNA. A high potency differential was also recorded for the inhibition of 'basic' type 1 5 alpha-R expressed in a baculovirus-directed-insect cell system by these two compounds, 4-MA being considerably more active than finasteride (Ki = 8.4 +/- 2.3 and 330 +/- 9 nM, respectively). This inhibition was competitive. On the other hand, inhibition by an n-hexane lipid/sterol extract of Serenoa repens (LSESr) was non-competitive and, when expressed in terms of recommended therapeutic doses, was 3-fold greater for LSESr than for finasteride. These studies suggest that LSESr might exert a regulatory inhibitory activity due to its specific lipid/sterol composition.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1995

Effects of 5 alpha-reductase inhibitors on intraprostatic androgens in the rat.

FCE 27837 is a novel inhibitor of 5 alpha-reductase, the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of human and rat prostatic enzymes, with IC50 values of 51 and 60 nM, respectively. The in vivo effect of FCE 27837 on 5 alpha-reductase was evaluated in adult male rats, treated orally at 10 mg/kg/day for 10 days. The compound caused 33 and 42% reductions in ventral prostate and seminal vesicle weights, respectively. The prostatic content of DHT, measured 6 h after the 10th dose of FCE 27837, was reduced by 75%, whereas T content increased by 442%. Similar effects were observed with 10 mg/kg/day of finasteride, whereas epristeride, tested at the same oral dose, was found to be the least effective compound, decreasing prostate weight by 22% and DHT content by 46%. Castration caused > 90% reductions in prostatic weight and prostatic DHT.

Androstadienes↗
PubMed1995

Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts.

We compare testosterone (T) metabolism in primary cultures of epithelial cells and fibroblasts separated from benign prostate hypertrophy (BPH) and prostate cancer tissues. In all cultures, androstenedione (delta 4) formed by oxidation of T by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) represented 80% of the metabolites recovered. The amounts of 5 alpha-dihydrotestosterone (DHT), formed by reduction of T by 5 alpha-reductase (5 alpha-R), were small: 5 and 2% (BPH) and 8 and 15% (adenocarcinoma) for epithelial cells and fibroblasts, respectively. Northern blot analysis of total RNA from epithelial cells (BPH or adenocarcinoma) attributed the reductive activity to the 5 alpha-reductase type 1 isozyme and oxidative activity to the 17 beta-HSD type 2. In cancer fibroblasts, only little 17 beta-HSD type 2 mRNA was detected. The 5 alpha-reductase inhibitors, 4-MA (17 beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and finasteride, inhibited DHT formation with a preferential action of 4-MA on epithelial cells (BPH or adenocarcinoma) and of finasteride on fibroblasts from adenocarcinoma. Neither inhibitor acted on delta 4 formation. On the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon) inhibited the formation of all the T metabolites studied [IC50 S = 40 and 200 micrograms/ml (BPH) and 90 and 70 micrograms/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively]. These results have important therapeutic implications when selecting appropriate treatment options for BPH.

17-Hydroxysteroid Dehydrogenases↗
PubMed1996

FCE 28260, a new 5 alpha-reductase inhibitor: in vitro and in vivo effects.

FCE 28260 is a novel inhibitor of 5 alpha-reductase (5 alpha R), the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 15 and 16 nM, respectively, compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5 alpha R type 2 and 1 isozymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isozymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult male rats, FCE 28260 reduced prostatic DHT concentrations 6 h after oral dosing with a potency similar to that of finasteride (65% reduction at 1 mg/kg) but was found to be markedly more potent than the reference compound at 24 h (74% reduction in prostate DHT at 10 mg/kg, compared to 26% reduction induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.

5-alpha Reductase Inhibitors↗
PubMed1996

MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase.

Steroid 5alpha-reductase is required for the conversion of testosterone to dihydrotestosterone. Localization of type 1 5alpha-reductase in the sebaceous gland of skin offers the possibility for selective inhibition of this isozyme as a treatment for acne. The goals of these studies are to demonstrate the mechanism of inhibition of MK386 and its selectivity for type 1 5alpha-reductase. The apparent potency of MK386 differed depending on the source of the enzyme (i.e. recombinant vs. native), yet selectivity for type 1 5alpha-reductase was unchanged. Our results indicate that the apparent potency of MK386 is modulated by the membrane concentration of the assay. These results suggest that MK386 has a high affinity for the lipid-rich membrane environment of 5alpha-reductase. MK386 was also found to be a slow binding inhibitor of type 1 5alpha-reductase. However, the cause of this time-dependent inhibition is unrelated to partitioning of the inhibitor into the membrane because similar studies with type 2 5alpha-reductase indicate that MK386 is a reversible, competitive inhibitor. A number of counterscreens were developed to demonstrate that MK386 is a poor inhibitor of other steroid metabolizing enzymes.

