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Summary Aim Comparison of gender personality traits in CAH-affected 46,XX patients with those in 46,XY patients with complete androgen insensitivity syndrome (AIS) or gonadal dysgenesis (GD). Patients and methods Thirty-six 46,XX CAH, three 46,XY AIS, four 46, XY GD patients. The Bem Sex-Role Inventory (BSRI) was used to measure masculinity, femininity and to research gender roles. Results The lowest femininity values were in the patients with CAH, the highest in patients with AIS. Age at study was not associated with the value of BSRI score. CAH patients with the Prader score 4 had lower median femininity score values than those who had the Prader score 3, however, the difference was statistically insignificant. Conclusion More masculinizied personality behavioral traits in females with CAH most likely result from exposure of the fetal brain to high levels of androgens.

Although the Sonic hedgehog (SHH) signaling pathway has been implicated in promoting malignant phenotypes of prostate cancer, details on how it is activated and exerts its oncogenic role during prostate cancer development and progression is less clear. Here, we show that GLI3, a key SHH pathway effector, is transcriptionally upregulated during androgen deprivation and posttranslationally stabilized in prostate cancer cells by mutation of speckle-type POZ protein (SPOP). GLI3 is a substrate of SPOP-mediated proteasomal degradation in prostate cancer cells and prostate cancer driver mutations in SPOP abrogate GLI3 degradation. Functionally, GLI3 is necessary and sufficient for the growth and migration of androgen receptor (AR)–positive prostate cancer cells, particularly under androgen-depleted conditions. Importantly, we demonstrate that GLI3 physically interacts and functionally cooperates with AR to enrich an AR-dependent gene expression program leading to castration-resistant growth of xenografted prostate tumors. Finally, we identify an AR/GLI3 coregulated gene signature that is highly correlated with castration-resistant metastatic prostate cancer and predictive of disease recurrence. Together, these findings reveal that hyperactivated GLI3 promotes castration-resistant growth of prostate cancer and provide a rationale for therapeutic targeting of GLI3 in patients with castration-resistant prostate cancer (CRPC). Implications: We describe two clinically relevant mechanisms leading to hyperactivated GLI3 signaling and enhanced AR/GLI3 cross-talk, suggesting that GLI3-specific inhibitors might prove effective to block prostate cancer development or delay CRPC.

Summary After the discovery of ERβ, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), an estrogen which does not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer. ERβ was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases (Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease), ERβ agonists are very effective in relieving symptoms and improving pathologies, this has not proven to be the case in humans. In this review we will focus on the main differences in ERβ signaling between rodents and humans and will make the point that a very important difference between the two species is in the splice variants which are expressed in humans and not rodents. The main conclusion at this point is that before we think of using ERβ agonists clinically, much more work on ERβ signaling in the human or in primates needs to be done.

PURPOSE The activity of androgen-deprivation therapy (ADT) in androgen receptor–positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC. METHODS This was a single-institution phase II trial. A two-stage Simon's design was applied. The primary end point was confirmed objective response rate. Secondary end points were disease control rate, safety, progression-free survival, and overall survival. Patients were eligible when the following criteria were met: histologic diagnosis of AR-overexpressing SGC, measurable disease according to RECIST 1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and luteinizing hormone-releasing hormone agonist until progression or unacceptable toxicities. RESULTS From 2015 to 2019, 24 AR+ patients with SGC (23 men; median age 65.8 years) were treated within the study. The overall response rate was 21% (5 partial responses), with a disease control rate of 62.5%. The median duration of response was 5.82 months. Median progression-free survival was 3.65 months (95% CI, 1.94 to 5.89), and median overall survival was 22.47 months (95% CI, 6.74 to not reached). Objective response to previous ADT did not correlate with the activity of abiraterone. Adverse events (AEs) were recorded in 22 cases (92%) with grade 3 AEs in six patients (25%): fatigue (two), flushing (one), supraventricular tachycardia (one), and two non–drug-related AEs. No drug-related grade 4 or 5 AEs were recorded. CONCLUSION Abiraterone plus luteinizing hormone-releasing hormone agonist is active and safe as a second-line option in AR-expressing, castration-resistant SGC.

Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA+), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA+ mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after next-generation androgen receptor–directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA+ identified by central plasma (n = 34), central tissue (n = 37), or local (n = 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA+ by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA+ mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.

Objective To highlight the management of massive ovarian edema in young reproductive-age women. Design A case report of a healthy female with clitoromegaly and elevated androgen levels secondary to massive ovarian edema. Setting Reproductive Endocrinology and Infertility Department of an academic hospital. Patient A healthy 20-year-old woman who presented for routine gynecological care and was found to have a 2-cm clitoromegaly and elevated androgen levels. Interventions The patient underwent a diagnostic laparoscopy and right oophorectomy. Main Outcome Measures Measurement of androgen levels. Results Final pathology showed massive edema of the ovary with no evidence of malignancy or androgen-secreting tumor cells. In addition, resolution of the elevated androgen levels was observed. Conclusions Massive ovarian edema due to asymptomatic subacute torsion should be included in the differential diagnosis of reproductive-age patients who present with ovarian mass and hyperandrogenemia within the tumor range. Although not performed in our case, conservative management that involves detorsion, ovarian biopsy, and oophoropexy to prevent a recurrence should be the treatment of choice.

