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The Journal of Steroid Biochemistry and... Dec 2023Polycystic ovary syndrome (PCOS) is a complex reproductive endocrine disease characterized by ovulation dysfunction with multiple etiologies and manifestations, and it...
Polycystic ovary syndrome (PCOS) is a complex reproductive endocrine disease characterized by ovulation dysfunction with multiple etiologies and manifestations, and it is widely believed that the disorders of hyper-androgen and glucose metabolism play a key role in its progression. There has been evidence that bone morphogenetic protein 4 (BMP4) is essential for the regulation of granulosa cells, but whether it regulates metabolism level of granulosa cells under hyperandrogenic environment remains unclear. In this study, Gene Expression Omnibus, clinical data and serum of PCOS patient were collected to detect androgen and BMP4 levels. KGN cells exposed to androgens as a model for simulating PCOS granulosa cells. Lactate/pyruvate kits, and Extracellular Acidification Rate and Oxygen Consumption Rate assay were performed to detect glycolysis and autophagy levels of granulosa cells. Lentivirus infection was used to investigate the effects of BMP4 on granulosa cells. RNA-seq were performed to explore the special mechanism. We found that BMP4 was increased in PCOS patients with hyper-androgen and granulosa cells with dihydrotestosterone treatment. Mechanically, on the one hand, hyperandrogenemia can up-regulate BMP4 secretion and induce glycolysis and autophagy levels. On the other hand, we found that hyperandrogenic-induced YAP1 upregulation may mediate BMP4 to increase glycolysis level and decrease autophagy, which plays a protective role in granulosa cells to ensure subsequent energy utilization and mitochondrial function. Overall, we innovated on the protective effect of BMP4 on glycolysis and autophagy disorders induced by excessive androgen in granulosa cells. Our study will provide guidance for future understanding of PCOS from a metabolic perspective and for exploring treatment options.
Topics: Female; Humans; Androgens; Autophagy; Bone Morphogenetic Protein 4; Glucose; Granulosa Cells; Polycystic Ovary Syndrome
PubMed: 37858799
DOI: 10.1016/j.jsbmb.2023.106410 -
European Journal of Endocrinology Jul 2023Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function.
DESIGN
In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days.
METHODS
We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters.
RESULTS
In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17β-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment.
CONCLUSIONS
Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function.ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36.
Topics: Female; Humans; Aldo-Keto Reductase Family 1 Member C3; Androgens; Androsterone; Dihydrotestosterone; Hydroxyprostaglandin Dehydrogenases; Progesterone; Steroids
PubMed: 37306288
DOI: 10.1093/ejendo/lvad063 -
Journal of the Endocrine Society Dec 2023Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major...
CONTEXT
Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure.
OBJECTIVE
We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS.
METHODS
In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms.
RESULTS
We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated , which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues.
CONCLUSION
We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice.
PubMed: 38169733
DOI: 10.1210/jendso/bvad162 -
Acta Pharmacologica Sinica Dec 2023Polycystic ovary syndrome (PCOS) is a disorder with endocrinal and metabolic problems in reproductive aged women. Evidence shows that PCOS is in a high prone trend to...
Polycystic ovary syndrome (PCOS) is a disorder with endocrinal and metabolic problems in reproductive aged women. Evidence shows that PCOS is in a high prone trend to develop kidney diseases. In this study, we investigated the mediators responsible for PCOS-related kidney injury. We found that tumor necrosis factor (TNF-α) levels were significantly increased in serum and primary cultured granulosa cells (GCs) from PCOS patients. Serum TNF-α levels were positively correlated with serum testosterone and luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, suggesting its positive role in the severity of PCOS. Serum TNF-α levels were also positively correlated with the levels of urinary KapU, LamU, α1-MU and β2-MU, the markers for renal tubular cell-derived proteinuria. We established a PCOS mouse model by resection of the right kidney, followed by daily administration of dihydrotestosterone (DHT, 27.5 μg, i.p.) from D7 for 90 days. We found that TNF-α levels were significantly increased in the ovary and serum of the mice, accompanied by increased renal tubular cell apoptosis, inflammation and fibrosis in kidneys. Furthermore, the receptor of TNF-α, tumor necrosis factor receptor 1 (TNFR1), was significantly upregulated in renal tubular cells. We treated human ovarian granulosa-like tumor cells (KGN) with DHT (1 μg/ml) in vitro, the conditioned medium derived from the granulosa cell culture greatly accelerated apoptotic injury in human proximal tubular epithelial cells (HKC-8), which was blocked after knockdown of TNF-α in KGN cells. Furthermore, knockdown of TNFR1 in renal tubular epithelial cells greatly ameliorated cell injury induced by granulosa cell-derived conditioned medium. These results suggest that serum TNF-α plays a key role in mediating inflammation and apoptosis in renal tubular cells associated with PCOS-related kidney injury.
