Androgen Synthesis Research Articles

Congenital Adrenal Hyperplasia (CAH) - Causes, Diagnosis, Symptoms, Treatment

Introduction and Purpose: Congenital adrenal hyperplasia represents a group of genetic disorders characterized by improper adrenal steroidogenesis, resulting in deficiency or absence of cortisol and/or aldosterone, and varying degrees of disturbances in sexual development. The aim of this study is to raise awareness about the disease, enabling early diagnosis and contributing to reducing neonatal mortality, as the first clinical manifestation of CAH can be the life-threatening salt-wasting syndrome. State of Knowledge: Congenital adrenal hyperplasia (CAH), also known as congenital adrenal hyperplasia, encompasses a group of inherited disorders affecting the adrenal glands located above the kidneys. Adrenal glands produce various hormones, including cortisol, aldosterone, and androgens. CAH involves deficiencies in the enzymes necessary for the production of these hormones, leading to hormonal disturbances. Summary: Congenital adrenal hyperplasia (CAH), also referred to as congenital adrenal hyperplasia (CAH), describes a group of genetic diseases causing defects in adrenal hormone synthesis. CAH results in deficiency or absence of cortisol and/or aldosterone. The most common causes are mutations in the CYP21 gene (21-hydroxylase deficiency), CYP11B2 gene (11β-hydroxylase deficiency), and HSD3B2 gene (3β-hydroxysteroid dehydrogenase deficiency). Enzymatic deficiencies lead to compensatory increases in CRH and ACTH secretion, causing adrenal hyperplasia and excessive androgen synthesis.

DDDR-32. EXPLORING ANDROGENIC MODULATION IN GLIOBLASTOMA: POTENCY AND SELECTIVITY OF NOVEL NORETHINDRONE DERIVATIVES

Abstract BACKGROUND Glioblastoma (GBM) represents the most frequently diagnosed malignant CNS tumor in adults and remains incurable. Despite the identification of several oncogenic drivers contributing to tumor formation, targeted therapy with brain-penetrant inhibitors has afforded little progress in survival outcomes. Interestingly, gender has been shown to increase the incidence of GBM, with men having roughly a 50-60% increase in incidence compared to women in the US. This statistic led to research on the involvement of and subsequent inhibition of androgen synthesis and signaling in cell culture models and tumor samples. METHODS To further investigate the potential involvement of steroidal hormones in GBM proliferation, our lab synthesized a series of norethindrone (NE) derivatives with varied molecular weights, steric bulk, and lipophilicity to modulate the androgenic activity of NE. The small library was tested in several GBM cell lines, including U87, A172, and T98G cells, using cell viability assays. RESULTS One derivative, a lipophilically modified version of NE synthesized via a one-pot click reaction, was shown to have improved potency compared with parental NE (>5-fold). The lipophilic NE derivative had IC50 value of 22 uM, 15 uM, and 35 uM in the U87, A172, and T98G cells, respectively. This molecule was tested in immortalized normal human astrocyte (NHA) cells and found to have an IC50 value of 34 uM suggesting some selectivity. DISCUSSION Given this derivative’s activity in GBM models and modest selectivity, we plan to screen it in additional GBM cell lines (LN-18 and U251) and eventually in glioma stem cell models. Future research will focus on identifying key targets involved in the mechanism of action, including the impact of lipophilic addition to the steroid nucleus and its effect on androgenic activity and downstream signaling. We will investigate these effects using RPPA and co-treatments with androgen receptor antagonists and 5-alpha reductase inhibitors.

Genetic diagnosis in XY disorders of sex development

XY disorders of sex development (XY DSD) comprise a class of heterogeneous genetic entities that result in discrepancies between chromosomal, gonadal, and phenotypic sex due to a reduction in androgen synthesis or action. The chief categories of disorders include gonadal dysgenesis, disorders with reduced androgen production (biosynthetic defect – either alone or in conjunction with impaired glucocorticoid and/or mineralocorticoid synthesis), and insensitivity to androgen action. While conventional diagnostic modalities, encompassing karyotyping, biochemistry, radiology, and, in a few cases, diagnostic laparoscopy, help in formulating a provisional diagnosis, molecular genetic testing is key to arriving at a precise etiology. Besides ending the diagnostic uncertainty, a molecular diagnosis helps to predict the natural course in terms of pubertal development and potential for fertility, thus contributing to decisions on the gender of rearing; and guides on surveillance for extragenital features and the risk of recurrence in subsequent pregnancies. This paper broadly discusses the genetic basis of XY DSD, different modalities of genetic testing, and their utility and limitations.

