Androgen Synthesis Pathway Research Articles

A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation.

This study was designed to develop and validate a short-term in vivo protocol termed the Fetal Phthalate Screen (FPS) to detect phthalate esters (PEs) and other chemicals that disrupt fetal testosterone synthesis and testis gene expression in rats. We propose that the FPS can be used to screen chemicals that produce adverse developmental outcomes via disruption of the androgen synthesis pathway more rapidly and efficiently, and with fewer animals than a postnatal one-generation study. Pregnant rats were dosed from gestational day (GD) 14 to 18 at one dose level with one of 27 chemicals including PEs, PE alternatives, pesticides known to inhibit steroidogenesis, an estrogen and a potent PPARα agonist and ex vivo testis testosterone production (T Prod) was measured on GD 18. We also included some chemicals with "unknown" activity including DMEP, DHeP, DHEH, DPHCH, DAP, TOTM, tetrabromo-diethyl hexyl phthalate (BrDEHP), and a relatively potent environmental estrogen BPAF. Dose-response studies also were conducted with this protocol with 11 of the above chemicals to determine their relative potencies. CD-1 mice also were exposed to varying dose levels of DPeP from GD 13 to 17 to determine if DPeP reduced T Prod in this species since there is a discrepancy among the results of in utero studies of PEs in mice. Compared to the known male reproductive effects of the PEs in rats the FPS correctly identified all known "positives" and "negatives" tested. Seven of eight "unknowns" tested were "negatives", they did not reduce T Prod, whereas DAP produced an "equivocal" response. Finally, a dose-response study with DPeP in CD-1 mice revealed that fetal T Prod can be inhibited by exposure to a PE in utero in this species, but at a higher dose level than required in rats.Key words. Phthalate Syndrome, Fetal endocrine biomarkers, Phthalate adverse outcome pathway, testosterone production, fetal rat testis.

Effect of simvastatin on castration-resistant prostate cancer cells

BackgroundIn castration-resistant prostate cancer (CRPC), recent evidence has demonstrated the persistence of the intratumoral androgens. The multi-step androgen synthesis pathway originates from cholesterol, which can be obtained by cells from several major sources including intracellular synthesis through an enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). The inhibition of this enzyme by the use of statins has been investigated in prostate cancer as a possible therapeutic target for blocking the de novo androgen synthesis resulting in decreased tumor growth. However, the effectiveness of statins in CRPC has not been investigated.MethodsCastration-resistant C4-2 and androgen-sensitive LNCaP cells were treated with Simvastatin for 48 hours. Dose-dependent responses to Simvastatin were analyzed using cell proliferation and cytotoxicity assays. Cellular growth curve was generated using haemocytometer. HMGCR activity was assessed using 14C-acetic acid detected by thin layer chromatography, and the protein expression was quantified using western blot analysis. Intracellular cholesterol and prostate specific antigen (PSA) levels were quantified using enzyme-linked immunosorbent assays (ELISA).ResultsSignificant decrease in cell viability and growth curve observed at 75 μM of Simvastatin compared to no treatment group in the castration-resistant C4-2 cells. HMGCR activity was significantly decreased up to 50% and 70% at 50 μM and 75 μM of Simvastatin respectively compared to the vehicle control in C4-2 cells. Simvastatin did not affect the protein expression. 80% decrease in the amount of total intracellular cholesterol levels was observed in 75 μM Simvastatin treatment group compared to vehicle control. PSA secretion levels were significantly reduced in the C4-2 cell line at 50 μM and 75 μM of Simvastatin compared to vehicle control.ConclusionThe inhibition of HMGCR via Simvastatin lowered the viability of castration-resistant C4-2 cells. Simvastatin’s ability to limit the endogenous supply of cholesterol contributes to the effects seen in cell viability.

