Androgen Precursors Androstenedione Research Articles

Relationship of Biological Markers of Body Fat Distribution and Corticosteroidogenic Enzyme Activities in Women with Polycystic Ovary Syndrome.

The aim of the study is to determine the impact of different anthropometric measurements of fat distribution on baseline sex-steroid concentrations and corticosteroidogenic enzyme activity in women with polycystic ovary syndrome compared to those with regular menstrual cycles. The current cross-sectional study included 106 normal cycling controls and 268 polycystic ovary syndrome patients. Patients with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided in normoandrogenemic (n=91) and hyperandrogenemic (n=177). Anthropometric, biochemical, and hormone parameters were assessed and correlated with corticosteroidogenic enzyme activities in all three groups. Corticosteroidogenic enzyme activities were calculated using product-to-precursor ratios. Regarding sex-steroids individually, anthropometric parameters correlated with the concentrations of several androgens in polycystic ovary syndrome patients, most of them in patients with biochemical hyperandrogenism. The androgen precursors androstenedione, 17-hydroxyprogesterone, and dehydroepiandrosterone were less correlated with anthropometric parameters. The 17,20 lyase activity, in both Δ4 and Δ5 pathways, correlated with several anthropometric measurements in normo- and hyperandrogenemic polycystic ovary syndrome patients. The 17,20 lyase enzyme activity (Δ4 pathway) also correlated with conicity index, visceral adiposity index, and lipid accumulation product in the control group. 17-Hydroxylase activity positively correlated with waist-height ratio in both polycystic ovary syndrome groups. In contrast, 17-hydroxilase negatively correlated with the conicity index. Anthropometric markers of adiposity are associated with androgen levels and their precursors in blood. Body fat distribution correlates with the activities of some steroidogenic enzyme in both normo-and hyperandrogenemic polycystic ovary syndrome phenotypes. The molecular mechanisms involved in these associations are largely unclear and more investigations are required.

Resveratrol reduces the levels of circulating androgen precursors but has no effect on, testosterone, dihydrotestosterone, PSA levels or prostate volume. A 4-month randomised trial in middle-aged men.

Resveratrol is a naturally occurring polyphenol with purported inhibitory effects on prostate growth and cancer development. A number of studies have demonstrated that resveratrol reduces prostate growth in animal models and reduces prostate cell growth in vitro. Based on these pre-clinical findings, interest in resveratrol is increasing in relation to the management of benign prostate hyperplasia (BPH) and prostate cancer. So far, no human trials have evaluated the effects of resveratrol on circulating androgens, prostate size, or biochemical markers of prostate size. In a randomized placebo controlled clinical study using two doses of resveratrol (150 mg or 1,000 mg resveratrol daily) for 4 months, we evaluated the effects on prostate size, prostate specific antigen (PSA) and sex steroid hormones in 66 middle-aged men suffering from the metabolic syndrome(MetS). At baseline, prostate size and PSA were positively correlated (R = 0.34, P < 0.007) as was prostate size and age (R = 0.37, P < 0.003). Prostate size did not correlate with testosterone, free testosterone, dihydrotestosterone (DHT), or any other androgen precursor at baseline. The highest dose of resveratrol lowered the serum level of androstenedione 24% (P = 0.052), dehydroepiandrosterone (DHEA) 41% (P < 0.01), and dehydroepiandrosterone-sulphate (DHEAS) 50% (p<0.001), compared to the control group. However, prostate size and levels of PSA, testosterone, free testosterone and DHT remained unchanged. In this population of middle-aged men suffering from MetS, high dose resveratrol (1,000 mg daily) administration for 4 months significantly lowered serum levels of the androgen precursors androstenedione, DHEA and DHEAS, whereas prostate size and circulating levels of PSA, testosterone, free testosterone, and dihydrotestosterone were unaffected. The present study suggests that resveratrol does not affect prostate volume in healthy middle-aged men as measured by PSA levels and CT acquired prostate volumes. Consequently, we find no support for the use of resveratrol in the treatment of benign prostate hyperplasia.

Does exposure to testosterone significantly alter endogenous metabolism in the marine mussel Mytilus galloprovincialis?

Mussels ( Mytilus galloprovincialis) were exposed to different concentrations of testosterone (T: 20, 200 and 2000 ng/L) in a semi-static water regime (1-day dosing intervals) for up to 5 days in an attempt to see whether endogenous steroid levels and steroid metabolism were altered by exogenous exposure to testosterone. Whole tissue levels of total testosterone (free + esterified) sharply increased in a concentration-dependent manner, from 2 ng/g in controls to 290 ng/g in organisms exposed to the highest concentration. In contrast, levels of free testosterone were only significantly elevated at the high-exposure group (5-fold increase with respect to controls). Increased activity of palmitoyl-CoA:testosterone acyltransferase (ATAT) was detected in organisms exposed to the highest concentration of testosterone, while those exposed to low and medium concentrations showed significant alterations in their polyunsaturated fatty acid profiles. The obtained results suggest that esterification of the excess of T with fatty acids might act as a homeostatic mechanism to maintain endogenous levels of free T stable. Interestingly, a decrease in CYP3A-like activity was detected in T-exposed mussels together with a significant decrease in the metabolism of the androgen precursor androstenedione to dihydrotestosterone (5α-DHT). Overall, the work contributes to the better knowledge of androgen metabolism in mussels.