The Effect of Androgen Deprivation Therapy on the Cardiovascular System in Advanced Prostate Cancer.

Androgen deprivation therapy (ADT) is a mainstay treatment for metastatic prostate cancer, improving progression-free survival. ADT suppresses the production of testosterone and reduces circulating levels of the hormone. Luteinizing hormone-releasing hormone (LH-RH) agonists are the most commonly used ADT modality. They can be given alone or in combination with androgen synthesis inhibitors or androgen receptor antagonists. An estimated 40% of prostate cancer patients will receive ADT as part of their therapy during their lifetime. However, ADT has numerous adverse effects, including an increased cardiovascular risk that impacts quality of life. Relugolix is an alternative form of ADT. It is the only oral gonadotropin-releasing hormone antagonist, circumventing injection site reactions, making it easier for patients to take, and thus increasing compliance. Testosterone suppression with relugolix is excellent and testosterone recovery after discontinuation is rapid. This paper reviews the ADT and anti-androgen treatment options for men with prostate cancer and the cardiovascular effects of these therapies. There is accumulating evidence that cardiovascular risk with relugolix is lower than with other ADT medications and also lower than with androgen synthesis inhibitors and androgen receptor antagonists. This paper provides insight into the use of different ADT regimens based on the cardiovascular status and circumstances. It explores strategies to mitigate negative cardiovascular consequences and highlights the need for further study.

8568 Prevalence of Raised Blood Pressure in Individuals With 46,XY DSD: an I-DSD Registry study

Abstract Disclosure: A.K. Lucas-Herald: None. J. Bryce: None. M. Chen: None. C. Naotunna: None. M. Sepich: None. L. Tack: None. M. Cools: None. S. Poyrazoglu: None. E. Globa: None. M. Stancampiano: None. H.L. Claahsen-van der Grinten: None. T. Guran: None. Z. Yavas Abali: None. L. de Vries: None. S.E. Hannema: None. A. Guven: None. D. Janus: None. H.A. AlShaikh: None. L. Guazzarotti: None. G. Herrmann: None. U. Probst: None. N. Lenherr-Taube: None. D. Konrad: None. M.W. O’Reilly: None. M. Steigert: None. A. Ucar: None. M. Wasniewska: None. R. Coco: None. P. Holterhus: None. V.M. Schwitzgebel: None. S.F. Ahmed: None. Introduction: Males with XY Differences of Sex Development (DSD) may have an increased risk of high blood pressure and accelerated vascular ageing. It is not clear which individuals are most at risk of this. Methods: Data were obtained from centres using the International Disorders of Sex Development (I-DSD) Registry on boys and men with 46,XY DSD. Blood pressure (BP) readings were requested as well as information on risk factors for hypertension (birthweight, obesity, family history, associated malformations) as well as ongoing management of any high BP readings. Results: In total BP readings from 208 individuals with 46,XY DSD were available from 22 centres worldwide. Of these, the median (range) age at the time of the BP reading was 13 years (1, 54). In total 97 (47%) had a non-specific XY DSD; 37 (18%) had a disorder of gonadal development; 34 (16%) had a disorder of androgen synthesis; 23 (11%) had a disorder of androgen action; 14 (7%) had hypogonadotrophic hypogonadism; and 3 (1%) had a disorder of Müllerian development. There were 77 (37%) cases ≥16 years of age, of whom 7 (10%) were classified as hypertensive. The median systolic BP of those adults with an underlying DSD was 120 mmHg (90, 153). Of the 131 (63%) individuals <16 years of age, 25 (19%) had a BP > 95th centile for age and height. The median BP standard deviation score (SDS) of those children with an underlying DSD was 0.3 (-2, 3). Of the 25 children with a raised BP, 6 (24%) had a BP >99.8th centile and 19 (76%) had a BP >98th centile. Boys with disorders of gonadal development had the highest median BP SDS at 0.9, although this was not significantly different to any other condition. There were no differences in BP SDS at the time of the study according to gestation at birth, birthweight, type of underlying of condition or presence of obesity or a co-existing anomaly however BP SDS was significantly associated with age. Of the 32 with hypertension, 3 (9%) were treated with antihypertensives; 2 (6%) had an echocardiogram and none (0%) are reported to have had ambulatory blood pressure monitoring. Conclusions: Up to 20% of young people with XY DSD have a BP in the hypertensive range during childhood at clinic compared to approximately 5% reported global prevalence in children. Our findings suggest that routine BP measurements should be recommended in this group as well as investigation to determine whether this is true hypertension or secondary to clinic anxiety. Management of these individuals requires adherence to international guidelines to prevent future cardiovascular damage. More research into the underlying cause of this phenomenon is required. Presentation: 6/1/2024

