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Brain, Behavior, & Immunity - Health Jul 2024Polycystic ovary syndrome (PCOS) is associated with an increased risk of psychological distress as well as enhanced responses to psychosocial stress. Recently, it was...
Polycystic ovary syndrome (PCOS) is associated with an increased risk of psychological distress as well as enhanced responses to psychosocial stress. Recently, it was hypothesized that PCOS patients may be at high risk of novel COVID-19 infections and worse clinical presentations during such infections. Here, we evaluated the effects of PCOS on stress responses to bacterial and viral mimetics using dihydrotestosterone-induced PCOS model rats. Lipopolysaccharide (LPS; a bacterial mimetic) or polyinosinic-polycytidylic acid (Poly-IC; a viral mimetic) was injected into PCOS model rats (PCOS) and non-PCOS rats (control), and the rats' stress responses were evaluated. In the PCOS group, the rats' anorectic and febrile responses to LPS injection were enhanced, whereas their anorectic and febrile responses to Poly-IC injection were unaltered. The PCOS group also exhibited greater changes in peripheral cytokine levels in response to LPS, but not Poly-IC. On the contrary, after the injection of Poly-IC depressed locomotor activity was more evident in the PCOS group, whereas no such changes were observed after LPS injection. These findings indicate that although the stress responses of PCOS model rats to infection may be enhanced, the patterns of change in stress responses and their underlying mechanisms may differ between bacterial and viral infections.
PubMed: 38650845
DOI: 10.1016/j.bbih.2024.100772 -
Steroids Jun 2024This study aimed to evaluate the effects of dehydroepiandrosterone (DHEA) and DHEA combined with a high-fat diet (HFD) treatment of reproductive and endocrine metabolism...
OBJECTIVE
This study aimed to evaluate the effects of dehydroepiandrosterone (DHEA) and DHEA combined with a high-fat diet (HFD) treatment of reproductive and endocrine metabolism in rats and then identify an ideal model of polycystic ovary syndrome (PCOS).
METHODS
Three-week-old female Sprague-Dawley rats were injected subcutaneously with DHEA or oil, fed with or without a HFD, for 21 days, during which body weight, feed intake, and estrous cycle monitoring were carried out. Fasting blood glucose was measured, and serum fasting insulin, testosterone, dihydrotestosterone (DHT), estradiol, progesterone, luteinizing hormone (LH), anti-Müllerian hormone (AMH), and follicle-stimulating hormone (FSH) were estimated by ELISA. Serum total cholesterol (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured by colorimetric assay. Whereas, histologic changes in rat ovaries were evaluated by H&E staining. Ovarian steroid hormone synthases and their protein levels (StAR, 3β-HSD2, 17β-HSD1, CYP11A1, CYP17A1, and CYP19A1) were examined by Western blotting.
RESULTS
Both DHEA and DHEA + HFD-treated rats lost a regular estrous cycle; had polycystic ovarian changes, significantly higher serum fasting insulin and testosterone levels; and increased ovarian StAR, 3β-HSD2, and CYP11A1 protein levels. Additionally, rats in the DHEA + HFD-treated group were obese; had elevated fasting blood glucose, TG, DHT, AMH levels and LH:FSH ratios; increased ovarian 17β-HSD1 protein levels.
CONCLUSION
DHEA combined with HFD treatment is more effective at inducing PCOS than DHEA alone. The reproductive and endocrine metabolic aspects of this method are more consistent with the clinical characteristics of PCOS patients.
Topics: Animals; Polycystic Ovary Syndrome; Female; Dehydroepiandrosterone; Rats, Sprague-Dawley; Diet, High-Fat; Rats; Disease Models, Animal; Ovary; Estrous Cycle
PubMed: 38642598
DOI: 10.1016/j.steroids.2024.109424 -
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 -
Animals : An Open Access Journal From... Apr 2024The porcine bulbourethral glands produce a gel-type secretion. Although the role of these contributions to reproductive success remains murky, the bulbourethral glands...
The porcine bulbourethral glands produce a gel-type secretion. Although the role of these contributions to reproductive success remains murky, the bulbourethral glands are major accessory sex glands in this species. Isometric growth in the early neonatal interval is followed by allometric growth in the late juvenile interval (6 to 11 weeks of age), while circulating endogenous steroids are low. The rate of allometric growth increases during the peripuberal interval (16 to 20 weeks of age) when systemic testosterone is relatively high. Gene expression for androgen receptor () and for the steroid 5 alpha-reductase 2 () enzyme that synthesizes the more potent androgen dihydrotestosterone from its precursor was evaluated by qPCR analyses of bulbourethral gland tissue. Tissues were collected from control boars (2 weeks to 40 weeks of age) and from littermates of these boars treated with letrozole to suppress endogenous estrogen synthesis. Gene expression for these two key proteins in androgen signaling was quite low during the initial allometric growth in the late juvenile and prepuberal intervals, suggesting that this initial growth was not primarily stimulated by androgens. These observations are consistent with a more direct estrogen-mediated inhibition of growth via GPER previously proposed, with the sensitivity extending into the late juvenile interval when estrogens as well as androgens are normally relatively low.