1,3-Dichloro-2-propanol inhibits progesterone production through the expression of steroidogenic enzymes and cAMP concentration in Leydig cells

1,3-Dichloro-2-propanol (1,3-DCP) is a well-known food processing contaminant that has been shown to impede male reproductive function. However, its mechanism of action remains elusive. In this study, the effects of 1,3-DCP on progesterone production were investigated using the R2C Leydig cell model. 1,3-DCP significantly reduced cell viability from 7.48% to 97.4% at doses comprised between 0.5 and 6mM. Single cell gel/comet assays and atomic force microscopy assays showed that 1,3-DCP induced early phase cell apoptosis. In addition, 1,3-DCP significantly reduced progesterone production detected by radioimmunoassay (RIA). The results from quantitative polymerase chain reaction and western blotting demonstrated that the mRNA expression levels of steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase were significantly down-regulated in R2C cells. Particularly, the change rhythm of Star expression was highly consistent with progesterone production. Furthermore, the cyclic adenosine monophosphate (cAMP) and the mitochondrial membrane potential mediated by ROS, which are involved in regulating progesterone synthesis were also decreased in response to the 1,3-DCP treatment. Overall, the data presented here suggested that 1,3-DCP interferes with the male steroidogenic capacity mainly by down-regulating the level of cAMP and the key enzymes involved in the androgen synthesis pathway.

Adiponectin and Its Receptors in the Ovary: Further Evidence for a Link between Obesity and Hyperandrogenism in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS), characterized by ovarian androgen excess, is the commonest endocrine disorder in women. Obesity increases androgen synthesis, a phenomenon attributed to the accompanying hyperinsulinemia. Our hypothesis was that adipokines, fat cell-derived hormones, play a direct role in modulating ovarian androgen secretion. Therefore, the aims of this study were to explore the effects of adipokines (in particular, adiponectin) on ovarian steroidogenesis and compare the expression of adiponectin receptors in ovaries from women with and without PCO. Sections of archived human ovaries (nine from women with normal ovaries and 16 with PCOS, classified histologically, with reference to menstrual history and ultrasound) were analysed by quantitative morphometry and the proportion of positive-labelling cells compared. In addition, studies of androgen production in relation to adipokine function in primary bovine theca cell culture were also performed. A significantly lower proportion of theca cells expressed adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) in polycystic ovaries than in normal ovaries. In cultured theca cells, adiponectin suppressed androstenedione production and gene expression of LH receptor and key enzymes in the androgen synthesis pathway. Moreover, knockdown of genes for AdipoR1 and AdipoR2 was associated with increased androstenedione secretion by bovine theca cells. These results provide evidence for a direct link between fat cell metabolism and ovarian steroidogenesis, suggesting that disruption of adiponectin and/or its receptors plays a key role in pathogenesis of hyperandrogenism in PCOS.

Escaping abiraterone

Although a lot is known about how castration-resistant prostate cancers become refractory to second-generation androgen receptor antagonists, the mechanism behind resistance to CYP17 inhibitors remains a mystery. An alternative androgen synthesis pathway identified by a team from the Cleveland Clinic may change the game.

21-Hydroxylase deficiency in the neonate – trends in steroid anabolism and catabolism during the first weeks of life

