Inhibition Of Testosterone Production Research Articles

How Per- and Poly-Fluoroalkyl Substances Affect Gamete Viability and Fertilization Capability: Insights from the Literature.

There has been emerging research linking per- and poly-fluoroalkyl substances (PFAS) to gamete viability and fertility. PFAS, prevalent in the environment and water supplies, undergo slow degradation due to their C-F bond and a long half-life (2.3-8.5 years). In females, PFAS inhibit the hypothalamic-pituitary-gonadal (HPG) axis, reducing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, leading to the inhibition of androgen and estradiol production. PFAS have been found to cause detrimental effects on egg quality through impairing folliculogenesis. In males, PFAS can impair sperm motility and morphology: two fundamental qualities of successful fertilization. PFAS exposure has been proven to inhibit testosterone production, sperm capacitation, and acrosomal reaction. After fertilization, the results of PFAS exposure to embryos have also been investigated, showing reduced development to the blastocyst stage. The aim of this review is to report the main findings in the literature on the impact of PFAS exposure to gamete competency and fertilization capability by highlighting key studies on both male and female fertility. We report that there is significant evidence demonstrating the negative impacts on fertility after PFAS exposure. At high doses, these environmentally abundant and widespread compounds can significantly affect human fertility.

METTL3-m6A-SIRT1 axis affects autophagic flux contributing to PM2.5-induced inhibition of testosterone production in Leydig cells

Epidemiological studies have found that long-term inhalation of PM2.5 is closely related to spermatogenesis disorders and infertility, but the underlying molecular mechanism is still unidentified. Testosterone, an essential reproductive hormone produced by Leydig cells, whose synthesis is disrupted by multiple environmental pollutants. In the current study, we explored the role of METTL3-m6A-SIRT1 axis-mediated abnormal autophagy in PM2.5-induced inhibition of testosterone production in in vivo and in vitro models. Our in vivo findings shown that long-term inhalation of PM2.5 decreased sperm count, increased sperm deformity rates, and altered testicular interstitial morphology accompanied by reduced testosterone in serum and testes. Further, data from the in vitro model displayed that exposure to PM2.5 caused an increase in m6A modification and METTL3 levels, followed by a decrease in testosterone levels and autophagy dysfunction in Leydig cells. The knockdown of METTL3 promotes autophagy flux and testosterone production in Leydig cells. Mechanistically, PM2.5 increased METTL3-induced m6A modification of SIRT1 mRNA in Leydig cells, bringing about abnormal autophagy. Subsequently, administration of SRT1720 (a SIRT1 activator) enhanced autophagy and further promoted testosterone biosynthesis. Collectively, our discoveries indicate that METTL3-m6A-SIRT1 axis-mediated autophagic flux contributes to PM2.5-induced inhibition of testosterone biosynthesis. This research offers a novel viewpoint on the mechanism of male reproductive injury following PM2.5 exposure.

Perfluorotetradecanoic acid exposure to adult male rats stimulates corticosterone biosynthesis but inhibits aldosterone production.

Perfluorotetradecanoic acid (PFTeDA) is a novel perfluoroalkyl substance that ubiquitously exists in the environment. However, whether PFTeDA affects adrenal cortex function remains unclear. Male Sprague-Dawley rats (age of 60 days) were daily administered with PFTeDA (0, 1, 5, and 10 mg/kg body weight) through gavage for 28 days. PFTeDA did not change body and adrenal gland weights. PFTeDA markedly elevated serum corticosterone level at 10 mg/kg but lowering serum aldosterone level at this dosage without influencing serum adrenocorticotropic hormone level. PFTeDA thickened zona fasciculata without affecting zona glomerulosa. PFTeDA remarkably upregulated the expression of corticosterone biosynthetic genes (Mc2r, Scarb1, Star, Cyp21, Cyp11b1, and Hsd11b1) and their proteins, whereas downregulating aldosterone biosynthetic enzyme Cyp11b2 and its protein, thereby distinctly altering their serum levels. PFTeDA markedly downregulated the expression of antioxidant genes (Sod1 and Sod2) and their proteins at 10 mg/kg. PFTeDA significantly decreased SIRT1/PGC1α and AMPK signaling while stimulating AKT1/mTOR signaling. Corticosterone significantly inhibited testosterone production by adult Leydig cells at >0.1 μM in vitro; however aldosterone significantly stimulated testosterone production at 0.1 nM. In conclusion, exposure to PFTeDA at male rat adulthood causes corticosterone excess and aldosterone deficiency via SIRT1/PGC1α, AMPK, and AKT1/mTOR signals, which in turn additively leads to testosterone deficiency.