Background: Phase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. Objective: To compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. Design, setting, and participants: Patients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. Intervention: Patients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. Outcome measurements and statistical analysis: The primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. Results and limitations: For the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1–17%], arm 2: 17.1% [95% CI: 7–32%], arm 3: 11.9% [95% CI: 4–26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9–36.1]) relative to degarelix (52.9 wk [95% CI: 49.0–56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. Conclusions: Rates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. Patient summary: We evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.

Epidemiological studies related to androgens and prostate cancer (PC) have focused on serum determination of testosterone, androstenedione (A4), and DHEA, with inconsistent results. Herein, we hypothesized that differences in androgen biosynthetic and metabolic pathways, rather than differences in specific androgen concentrations, are associated with prostatic carcinogenesis. Therefore, spot urine samples from 111 incident PC cases with Gleason score at diagnosis and 227 healthy population controls, were analyzed. Urinary androgen concentrations (nanograms/milligrams of creatinine) were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Using a factor analysis, we identified three androgen urinary excretion patterns. In a subsample, we evaluated a modification effect of the androgen receptor (AR) CAG polymorphism. Pattern I, characterized by A4 and testosterone hydroxylated metabolites (11β-OHT; 2β-OHT; 15β-OHT; 2α-OHT; 6β-OHT), was associated with high PC odds among carriers of AR gene (CAG)>19 repeats (OR: 3.67 95% CI: 1.23–11.0; P for interaction= 0.009). Conversely, higher testosterone excretion (pattern III), was marginally associated with lower (OR: 0.35 95% CI: 0.12–1.00, P for trend= 0.08) poorly differentiated PC (Gleason ≥8). No clear association was observed with pattern II (DHEA; 16α and 16β-OHT). Our results were consistent with the previous evidence which suggests that the C11-oxy backdoor pathway is important for prostatic carcinogenesis. Androgen urine excretion analysis could be useful for PC diagnosis, treatment, and prognosis; however, further studies with a larger number of samples and the urinary determination of 11-ketoandrogens are necessary.

Background: Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder characterized by high androgen levels. The aim of this study was to evaluate the effects of hyperandrogenism on the hypothalamus and subsequently on the food intake and obesity in females. Methods: A dihydroxy testosterone (DHT)-induced rat model was established to recapitulate the hyperandrogenism features of PCOS patients. Body weight and food intake of the rats were recorded. The food intake of DHT-induced rats was restricted by pair feeding to exclude possible effects of weight gain on the hypothalamus. The expression levels of relevant proteins and mRNAs in the hypothalamus and primary hypothalamic neurons exposed to DHT were analyzed by Western blotting and RT-PCR, respectively. The leptin levels in the serum and cerebrospinal fluid (CSF) were measured, and leptin was injected via the intracerebroventricular (ICV) route to test the leptin sensitivity of the hypothalamus. Results: The excessive prepuberty androgen levels in the DHT-induced rats markedly elevated food intake prior to weight gain. Consistent with this, the expression of neuropeptide Y and agouti-related peptide mRNAs was upregulated, which occurred prior to obesity and even with restricted food intake. In addition, the hypothalamic sensitivity to insulin and leptin was also impaired in the DHT-induced rats before obesity and with restricted food intake. DHT significantly reduced the leptin levels in the CSF, and ICV injection of leptin inhibited the DHT-induced increase in food intake. Conclusions: Androgen excess increased food intake in rats and promoted obesity by downregulating insulin and leptin signaling in the hypothalamus, most likely by suppressing leptin levels in the CSF.

Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed. Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan–Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS). Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of castration-resistant development was higher in the Bica compared to Abi group (50.6 vs. 25.2%, p

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450–42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

Steroid 5α-reductase type 2 deficiency (5α-RD2) and androgen insensitivity syndrome (AIS) are difficult to distinguish clinically and biochemically, and adrenal-derived androgens have not been investigated in these conditions using modern methods. The objective of the study was to compare Chinese patients with 5α-RD2, AIS, and healthy men. Sixteen patients with 5α-RD2, 10 patients with AIS, and 39 healthy men were included. Serum androgen profiles were compared in these subjects using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Based on clinical features and laboratory tests, 5α-RD2 and AIS were diagnosed and confirmed by genotyping. Dihydrotestosterone (DHT) and testosterone (T) were both significantly lower in patients with 5α-RD2 than AIS (p < 0.0001). The T/DHT ratio was higher in 5α-RD2 (4.5-88.6) than AIS (13.4-26.7) or healthy men (7.6-40.5). Using LC-MS/MS, a cutoff T/DHT value of 27.3 correctly diagnosed 5α-RD2 versus AIS with sensitivity 93.8% and specificity 100%. Among the adrenal-derived 11-oxygenated androgens, 11β-hydroxyandrostenedione (11OHA4) and 11-ketoandrostenedione (11KA4) were also lower in patients with 5α-RD2 than those of patients with AIS. In contrast, 11β-hydroxytestosterone (11OHT) was higher in 5α-RD2 than AIS. Furthermore, a 11OHT/11OHA4 cutoff value of 0.048 could also distinguish 5α-RD2 from AIS. Thus, both elevated T/DHT values above 27.3 and the unexpected 11-oxygenated androgen profile, with a 11OHT/11OHA4 ratio greater than 0.048, distinguished 5α-RD2 from AIS. These data suggest that the metabolism of both gonadal and adrenal-derived androgens is altered in 5α-RD2.