Deficiency of 21-hydroxylase provides an in vivo model of intrauterine induction of enzymes participating in steroid anabolism and catabolism. Quantitative data for 93 steroid metabolites in urine from 111 patients and 7 controls (25 samples) were compared over the first six weeks of life. Net flux through the key anabolic enzymes was examined by comparison of the totals of steroids derived from the intermediates prior to and following each enzymatic step. Metabolic relationships were established on structural grounds and by Pearson correlation. The relative importance of each catabolic route was evaluated after summing metabolites classified according to their structure as fetal, neonatal, and classical (adult) type.Hierarchical cluster analysis identified the structure at C3–C5 as a key distinguishing feature of the major catabolic streams and demonstrated a split point in metabolic pattern in patients at 7 days. Changes with time in steroid metabolism, larger in patients than in controls, could be interpreted as reflecting increased cortisol demand post partum, the clinical onset of salt-wasting and a transition in catabolism from fetal to postnatal life. Faster involution of the fetal zone and pronounced enhancement of steroid production in zona fasciculata and zona glomerulosa were indicated in patients. Predominant at birth were ‘planar’ fetal-type 5α-reduced metabolites, adapted to placental excretion, which gave way to additionally hydroxylated neonatal-type metabolites, facilitating renal excretion. Classical metabolism made gains over the study period. Overproduction of steroids in utero in 21-hydroxylase deficiency would have induced fetal catabolic pathways dependent on 5α-reduction. A progressive increase of steroids likely to arise from 5α-reductase type 2 activity, again more distinct in disease, was observed.We demonstrate that the key intermediates in the hypothetical ‘backdoor’ pathway of androgen synthesis are part of a broader catabolic network and should not be examined in isolation.

Androgen Synthesis in Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

A hallmark of severe congenital adrenal hyperplasia due to 21-hydroxylase deficiency is pre- and postnatal virilization. The most characteristic biochemical abnormality is the elevation of 17α-hydroxyprogesterone, which is metabolized to the most potent androgen receptor agonist dihydrotestosterone. 17α-Hydroxyprogesterone can be metabolized to dihydrotestosterone via 4-androstenedione through the classical Δ⁴-pathway or via 17α-hydroxypregnenolone and dehydroepiandrosterone through the classical Δ⁵-pathway, as well as through an alternative route, called the 'backdoor pathway', that bypasses dehydroepiandrosterone, 4-androstenedione, and testosterone as intermediates. This review article will summarize recent advances in the understanding of the activities of androgen synthesis pathways in patients with 21-hydroxylase deficiency obtained by urinary steroid metabolomics based on gas chromatography-mass spectrometry. Compared with healthy controls, the relative activities of the backdoor and Δ⁴-pathways increase in patients with congenital adrenal hyperplasia during neonatal age and infancy, whereas the activity of the Δ⁵-pathway remains unchanged. Thereafter, the activity of the Δ⁵-pathway dominates, whereas a decreasing 5α-reductase activity leads to a diminished role of the backdoor pathway for androgenic steroid production. Beside the backdoor pathway, the Δ⁴-pathway seems to be responsible for increased androgen generation in patients with 21-hydroxylase deficiency before the onset of adrenarche, whereas the Δ⁵-pathway might contribute to the increased androgen formation in those patients only after the onset of adrenarche.

Der alternative Androgensyntheseweg des Menschen

During the last year, alternative androgen synthesis pathways have been discovered in humans. This review article highlights these new concepts of androgen synthesis.We performed a selective literature research using PubMed.After the discovery of a new androgen synthesis pathway in marsupials, this new path-way of androgen synthesis could be established in humans during the last year from two independent studies. One of them could demonstrate that two pathways of androgen synthesis are needed for male sexual differentiation in humans; the other study established that the new pathway is an important source of androgen synthesis in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Additionally, it has been shown that an alternative androgen synthesis pathway that bypasses testosterone drives castration resistant prostate cancer.New and alternative androgen path-ways occur in humans. Importantly, these path-ways remain cryptic for the clinician, because the androgen synthesis circumvents classical intermediates like dehydroepiandrosterone, androstenedione and testosterone.

Steroid 5-alpha-reductase type 2 (SRD5A2) V89L and A49T polymorphisms and sporadic prostate cancer risk: a meta-analysis