Topics: Female; Humans; Mice; Animals; Adult; Polycystic Ovary Syndrome; Tumor Necrosis Factor-alpha; NF-kappa B; Receptors, Tumor Necrosis Factor, Type I; Culture Media, Conditioned; Granulosa Cells; Inflammation; Kidney; Apoptosis
PubMed: 37507430
DOI: 10.1038/s41401-023-01128-0 -
Andrology Mar 2024Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α-reductase (i.e., the enzyme converting testosterone, T, into...
Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α-reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so-called post-finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α-reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO levels, and a decrease in ornithine transcarbamylase (OTC) activity, measured by citrulline/ornithine ratio. Interestingly, the T levels are negatively correlated with NOS activity, while those of DHT are positively correlated with OTC activity. Finasteride treatment also induced alterations in the levels of other molecules involved in the control of penile erection, such as norepinephrine and its metabolite, epinephrine. Indeed, plasma levels of norepinephrine and epinephrine were significantly increased and decreased, respectively, suggesting an impairment of these mediators. Interestingly, these modifications were restored by suspension of the drug. Altogether, the results reported here indicate that finasteride treatment, but not its withdrawal, affects T metabolism in the rat corpus cavernosum, and this alteration was linked to mechanisms associated with erectile dysfunction. Data here reported could also suggest that the PFS sexual side effects are more related to dysfunction in a sexual central control rather than peripheral compromised condition.
Topics: Male; Humans; Rats; Animals; Finasteride; Erectile Dysfunction; Citrulline; Dihydrotestosterone; Epinephrine; Norepinephrine; 5-alpha Reductase Inhibitors
PubMed: 37621185
DOI: 10.1111/andr.13515 -
Frontiers in Pharmacology 2023Prostate cancer is the second leading cause of cancer death among men in the United States. Castration-Resistant Prostate Cancer (CRPC) often develops resistance to...
YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy.
Prostate cancer is the second leading cause of cancer death among men in the United States. Castration-Resistant Prostate Cancer (CRPC) often develops resistance to androgen deprivation therapy. Resistance in CRPC is often driven by AR variants and glucocorticoid receptor (GR). Thus, drugs that target both could be vital in overcoming resistance. Utilizing the STAR Drug Discovery Platform, three hundred medicinal plant extracts were examined across 25 signaling pathways to identify potential drug candidates. Effects of the botanical drug YIV-818-A, derived from optimized water extracts of Rubia cordifolia (R.C.), on Dihydrotestosterone (DHT) or Dexamethasone (DEX) induced luciferase activity were assessed in 22RV1 cells harboring the ARE luciferase reporter. Furthermore, the key active compounds in YIV-818-A were identified through activity guided purification. The inhibitory effects of YIV-818-A, RA-V, and RA-VII on AR and GR activities, their impact on AR target genes, and their roles in modifying epigenetic status were investigated. Finally, the synergistic effects of these compounds with established CRPC drugs were evaluated both and . YIV-818-A was found to effectively inhibit DHT or DEX induced luciferase activity in 22RV1 cells. Deoxybouvardin (RA-V) was identified as the key active compound responsible for inhibiting AR and GR activities. Both YIV-818-A and RA-V, along with RA-VII, effectively downregulated AR and AR-V proteins through inhibiting protein synthesis, impacted the expression of AR target genes, and modified the epigenetic status by reducing levels of Bromodomain and Extra-Terminal proteins (Brd2/Brd4) and H3K27Ac. Furthermore, these compounds exhibited synergistic effects with apalutamide, darolutamide, or enzalutamide, and suppressed AR mediated luciferase activity of 22RV1 cells. Co-administration of YIV-818-A and enzalutamide led to a significant reduction of 22RV1 tumor growth in vivo. Different sources of R.C. had variable levels of RA-V, correlating with their potency in AR inhibition. YIV-818-A, RA-V, and RA-VII show considerable promise in addressing drug resistance in CRPC by targeting both AR protein and GR function, along with modulation of vital epigenetic markers. Given the established safety profile of YIV-818-A, these findings suggest its potential as a chemopreventive agent and a robust anti-prostate cancer drug.