Comparative study on the metabolism of the androgen precursor androstenedione in two gastropod species: In vitro alterations by TBT and TPT

A comparative study was performed to assess the metabolism of the androgen precursor androstenedione (AD) in two gastropod species from the Muricidae family: Bolinus brandaris and Hexaplex trunculus. AD was mainly converted to 5α-dihydrotestosterone by microsomal fractions isolated from Bolinus brandaris, whereas it was primarily metabolized to testosterone by Hexaplex trunculus. Sex differences in the metabolism of AD were only detected in Bolinus brandaris and attributed to higher 5α-reductase activity in males. Thereafter, the effect of the organotin compounds, tributyltin (TBT) and triphenyltin (TPT), on the metabolism of AD was investigated. A significant interference was only detected in females, and differences between the modes of action of the two compounds were observed: TPT was a strong inhibitor of 5α-reductase activity in B. brandaris at a concentration as low as 100 nM whereas only TBT (10 µM) altered the metabolism of AD in H. trunculus by increasing the activity 17β-hydroxysteroid dehydrogenase (17β-HSD). Thus, this work shows that the metabolism of the androgen precursor AD strongly differs among gastropod species, both in terms of activity and metabolic profile, and further demonstrates the ability of TBT and TPT to interfere with key enzymatic pathways involved in androgen synthesis.

Short-term exposure to the organotin compound triphenyltin modulates esterified steroid levels in females of Marisa cornuarietis

Long-term exposures to organotin compounds have shown alterations on endogenous steroid levels in gastropods together with the development of imposex. However, information regarding short-term effects of these compounds on the endocrine system of gastropods is lacking. This work aimed at investigating those responses in the ramshorn snail Marisa cornuarietis by looking at both endogenous levels of free and esterified steroids and the metabolism of the androgen precursor androstenedione by digestive gland/gonad microsomal fractions. One-week exposure to the organotin compound triphenyltin (TPT) led to a significant increase in esterified testosterone (60–85%) and a decrease in esterified estradiol (50–84%) in females, but had no effect on males. The observed alterations in esterified steroids were not directly related to changes in P450 aromatase activity that remained unchanged in exposed females. The enzymes involved in the metabolism of the androgen precursor androstenedione, namely 17β-hydroxysteroid dehydrogenases and 5α-reductases, were not significantly altered by TPT exposure, suggesting that such enzymes are not primary targets of TPT in M. cornuarietis. Additional studies are needed to fully understand the significance of the observed alterations in females and their potential relationship with the development of imposex.

Androstenedione and progesterone in the sediment of a river receiving paper mill effluent.

The Fenholloway River near Perry, Florida, receives effluent from a paper mill and contains populations of masculinized female eastern mosquitofish, Gambusia holbrooki. A previous study identified the androgen precursor androstenedione at a low concentration (0.14 nM) in water samples from the river. The present study makes use of a toxicity identification and evaluation approach that includes solid phase extraction and high pressure liquid chromatography purification, androgen receptor transcription assays, and liquid chromatography mass spectroscopy to identify and characterize steroids in the Fenholloway River sediment. Androstenedione (2.4 nM) and progesterone (155 nM) were identified in the river sediment at concentrations greater than in the river water column (0.14 nM androstenedione, and 6.5 nM progesterone). Spring Creek, a comparison stream that does not receive mill effluent, contained low levels of progesterone (0.3 nM) but no androstenedione in the sediment. The data are consistent with the hypothesis that pine pulp-derived phytosteroids in the paper mill effluent accumulate in river sediment where they are converted by microbes into progesterone and this into androstenedione and other bioactive steroids. Equally important is that normal streams with much less organic matter still contain progesterone, but at dramatically lower levels. The presence of androgens and androgen precursors in the river water and sediment likely contributes to the masculinized phenotype of the female Gambusia holbrooki in the Fenholloway River.

Recent advances in studies on estrogen biosynthesis

Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors androstenedione and testosterone to yield estrone and estradiol respectively. In men the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species. The production of estrogens by the testis is not clear but it may modify testosterone secretion. Estrogen produced locally in the brain may play an important role in male and female sex differentiation and sex behavior. Extraovarian estrogen has been known to maintain growth of estrogen-dependent tumors. Recently developed inhibitors have been used to identify aromatization reaction and to elucidate roles of estrogen in various tissues. They also have the potential of controlling estrogen production in estrogen-dependent diseases.