Dehydroepiandrosterone acetate

Dehydroepiandrosterone (DHEA) supplementation and IVF outcome in poor responders.[Pubmed:27927044]

Hum Fertil (Camb). 2017 Jun;20(2):80-87.

Ovarian stimulation of poor ovarian responders still remains a challenging issue. The incidence of poor responders among infertile women is reported in 9-24% IVF cycles and is associated with very low clinical pregnancy rates. Different treatments have been reported in the literature in an attempt to identify the best stimulation protocol for those patients. Administration of Dehydroepiandrosterone acetate (DHEA) was suggested as a promising treatment. It is well known that androgens can influence ovarian follicular growth, augment steroidogenesis, promote follicular recruitment and increase the number of primary and pre-antral follicles. The purpose of this review is to evaluate the effect of DHEA supplementation on women with diminished ovarian reserve. Because of the uncertainty of published data, we suggest that well-designed multicentre RCTs are required to provide more insight on the effectiveness of DHEA. The absence of significant side effects should not be considered as an argument to support DHEA treatment.

[A search for microscopic fungi with directed hydroxylase activity for the synthesis of steroid drugs].[Pubmed:29509389]

Prikl Biokhim Mikrobiol. 2016 May-Jun;52(3):324-32.

The hydroxylase activities of new strains such as Curvularia lunata, C. geniculata, C. eragrostidis, C. prasadii, Ulocladium botrytis, Alternaria tenuis, and Fusarium oxysporum toward three steroid substrates, namely, androstenedione (AD), cortexolone (S), and Dehydroepiandrosterone acetate (DAA), were characterized. The 9alpha-hydroxylase activity of C. lunata 1011 cells against S to form 9alpha-hydroxy-S was shown for the first time. It was found that C. geniculata 837 and F. oxysporum 11dn1 strains can hydroxylate substrates to form pharmacologically promising 7alpha-hydroxysteroids. C. geniculata 837 cells selectively hydroxylate AD, resulting in 7alpha-hydroxytestosterone, whereas F. oxysporum 11dn1 leads to the transformation of DAA to 7alpha-hydroxydehydroepiandrosterone.

Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5alpha-reductase inhibitors.[Pubmed:26780831]

Bioorg Med Chem. 2016 Feb 15;24(4):779-88.

In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from Dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5alpha-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5alpha-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM).

Design and synthesis of D-ring steroidal isoxazolines and oxazolines as potential antiproliferative agents against LNCaP, PC-3 and DU-145 cells.[Pubmed:24910245]

Steroids. 2014 Sep;87:93-8.

Two series of novel steroidal isoxazolines and oxazolines were synthesized through different routes from Dehydroepiandrosterone acetate and pregnenolone acetate, respectively. The synthesis of the analogs of both series is multistep and proceeds in good overall yields. While the key step in the synthesis of former is the cycloaddition of aromatic nitrile oxides across alpha,beta-unsaturated olefins, it is the condensation of alpha,beta-azidoalcohols with aromatic aldehydes in the later. Compounds of both the series were tested for their cytotoxic activities against LNCaP, PC-3 and DU-145 prostate cancer cell lines. Amongst all the compounds of both the series screened for their prostate cancer activity, compound 6a, 6e and 12a are the most active especially against LNCaP and DU-145 cancer cell lines.

Synthesis and biological evaluation of novel unsaturated carboxysteroids as human 5alpha-reductase inhibitors: a legitimate approach.[Pubmed:22776417]

Eur J Med Chem. 2012 Aug;54:728-39.

In the present study, novel steroidal 17a-substituted 3-cyano-17a-aza-D-homo-3,5-androstadien-17-ones (12-19) and 17a-substituted 17-oxo-17a-aza-D-homo-3,5-androstadien-3-oic acids (20-26) were synthesized from Dehydroepiandrosterone acetate (6) along with 17-oxo-19-nor-3,5-androstadien-3-oic acid (30) through a multistep synthesis. Compounds were evaluated for their in vitro 5alpha-reductase inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5alpha-reductase inhibitory activity was also determined using rat prostate weighing method. Compounds 21-23 and 25 showed potent inhibition of 5alpha-reductase II enzyme with IC(50) values of 54.1 +/- 9.5, 22.1 +/- 2.4, 72.8 +/- 2.3 and 26.5 +/- 4.4 nM respectively as compared to Finasteride (30.3 nM) along with a significant (p < 0.05) reduction in rat prostate weight.

Synthesis of novel steroidal D-ring substituted isoxazoline derivatives of 17-oxoandrostanes.[Pubmed:18166206]

Steroids. 2008 Mar;73(3):370-4.

A facile synthesis of isoxazoline derivatives of 17-oxoandrostane at the side chain of D-ring is reported. The scheme involves the transformation of the starting Dehydroepiandrosterone acetate (ketone) to the Knoevenegel product, reduction to the nitrile, and elimination to the carboxaldehyde. Cycloaddition of nitrileoxides across olefinic aldehyde intermediate led to the synthesis of novel side chain isoxazoline derivatives.

Synthesis and evaluation of novel 17-indazole androstene derivatives designed as CYP17 inhibitors.[Pubmed:17884122]

Steroids. 2007 Dec;72(14):939-48.

A series of novel 1H- and 2H-indazole derivatives of the commercially available Dehydroepiandrosterone acetate have been synthesized and tested for inhibition of human cytochrome 17alpha-hydroxylase-C(17,20)-lyase (CYP17), androgen receptor (AR) binding affinity, and cytotoxic potential against three prostate cancer (PC) cell lines.

Preventive effects of dehydroepiandrosterone acetate on the fatty liver induced by orotic acid in male rats.[Pubmed:10067169]

Exp Anim. 1998 Oct;47(4):257-60.