PubMed: 37860121
DOI: 10.3389/fphar.2023.1244655 -
Clinical, Cosmetic and Investigational... 2023Androgenetic alopecia (AGA) is the most common type of hair loss in humans, affecting self-esteem and emotional well-being. This study aimed to assess the safety and... (Clinical Trial)
Clinical Trial
Oral and Topical Administration of a Standardized Saw Palmetto Oil Reduces Hair Fall and Improves the Hair Growth in Androgenetic Alopecia Subjects - A 16-Week Randomized, Placebo-Controlled Study.
PURPOSE
Androgenetic alopecia (AGA) is the most common type of hair loss in humans, affecting self-esteem and emotional well-being. This study aimed to assess the safety and efficacy of VISPO, a standardized saw palmetto oil (2-3% β-sitosterol), in subjects with mild-to-moderate AGA.
METHODS
In a double-blind, placebo-controlled, four-arm clinical study, 80 healthy male and female subjects aged 18-50 years were randomly allocated (1:1:1:1) to receive either 400 mg capsules of VISPO or 5 mL of a topical formulation containing 20% VISPO or the respective placebo once daily for 16 weeks. The primary endpoints included hair count (hair comb and hair pull tests) and the self-assessment of perceived efficacy. Objective evaluation was performed using the global photographic assessment score. Hair density, thickness, and anagen/telogen ratio were evaluated using phototrichogram analysis.
RESULTS
At the end of the study, oral and topical formulations of VISPO reduced hair fall by up to 29% (<0.001) and 22.19% (<0.01) from the baseline, respectively. Hair density increased by 5.17% and 7.61% in the oral and topical VISPO groups, respectively (<0.001). In addition, oral ingestion of VISPO resulted in a marked reduction in serum dihydrotestosterone (DHT) levels in the subjects compared to placebo (<0.001). However, the effect of the VISPO formulations on the anagen/telogen ratio was insignificant. No serious adverse effects were observed during the study.
CONCLUSION
VISPO formulations reduced hair fall and promoted hair regrowth and scalp appearance in AGA patients.
PubMed: 38021422
DOI: 10.2147/CCID.S435795 -
Endocrine Jan 2024Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic condition affecting 5-10% of reproductive-aged women and characterized by hyperandrogenism, insulin...
PURPOSE
Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic condition affecting 5-10% of reproductive-aged women and characterized by hyperandrogenism, insulin resistance (IR), and hyperinsulinemia. CFTR is known to be regulated by steroid hormones, and our previous study has demonstrated an essential role of CFTR in β-cell function. This study aims to investigate the contribution of androgen and CFTR to hypersecretion of insulin in PCOS and the underlying mechanism.
METHODS
We established a rat PCOS model by subcutaneously implanting silicon tubing containing Dihydrotestosterone (DHT). Glucose tolerance test with insulin levels was performed at 9 weeks after implantation. A rat β-cell line RINm5F, a mouse β-cell line β-TC-6, and mouse islets were treated with DHT, and with or without the androgen antagonist flutamide for CFTR and insulin secretion-related functional assays or mRNA/protein expression measurement. The effect of CFTR inhibitors on DHT-promoted membrane depolarization, glucose-stimulated intracellular Ca oscillation and insulin secretion were examined by membrane potential imaging, calcium imaging and ELISA, respectively.
RESULTS
The DHT-induced PCOS model showed increased body weight, impaired glucose tolerance, and higher blood glucose and insulin levels after glucose stimulation. CFTR was upregulated in islets of PCOS model and DHT-treated cells, which was reversed by flutamide. The androgen receptor (AR) could bind to the CFTR promoter region, which was enhanced by DHT. Furthermore, DHT-induced membrane depolarization, enhanced glucose-stimulated Ca oscillations and insulin secretion, which could be abolished by CFTR inhibitors.