The impact of tetrachlorobisphenol A exposure during puberty: Altered Leydig cell development and induced endoplasmic reticulum stress in male mice

Tetrachlorobisphenol A (TCBPA), a halogenated flame retardant and endocrine disruptor, has been detected in human urine and serum. While previous research has shown its impact on the reproductive system, investigations into its mechanisms during puberty remain limited. This study aims to explore the effects of TCBPA on Leydig cells in adolescent mice and potential underlying mechanisms. Male C57 mice of age 28 days were gavaged with 50, 100, and 200 mg/kg/day for 28 days. TCBPA did not alter body weight and testis weight but lowered testosterone levels at 100 and 200 mg/kg and reduced sperm count in the epididymis at 200 mg/kg. TCBPA lowered Leydig cell number at 200 mg/kg while it downregulated key Leydig cell gene (Lhcgr, Scarb1, Cyp11a1, Cyp17a1, Hsd3b6, Hsd17b3 and Insl3) as low as 50 mg/kg. Further study indicated that TCBPA induced reactive oxygen species and caused endoplasmic reticulum stress. In vitro study in TM3 mouse Leydig cells showed that TCBPA indeed induced reactive oxygen species and caused endoplasmic reticulum stress at 75 μM and inhibited testosterone production at this concentration and addition of antioxidant tocopherol can reverse it. These discoveries provide new insights and references for a deeper understanding of the toxic mechanisms of TCBPA on Leydig cells during puberty.

THE EFFECT OF IMPROVAC ON TESTOSTERONE LEVEL AND LIVE WEIGHT OF BULLS

There are many castration methods of bulls and it is believed that the best ones are those that lead to gonadopause or inhibit the function of the gonads, contribute to a significant increase in the quantity and quality of the products obtained. It is currently considered that immunocastration, compared with chemical and surgical castration, is painless and effectively inhibits testosterone production and spermatogenesis. In order to suppress sexual activity in bulls, it is recommended to accomplish immunocastration with Improvac at a dose of 2 ml subcutaneously, with an interval of at least 4 weeks. After 4 weeks of the first injection of Improvac testosterone level decreased to 7.86 ± 1.9 n.gml. With the second injection of the medication the testosterone level decreased to 1.8 ± 0.6 ng/ml in 80% of the animals. The immunocastration method in bulls with a live weight of 248.6±11.0 to 268±12.4 kg showed the increase in live weight of 34.9±12.9 kg in 60 days. Based on the data obtained the Improvac can be recommended for suppression of activity in bulls, while this method is less invasive compared to surgical methods of castration. There is a fairly high percentage of decrease of testosterone level. This accordingly affects meat productivity, which tends to increase.

Role of miR-300-3p in Leydig cell function and differentiation: A therapeutic target for obesity-related testosterone deficiency

MicroRNAs (miRNAs) regulate various cellular functions, but their specific roles in the regulation of Leydig cells (LCs) have yet to be fully understood. Here, we found that the expression of miR-300-3p varied significantly during the differentiation from progenitor LCs (PLCs) to adult LCs (ALCs). High expression of miR-300-3p in PLCs inhibited testosterone production and promoted PLC proliferation by targeting the steroidogenic factor-1 (Sf-1) and transcription factor forkhead box O1 (FoxO1) genes, respectively. As PLCs differentiated into ALCs, the miR-300-3p expression level significantly decreased, which promoted testosterone biosynthesis and suppressed proliferation of ALCs by upregulating SF-1 and FoxO1 expression. The LH/METTL3/SMURF2/SMAD2 cascade pathway controlled miR-300-3p expression, in which luteinizing hormone (LH) upregulated SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) expression through methyltransferase like 3 (METTL3)-mediated Smurf2 N6-methyladenosine modification. The Smurf2 then suppressed miR-300 transcription by inhibiting SMAD family member 2 (SMAD2) binding to the promoter of miR-300. Notably, miR-300-3p was associated with an obesity-related testosterone deficiency in men and the inhibition of miR-300-3p effectively rescued testosterone deficiency in obese mice. These findings suggested that miR-300-3p plays a pivotal role in LC differentiation and function, and could be a promising diagnostic or therapeutic target for obesity-related testosterone deficiency.