Steroid 5-α-reductase type 2 (SRD5A2) V89L and A49T polymorphisms are thought to play a crucial role in the androgen synthesis and metabolic pathway, but their associations with prostate cancer risk remain controversial. To provide a more precise estimation of the associations between V89L and A49T polymorphisms and prostate cancer risk, we performed a meta-analysis using all published case-control studies of prostate cancer since January 1995. We used odds ratio (OR) and its 95% confidence interval (CI) to assess the strength of the association under various genetic models in both overall and stratified analyses. We also calculated the false-positive report probability, the power of the current study, and the observed P value for significant findings. This analysis included 45 eligible studies of a total of 15,562 cases and 15,385 controls, in which no significant associations were found for the V89L polymorphisms under all genetic models. However, small excess prostate cancer risk was associated with the 49T allele in mixed populations compared with the 49A allele (OR = 1.24, 95% CI = 1.02-1.50), and similar results were observed in Caucasians (OR = 1.24, 95% CI = 1.01-1.53). The sensitivity analysis further strengthened the validity of these findings without publication bias. Although there was no overall association between V89L and prostate cancer risk, A49T might play a role in the etiology of prostate cancer among Caucasians. Additional large and well-designed studies are warranted to validate these findings.

Current Status of 5α-Reductase Inhibitors in Prostate Disease Management

The key enzyme in the androgen synthesis and androgen receptor pathways is 5α-reductase (5-AR), which occurs as three isoenzymes. Types I and II 5-ARs the most important clinically, and two different 5-AR inhibitors (5-ARIs), finasteride and dutasteride, have been developed. Several urology associations have recommended and upgraded the use of 5-ARIs for an enlarged prostate with lower urinary tract symptoms. In the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events Trial, 5-ARIs reduced the incidence of low-grade prostate cancer. However, despite the documented reductions in the overall incidence of prostate cancer, 5-ARIs are at the center of a dispute. The American Society of Clinical Oncology (ASCO) and the American Urology Association (AUA) presented clinical guidelines for the use of 5-ARIs for chemoprevention of prostate cancer in 2008. However, ASCO/AUA has eliminated these from the main "Clinical Guidelines" in 2012, because the U.S. Food and Drug Administration denied a supplemental New Drug Application for the use of dutasteride for prostate cancer chemoprevention. The 5-ARIs can also be used to manage hemospermia and prostatic hematuria, and to prevent intraoperative bleeding, although there is insufficient evidence for a standard strategy. This review summarizes the current use of 5-ARIs for prostate disease, including benign prostate hyperplasia, prostate cancer, prostate-related bleeding, and hemospermia.

Steroids excreted in urine by neonates with 21-hydroxylase deficiency. 3. Characterization, using GC–MS and GC–MS/MS, of androstanes and androstenes

Urine from neonates with 21-hydroxylase deficiency contains a large range of androstane(ene)s, many of which have not been previously described. We present their characterization as the third part of a comprehensive study of urinary steroids, aiming to enhance the diagnosis of this disorder and to further elucidate steroid metabolism in neonates.Steroids were analyzed, after extraction and enzymatic conjugate hydrolysis, as methyloxime-trimethylsilyl ether derivatives on gas-chromatographs coupled to quadrupole and ion-trap mass-spectrometers. GC–MS and GC–MS/MS spectra were used together to determine the structure of hitherto undescribed androstane(ene)s.GC–MS/MS was pivotal for the structural characterization of 2-hydroxylated androstenediones but GC–MS was generally more informative for androstane(ene)s, in contrast to 17-hydroxylated pregnane(ene)s. Parallels were found between the GC–MS and GC–MS/MS characteristics of structurally similar androstenediones and progesterones without a substituent on the D-ring, but not with those of 17-hydroxylated progesterones. Assignment of 5α(β) orientation, based on GC–MS characteristics, was possible for 11-oxo-androstanes.The major endogenous 3β-hydroxy-5-enes in 21-hydroxylase deficiency did not differ from those in unaffected neonates. The key qualitative and quantitative differences encompassed 5α(β)-androstanes and 3-oxo-androst-4-enes. Major positions of hydroxylation in these were C2, C6, C11, C16 and C18. Additional oxo-groups were common at C6, C11 and C16.We conclude that the presence of multiple further oxygenated metabolites of androstenedione in urine from neonates with 21-hydroxylase deficiency and their pattern indicate a predominance of the classical pathway of androgen synthesis and reflect an increased demand for clearance. The positions of oxygenation in androstane(ene)s are dependent on the configuration at C3–C5.