PURPOSE To retrospectively estimate the impact of radiotherapy as a progression-directed therapy (PDT) in oligoprogressive metastatic castration-resistant prostate cancer (mCRPC) patients under androgen receptor-target therapy (ARTT). MATERIALS AND METHODS mCRPC patients are treated with PDT. End-points were time to next-line systemic treatment (NEST), radiological progression-free survival (r-PFS) and overall survival (OS). Toxicity was registered according to Common Terminology Criteria for Adverse Events v4.0. Survival analysis was performed using the Kaplan-Meier method; univariate and multivariate analyses were performed. RESULTS Fifty-seven patients were analyzed. The median follow-up after PDT was 25.2 months (interquartile, 17.1-44.5). One-year NEST-free survival, r-PFS and OS were 49.8%, 50.4% and 82.1%, respectively. At multivariate analysis, polymetastatic condition at diagnosis of metastatic hormone-sensitive prostate cancer (mHSPC) (HR 2.82, p = 0.004) and PSA doubling time at diagnosis of mCRPC (HR 2.76, p = 0.006) were associated with NEST-free survival. The same variables were associated with r-PFS (HR 2.32, p = 0.021; HR 2.24, p = 0.021). One patient developed late grade ≥ 2 toxicity. CONCLUSION Our study shows that radiotherapy in oligoprogressive mCRPC is safe, is effective and seems to prolong the efficacy of ARTT in patients who otherwise would have gone systemic treatment switch, positively affecting disease progression. Prospective trials are needed.

Prostate cancer is an important disease in current oncological urology. Radical treatment of patients with localized and locally advanced prostate cancer, including surgical and radiological treatments, often does not cure patients from this pathology, especially in the group with high risk of disease progression; the risk of biochemical recurrence in this patient group can be up to 40-60 %. Widespread application of radical treatment allowed to significantly increase survival of patients from this group. However, in case of biochemical recurrence, the majority of patients require longterm androgen-depriving therapy for suppression of natural testosterone level. In some of these patients during longterm castration therapy, non-metastatic castration-resistant prostate cancer develops (CRPC) in the absence of signs of radiological disease progression. Results of large randomized trials show the necessity of stratification of these patients in the group with high risk of progression considering short doubling period of prostate-specific antigen and realization of distant metastases. The main therapy concept for this patient group is use of new-generation inhibitors of androgen signal to increase time to CRPC metastases and overall life expectancy. The article presents results of large trials performed in patients with non-metastatic CRPC and characterizes the role of one of the most effective drugs, darolutamide, used for treatment in this patient cohort.

Background Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid. Methods Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia. Summary Therapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. Conclusions CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

ContextAdrenal-derived 11-oxygenated androgens (11oAs) are known important contributors to human physiology and disease but have not been studied in pregnancy.ObjectiveWe characterize 11oAs in normal human pregnancy and neonatal period and assess the ratios between 11oAs and compare with ratios of other steroids that undergo placental metabolism.DesignProspective cohort study, 2010-2018.SettingAcademic institution.PatientsPairs of pregnant women and newborns (n = 120) were studied. Inclusion criteria were maternal age between 18 and 42 years old, spontaneous singleton pregnancies, and intention to deliver at University of Michigan.InterventionMaternal venous blood was collected during first trimester and at term. Neonatal cord blood was collected following delivery. Steroids were measured via liquid chromatography-tandem mass spectrometry.Main Outcome MeasuresLevels of 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone, and 11-ketotestoterone (11KT) in maternal first trimester, maternal term, and neonatal cord blood were compared. 11OHA4-to-11KA4 ratios were correlated with cortisol-to-cortisone ratios.ResultsDominant 11oAs in pregnancy and the cord blood are 11OHA4 and 11KA4, compared to 11OHA4 and 11KT in adult men and nonpregnant women. We found a rise in 11oA concentrations, particularly 11KA4, from first to third trimester. In cord blood, the concentration of 11KA4 exceeded those of both 11OHA4 and 11KT, reflecting placental 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and 17β-hydroxysteroid dehydrogenase (17βHSD2) activities, respectively. 11OHA4-to-11KA4 ratios are concordant with cortisol-to-cortisone ratios across all maternal and fetal compartments, reflecting placental 11βHSD2 activity.ConclusionsPlacental 17βHSD2 activity defends the fetus against the androgen 11KT. Our normative values may be used in future studies of 11oAs in complicated pregnancies.

Context Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. Objective This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Methods This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (–66%), 17OHP (–64%), and androstenedione (–64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios. Conclusion Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

Background Diagnosing hyperandrogenemia in postmenopausal women is very difficult. It occasionally manifests as excessive hair growth or with no clinical manifestations, and is therefore often misdiagnosed or missed altogether. Ovarian steroid cell tumors that cause hyperandrogenemia in women account for approximately 0.1% of all ovarian tumors. Due to the low incidence, corresponding imaging reports are rare, so ovarian steroid cell tumors lacks typical imaging findings to differentiate it from other ovarian tumors. Therefore, we summarized its clinical and imaging characteristics through this case series, and elaborated on the differential diagnosis of steroid cell tumors. Case summary We report three cases of postmenopausal women with hyperandrogenemia. Only 1 patient showed virilization symptoms, the other two patients were completely asymptomatic. All patients underwent total hysterectomy + bilateral adnexectomy. Histological results showed one case of Leydig cell tumor and two cases of benign, non-specific steroid cell tumor. After the operation, the androgen levels of all patients returned to normal, and there was no clinical recurrence since follow-up. Conclusion Although virilization caused by increased serum testosterone levels is an important clinical feature of ovarian steroid cell tumors, it is often asymptomatic. A solid, slightly hypoechoic, round or oval mass with uniform internal echo, richer blood flow in the solid part, and low resistance index are typical imaging features of ovarian steroid cell tumors. Diagnosis of ovarian steroid cell tumors after menopause is challenging, but surgery can be used for both diagnosis and clear treatment.