PubMed: 38612354
DOI: 10.3390/ani14071115 -
The World Journal of Men's Health Apr 2024The aim of this study was to investigate the efficacy of ethanol extracts of (ECA) against benign prostatic hyperplasia (BPH) and .
Ethanol Extracts of Improve Benign Prostatic Hyperplasia by Inhibiting Prostate Cell Proliferation through Modulating 5 Alpha-Reductase/Androgen Receptor Axis-Mediated Signaling.
PURPOSE
The aim of this study was to investigate the efficacy of ethanol extracts of (ECA) against benign prostatic hyperplasia (BPH) and .
MATERIALS AND METHODS
The prostate stromal cells (WPMY-1) and epithelial cells (RWPE-1) were used to examine the action mechanism of ECA in BPH . ECA efficacy was evaluated using a testosterone propionate (TP)-induced BPH rat model.
RESULTS
Treatment with ECA inhibited the proliferation of prostate cells by inducing G1-phase cell cycle arrest through the regulation of positive and negative proteins. Treatment of prostate cells with ECA resulted in alterations in the mitogen-activated protein kinases and protein kinase B signaling pathways. The transcriptional binding activity of the NF-κB motif was suppressed in both ECA-treated prostate cells. In addition, treatment with ECA altered the level of BPH-associated axis markers (5α-reductase, fibroblast growth factor-2, androgen receptor, epidermal growth factor, Bcl-2, and Bax) in both cell lines. Finally, the administration of ECA attenuated the enlargement of prostatic tissues in the TP-induced BPH rat model, accompanied by histology, immunoblot, and serum dihydrotestosterone levels.
CONCLUSIONS
These results demonstrated that ECA exerted beneficial effects on BPH both and and might provide valuable information in the development of preventive or therapeutic agents for improving BPH.
PubMed: 38606866
DOI: 10.5534/wjmh.230200 -
The Journal of Pathology Jul 2024Steroid 5α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and is crucial for prostatic development. 5α reductase inhibitors (5ARI) reduce prostate...
Steroid 5α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and is crucial for prostatic development. 5α reductase inhibitors (5ARI) reduce prostate size in benign prostate hyperplasia (BPH) and ameliorate lower urinary tract symptoms secondary to BPH. However, the mechanisms of 5ARI functioning are still not fully understood. Here, we used a Srd5a2 mouse model and employed single-cell RNA sequencing to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial cell (LE) populations were observed, alongside an increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1) LE2 cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting an alternative pathway for prostate growth when SRD5A2 is absent. Human prostate biopsy analysis revealed an inverse correlation between the expressions of SRD5A2 and LE2 markers (ESR1/PKCα), and an inverse correlation between SRD5A2 and the clinical efficiency of 5ARI. These findings provide insights into 5ARI resistance mechanisms and potential alternative therapies for BPH-related lower urinary tract symptoms. © 2024 The Pathological Society of Great Britain and Ireland.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Male; Animals; Estrogen Receptor alpha; Prostate; Humans; Prostatic Hyperplasia; Epithelial Cells; Membrane Proteins; Mice, Knockout; Mice; 5-alpha Reductase Inhibitors; Cell Proliferation; Disease Models, Animal; Cell Differentiation; Lower Urinary Tract Symptoms
PubMed: 38606616
DOI: 10.1002/path.6283 -
In Silico Pharmacology 2024Androgen receptor (AR) is known to play a crucial role in the development and progression of prostate cancer, and compounds that inhibit its activity are regarded as...
Androgen receptor (AR) is known to play a crucial role in the development and progression of prostate cancer, and compounds that inhibit its activity are regarded as promising for the development of drugs to treat the disease. This study aimed to investigate the AR-inhibiting potential of fruit compounds for prostate cancer drug development. Following HPLC identification, the binding energies, molecular interactions, and pharmacological potentials of the compounds against AR were elucidated using in silico techniques such as, molecular docking, induced-fit docking, molecular dynamics simulation, and ADMET prediction. Some of the compounds found to be present in fruit included flavonoids such as proanthocyanin, naringin, flavan 3 ol, flavonones, naringenin, epicatechin, citrulline, and catechin. Naringenin exhibited the highest docking score in the molecular docking analysis, followed by resveratrol, ribalinidine, and epicatechin. These compounds share a common AR binding site with the standard ligand, dihydrotestosterone (DHT). Some of the compounds showed favorable ADMET profiles, while others showed at least one toxicity potential. The induced-fit docking of naringenin with AR yielded a higher docking score than the initial score obtained from standard docking while preserving stable molecular contacts with the interacting amino acids. Consistent hydrogen bond interactions of naringenin with PHE 764, ASN 705, and THR 877 of AR, including a persistent pi-pi stacking contact with PHE 764, were observed from the molecular dynamic simulation. The compounds, particularly naringenin, may therefore be considered for further research towards the development of drugs for prostate cancer therapy.