8568 Prevalence of Raised Blood Pressure in Individuals With 46,XY DSD: an I-DSD Registry study

Abstract Disclosure: A.K. Lucas-Herald: None. J. Bryce: None. M. Chen: None. C. Naotunna: None. M. Sepich: None. L. Tack: None. M. Cools: None. S. Poyrazoglu: None. E. Globa: None. M. Stancampiano: None. H.L. Claahsen-van der Grinten: None. T. Guran: None. Z. Yavas Abali: None. L. de Vries: None. S.E. Hannema: None. A. Guven: None. D. Janus: None. H.A. AlShaikh: None. L. Guazzarotti: None. G. Herrmann: None. U. Probst: None. N. Lenherr-Taube: None. D. Konrad: None. M.W. O’Reilly: None. M. Steigert: None. A. Ucar: None. M. Wasniewska: None. R. Coco: None. P. Holterhus: None. V.M. Schwitzgebel: None. S.F. Ahmed: None. Introduction: Males with XY Differences of Sex Development (DSD) may have an increased risk of high blood pressure and accelerated vascular ageing. It is not clear which individuals are most at risk of this. Methods: Data were obtained from centres using the International Disorders of Sex Development (I-DSD) Registry on boys and men with 46,XY DSD. Blood pressure (BP) readings were requested as well as information on risk factors for hypertension (birthweight, obesity, family history, associated malformations) as well as ongoing management of any high BP readings. Results: In total BP readings from 208 individuals with 46,XY DSD were available from 22 centres worldwide. Of these, the median (range) age at the time of the BP reading was 13 years (1, 54). In total 97 (47%) had a non-specific XY DSD; 37 (18%) had a disorder of gonadal development; 34 (16%) had a disorder of androgen synthesis; 23 (11%) had a disorder of androgen action; 14 (7%) had hypogonadotrophic hypogonadism; and 3 (1%) had a disorder of Müllerian development. There were 77 (37%) cases ≥16 years of age, of whom 7 (10%) were classified as hypertensive. The median systolic BP of those adults with an underlying DSD was 120 mmHg (90, 153). Of the 131 (63%) individuals <16 years of age, 25 (19%) had a BP > 95th centile for age and height. The median BP standard deviation score (SDS) of those children with an underlying DSD was 0.3 (-2, 3). Of the 25 children with a raised BP, 6 (24%) had a BP >99.8th centile and 19 (76%) had a BP >98th centile. Boys with disorders of gonadal development had the highest median BP SDS at 0.9, although this was not significantly different to any other condition. There were no differences in BP SDS at the time of the study according to gestation at birth, birthweight, type of underlying of condition or presence of obesity or a co-existing anomaly however BP SDS was significantly associated with age. Of the 32 with hypertension, 3 (9%) were treated with antihypertensives; 2 (6%) had an echocardiogram and none (0%) are reported to have had ambulatory blood pressure monitoring. Conclusions: Up to 20% of young people with XY DSD have a BP in the hypertensive range during childhood at clinic compared to approximately 5% reported global prevalence in children. Our findings suggest that routine BP measurements should be recommended in this group as well as investigation to determine whether this is true hypertension or secondary to clinic anxiety. Management of these individuals requires adherence to international guidelines to prevent future cardiovascular damage. More research into the underlying cause of this phenomenon is required. Presentation: 6/1/2024