Exposure to acrylamide inhibits testosterone production in mice testes and Leydig cells by activating ERK1/2 phosphorylation.

Acrylamide (ACR) is formed during the cooking of starchy foods at high temperatures. Accumulating evidence has shown that ACR has toxic effects, but the mechanism of its potential reproductive toxicity remains unclear. In this study, we observed that ACR caused weight loss in mice. There was no significant difference in the weight of testis and epididymis between the low/medium-dose ACR group and the control group. And the number of epididymal sperms, testicular Leydig cells, serum testosterone level, testicular steroidogenic genes and enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1) and cytochrome P450 family 17 subfamily A member 1 (CYP17A1), were decreased in the medium/high-dose ACR group. Additional cell experiments showed that the apoptosis rate and the level of reactive oxygen species (ROS) were increased, and testosterone levels and CYP17A1 protein expression were reduced in Leydig cells with treated ACR. Furthermore, the phosphorylation levels of extracellular signal-regulated kinases (ERK1/2) increased significantly; however, there was no significant difference in the levels of serine-threonine protein kinase (AKT) phosphorylation in the testis of mice and Leydig cells treated with ACR. These results suggest that ACR exposure leads to the damage of testicular structure and function and a decline in testosterone synthesis in Leydig cells and mouse testis, which may be related to the activated phosphorylation of ERK1/2.

Bisphenol F blocks Leydig cell maturation and steroidogenesis in pubertal male rats through suppressing androgen receptor signaling and activating G-protein coupled estrogen receptor 1 (GPER1) signaling

Bisphenol F (BPF) is a new analog of bisphenol A (BPA). BPA has deleterious effects on the male reproductive system, but the effect of BPF has not been studied in detail. In this study we focus on the effect of BPF on Leydig cell maturation. Male Sprague-Dawley rats were gavaged with 0, 1, 10, or 100 mg/kg BPF from postnatal days 35–56. BPF significantly reduced serum testosterone levels and sperm count in cauda epididymis at dose ≥1 mg/kg. It significantly down-regulated the expression of steroidogenic enzymes, while increasing FSHR and SOX9 levels at 10 and 100 mg/kg. Further studies showed that BPF reduced NR3C4 expression in Leydig and Sertoli cells without affecting its levels in peritubular myoid cells. BPF markedly increased GPER1 in Leydig cells at 100 mg/kg, and it significantly reduced SIRT1 and PGC1α levels in the testes at 100 mg/kg. BPF significantly inhibited testosterone production by immature Leydig cells at 50 μM after 24 h of treatment, which was completely reversed by NR3C4 agonist 7α-methyl-19-nortestosterone and partially reversed by GPER1 antagonist G15 not by ESR1 antagonist ICI 182,780. In conclusion, BPF negatively affects Leydig cell maturation in pubertal male rats through NR3C4 antagonism and GPER1 agonism.

Activation of Autophagy by Low-Dose Silica Nanoparticles Enhances Testosterone Secretion in Leydig Cells.