928P - Lhrh Agonist-Induced Suppression of the Androgen Synthesis Pathway in Prostate Cancer

Background: Standard first-line therapy for advanced prostate cancer (PC) includes the use of a luteinizing hormone releasing hormone (LHRH) agonist. While the primary site of action for these agents is the pituitary-hypothalamic-gonadal axis, receptors for LHRH are also present in the membrane of PC cells and mediate a direct anti-tumor effect. The mechanism of this effect has been largely unexplored and may harbor a context of vulnerability. Previously, we have demonstrated that luteinizing hormone (LH) increases de novo steroidogenesis in PC cells and silencing of the LH receptor leads to downregulation of steroidogenesis. Here, we examined the impact of LHRH agonists on this process at the cellular level. Methods: LNCaP PC cells were treated with the LHRH agonist buserelin for 8 hours in the presence or absence of the LHRH antagonist antide. Gene expression of LH and androgen synthesis enzymes was quantified by real-time polymerase chain reaction and protein expression was measured with Western blot. Cell proliferation was assessed in these cells using MTS assays. Results: The LHRH agonist buserelin significantly suppressed the gene expression of LH and the androgen synthesis enzymes AKR1C1, AKR1C2, AKR1C3, CYP11A1 and RDH5 (p<0.05). Protein expression of LH, AKR1C1, AKR1C3 and CYP17A1 was also inhibited by buserelin treatment (p<0.05). Buserelin also suppressed LNCaP cell proliferation in a dose-dependent manner (p<0.05). The suppressive effects of buserelin on gene expression, protein expression and cell proliferation were mitigated by the LHRH antagonist antide. Conclusion: These data implicate the LHRH agonist buserelin in the direct inhibition of de novo tumoral steroidogenesis, which may be mediated by suppression of LH. The LH pathway warrants further investigation as a therapeutic target. The treatment of advanced prostate cancer relies on androgen deprivation, often with an LHRH agonist. These agents induce the downregulation of LHRH receptors in pituitary gonadotrophs that ultimately leads to a decrease in gonadal testosterone synthesis. LHRH receptors are also highly expressed on prostate cancer cells. Unlike their pituitary counterparts, prolonged exposure to LHRH agonists does not lead to their downregulation. The role of these tumoral LHRH receptors remains unclear. Our data suggest that the LH pathway may play a role in tumoral steroidogenesis. Here, we explore the impact of LHRH agonist therapy on LH expression and tumoral steroidogenesis.

The activities of 5α-reductase and 17,20-lyase determine the direction through androgen synthesis pathways in patients with 21-hydroxylase deficiency

ObjectiveThe ‘backdoor’ pathway provides an efficient route from 17α-hydroxyprogesterone (17-OHP) to dihydrotestosterone (DHT) in patients with 21-hydroxylase deficiency (21-OHD). 17-OHP is a good substrate for 5α-reductase leading to 17α-hydroxyallopregnanolone, which is an excellent substrate for the 17,20-lyase activity of CYP17A1. 5α-Reductase and CYP17A1 are therefore two crucial enzymes in the backdoor route. The 17,20-lyase activity of CYP17A1 additionally promotes the conversion of 17-OHP and 17α-hydroxypregnenolone to androgens in the classical Δ4 and Δ5 pathways. Thus, we hypothesised that the activities of 5α-reductase and 17,20-lyase should determine the flux through the androgen synthesis pathways in patients with 21-OHD. Design and methodsWe compared retrospectively urinary steroid hormone profiles determined by gas chromatography–mass spectrometry of 142 untreated 21-OHD patients (age range: 1day to 25.4years; 51 males) with 138 control subjects. ResultsThe relative activities of the backdoor pathway and 5α-reductase correlated significantly (p<0.0001). Neonates with 21-OHD demonstrated a moderate activity of the 5α-reductase leading to moderate 17α-hydroxyallopregnanolone generation in the backdoor pathway. Due to substantial 17,20-lyase activity, 17α-hydroxyallopregnanolone is converted rapidly to androsterone. During infancy, the activity of 5α-reductase is very high leading to a high activity of the backdoor pathway until the generation of 17α-hydroxyallopregnanolone. Only a moderate androsterone production is the result of low 17,20-lyase activity. Children show a low 5α-reductase and a high 17,20-lyase activity leading to a low androsterone generation via the backdoor pathway. ConclusionThe 5α-reductase is the gatekeeper of the backdoor pathway, whereas the 17,20-lyase activity of CYP17A1 is the regulator of the flux through the androgen pathways.