The Association of Statin Use With Survival Outcomes in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Androgen Receptor Targeted Therapies (ART)

BackgroundStatins may provide a compounded effect on ART by decreasing cholesterol levels thus decreasing de novo androgen synthesis and tumor cell viability. We investigated the clinical efficacy of concurrent statin use on outcomes of patients with mCRPC taking ART. MethodsA single-institution retrospective analysis of patients with mCRPC receiving ART from 2010 to 2021 was performed. Our primary outcome was PSA progression free survival (PFS), and our secondary outcomes were overall survival (OS). Patient characteristics were collected in addition to ART treatment course, statin treatment, and survival outcomes. Cox proportional hazards regression model was used to estimate hazard ratios (HR) for OS and PSA PFS and multivariable logistic regression to determine risk factors. Results153 patients with mCRPC treated with ART were included. A total of 67 patients (43.8%) received concurrent statins. Median PSA PFS was 20.4 months for patients that received statins versus 15.3 months for patients who did not receive statins. Median OS was 45.1 months for patients who received concurrent statins versus 29.7 months for patients who did not. On univariate and multivariate survival analyses, there was no statistically significant difference between groups for PSA PFS (HR 0.7; CI 0.44-1.1; P = .123) and OS (HR 0.67; CI 0.42-1.06; P = .089). ConclusionsOur analysis suggests that statins do not significantly improve clinical outcomes in patients with mCRPC. Ultimately, current understanding remains limited, and prospective studies are needed, but here we provide a cost-effective, timely, and selective preliminary analysis.

High concentrations of progesterone inhibit the expression of genes related to steroid metabolism in MA-10 Leydig cells

Leydig cells are the main testosterone-producing cells in males. During androgen synthesis, cholesterol enters the mitochondria via the STAR protein and is converted into pregnenolone by the CYP11A1 enzyme. This steroid is then exported from the mitochondria to be metabolized to progesterone by the HSD3B1 enzyme in the endoplasmic reticulum. In this study, we used 3′Tag-RNA-Seq to identify progesterone-regulated genes in MA-10 Leydig cells. Our results indicate that high concentrations of progesterone (30 μM) are involved in a negative feedback loop that inhibits cAMP/PKA-dependent activation of Star and Cyp11a1 expression and participate in cAMP/PKA-dependent down-regulation of genes related to the metabolism of steroid hormones. Linked to activation of the MAPK signaling pathway, endoplasmic reticulum stress and apoptosis, most of the genes encoding bZIP transcription factors are upregulated by progesterone in MA-10 Leydig cells. However, only DDIT3 protein levels are increased in response to progesterone in MA-10 Leydig cells. Like normal Leydig cells, MA-10 cells very weakly express the classical nuclear receptor for progesterone, suggesting that gene regulation by progesterone is rather mediated by one of the non-classical membrane receptors for progesterone However, current findings suggest that the inhibitory effect of progesterone on STAR protein increase in response to forskolin is not dependent on PGRMC1/2 or PAQR9. Furthermore, the increase in progesterone synthesis in response to activation of the cAMP/PKA pathway is rather inhibited by siRNA-mediated knockdown of PAQR9. Overall, this study shows that progesterone produced by Leydig cells participates in the regulation of steroidogenesis through autocrine action involving negative feedback upon activation of the cAMP/PKA pathway.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Amino polycarboxylic acids-modified abiraterone derivatives as potential injectable anti-prostate cancer agents

Abiraterone (Abi), an effective cytochrome oxidase P450 C17 (CYP17) inhibitor, inhibits androgen synthesis in testes, adrenal glands, and prostate tumors. However, their low bioavailability and dissolution rate due to their poor solubility and toxic side effects have hindered their clinical applications. In this study, water-soluble and injectable Abi derivatives were developed by introducing amino polycarboxylic acids into Abi, and their antiproliferation effects in vitro, mechanism of action, antitumor activities in vivo, pharmacokinetics, and toxicity were investigated. Compared to Abi, the water-soluble derivative Abi-DTPA exhibited excellent antitumor activity in vitro and in vivo. It decreased cell migration, invasion, and mitochondrial membrane potential. A mechanistic study revealed that it still targeted the CYP17 enzyme and increased the expression levels of apoptosis-related proteins, including cleaved caspase 9, cleaved PARP, and cleaved caspase 3. Abi-DTPA was the main form in the plasma and exhibited lower toxicity after intravenous administration. These findings suggest that Abi-DTPA can be used as a novel injectable anti-prostate cancer agent.