Silica nanoparticles (SNPs) can cause abnormal spermatogenesis in male reproductive toxicity. However, the toxicity and toxicological mechanisms of SNPs in testosterone synthesis and secretion in Leydig cells are not well known. Therefore, this study aimed to determine the effect and molecular mechanism of low doses of SNPs in testosterone production in Leydig cells. For this, mouse primary Leydig cells (PLCs) were exposed to 100 nm Stöber nonporous spherical SNPs. We observed significant accumulation of SNPs in the cytoplasm of PLCs via transmission electron microscopy (TEM). CCK-8 and flow cytometry assays confirmed that low doses (50 and 100 μg/mL) of SNPs had no significant effect on cell viability and apoptosis, whereas high doses (more than 200 μg/mL) decreased cell viability and increased cell apoptosis in PLCs. Monodansylcadaverine (MDC) staining showed that SNPs caused the significant accumulation of autophagosomes in the cytoplasm of PLCs. SNPs activated autophagy by upregulating microtubule-associated protein light chain 3 (LC3-II) and BCL-2-interacting protein (BECLIN-1) levels, in addition to downregulating sequestosome 1 (SQSTM1/P62) level at low doses. In addition, low doses of SNPs enhanced testosterone secretion and increased steroidogenic acute regulatory protein (StAR) expression. SNPs combined with rapamycin (RAP), an autophagy activator, enhanced testosterone production and increased StAR expression, whereas SNPs combined with 3-methyladenine (3-MA) and chloroquine (CQ), autophagy inhibitors, had an opposite effect. Furthermore, BECLIN-1 depletion inhibited testosterone production and StAR expression. Altogether, our results demonstrate that low doses of SNPs enhanced testosterone secretion via the activation of autophagy in PLCs.

Oncostatin M stimulates immature Leydig cell proliferation but inhibits its maturation and function in rats through JAK1/STAT3 signaling and induction of oxidative stress in vitro.

Oncostatin M (OSM) is a member of the interleukin-6 group of cytokines, which can regulate cell proliferation, growth, and function. Immature Leydig cells have the ability to proliferate and differentiate, and adult Leydig cells have the function of testosterone synthesis. However, the role and underlying mechanisms of OSM on the proliferation and function of Leydig cells remain unclear. The effects of OSM on the proliferation, apoptosis, and function of immature Leydig cells isolated from 35-day-old rats and the function of adult Leydig cells isolated from 63-day-old rats in vitro. OSM stimulated immature Leydig cell proliferation after up-regulating the expression of Ccnd1 and Cdk4 to drive the transition of G1 phase to M2 phase in the cell cycle at 10 and 100 ng/ml. OSM did not affect the apoptosis of immature Leydig cells up to 100 ng/ml. OSM inhibited testosterone production in immature and adult Leydig cells by down-regulating the expression of Lhcgr, Star, Cyp11a1, Hsd3b1, and Cyp17a1 at 1-100 ng/ml. OSM induced reactive oxygen species and down-regulated the expression of antioxidant genes and lowered mitochondrial membrane potential at 10 and 100 ng/ml in both Leydig cells. Janus kinase 1 (JAK1) antagonist filgotinib and signal transducer and activator of transcription 3 (STAT3) antagonist S3I-201 reversed the effect of OSM, indicating that it acts on JAK1/STAT3 signaling. Oncostatin M stimulates immature Leydig cell proliferation while inhibiting the function of immature and adult Leydig cells.

Nano-TiO₂ Reduces Testosterone Production in Primary Cultured Leydig Cells from Rat Testis Through the Cyclic Adenosine Phosphate/Cyclic Guanosine Phosphate/Epidermal Growth Factor Receptor/Matrix Metalloproteinase Signaling Pathway.

Nano-titanium dioxide (nano-TiO₂) has been shown to inhibit testosterone synthesis in male mice or rats; however, the mechanisms underlying these effects have yet to be elucidated. In this study, we investigated whether the inhibition of testosterone synthesis by nano-TiO₂ on Leydig cells (LCs) was related to the dysfunction of the cAMP/CGMP/EGFR/MMP signaling pathway in primary cultures of LCs prepared from rat testis exposed to nano-TiO₂. We found that the early apoptotic rate of LCs increased by 4.34 and 4.94 times, respectively, after exposure to 20 g/mL and 40 g/mL nano-TiO₂ ; we also found that NO increased by 1.1 and 2.86 times, respectively. ROS increased by times of 0.71, 3.15 and 3.43; RNS increased by 0.62, 1.34 and 1.14 times; and SOD activity decreased by 18.3%, 28.16%, and 67.6%, respectively, when the concentration of nano-TiO₂ was 10, 20 and 40 g/mL. These results indicated that nano-TiO₂ treatment resulted caused damage to the LCs, including an imbalance of oxidation and antioxidation. Following nano-TiO₂ treatment, the cAMP content had decreased by 48%, 48% and 47.6%; cGMP content had decreased by 18.7%, 52.2% and 56.7%; the levels of ATP in the LCs had decreased by 15.15%, 45.75% and 66.67%; the expression of HCGR protein had decreased by 26.7%, 45.07% and 74.64%; the expression of LHR protein had decreased by 18.3%, 28.16% and 67.6%; and the levels of T had decreased by 34.48%, 46.62% and 44.12%. Collectively, our results indicated that the inhibition of testosterone production by nano-TiO₂ is related to the dysfunction of the cAMP/CGMP/EGFR/MMP signaling pathway.