Breast cancer is heterogeneous in prognoses and drug responses. To organize breast cancers by gene expression independent of statistical methodology, we identified the Breast Cancer Consensus Subtypes (BCCS) as the consensus groupings of six different subtyping methods. Our classification software identified seven BCCS subtypes in a study cohort of publicly available data (n = 5950) including METABRIC, TCGA-BRCA, and data assayed by Affymetrix arrays. All samples were fresh-frozen from primary tumors. The estrogen receptor-positive (ER+) BCCS subtypes were: PCS1 (18%) good prognosis, stromal infiltration; PCS2 (15%) poor prognosis, highly proliferative; PCS3 (13%) poor prognosis, highly proliferative, activated IFN-gamma signaling, cytotoxic lymphocyte infiltration, high tumor mutation burden; PCS4 (18%) good prognosis, hormone response genes highly expressed. The ER− BCCS subtypes were: NCS1 (11%) basal; NCS2 (10%) elevated androgen response; NCS3 (5%) cytotoxic lymphocyte infiltration; unclassified tumors (9%). HER2+ tumors were heterogeneous with respect to BCCS.

Polycystic ovary syndrome (PCOS) is considered the commonest endocrinological disorder in childbearing age women with an incidence of 10%. Vitamin D has been shown in several studies to have a positive impact on female reproductive diseases, as well as PCOS. The diagnosis of PCOS, clinical symptoms, pathophysiology, hypovitaminosis D, insulin resistance, and the various methods for vitamin D and insulin assessment are all covered in this study. Androgen hypersecretion, oligo-ovulation, and/or ovarian morphologic features are used to diagnose this condition. Androgen excess, neuroendocrine causes, and insulin resistance are all part of the pathophysiology. Some female genital organs have been found to contain vitamin D receptors. Insulin regulates steroid biosynthesis in the ovaries and follicular maturation, so vitamin D is essential.

Duplication of MECP2 (methyl-CpG-binding protein 2) gene causes a serious neurological and developmental disorder called MECP2 duplication syndrome (MDS), which is usually found in males. A previous clinical study reported that MDS patient has precocious puberty with hyperandrogenism, suggesting increased MeCP2 may cause male hyperandrogenism. Here we use an MDS mouse model and confirm that MECP2 duplication significantly upregulates androgen levels. We show for the first time that MeCP2 is highly expressed in the Leydig cells of testis, where androgen is synthesized. Mechanistically, MECP2 duplication increases androgen synthesis and decreases androgen to estrogen conversion through either the upregulation of luteinizing hormone receptor (LHCGR) in testis, as a result of MeCP2 binds to G-quadruplex structure of Lhcgr promoter and recruits the transcription activator CREB1 or the downregulation of the expression of aromatase in testis by binding the CpG island of Rorα, an upstream regulator of aromatase. Taken together, we demonstrate that MeCP2 plays an important role in androgen synthesis, supporting a novel non-CNS function of MeCP2 in the process of sex hormone synthesis.

Background Androgen receptor (AR) is an essential transcriptional factor that contributes to the development and progression of prostate cancer (PCa). NCAPD3 is a component of the condensin II complex and plays a critical role in cell mitosis by regulating chromosome condensation; however, the relationship between NCAPD3 and AR remains unknown. Methods Transcriptome sequencing assay is carried out to analyze the expression of the NCAP family in clinic samples. Chromatin immunoprecipitation (ChIP) sequencing, ChIP assay, and dual-luciferase assay are used to identify the androgen-responsive element in NCAPD3 enhancer. Immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and western-blot assay are employed to check the expression of genes in PCa tissues and in PCa cells. Confocal immunofluorescence microscopy analysis is used for identifying the regulation of AR on NCAPD3-mediated chromosome condensation. Colony formation, cell cycle assay, wound healing assay, and transwell experiments are used to explore the regulation of AR on the functions of NCAPD3. In vivo experiment is employed to identify in vitro experimental results. Results NCAPD3 is an androgen/AR axis-targeted gene and is involved in AR-induced PCa cell proliferation, migration, and invasion in vitro and in vivo. Androgen treatment and AR overexpression increase the expression of NCAPD3 in PCa cell lines. The canonical exist in the enhancer region of NCAPD3. Androgen/AR axis regulates NCAPD3-invovled chromosome condensation during cell mitosis. Conclusions Our report demonstrated that NCAPD3 is an androgen-responsive gene and upregulated by androgen/AR axis and involved in AR-promoted progression of PCa, suggesting a potential role of NCAPD3 in the PCa development.