Decoding 11-Oxygenated Androgen Synthesis: Insights from Enzyme Gene Expression and LC‒MS/MS Quantification.

Adrenal-origin and peripheral tissue-transformed 11-oxygenated androgens are recognized as significant androgens. However, our current understanding of the synthesis of 11-oxygenated androgens, including the organs and cell types involved, remains limited. We performed comprehensive analyses on an extensive dataset of normal human tissues, which included bulk RNA data from 30 tissues, single-cell RNA sequencing (scRNA) data from 16 tissues and proteomics data from 29 tissues, to characterize the expression profiles of enzyme-encoding genes. To validate the findings, immunohistochemical and liquid chromatography-tandem mass spectrometry (LC‒MS/MS) techniques were employed. Our investigation revealed that the gene expression levels of the enzymes HSD11B2 and AKR1C3 were notably elevated in the kidney and intestines. Intriguingly, within these organs, we observed an increasing trend in enzyme expression with age in women, while a decreasing trend was apparent in men. Sc-RNA analysis revealed that HSD11B2 was predominantly expressed in collecting duct principal cells in the kidney, while AKR1C3 was primarily expressed in the proximal tubules. Intriguingly, nearly all epithelial cells in the intestine expressed these key enzymes. Further analysis using LC‒MS/MS revealed that the kidney exhibited the highest levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) among the seven tissues examined, and substantial synthesis of 11KA4 and 11KT was also observed in the intestine. Finally, we developed the TransMap website (http://gxmujyzmolab.cn:16245/TransMap/) to provide comprehensive visualization of all currently available transcriptome data. This study offers an overarching perspective on tracing the synthesis of 11-oxygenated androgens in peripheral tissues, thereby providing valuable insights into the potential role of these androgens in humans.

Whole-transcriptome sequencing analysis to identify key circRNAs, miRNAs, and mRNAs in the development of yak testes

BackgroundThe Testis is an important reproductive organ in male mammals and the site for spermatogenesis, androgen synthesis, and secretion. Non-coding RNAs (ncRNAs) play an important regulatory role in various biological processes. However, the regulatory role of ncRNAs in the development of yak testes and spermatogenesis remains largely unclear.ResultIn this study, we compared the expression profiles of circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in yak testicular tissue samples collected at 6 months (Y6M), 18 months (Y18M), and 4 years (Y4Y). Using RNA sequencing (RNA-Seq), we observed a significant difference in the expression patterns of ncRNAs in the samples collected at different testicular development stages. Twenty-two differentially expressed (DE) circRNAs, 69 DE miRNAs, and 64 DE mRNAs were detected in Y6M, Y18M, and Y4Y testicular samples, respectively. The results of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the source genes of DE circRNAs, predicted target genes of DE miRNAs, and DE mRNAs were specifically associated with signaling pathways and GO terms that were related to sperm synthesis, sperm vitality, and testicular development, such as cell cycle, Wnt signaling pathway, MAPK signaling pathway, GnRH signaling pathway, and spermatogenesis. The analysis of the circRNA-miRNA-mRNA network revealed that some DE ncRNAs, including miR-574, miR-449a, CDC42, and CYP11A1, among others, may be involved in testicular spermatogenesis. Concurrently, various circRNA-miRNA interaction pairs were observed.ConclusionOur findings provide a database of circRNAs, miRNAs, and mRNAs expression profiles in testicular tissue of yaks at different developmental stages and a detailed understanding of the regulatory network of ncRNAs in yak testicular development and provide data that can help elucidate the molecular mechanisms underlying yak testicular development.