Association study of CYP17 and HSD11B1 in polycystic ovary syndrome utilizing comprehensive gene coverage

Cytochrome P450-C17 enzyme (CYP17) is an important component of the androgen synthesis pathway, a pathway that is dysfunctional in polycystic ovary syndrome (PCOS). Variation in 11-beta hydroxysteroid dehydrogenase (HSD11B1) is associated with cortisone reductase deficiency, a condition with a phenotype similar to PCOS. Both CYP17 and HSD11B1 genes have been previously studied for their possible relationship with PCOS, yielding inconsistent results. In this study, we evaluated the association between variation in these genes and PCOS. Two-hundred and eighty-seven Caucasian PCOS women and 187 Caucasian controls were genotyped for single nucleotide polymorphisms (SNPs) that were specifically chosen to allow full coverage of CYP17 and HSD11B1, including four SNPs in CYP17 and eight SNPs in HSD11B1. SNP and haplotype association analyses were conducted. Our results indicate that variants in the two genes are not associated with PCOS, or with the quantitative traits characteristic of PCOS, suggesting that these genes are not major risk factors for the syndrome.

Knockdown of scavenger receptor Class B Type I reduces prostate specific antigen secretion and viability of prostate cancer cells

Scavenger Receptor Class B Type I (SR-BI) facilitates influx of cholesterol to the cell from lipoproteins in the circulation. This influx of cholesterol may be important for many cellular functions, including synthesis of androgens. Castration-resistant prostate cancer tumors are able to synthesize androgens de novo in order to supplement the loss of exogenous sources often induced by androgen deprivation therapy. Silencing of SR-BI may impact the ability of prostate cancer cells, particularly those of castration-resistant state, to maintain the intracellular supply of androgens by removing a supply of cholesterol. SR-BI expression was knocked down using small interfering RNA in LNCaP and C4-2 cells. The effect of down-regulation of SR-BI on PSA production, cell toxicity, and cell viability was measured in both cell types. In addition, compensatory cholesterol synthesis activity was measured using the radiolabeled precursor, (14) C-acetate. SR-BI protein expression is higher basally in C4-2 cells than LNCaP cells. Silencing of SR-BI expression to greater than 85% reduced PSA production in LNCaP and C4-2 SRBI-KD cells by 55% and 58% compared to negative control cells, respectively. SR-BI-KD C4-2 cells demonstrated significantly reduced cell viability (>25%) compared the NC cells. The down-regulation of SR-BI significantly impacts PSA production of prostate cancer cells, as well as the viability of C4-2 cells in the presence and absence of HDL. This may indicate a deficiency in cholesterol availability to the androgen synthesis pathway or may implicate a role for SR-BI in prostate cancer signal transduction pathways.