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

Disorder of Sex Development (DSD) is a congenital disorder that occurs in the development of chromosomes, gonads, and internal or external genital organ. DSD of 46 XY is a condition where the children with XY genotype is not able to have complete virilization of external genital. Determination phase is an initial phase of reproductive system development. Disruption of this phase may potentially lead to DSD. Optimal care for children with Disorder of Sex Development requires a multidisciplinary team starting since neonatal period. Family and pregnancy history, complete physical examination and assessment of genital organ are the first step of ensuring the diagnose. Management of children with DSD are focusing on gender determination, hormone support therapy and surgical management. On the other hand, Children with XY genotype should be raised as a boy however if there is no responsive evidence in administration of androgen the children should be raised as a girl. Subsequent to prescribe the gender of the children, surgical management is a required treatment for removing unnecessary genital afterward. Keywords: Disorders of Sex Development, DSD, 46 XY DSD

Purpose of review The purpose of this review is to examine the recent evidence regarding the effects of exogenous androgens on the brain. Understanding these effects is of high importance, as the consequences of androgens on the reproductive and endocrine system are well documented, while fewer studies have focused on the neural and cerebral consequences of androgen use. Recent findings Supraphysiological doses of androgens have been shown to contribute to neurodegeneration, decreased brain-derived neurotrophic factor, increased inflammation and decreased neuronal density in animal studies, which may correspond to changes in mood, cognition and aggression. Findings from human studies suggest that similar behavioural and cognitive deficits may occur as a result of prolonged use of androgens. Additional evidence suggests that androgen use, particularly in high doses, may contribute to brain ageing and cerebrovascular problems. Summary Findings from recent human and animal studies indicate that androgen use likely contributes to brain alterations, which may cause the frequently observed deficits in cognitive and emotional functioning. Although exogenous testosterone in appropriate doses for therapeutic purposes likely have some neurobiological benefits for certain populations, supraphysiological doses may cause multiple mental and physical health problems, indicating a need for additional large-scale studies in humans.

Glucuronidation controls androgen levels in the prostate and the dysregulation of enzymes in this pathway is associated with castration resistant prostate cancer. UDP-glucose dehydrogenase (UGDH) produces UDP-glucuronate, the essential precursor for glucuronidation, and its expression is elevated in prostate cancer. We compared protein and metabolite levels relevant to the glucuronidation pathway in five prostate cancer patient-derived xenograft models paired with their isogenic counterparts that were selected in vivo for castration resistant (CR) recurrence. All pairs showed changes in UGDH and associated enzymes and metabolites that were consistent with those we found in an isogenic androgen dependent (AD) and CR LNCaP prostate cancer model. Ectopic overexpression of UGDH in LNCaP AD cells blunted androgen-dependent gene expression, increased proteoglycan synthesis, significantly increased cell growth compared to controls, and eliminated dose responsive growth suppression with enzalutamide treatment. In contrast, the knockdown of UGDH diminished proteoglycans, suppressed androgen dependent growth irrespective of androgens, and restored androgen sensitivity in CR cells. Importantly, the knockdown of UGDH in both LNCaP AD and CR cells dramatically sensitized these cells to enzalutamide. These results support a role for UGDH in androgen responsiveness and a target for therapeutic strategies in advanced prostate cancer.

Tamoxifen is a selective oestrogen receptor modulator (SERM). SERMs act on oestrogen receptors to inhibit oestradiol mediated negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, thereby upregulating gonadotrophin secretion and release from the pituitary. Hence, Tamoxifen is used to upregulate activation of the HPG axis in the treatment of male-factor infertility. However, due to a lack of robust evidence, Tamoxifen has not been FDA approved for use in male-factor infertility and so its use is currently off-label. In this study, we performed a literature search of the OVID medline database and identified 37 studies describing the effects of tamoxifen which we then reviewed. Evidence suggests Tamoxifen effectively increases androgen levels and sperm concentrations in males with idiopathic oligozoospermia. Evidence for increased motility and pregnancy rates in these patients is less conclusive. Further randomised control trials are needed to elucidate the safety of Tamoxifen combination therapies and their efficacy in improving pregnancy rates.

ContextNonalcoholic fatty liver disease (NAFLD) describes a spectrum of liver damage due to excessive hepatic lipid accumulation. Recent research has demonstrated a high prevalence of NAFLD in women with polycystic ovary syndrome (PCOS).ResultsStrong associations independent of body mass index (BMI) have been found between high androgen levels characteristic of PCOS, as well as insulin resistance, and the presence of NAFLD in these women, suggesting that these factors contribute to liver injury more significantly than obesity. Current studies indicate the occurrence of NAFLD in normal weight women with PCOS in addition to the commonly researched women who are overweight and obese. While the majority of studies address NAFLD in adult, premenopausal women (ages 25-40 years), the occurrence of NAFLD in young and adolescent women has gone largely unaddressed. Research in this field lacks diversity; a majority of studies either focus on populations of White women or are missing demographic information entirely.ConclusionsFuture studies should include larger, more racially and ethnically inclusive populations and particular attention should be paid to how excess androgens and insulin resistance contribute to the increased risk of NAFLD seen in women with PCOS of varying weights, ages, and ethnicities.Objective and MethodsHere, we review NAFLD in women with PCOS with subsections focused on the impact of hyperandrogenism, BMI, insulin resistance and age. Most notably, we present the most up-to-date racially and ethnically diverse worldwide prevalence of NAFLD in women with PCOS compared with women without PCOS (51.56% vs 29.64%, P < .001, respectively).