Abstract P148: Loss of Ovarian Estrogen Downregulates Renal Steroidogenesis

Hypertension impacts half of US adults and importantly is more prevalent in men than premenopausal women. Sex hormones, particularly estrogen, have been implicated in this sex-difference. Recently we showed renal medullary estrogenic signaling via the G protein-coupled estrogen receptor 1 promotes sodium excretion in female, but not male, Sprague Dawley (SD) rats which implicates estrogen as a possible female-specific natriuretic factor. This led us to question whether the kidney could produce its own steroids, including estrogen, to respond to salt load changes locally. Evidence in cultured COS-7 and fetal kidney cells indicates the expression and activity of steroidogenic enzymes. Recently, we showed the outer medulla of the female SD rat kidney expresses key enzymes and metabolites involved in sex steroid biosynthesis. It is unknown how ovarian estrogen regulates steroidogenesis in the kidney. We hypothesize that ovarian estrogen stimulates the intrarenal capacity to biosynthesize sex steroids. To test this, we measured mRNA expression of several steroidogenic enzymes in the renal outer medulla of gonadally-intact female or ovariectomized SD rats (N=6). Cholesterol is the initial substrate for steroid synthesis. Thus, we first measured HMG-CoA reductase (HMGCR), the key synthesizing enzyme for cholesterol and steroidogenic acute regulatory protein (StAR), which helps commit cholesterol to steroid synthesis. Ovariectomy (OVX) reduced mRNA expression of both when compared to intact females (HMGCR: 63.5 ± 6.2 vs 100.0 ± 10.7 P=0.0169; StAR: 66.6 ± 12.4 vs 100.0 ± 6.4 P=0.0298). Although not significantly different, OVX seemed to reduce the expression of hydroxysteroid 3-β Dehydrogenase, which converts several intermediate steps in androgen and estrogen synthesis, compared to intact females (73.4 ± 13.3 vs 100.0 ± 9.7 P=0.1283). Hydroxysteroid 17-β Dehydrogenase (17β-HSD) 1, which converts estrone to estradiol, was unchanged in OVX compared to intact females (107.6 ± 13.2 vs 100.0 ± 10.1 P=0.6537). OVX reduced expression of 17β-HSD2 (28.34 ± 7.8 vs 100.0 ± 12.85 P=0.0008) and 17β-HSD3 (71.1 ± 7.5 vs 100.0 ± 5.7 P=0.0097) which interconvert androstenedione and testosterone compared to intact females. Combined these data suggest that ovariectomy blunts the intrarenal machinery for steroidogenesis. Additional experiments are required to test whether menopause downregulates renal sex steroid biosynthesis and predisposes postmenopausal women to hypertension.

Zinc and Its Impact on the Function of the Testicle and Epididymis.

Zinc (Zn) is an essential trace element; it exhibits a plethora of physiological properties and biochemical functions. It plays a pivotal role in regulating the cell cycle, apoptosis, and DNA organization, as well as in protein, lipid, and carbohydrate metabolism. Among other important processes, Zn plays an essential role in reproductive health. The ZIP and ZnT proteins are responsible for the mobilization of Zn within the cell. Zn is an inert antioxidant through its interaction with a variety of proteins and enzymes to regulate the redox system, including metallothioneins (MTs), metalloenzymes, and gene regulatory proteins. The role of Zn in the reproductive system is of great importance; processes, such as spermatogenesis and sperm maturation that occur in the testicle and epididymis, respectively, depend on this element for their development and function. Zn modulates the synthesis of androgens, such as testosterone, for these reproductive processes, so Zn deficiency is related to alterations in sperm parameters that lead to male infertility.

In-depth exploration of differences of sex development: 5-year experience in a tertiary center.