Perfluoroheptanoic acid induces Leydig cell hyperplasia but inhibits spermatogenesis in rats after pubertal exposure

Perfluoroheptanoic acid (PFHpA) is a short-chain alternative to long-chain perfluoroalkyl substances, which have been reported to possess reproductive toxicity. However, it is unclear whether PFHpA affects Leydig cell development during puberty. The 35-day-old Sprague Dawley male rats were exposed to PFHpA by gavage with 0 (corn oil), 10, 50, and 100 mg/kg/day for 21 days. PFHpA did not affect the body weight of rats, but it reduced testis weight, relative testis weight, and epididymis weight at 100 mg/kg. It significantly increased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels at a dose of 100 mg/kg without affecting serum estradiol levels. PFHpA suppressed sperm production at a dose of 100 mg/kg. PFHpA induced Leydig cell hyperplasia (increased number of CYP11A1-positive Leydig cells) at a dose of 100 mg/kg, but down-regulated the expression of Cyp11a1, Hsd3b1, and Cyp17a1 in individual Leydig cell pe se and up-regulated the expression of Fshr in the Sertoli cell pe se. PFHpA did not affect the number of HSD11B1 (a biomarker for more mature Leydig cells) positive Leydig cells and SOX9 positive Sertoli cells. PFHpA increased BCL2, and the phosphorylation of AKT1, AKT2, ERK1/2, and JNK, but decreased BAX levels. However, it had no effect on SIRT1 and PGC-1α levels. In conclusion, PFHpA induces Leydig cell hyperplasia due to the increase in the secretion of luteinizing hormone through negative feedback after down-regulating the expression of steroidogenic enzymes and inhibiting testosterone production in individual Leydig cells. This proliferation may be mediated by increasing BCL2 and phosphorylation of AKT, ERK1/2, and JNK, and decreasing BAX level.

Metabolic changes in patients with prostate cancer with androgen deprivation therapy

Prostate cancer is the most common type of cancer among men. Androgen deprivation therapy (ADT) is the most effective treatment for this disease. The cornerstone of prostate cancer treatment is the inhibition of testosterone production, which interrupts testosterone-induced growth of the prostate tumour. A sharp decrease in testosterone, however, has several undesirable effects on the metabolic profile and bone metabolism and can also lead to fatigue, loss of libido, gynecomastia and anaemia, provoke vasomotor hyperaemia and generally affect the quality of life. To increase the good (long-term) survival of patients with prostate cancer, studying the side effects associated with treatment is important, and therefore, in every clinical situation, the benefits of ADT must be compared with the side effects associated with the treatment. This article focuses on the described metabolic complications of ADT, including obesity, diabetes, lipid changes, metabolic syndrome and cardiovascular diseases. It also contains practical recommendations for managing the side effects and complications based on the available guidelines issued by the medical professional community.

A Mansonone Derivative Coupled with Monoclonal Antibody 4D5-Modified Chitosan Inhibit AKR1C3 to Treat Castration-Resistant Prostate Cancer.