PubMed: 38596366
DOI: 10.1007/s40203-024-00193-5 -
Frontiers in Cell and Developmental... 2024The gut microbiome is implicated in the pathogenesis of polycystic ovary syndrome (PCOS), and prenatal androgen exposure is involved in the development of PCOS in later...
Effects of the prenatal and postnatal nurturing environment on the phenotype and gut microbiota of mice with polycystic ovary syndrome induced by prenatal androgen exposure: a cross-fostering study.
The gut microbiome is implicated in the pathogenesis of polycystic ovary syndrome (PCOS), and prenatal androgen exposure is involved in the development of PCOS in later life. Our previous study of a mouse model of PCOS induced by prenatal dihydrotestosterone (DHT) exposure showed that the reproductive phenotype of PCOS appears from puberty, followed by the appearance of the metabolic phenotype after young adulthood, while changes in the gut microbiota was already apparent before puberty. To determine whether the prenatal or postnatal nurturing environment primarily contributes to these changes that characterize prenatally androgenized (PNA) offspring, we used a cross-fostering model to evaluate the effects of changes in the postnatal early-life environment of PNA offspring on the development of PCOS-like phenotypes and alterations in the gut microbiota in later life. Female PNA offspring fostered by normal dams (exposed to an abnormal prenatal environment only, fostered PNA) exhibited less marked PCOS-like phenotypes than PNA offspring, especially with respect to the metabolic phenotype. The gut microbiota of the fostered PNA offspring was similar to that of controls before adolescence, but differences between the fostered PNA and control groups became apparent after young adulthood. In conclusion, both prenatal androgen exposure and the postnatal early-life environment created by the DHT injection of mothers contribute to the development of PCOS-like phenotypes and the alterations in the gut microbiota that characterize PNA offspring. Thus, both the pre- and postnatal environments represent targets for the prevention of PCOS and the associated alteration in the gut microbiota in later life.
PubMed: 38590777
DOI: 10.3389/fcell.2024.1365624 -
Zoological Science Feb 2024Androgen(s) is one of the sex steroids that are involved in many physiological phenomena of vertebrate species. Although androgens were originally identified as male sex...
Androgen(s) is one of the sex steroids that are involved in many physiological phenomena of vertebrate species. Although androgens were originally identified as male sex hormones, it is well known now that they are also essential in females. As in the case of other steroid hormones, androgen is produced from cholesterol through serial enzymatic reactions. Although testis is a major tissue to produce androgens in all species, androgens are also produced in ovary and adrenal (interrenal tissue). Testosterone is the most common and famous androgen. It represents a major androgen both in males and females of almost vertebrate species. In addition, testosterone is a precursor for producing significant androgens such as11-ketotestosterone, 5α-dihydrotestosterone, 11-ketodihydrotestosterones and 15α-hydroxytestosterone in a species- or sex-dependent manner for their homeostasis. In this article, we will review the significance and characteristics of these androgens, following a description of the history of testosterone discovery and its synthetic pathways.
Topics: Male; Animals; Female; Androgens; Testosterone; Ovary; Testis; Vertebrates
PubMed: 38587520
DOI: 10.2108/zs230064 -
The Journal of Steroid Biochemistry and... Jul 2024Epitestosterone is a stereoisomer of the active androgen testosterone and its circulating concentrations are similar to those of testosterone in women and children....
Epitestosterone is a stereoisomer of the active androgen testosterone and its circulating concentrations are similar to those of testosterone in women and children. However, its biological function and pathways of metabolism remain unknown. The structural similarity to testosterone suggests a potential function in the modulation of androgen receptor signalling. It is well established that the conversion of testosterone to 5α-dihydrotestosterone enhances local androgen receptor signalling. In this study, we show that epitestosterone is metabolized to 5α-dihydroepitestosterone by both human steroid 5α-reductase isoforms, SRD5A1 and SRD5A2. Using two different variations of a reporter assay for transactivation of the human androgen receptor, we show that epitestosterone is a partial AR agonist and that the 5α-reduction of epitestosterone increases its androgenic activity. In line with this, we show that 5α-reduction of epitestosterone reduces its ability to antagonize 5α-dihydrotestosterone-induced androgen receptor transactivation. In conclusion, we provide evidence that steroid 5α-reductases regulate the modulatory effect of epitestosterone on androgen receptor signalling.
Topics: Humans; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Receptors, Androgen; Transcriptional Activation; Membrane Proteins; Epitestosterone; Dihydrotestosterone; Androgens; Oxidation-Reduction
PubMed: 38582131
DOI: 10.1016/j.jsbmb.2024.106516