Differences/disorders of sex development (DSD) encompass a wide range of conditions. Their clinical spectrum and etiological diagnosis have not been reported in Moroccan patients. The study aims to highlight the clinical spectrum, etiological diagnosis, and management of patients with DSD. This is a retrospective study of all patients diagnosed with DSD under the age of 18 years, who were referred to the Pediatric Endocrinology Department and the Medical Genetics Laboratory at HASSAN II University Hospital of Fez between June 2018 and June 2023. Out of 57 patients, 54.4% (n = 31) were diagnosed with 46,XX DSD, the most common type, while 45.6% (n = 26) had 46,XY DSD. Patients with 46,XX DSD presented earlier than those with 46,XY DSD, at a median age of 0.08 years and 0.96 years, respectively. The most commonly reported complaint was atypical genitalia. At the first presentation, the sex of rearing was already assigned to 26 males and 27 females. All patients with 46,XX DSD were diagnosed with congenital adrenal hyperplasia (CAH) at a median age of diagnosis of 0.92 years. Of these, 11 patients were raised as males. Disorders of androgen action or synthesis were more common in XY patients (69.2%). The consanguinity rate was 46.5%, and there were 19 cases with a positive family history, with 10 siblings having died. DSD are not rare in Morocco. Overall, CAH remains the most frequent DSD etiology. Molecular genetic analyses are needed to determine the accurate etiological distribution of DSD, especially in XY patients.

Assessment of Cardiovascular Events Caused by New-Generation Androgen Receptor Pathway Inhibitors Used for Prostate Cancer: A Real-World Study in Japan.

Androgen receptor pathway inhibitors (ARPIs) that significantly improve the prognosis of patients with prostate cancer include abiraterone acetate (androgen synthesis inhibitor) and enzalutamide (androgen receptor inhibitor). A recent analysis of ARPI and cardiovascular events using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) has been reported; however, the evidence on cardiovascular events for abiraterone acetate and enzalutamide in real-world clinical practice is insufficient. Using a large Japanese database of medical institutions, the Japanese Medical Data Center (JMDC) medical institution database (JMDC Inc., Tokyo, Japan), this study tested the hypothesis that the risk of cardiovascular events with enzalutamide is lower than that with abiraterone acetate. Using the JMDC medical institution database, patients with new use of abiraterone acetate or enzalutamide who had not experienced a major cardiovascular event between October 2014 and February 2022 were included. After adjusting for age, comorbidities, and concomitant medications using propensity score matching, cumulative incidence rates were compared for cardiovascular death and all cardiovascular events as the primary endpoints, and major cardiovascular events, myocardial infarction, heart failure, and stroke as secondary endpoints. A total of 3,033 patients in the enzalutamide group and 2,021 in the abiraterone group met the eligibility criteria. After propensity score matching, the cohort included 1,940 patients in the enzalutamide group and 1,940 patients in the abiraterone group. Enzalutamide was associated with significantly lower cumulative rates of cardiovascular death (hazard ratio [HR]: 0.30, 95% confidence interval [CI]: 0.10-0.93), all cardiovascular events (HR: 0.79, 95% CI: 0.64-0.98), major cardiovascular events (HR: 0.79, 95% CI: 0.64-0.97), and myocardial infarction (HR: 0.62, 95% CI: 0.46-0.84) compared to abiraterone. In a national sample of males with prostate cancer, those newly treated with enzalutamide had a lower risk of adverse cardiovascular events than those treated with abiraterone acetate.

The Influence of β-Carotene and Its Liposomal Form on the Expression of EMT Markers and Androgen-Dependent Pathways in Different Prostate Cell Lines.

Prostate cancer (PCa) is the most common malignancy in men. Although the prognosis in the early stages is good, the treatment of advanced PCa remains a formidable challenge. Even after an initial response to hormone therapy or chemotherapy, recurrences are frequent and resistance to any systemic treatment is common. β-Carotene (BC), a plant-derived tetraterpene, is known for its antioxidant capacity and can modulate multiple cellular signaling pathways, potentially affecting androgen synthesis. We investigated the influence of BC (dissolved in EtOH/THF with a cell culture medium or encapsulated in liposomes (LP-BCs)) on the viability, migration potential, and connective tissue cleavage capabilities of several PCa cell lines (Du145, LNCaP, PC-3, and 22Rv1) and a healthy prostate model (RWPE cells). BC significantly reduced the proliferative capacity of all investigated cell lines at various concentrations (1.5-30 µM) and decreased cell migration. However, it significantly increased the expression of epidermal-mesenchymal transition (EMT) master proteins in all cancer cell lines and RWPE (p < 0.05) These effects were not observed with LP-BCs. This study suggests that LP-BCs, with their higher antiproliferative capabilities and pronounced inhibition of the EMT, may be a more effective form of possible PCa prevention or treatment than the free form. LPs may also modulate lipid metabolism in PCa cells.