Obesity has major adverse effects on reproductive performance and fertility potential especially in women with polycystic ovary syndrome. In this study, we aimed to evaluate the consequences of excess weight reduction by bariatric surgery on androgen levels, and ovarian volume by ultrasonography in obese polycystic ovary patients. This one year Cohort study was carried out in Zagazig university hospitals. The study included 36 infertile women with PCOS and obesity, who underwent bariatric surgery(sleeve gastrectomy or gastric bypass). Patients were evaluated for free and total serum testosterone levels, Sex hormone binding globulin (SHBG), free androgen index (FAI) and also ovarian volume by ultrasound pre-operatively, 6 months and 1 year after surgery. The results showed significant reduction in Body Mass Index, free and total serum testosterone levels and rise in SHBG and regulation of menstrual cycle at 6 and 12 months after operation. Free androgen index and ovarian volume by ultrasound also significantly decreased (p

Polycystic ovary syndrome (PCOS) is the most common endocrinopathies affecting the early reproductive age in women, whose pathophysiology perplexes many researchers till today. This syndrome is classically categorized by hyperandrogenism and/or hyperandrogenemia, menstrual and ovulatory dysfunction, bulky multi follicular ovaries on Ultrasonography (USG), and metabolic abnormalities such as hyperinsulinemia, dyslipidemia, obesity. The etiopathogenesis of PCOS is not fully elucidated, but it seems that the hypothalamus-pituitary-ovarian axis, ovarian, and/or adrenal androgen secretion may contribute to developing the syndrome. Infertility and poor reproductive health in women’s lives are highly associated with elevated levels of androgens. Studies with ovarian theca cells taken from PCOS women have demonstrated increased androgen production due to augmented ovarian steroidogenesis attributed to mainly altered expression of critical enzymes (Cytochrome P450 enzymes: CYP17, CYP21, CYP19, CYP11A) in the steroid hormone biosynthesis pathway. Despite the heterogeneity of PCOS, candidate gene studies are the widely used technique to delineate the genetic variants and analyze for the correlation of androgen biosynthesis pathway and those affecting the secretion or action of insulin with PCOS etiology. Linkage and association studies have predicted the relationship between genetic variants and PCOS risk among families or populations. Several genes have been proposed as playing a role in the etiopathogenesis of PCOS, and the presence of mutations and/or polymorphisms has been discovered, which suggests that PCOS has a vital heritable component. The following review summarizes the influence of polymorphisms in crucial genes of the steroidogenesis pathway leading to intraovarian hyperandrogenism which can result in PCOS.

It is unclear whether testosterone replacement therapy (TRT) in adolescent boys, affected by a range of endocrine diseases that may be associated with hypogonadism, is particularly common. The aim of this study was to assess the contemporary practice of TRT in boys included in the I-DSD Registry. All participating centres in the I-DSD Registry that had boys between 10 and 18 years of age and with a condition that could be associated with hypogonadism were invited to provide further information in 2019. Information on 162 boys was collected from 15 centres that had a median (range) number of 6 boys per centre (1.35). Of these, 30 (19%) from 9 centres were receiving TRT and the median (range) age at the start was 12.6 years (10.8–16.2), with 6 boys (20%) starting at

We evaluated the relationship between hyperinsulinemia and anthropometric, metabolic, and hormonal parameters that might contribute to risk for coronary heart disease in 104 peri and postmenopausal women. Plasma glucose, insulin, LH, FSH, sex hormone binding globulin (SHBG), and total testosterone (TT) were determined. Free androgen index (FAI) and fasting insulin to glucose ratio (IGR) were calculated. The cut-off point to define hyperinsulinemia was established at 23 mIU/mg. Mean age was 54.8 years. Mean age at menopause was 47.7 years. Body mass index (BMI) was >25 in 46 patients, and 28 (26.9%) were hyperinsulinemic.BMI, waist circumference, triglycerides, and 2-hour post-glucose insulin levels were significantly higher in hyperinsulinemic patients. Hyperinsulinemic patients had higher TT levels (p=0.02), FAI (p=0.0001), and lower SHBG levels (p=0.003). Positive correlations were observed between IGR and BMI, waist to hip ratio, waist circumference, and triglycerides. IGR and HDL-C were negatively correlated. IGR presented a positive association with TT and FAI, and a negative association with SHBG. FAI contributed positively to IGR, independently of BMI, age, or time since menopause. In conclusion, androgen levels may be important determinants of cardiovascular risk in peri and postmenopausal women. However, this observation should be confirmed by longitudinal studies. We evaluated the relationship between hyperinsulinemia and anthropometric, metabolic, and hormonal parameters that might contribute to risk for coronary heart disease in 104 peri and postmenopausal women. Plasma glucose, insulin, LH, FSH, sex hormone binding globulin (SHBG), and total testosterone (TT) were determined. Free androgen index (FAI) and fasting insulin to glucose ratio (IGR) were calculated. The cut-off point to define hyperinsulinemia was established at 23 mIU/mg. Mean age was 54.8 years. Mean age at menopause was 47.7 years. Body mass index (BMI) was >25 in 46 patients, and 28 (26.9%) were hyperinsulinemic.BMI, waist circumference, triglycerides, and 2-hour post-glucose insulin levels were significantly higher in hyperinsulinemic patients. Hyperinsulinemic patients had higher TT levels (p=0.02), FAI (p=0.0001), and lower SHBG levels (p=0.003). Positive correlations were observed between IGR and BMI, waist to hip ratio, waist circumference, and triglycerides. IGR and HDL-C were negatively correlated. IGR presented a positive association with TT and FAI, and a negative association with SHBG. FAI contributed positively to IGR, independently of BMI, age, or time since menopause. In conclusion, androgen levels may be important determinants of cardiovascular risk in peri and postmenopausal women. However, this observation should be confirmed by longitudinal studies.