PurposeAldo-ketoreductase (AKR) 1C3 is crucial for testosterone synthesis. Abnormally high expression/activity of AKR1C3 can promote castration-resistant prostate cancer (CRPC). A mansonone derivative and AKR1C3 inhibitor, 6e, was combined with 4D5 (extracellular fragment of the monoclonal antibody of human epidermal growth factor receptor-2)-modified chitosan to achieve a nanodrug-delivery system (CS-4D5/6e) to treat CRPC.Materials and MethodsMorphologies/properties of CS-4D5/6e were characterized by atomic force microscopy, zeta-potential analysis, and Fourier transform-infrared spectroscopy. CS-4D5/6e uptake was measured by immunofluorescence under confocal laser scanning microscopy. Testosterone in LNCaP cells overexpressing human AKR1C3 (LNCaP-AKR1C3) and cell lysates was measured to reflect AKR1C3 activity. Androgen receptor (AR) and prostate-specific antigen (PSA) expression was measured by Western blotting. CS-4D5/6e-based inhibition of AKR1C3 was evaluated in tumor-xenografted mice.ResultsCS-4D5/6e was oblate, with a particle size of 200–300 nm and thickness of 1–5 nm. Zeta potential was 1.39±0.248 mV. 6e content in CS-4D5/6e was 7.3±1.4% and was 18±3.6% for 4D5. 6e and CS-4D5/6e inhibited testosterone production significantly in a concentration-dependent manner in LNCaP-AKR1C3 cells, and a decrease in expression of AKR1C3, PSA, and AR was noted. Half-maximal inhibitory concentration of CS-4D5/6e on LNCaP-AKR1C3 cells was significantly lower than that in LNCaP cells (P<0.05). CS-4D5/6e significantly reduced growth of 22Rv1 tumor xenografts by 57.00% compared with that in the vehicle group (P<0.01).ConclusionWe demonstrated the antineoplastic activity of a potent AKR1C3 inhibitor (6e) and its nanodrug-delivery system (CS-4D5/6e). First, CS-4D5/6e targeted HER2-positive CRPC cells. Second, it transferred 6e (an AKR1C3 inhibitor) to achieve a reduction in intratumoral testosterone production. Compared with 6e, CS-4D5/6e showed lower systemic toxicity. CS-4D5/6e inhibited tumor growth effectively in mice implanted with tumor xenografts by downregulating testosterone production mediated by intratumoral AKR1C3. These results showed a promising strategy for treatment of the CRPC that develops invariably in prostate-cancer patients.

The GC-IGF1 axis-mediated testicular dysplasia caused by prenatal caffeine exposure

Prenatal caffeine exposure (PCE) can induce testicular developmental toxicity. Here, we aimed to explore the underlying mechanism of this process in reference to its intrauterine origin. Pregnant rats were intragastrically administrated caffeine (30 and 120 mg/kg/day) from gestational days 9 to 20. The results showed that the male fetuses exposed to high dose of caffeine (120 mg/kg/day) had a decreased bodyweight and inhibited testosterone synthetic function. Meanwhile, their serum corticosterone concentration was elevated and their testicular insulin-like growth factor 1 (Igf1) expression was decreased. Moreover, the histone 3 lysine 14 acetylation (H3K14ac) level in the Igf1 promoter region was reduced. Low-dose (30 mg/kg/day) caffeine exposure, however, increased steroidogenic enzymes expression in male fetuses. After birth, the serum corticosterone concentration gradually decreased in the PCE (120 mg/kg/day) offspring rats, whereas the expression and H3K14ac level of Igf1 gradually increased, with obvious catch-up growth and testicular development compensation. Intriguingly, when we subjected the offspring to 2 weeks of chronic stress to elevate the serum corticosterone concentration, the expression of Igf1 and testosterone synthesis were inhibited again in the PCE (120 mg/kg/day) group, accompanied by a decrease in the H3K14ac level in the Igf1 promoter region. In vitro, corticosterone (rather than caffeine) was proved to inhibit testosterone production in Leydig cells by altering the H3K14ac level and the expression of Igf1. These observations suggested that PCE-induced testicular developmental toxicity is related to the negative regulation of corticosterone on H3K14ac levels and the expression of Igf1.

In vitro effects of single and binary mixtures of regulated mycotoxins and persistent organochloride pesticides on steroid hormone production in MA-10 Leydig cell line