CONCLUSIONS
Excessive androgen enhances glucose-stimulating insulin secretion through upregulation of CFTR, which may contribute to hyperinsulinemia in PCOS.
Topics: Mice; Female; Rats; Humans; Animals; Adult; Polycystic Ovary Syndrome; Androgens; Cystic Fibrosis Transmembrane Conductance Regulator; Flutamide; Up-Regulation; Hyperinsulinism; Insulin Resistance; Insulin; Dihydrotestosterone; Glucose
PubMed: 37922092
DOI: 10.1007/s12020-023-03516-2 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Feb 2024Benign prostatic hyperplasia(BPH) is a common disease of the male urinary system, and its incidence rate in China is increasing. However, the mechanism underlying the... (Review)
Review
Benign prostatic hyperplasia(BPH) is a common disease of the male urinary system, and its incidence rate in China is increasing. However, the mechanism underlying the pathogenesis of BPH remains unclear. Some studies demonstrated that the incidence of BPH was related to the change in the levels of steroid hormones. Too high content of dihydrotestosterone(DHT) in the body may cause BPH and other related diseases. Testosterone(T) is converted to DHT by 5α-reductase(SRD5A). By inhibiting the activity of this enzyme, the production of DHT can be reduced, and then the incidence of BPH can be lowered. Therefore, it has drawn great attention to screen and discover safer and more effective 5α-reductase inhibitors from natural medicines to treat prostatic hyperplasia without affecting the physiological function of men. This review summarizes the characteristics and tissue distribution of 5α-reductase, the discovery of 5α-reductase inhibitors in traditional Chinese medicine and natural medicines, 5α-reductase inhibitors commonly used in clinical practice and their side effects, as well as the animal models of prostatic hyperplasia and common detection indicators, aiming to provide a reference for more in-depth understanding and research about BPH and development of drugs.
Topics: Animals; Humans; Male; 5-alpha Reductase Inhibitors; Cholestenone 5 alpha-Reductase; Dihydrotestosterone; Prostatic Hyperplasia; Testosterone
PubMed: 38621893
DOI: 10.19540/j.cnki.cjcmm.20231113.601 -
The World Journal of Men's Health Feb 2024This study elucidates the mechanism of the physiological effect of cannabidiol (CBD) by assessing its impact on lipopolysaccharide (LPS)-induced inflammation in RWPE-1...
PURPOSE
This study elucidates the mechanism of the physiological effect of cannabidiol (CBD) by assessing its impact on lipopolysaccharide (LPS)-induced inflammation in RWPE-1 cells and prostatitis-induced by 17β-estradiol and dihydrotestosterone in a rat model, focusing on its therapeutic potential for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
MATERIALS AND METHODS
RWPE-1 cells were stratified into three groups: (1) controls, (2) cells with LPS-induced inflammation, and (3) cells with LPS-induced inflammation and treated with CBD. Enzyme-linked immunosorbent assays and western blots were performed on cellular components and supernatants after administration of CBD. Five groups of six Sprague-Dawley male rats were assigned: (1) control, (2) CP/CPPS, (3) CP/CPPS and treated with 50 mg/kg CBD, (4) CP/CPPS and treated with 100 mg/kg CBD, and (5) CP/CPPS and treated with 150 mg/kg CBD. Prostatitis was induced through administration of 17β-estradiol and dihydrotestosterone. After four weeks of CBD treatment, a pain index was evaluated, and prostate tissue was collected for subsequent histologic examination and western blot analysis.
RESULTS
CBD demonstrated efficacy for CP/CPPS and for inflammation. It inhibited the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway by activating the CB2 receptor, reducing expression of interleukin-6, tumor necrosis factor-alpha, and cyclooxygenase-2 (COX2) (p<0.01). CBD exhibited analgesic effects by activating and desensitizing the TRPV1 receptor.
CONCLUSIONS
CBD inhibits the TLR4/NF-κB pathway by activating the CB2 receptor, desensitizes the TRPV1 receptor, and decreases the release of COX2. This results in relief of inflammation and pain in patients with CP/CPPS, indicating CBD as a potential treatment for CP/CPPS.
PubMed: 38449457
DOI: 10.5534/wjmh.230352