Огляд літератури присвячений доброякісному розростанню залозистої тканини грудної залози у чоловіків. Поширеність гінекомастії досягає 32–65 % залежно від віку та критеріїв, що використовуються для визначення. Гінекомастія у дитячому віці та впродовж періоду статевого дозрівання розглядається як доброякісний стан, який у більшості випадків минає спонтанно. Гінекомастія в дорослому віці частіше трапляється серед людей похилого віку, і при цільовому обстеженні можна виявити основну патологію в 45–50 % випадків. На сьогодні більшість причин гінекомастії залишаються не з’ясованими й обговорюються на рівні гіпотез. Тканина молочних залоз закладається однаково незалежно від статі дитини. Розвиток молочних залоз залежить від андроген-естрогенного співвідношення (АЕС). При переважанні в пубертатному періоді естрогенів і низькій активності андрогенів розвиток і диференціювання тканини молочних залоз здійснюється за жіночим типом. При зворотному АЕС тканина грудних залоз не розвивається. Необхідно враховувати можливість ендокринного або системного захворювання. Зазвичай достатньо визначити базальні рівні тестостерону, естрадіолу, лютеїнізуючого й фолікулостимулюючого гормонів. При простій підлітковій гінекомастії будь-які постійні гормональні зрушення відсутні. Важливо оцінити ступінь загальної андрогенізації пацієнта. Лабораторні дослідження (клініко-біохімічні, гормональні) повинні відповідати конкретному клінічному стану кожного пацієнта. Ефективність терапевтичного лікування гінекомастії у пацієнтів без явних ендокринних розладів із застосуванням гормональних засобів (тестостерон, дигідротестостерон), а також тамоксифену, даназолу, кломіфену слід вважати недоведеною. Хірургічне лікування рекомендується лише для пацієнтів з тривалою гінекомастією, яка не регресує спонтанно або після медикаментозної терапії. Обсяг і тип операції залежать від розміру збільшення грудей та кількості жирової тканини.

Erectile dysfunction (ED) is one of the most common sexual disorders in men. During the past 30 years, there has been no new drug development for ED. Thus, exploring the genetic basis of ED deserves further study, in hope of developing new pharmacological treatments for ED. In this study, Real-Time PCR analysis was used to assess the expression of androgen regulatory protein (Andpro) and pyruvate dehydrogenase kinase 4 (Pdk4) genes in ED. For this purpose, the experiment was performed on 20 men with severe ED and 20 potent men. IIEF-15 was used to determine the ED severity. The study was conducted in the Department of Sexual Medicine of the Kermanshah University of Medical Sciences, Kermanshah, Iran. The EDTA-Na vacuum blood tube was taken from ED patients and controls. Informed consent was obtained from all participants. After blood sampling, RNA was extracted from whole blood. Then cDNA was synthesized. The gene expression was analyzed through the qPCR method. The ß-actin was used as a reference gene. To further study these two proteins, their three-dimensional structures were predicted through I-TASSER. Compared with controls, in ED patients, the expression of the Andpro gene decreased, while the expression of the Pdk4 gene increased (p

Androgen insensitivity syndrome (AIS) is a sex-development disorder resulting from mutations in the androgen receptor. In its complete form, patients are genetically male but phenotypically female, presenting with primary amenorrhea. We report three cases of AIS highlighting the multifaceted role of magnetic resonance imaging (MRI) for presurgical planning by evaluating location and type of gonads and detecting complications. All patients presented at the Gynaecology Out-patient Department of Command Hospital, Bangalore, India, between 2013–2016 with primary amenorrhea and MRI accurately localised testes in all; one patient had bilateral inguinal testes; two had intraabdominal testes. Intraabdominal testes were not localised on ultrasonography. MRI also depicted Sertoli cell adenomas and Wolffian duct remnants. MRI provides comprehensive imaging before surgical treatment and can, thus, be considered a ‘one-stop shop’ for AIS imaging. All patients underwent laparoscopic gonadectomy which is the standard of care, with preoperative counselling about fertility. Postoperatively, they were started on oestrogen therapy. Keywords: Amenorrhea; Androgen Insensitivity Syndrome; Magnetic Resonance Imaging; Case Report; India.

Purpose: In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response. Experimental Design: We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2,000 mg at progression. Results: Twenty-nine of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (P < 0.001). Serum and tissue dehydroepiandrosterone sulfate (DHEAS) remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pretreatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on-therapy) associated with rapid progression (20 vs. 48 weeks, P = 0.0018; 20 vs. 52 weeks, P = 0.0003; 14 vs. 40 weeks, P = 0.0001; 20 vs. 56 weeks, P = 0.02, respectively). One of 16 men escalating to 2,000 mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild-type (WT) PTEN status associated with longer response (61 vs. 33 weeks, P = 0.02). Conclusions: Low-circulating adrenal androgen levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. Patients with CRPC with higher serum DHEAS levels may benefit from dual androgen receptor (AR)-pathway inhibition, while those in the lowest quartile may require combinations with non–AR-directed therapy.

Aim: Sex differences in COVID-19 outcomes might be explained from a sex hormones (SexHs) perspective. Materials & methods: PubMed, Scopus, Web of Science, EMBASE and Google Scholar were searched up to March 2021. Results: Based on the literature review, the crosstalk between SexHs (estrogens, progesterone and testosterone), their receptors (estrogen α and β, androgen, and progesterone) and the immune system shaped the sex-related differences in immune responses against COVID-19. Differential production of SexHs over the lifespan (during pregnancy, reproductive years, menopause and andropause) and over different seasons may result in disparities in body response toward COVID-19. Moreover, SexHs-specific differences might affect vaccine efficacy and response to treatment. Conclusion: The roles of SexHs need to be considered in vaccine development and even treatment of COVID-19., Lay abstract Female and male sex hormones (SexHs) play a pivotal role in the body’s defense against viral infections. SexHs and their binding molecules are among the main possible indicators of sex disparities in COVID-19 severity and response to treatment. Changes in the levels of SexHs from the childbearing age to menopause and pregnancy in females, and the aging process in males affect the immune function. This article sheds light on how physiologic hormonal differences in different sexes and in different stages of life affect COVID-19 severity. As a consequence the role of SexHs should be considered in vaccine development and treatment of COVID-19, especially for patients who suffer from hormone-related medical conditions in different stages of life.