5-alpha Reductase Inhibitors↗
PubMed2006

Hybrid aza-steroid alkylators in the treatment of colon cancer.

We tested two alkylating homo-aza-steroid esters, lactandrate and lactestoxate, for antineoplastic activity against colon adenocarcinoma in vitro and in vivo. Cytostatic and cytotoxic activity was evaluated in vitro with the SRB colormetric assay against nine human colon adenocarcinoma cell lines. The in vivo anti-tumour effect was determined against two rodent colon carcinomas, the Colon 26 and the relatively chemoresistant Colon 38 carcinoma, as well as against the human xenograft CX-1 colon carcinoma. Both of the tested compounds displayed a very satisfactory anti-cancer activity in vitro and in vivo. Lactestoxate produced a significantly higher overall activity than lactandrate.

Alkylating Agents↗
PubMed2005

Functional characterisation of human glycine receptors in a fluorescence-based high throughput screening assay.

The human glycine receptor subtypes alpha1beta and alpha2 have been expressed stably in HEK293 cells, and the functional characteristics of the receptors have been characterised in the FLIPR Membrane Potential Assay. The pharmacological properties obtained for nine standard ligands at the two receptors in this assay were found to be in good agreement with those from electrophysiology studies of the receptors expressed in Xenopus oocytes or mammalian cell lines. Hence, this high throughput screening assay will be of great use in future pharmacological studies of glycine receptors, particular in the search for novel compound structures acting at them.

Androstanes↗
PubMed2004

Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia.

OBJECTIVES: Dutasteride, a dual inhibitor of Type 1 and Type 2 5 alpha-reductase, has been shown to improve disease measures in patients with symptomatic benign prostatic hyperplasia (BPH) in three randomised, placebo-controlled, large-scale, 2-year Phase III clinical studies. This paper reports the pooled results of a 2-year open-label extension of the three randomised studies assessing the long-term efficacy and safety of dutasteride. METHODS: Patients randomised to dutasteride or placebo in the double-blind portion of the Phase III studies were eligible for a 2-year open-label extension, where all patients received dutasteride 0.5mg daily (dutasteride/dutasteride [D/D] group and placebo/dutasteride [P/D group]). RESULTS: Significant improvements in AUA-SI score and Q(max) were observed from Month 24 to 48 in both study groups. At Month 48, patients in the D/D group had significantly greater improvements in AUA-SI score and Q(max), and significantly greater reductions in prostate volume, than those in the P/D group. Acute urinary retention and BPH-related surgery occurred in a small percentage of patients during the open-label phase. No new safety issues were noted with long-term therapy. Onset of new drug-related adverse events were reported most frequently at the start of therapy and declined over time in patients receiving dutasteride. CONCLUSIONS: Long-term treatment with dutasteride results in continuing improvements in urinary symptoms and flow rate, and further reductions in TPV, in men with symptomatic BPH. The reduction in risk of AUR and BPH-related surgery, seen in the double-blind phase, was durable over 4-year treatment. Dutasteride was also well tolerated in long-term use.

5-alpha Reductase Inhibitors↗
PubMed2005

On the formation of 4-[N,N-bis(2-chloroethyl)amino]phenyl acetic acid esters of hecogenin and aza-homo-hecogenin and their antileukemic activity.

The p-[N,N-bis(2-chloroethyl)amino]phenylacetic acid esters of hecogenin and aza-homo-hecogenin have been prepared and their antineoplastic activity was evaluated against two basic drug screening systems in rodents, P388 lymphocytic and L1210 lymphoid murine leukemias. Among the compounds tested, the p-[N,N-bis(2-chloroethyl)amino]phenylacetic acid ester of aza-homo-hecogenin was appeared to possess a significant higher antileukemic effect. These results support that the alkylating esters of hecogenin produce important antitumor activity as well as, indicate that the aza-homo-hecogenin ester exhibits significantly higher activity due to lactam group (-NHCO-) modification.

Animals↗
PubMed2006

The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride.