Epidemiological studies have shown strong deterioration in male reproductive health globally due to compromised testosterone production leading to altered spermatogenesis and poor sperm quality. However, the effects and mechanisms through which mycotoxins and persistent organochloride pesticides contribute to poor reproductive health in males remain unclear. The effects of single and binary combinations of ochratoxin A, deoxynivalenol, zearalenone, alpha-zearalenol, beta-zearalenol and 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane on testicular steroidogenesis were evaluated using the MA-10 Leydig cell line after 48 h of exposure. Zearalenone exposure, especially at 16 μM, had a stimulatory effect on progesterone secretion (4.7 ± 0.48 ng/mL compared to 0.60 ± 0.07 ng/mL in control), but inhibited testosterone production after 48 h compared to the solvent control. Ochratoxin A treatment significantly increased both progesterone and testosterone levels. Combination of alpha-zearalenol with beta-zearalenol showed a synergistic stimulation of progesterone hormone level at 1 and 8 μM. The results presented here show that the MA-10 Leydig cell line is a useful model for assessing the effects of xenoestrogens on testicular steroidogenesis. In addition, the inhibitory effects of zearalenone, alpha-zearalenol and beta-zearalenol on testosterone production was enhanced by co-exposure with 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane, further compounding the threat posed by these mycotoxins to male reproductive health.

Effect of glucocorticoids on androgen biosynthesis in the testes of the toad Rhinella arenarum (Amphibia, Anura)

In rat Leydig cells, glucocorticoids (GCs) inhibit testosterone production through the interaction with the glucocorticoid receptor (GR). However, the sensitivity of those cells to GCs is regulated by the enzyme 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD1). In the testes of the toad Rhinella arenarum, the presence of an 11β-HSD similar to type 2 and a cytosolic GR has also been described. However, there is a lack of information regarding the effects of GCs on amphibian testicular steroidogenesis. In this study, the effects of corticosterone on androgen production, and the activity of two steroidogenic enzymes in toad testes were reported. Corticosterone inhibits androgen production via the GR because the GR antagonist RU486 prevents corticosterone-induced inhibition of testosterone. Corticosterone also reduced the activity of the cytochrome P450 17-hydroxylase, C17,20-lyase (Cyp450 c17 ) without affecting the 3β-hydroxysteroid dehydrogenase/isomerase activity. This effect on Cyp450 c17 was likewise inhibited by RU486. On the other hand, corticosterone had no effect on the amount of steroidogenic acute regulator protein. These results suggest that GCs inhibit steroidogenesis in toad testes by reducing of Cyp450 c17 activity via a GR-mediated mechanism.

Expanding the use of abiraterone in prostate cancer: Is earlier always better?

Androgen deprivation therapy (ADT), the inhibition of testosterone production via orchiectomy or the administration of a luteinizing hormone-releasing hormone (LHRH) agonist (e.g. leuprolide, goser...

Adverse effects of androgen deprivation therapy in patients with prostate cancer: focus on metabolic complications.

Prostate cancer is the most common cancer among men and androgen deprivation therapy (ADT) is the most effective treatment for this disease. The cornerstone of the treatment of prostate cancer is inhibition of testosterone production which interrupts testosterone-induced growth of the prostate tumor. The dramatic decrease in testosterone levels, however, has several undesirable effects on the metabolic profile and bone metabolism and can also lead to fatigue, loss of libido, gynecomastia, and anemia, provoke vasomotor flushing, and generally affect the quality of life. Due to the long-term survival rates of patients with prostate cancer, treatment-related adverse effects are highly relevant and thus, in each clinical setting, the benefits of ADT must be weighed against treatment-related adverse effects. The current review focuses on the more recently described metabolic complications of androgen deprivation therapy, including obesity, diabetes, lipid alterations, metabolic syndrome, and cardiovascular disease. In addition, it provides practical management recommendations drawn from the available guidelines issued by the American Diabetes Association and American Heart Association.

Iron and Testosterone: Interplay and Clinical Implications

The purpose of this review is to investigate the crosstalk between testosterone and iron metabolism in men and discuss the clinical implications. Testosterone directly regulates body iron levels through inhibition of the master regulator of iron metabolism, hepcidin. There is significant overlap between the side effects of exogenous testosterone administration and iron overload. Testosterone increases dietary iron absorption, providing a direct link between the two. As the body is unable to eliminate excess iron, a negative feedback mechanism allowing iron to inhibit testosterone production to maintain body iron homeostasis is proposed. This review discusses the recent data demonstrating the regulation of body iron stores by testosterone, as well as data suggesting testosterone may be reciprocally regulated by iron. Crosstalk between testosterone and iron has significant implications in testosterone deficiency and therapy. Additionally, the regulation of testosterone by iron may indicate a significant role for iron in the development of the hypogonadotropic hypogonadism of aging and chronic disease.