Preventive effects of dehydroepiandrosteone acetate (DHEA-A) and clofibrate (positive control substance) on the fatty liver induced by orotic acid (OA) were examined on the male Sprague-Dawley rats fed a high sucrose based diet containing 1% OA and this diet further mixed with 0.5% DHEA-A or 0.5% clofibrate for 2 weeks. Numerous lipid droplets were observed in the hepatocytes of the rats treated with OA alone, but not in those treated with DHEA-A or clofibrate. In comparison to the group with OA alone, the DHEA-A or clofibrate treated rats showed a larger relative liver weight (to body weight) which was accompanied by increased peroxisomes in the hepatocytes. These results indicate that DHEA-A, as well as clofibrate, may prevent OA-induced fatty liver.

Chronic neurosteroid treatment prevents the development of morphine tolerance and attenuates abstinence behavior in mice.[Pubmed:9389376]

Eur J Pharmacol. 1997 Oct 15;337(1):19-25.

The effect of neurosteroids on the development of morphine tolerance and dependence was examined in mice. Development of tolerance to the antinociceptive effect of morphine sulfate (10 mg/kg, twice daily for 9 days) was measured in the tail-flick test and dependence was assessed from naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 of testing. Concomitant chronic administration of neurosteroids, allopregnanolone (0.5 mg/kg), pregnenolone sulfate (2 and 5 mg/kg) or dehydroepiandrosterone sulfate (2 and 5 mg/kg), followed by morphine (10 mg/kg) prevented the development of tolerance to the antinociceptive effect of morphine and suppressed the naloxone-precipitated withdrawal jumps. In contrast, Dehydroepiandrosterone acetate (5 mg/kg) failed to modulate the morphine tolerance and dependence. The inhibitory effect was also seen upon concomitant administration of a neurosteroid precursor, progesterone (1-10 mg/kg), and a mitochondrial diazepam binding inhibitor receptor agonist, 4'-chlordiazepam (0.25-1 mg/kg), while an adrenocorticosteroid, hydrocortisone (1 and 10 mg/kg), failed to do so. However, acute treatment with these neurosteroids was not associated with any decrease in withdrawal jumping behavior in morphine-dependent mice. Neurosteroids themselves, at doses employed in the study, did not exert any effects on antinociception. These results support a role for neurosteroids in the development of tolerance to and dependence on morphine and suggest the potential utility of specific neuroactive steroids in its treatment.

[Synthesis and antifertility activity of a-nor-5 alpha-androstane derivatives].[Pubmed:8701730]

Yao Xue Xue Bao. 1995;30(10):745-51.

In order to study the relationship between the structure of A-nor-5 alpha-androstane derivatives and their antifertility activity, we designed and synthesized 16 A-nor-5 alpha-androstane compounds through several reaction steps with Dehydroepiandrosterone acetate as a starting material. Their structures were confirmed by IR, 1HNMR, MS, elemental analyses, etc. Preliminary pharmacological tests showed that compounds 8, 9, 10 and 16 possess antiimplantation activity to some extent (2.5 mg.kg-1, administered po, gave 67-75% antiimplantation rate). Other compounds showed low activity. The possible relationship between compound structures and their activities is analysed briefly.

C19 adrenal steroids enhance prostaglandin F2 alpha output by human endometrium in vitro.[Pubmed:2970223]

Am J Obstet Gynecol. 1988 Aug;159(2):500-4.

Dehydroepiandrosterone sulfate significantly increased prostaglandin F2 alpha output by fragments of human secretory endometrium during the first and second 24-hour periods of incubation in Ham's F-10 medium containing 10% charcoal-treated calf bovine serum. The effects of dehydroepiandrosterone sulfate were noted at 10(-6) mol/L concentrations, which are close to the normal plasma levels of this compound. For the purpose of comparison, the effects of estradiol at 10(-8) mol/L and those of unconjugated dehydroepiandrosterone, Dehydroepiandrosterone acetate, 5-androstene-3 beta, 17 beta-diol, or 5 alpha-dihydrotestosterone were evaluated at 10(-8) to 10(-8) mol/L concentrations in parallel experiments. All of the delta 5-C19 steroids tested enhanced prostaglandin F2 alpha output at 10(-6) mol/L but not at 10(-8) mol/L; 5 alpha-dihydrotestosterone was inactive at 10(-6) mol/L but showed a stimulatory effect at 10(-5) mol/L in two experiments. The stimulation of prostaglandin F2 alpha production by the adrenal steroids was significantly reduced by the antiestrogen 4-hydroxytamoxifen at 10(-6) mol/L (a finding consistent with the reported utilization of the estrogen receptor for their actions on other systems) but was not affected by the antiandrogen 4-hydroxyflutamide at 10(-6) mol/L. Progesterone (10(-7) mol/L) also lowered the effects of dehydroepiandrosterone (10(-6) mol/L) and 5-androstene-3 beta,17 beta-diol (10(-6) mol/L), as well as those of estradiol (10(-8) mol/L). delta 5-C19 steroids at 10(-6) mol/L levels did not antagonize the effect of 10(-8) mol/L estradiol, whereas 5 alpha-dihydrotestosterone reduced it by 50% at these concentrations. The significant effect of 5 alpha-dihydrotestosterone points to potential antiestrogenic effects of the C19 compounds that may be manifested in vivo at particular C19/estradiol concentration ratios. The demonstration of direct estrogenic effects of delta 5-C19 steroids, which are not significantly converted to estrogens in vivo, justifies their use in estrogen replacement preparations and indicates that aromatase inhibitors may not eliminate completely the stimulation of estrogen-responsive breast and endometrial tumors by the patient's adrenal steroids.