BACKGROUND: Male pattern hair loss (MPHL) is a potentially reversible condition in which dihydrotestosterone is an important etiologic factor. OBJECTIVE: Our aim was to evaluate the efficacy of the type 1 and 2 5alpha-reductase inhibitor dutasteride in men with MPHL. METHODS: Four hundred sixteen men, 21 to 45 years old, were randomized to receive dutasteride 0.05, 0.1, 0.5 or 2.5 mg, finasteride 5 mg, or placebo daily for 24 weeks. RESULTS: Dutasteride increased target area hair count versus placebo in a dose-dependent fashion and dutasteride 2.5 mg was superior to finasteride at 12 and 24 weeks. Expert panel photographic review and investigator assessment of hair growth confirmed these results. Scalp and serum dihydrotestosterone levels decreased, and testosterone levels increased, in a dose-dependent fashion with dutasteride. LIMITATIONS: The study was limited to 24 weeks. CONCLUSION: Dutasteride increases scalp hair growth in men with MPHL. Type 1 and type 2 5alpha-reductase may be important in the pathogenesis and treatment of MPHL.

5-alpha Reductase Inhibitors↗
PubMed2004

Selective and rapid liquid chromatography-tandem mass spectrometry assay of dutasteride in human plasma.

A simple, rapid, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of dutasteride (I), a potent and the first specific dual inhibitor of 5alpha-reductase, in human plasma. The analyte and internal standard (finasteride (II)) were extracted by liquid-liquid extraction with diethyl ether/dichloromethane (70/30, v/v) using a Glas-Col Multi-Pulse Vortexer. The chromatographic separation was performed on a reverse phase Xterra MS C18 column with a mobile phase of 10 mM ammonium formate/acetonitrile (15/85, v/v, pH adjusted to 3.0 with formic acid). The protonated analyte was quantitated in positive ionization by multiple reaction monitoring with a mass spectrometer. The mass transitions m/z 529.5 --> 461.5 and m/z 373.3 --> 317.4 were used to measure I and II, respectively. The assay exhibited a linear dynamic range of 0.1-25.0 ng/mL for dutasteride in human plasma. The lower limit of quantitation was 100 pg/mL with a relative standard deviation of less than 15%. Acceptable precision and accuracy were obtained for concentrations over the standard curve ranges. A run time of 1.2 min for each sample made it possible to analyze a throughput of more than 400 human plasma samples/day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability or bioequivalence studies.

Azasteroids↗
PubMed2006

Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment.

Recent evidence indicates that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that breast carcinoma and tumorigenic breast cell lines have higher 5alpha-reductase and lower 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO) and 20alpha-HSO activities and mRNA expression levels than normal tissue and non-tumorigenic cell lines. The 5alpha-reduced progesterone metabolites such as 5alpha-dihydroprogesterone (5alphaP) promote both mitogenic and metastatic activity in breast cell lines in culture, whereas the 4-pregnene metabolites, 4-pregnen-3alpha-ol-20-one (3alphaHP) and 4-pregnen-20alpha-ol-3-one (20alphaHP) have the opposite (anti-cancer-like) effects. The 5alpha-reductase inhibitor dutasteride has been shown to inhibit 5alpha-reduction of testosterone to 5alpha-dihydrotestosterone in prostate tissue, resulting in decreased prostate volume. The aim of this study was to determine if dutasteride is an effective inhibitor of progesterone 5alpha-reduction in human breast cell lines and if such inhibition reduces mammary cell proliferation and detachment. The effect of dutasteride on progesterone metabolizing enzyme activities and mRNA expression were examined in tumorigenic MCF-7 and non-tumorigenic MCF-10A human breast cell lines. Dutasteride (10(-6)M) inhibited progesterone conversion to 5alpha-pregnanes by >95% and increased 4-pregnene production. The results indicated that effects of dutasteride on the progesterone metabolizing enzymes are due to direct inhibition of 5alpha-reductase activity and to altered levels of expression of 5alpha-reductase and HSO mRNAs. Treatment of cells with progesterone without medium change for 72 h resulted in significant conversion to 5alpha-pregnanes and increases in cell proliferation and detachment. The increases in proliferation and detachment were blocked by dutasteride and were reinstated by concomitant treatment with 5alphaP, providing proof-of-principle that the effects were due not to progesterone but to the 5alpha-reduced metabolites. This study provides the first evidence that dutasteride is a potent progesterone 5alpha-reductase inhibitor and that such inhibition may be beneficial in breast cancer.

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