Obesity Is Associated with Increased 11-Oxyandrogen Serum Concentrations during Puberty

Introduction: While the influence of various factors on classical androgen synthesis in children and adolescents and its impact on puberty has been widely investigated, there appear to be gaps and contradictory findings regarding the association of overweight and obesity with the synthesis of adrenal-derived 11-oxygenated androgen (11-OA) serum levels. With this study, we aimed to examine how overweight and obesity affect 11-OA serum levels during puberty in a large cohort of children and adolescents. Methods: Our cohort comprised 1,054 healthy children aged 6–19 years providing serum samples at a total of 1,734 visits. Liquid chromatography-tandem mass spectrometry was used to quantify 11-ketotestosterone (11-KT), 11-ketoandrostendione (11-KA4), 11-β-hydroxytestosterone (11-OHT), 11-β-hydroxyandrostendione (11-OHA4), testosterone, androstenedione, and DHEAS. In addition, we assessed BMI-SDSs, skinfold thicknesses, and Tanner stages. The significance level α was set to α = 0.05. Results: Increases in 11-KT, 11-KA4, 11-OHT, and 11-OHA4 levels were observed in boys and girls during puberty. 11-KT (β = 0.2, p < 0.001), 11-KA4 (β = 0.16, p < 0.001), and 11-OHA4 (β = 0.12, p = 0.003) were positively correlated with BMI in boys aged 13 years and under. 11-KT (β = 0.1, p = 0.047) was positively correlated with BMI in girls aged 11 years and under. 11-OHT was positively correlated with BMI independent of age (boys 13 years and under: β = 0.17, p < 0.001; over 13 years: β = 0.14, p = 0.001; girls 11 years and under: β = 0.17, p < 0.001; over 11 years: β = 0.18, p < 0.001). Conclusion: We found increasing 11-OA serum levels throughout all Tanner stages. 11-OAs were observed to be associated with BMI and skinfold thickness, suggesting that overweight and obesity may be associated with pubertal alterations in 11-OA serum levels.

Body composition as a determinant of the therapeutic index with androgen signaling inhibition.

Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC). A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma. Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48). Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.

Loss of Function of Vasoactive-intestinal Peptide Alters Sex Ratio and Reduces Male Reproductive Fitness in Zebrafish.

Vasoactive-intestinal peptide (Vip) is a pleiotropic peptide with a wide range of distribution and functions. Zebrafish possess 2 isoforms of Vip (a and b), in which Vipa is most homologous to the mammalian form. In female zebrafish, Vipa can stimulate LH secretion from the pituitary but is not essential for female reproduction, as vipa-/- females display normal reproduction. In contrast, we have found that vipa-/- males are severely subfertile and sex ratio of offspring is female-biased. By analyzing all aspects of male reproduction with wild-type (WT) males, we show that the testes of vipa-/- are underdeveloped and contain ∼70% less spermatids compared to WT counterparts. The sperm of vipa-/- males displayed reduced potency in terms of fertilization (by ∼80%) and motility span and duration (by ∼50%). In addition, vipa-/- male attraction to WT females was largely nonexistent, indicating decreased sexual motivation. We show that vipa mRNA and protein is present in Leydig cells and in developing germ cells in the testis of WT, raising the possibility that endogenous Vipa contributes to testicular function. Absence of Vipa in vipa-/- males resulted in downregulation of 3 key genes in the androgen synthesis chain in the testis, 3β-hsd, 17β-hsd1, and cyp11c1 (11β-hydrogenase), associated with a pronounced decrease in 11-ketotestosterone production and, in turn, compromised reproductive fitness. Altogether, this study establishes a crucial role for Vipa in the regulation of male reproduction in zebrafish, like in mammals, with the exception that Vipa is also expressed in zebrafish testis.