A 28-day oral dose toxicity study in Wistar rats enhanced to detect endocrine effects of decabromodiphenyl ether (decaBDE)

Decabromodiphenyl ether (decaBDE) is a widely used brominated flame retardant, considered to be of low toxicity. However, previous toxicity studies applied exposure methods with low bioavailability of this compound, and the actual hazard of decaBDE for humans, which are environmentally exposed to decaBDE, may thus be underestimated in current risk assessments. The present 28 days oral toxicity study in Wistar rats was designed to facilitate detection of endocrine and immune modulating effects of decaBDE using an exposure protocol with improved bioavailability. A technical preparation of high purity decaBDE was thus tested by daily exposure through gavage with an emulsion of soy phospholipon/lutrol as a carrier. Most sensitive effect in males were increased weight of seminal vesicle/coagulation gland with BMDL of 0.2 mg/kg bw/day and increased expression of hepatic CYP1A and CYP2B (BMDLs 0.5–0.7 mg/kg bw/day). In females the most sensitive effect was decreased activity of P450c17 (CYP17), which is a key enzyme in the androgen synthesis pathway, in adrenals (BMDL 0.18 mg/kg bw/day). These results suggest that decaBDE may represent an as yet unreported hazard for reproductive health.

Selection for Rapid Embryo Development Correlates with Embryo Exposure to Maternal Androgens among Passerine Birds

Greater offspring predation favors evolution of faster development among species. We hypothesized that greater offspring predation exerts selection on mothers to increase levels of anabolic androgens in egg yolks to achieve faster development. Here, we tested whether (1) concentrations of yolk androgens in passerine species were associated with offspring predation and (2) embryo and nestling development rates were associated with yolk androgen concentrations. We examined three androgens that increase in potency along the synthesis pathway: androstenedione (A(4)) to testosterone (T) to 5 alpha -dihydrotestosterone (5 alpha -DHT). Concentrations of none of these steroids were related to clutch size; only A(4) was allometrically related to egg volume. Species that experience greater predation showed higher yolk concentrations of T and 5 alpha -DHT. Higher concentrations of T and particularly 5 alpha -DHT were strongly correlated with faster development during the embryo period and less so during the nestling period. Development rates were most strongly correlated with 5 alpha -DHT, suggesting that potency increases along the androgen synthesis pathway and that effects are mediated by the androgen receptor pathway. These results are consistent with the hypothesis that selection for faster development by time-dependent offspring mortality may be achieved epigenetically by varying embryo exposure to maternal anabolic steroids.

Selection for Rapid Embryo Development Correlates with Embryo Exposure to Maternal Androgens among Passerine Birds

Greater offspring predation favors evolution of faster development among species. We hypothesized that greater offspring predation exerts selection on mothers to increase levels of anabolic androgens in egg yolks to achieve faster development. Here, we tested whether (1) concentrations of yolk androgens in passerine species were associated with offspring predation and (2) embryo and nestling development rates were associated with yolk androgen concentrations. We examined three androgens that increase in potency along the synthesis pathway: androstenedione (A4) to testosterone (T) to 5α‐dihydrotestosterone (5α‐DHT). Concentrations of none of these steroids were related to clutch size; only A4 was allometrically related to egg volume. Species that experience greater predation showed higher yolk concentrations of T and 5α‐DHT. Higher concentrations of T and particularly 5α‐DHT were strongly correlated with faster development during the embryo period and less so during the nestling period. Development rates were most strongly correlated with 5α‐DHT, suggesting that potency increases along the androgen synthesis pathway and that effects are mediated by the androgen receptor pathway. These results are consistent with the hypothesis that selection for faster development by time‐dependent offspring mortality may be achieved epigenetically by varying embryo exposure to maternal anabolic steroids.

MP-08.26: Genetic polymorphisms of genes involved in androgen metabolism and synthesis pathway and prostate cancer risk among Chinese population

MP-08.26: Genetic polymorphisms of genes involved in androgen metabolism and synthesis pathway and prostate cancer risk among Chinese population

265: Genetic Polymorphisms of Genes Involved in Androgen Metabolism and Synthesis Pathway and Prostate Cancer Risk among Chinese Population

265: Genetic Polymorphisms of Genes Involved in Androgen Metabolism and Synthesis Pathway and Prostate Cancer Risk among Chinese Population