Background: Recent studies reported lower androgen levels in coronavirus disease 2019 (COVID-19) hospitalized patients which linked to a worse prognosis. However, these studies were conducted in patients with active disease and long-term consequences are still not yet known. Therefore, we aimed to evaluate the late impact of COVID-19 pneumonia on testosterone levels in late recovered, post-hospitalized males. Methods: We enrolled 55 COVID-19 pneumonia-recovered, post-hospitalized male patients after an average of 60 days of discharge from the hospital and 40 age, body mass index (BMI), and waist-matched participants enrolled in this case-control study. The total testosterone cut-off point was set as 300 ng/dL and the cut-off point for luteinizing hormone (LH) was set as 9.4 IU/L. Results: Testosterone deficiency prevalence was 50.9%, and testosterone deficiency was mainly hypogonadotropic (60.7%). Late recovered COVID-19 pneumonia patients had significantly lower total testosterone and calculated free testosterone and higher testosterone to LH ratio and prevalence of testosterone deficiency in comparison with the control group. Testosterone-deficient COVID-19 pneumonia patients had significantly higher anthropometric parameters such as waist circumference and BMI, higher Charlson Comorbidity Index, and longer hospitalization time in comparison with testosterone-sufficient patients. Visceral obesity estimated with waist circumference was a significant predictor for total testosterone levels in COVID patients in regression analysis. Conclusion: Late recovered post-hospitalized COVID-19 pneumonia patients still have lower androgen levels and a higher prevalence of testosterone deficiency in comparison with matched control participants. Moreover, visceral obesity was the most significant predictor of low testosterone levels in recovered COVID-19 patients. J Endocrinol Metab. 2021;11(3-4):76-82 doi: https://doi.org/10.14740/jem749

In this issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of hormone ablation as treatment for metastatic prostate cancer. Our understanding has evolved from the observation that androgen withdrawal, either surgical or pharmacological, resulted in prostatic atrophy in animal models, to its application in patients, to investigation of the mysterious way in which prostate cancer escapes androgen dependence. We are now in an era of novel AR pathway inhibitors, the combination of androgen ablation with chemotherapy, PARP inhibitors, immunotherapies, guided radiotherapy, and novel drug application based upon genetic testing of individual tumors. In this special issue, we bring together a collection of eight reviews that cover not only the history of 80 years of progress after the initial identification of androgen ablation as an effective treatment of prostate cancer, but subsequent improvements in the understanding of the biology of the disease, development of novel treatment paradigms, resistance to those treatments and disease progression following that resistance.

Introduction Treatment-refractory metastatic castration-resistant prostate cancer is a heterogeneous disease classified into androgen receptor-high prostate cancer, androgen receptor-low prostate cancer, amphicrine prostate cancer co-expressing androgen receptor and neuroendocrine genes, double-negative prostate cancer lacking androgen receptor and neuroendocrine gene expression, and small cell or neuroendocrine prostate cancer without androgen receptor activity. Double-negative tumors can convert to the squamous phenotype. Case presentation A 62-year-old man was newly diagnosed with prostate cancer (serum prostate-specific antigen 2613 ng/mL, Gleason score 4 + 5 = 9, cT3aN1M1b) that progressed to castration resistance 4 months after starting abiraterone with androgen deprivation therapy. After enzalutamide and docetaxel failed, a right ilium metastasis newly emerged. Needle biopsy confirmed a metastatic tumor with squamous differentiation that was CK5/6-positive and chromogranin A-, synaptophysin-, and androgen receptor-negative. Conclusion We encountered a case of double-negative prostate cancer with squamous differentiation identified by needle biopsy of a right ilium metastasis after abiraterone, enzalutamide, and docetaxel failure.

We sought to explore the genomic features of bone-only metastasis, hepatic metastasis and pulmonary metastasis without liver involvement in prostate cancer using targeted next-generation sequencing.A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor, DNA damage response and other clinical relevant drivers.We successfully sequenced circulating tumor DNA from 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (metastatic castration-resistant prostate cancer). We observed distinct genomic profiles of metastatic castration-resistant prostate cancer across various metastatic sites. High prevalence ofThrough genomic profiling of prostate cancer across various metastatic sites, we identified an extremely low frequency of

Background/aim Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common cancer in the world and human papillomavirus (HPV) is an important risk factor for this neoplasm. Recent studies showed an association between sex hormone receptors and pathogenesis and/or prognosis in patients with HNSCC. The aim of this study was to clarify the expression patterns of sex hormone receptors in HPV-positive and HPV-negative HNSCC and their associations with tumour biopathology and biological behaviour. Materials and methods Scientific literature indexed in PubMed about sex hormone receptors in HNSCC was retrieved and critically analyzed, to obtain an overview of expression patterns and their possible implications for tumour biopathology and prognosis. Results Sex hormone receptors were more frequently detected in oropharyngeal tumours compared with HNSCC from other locations. ERα was associated with HPV-positive tumours. The androgen and progesterone receptors were associated with poor patient prognosis. Estrogen receptor alpha (ERα) is implicated in the biopathology of HNSCC in different ways, by promoting DNA hypermutation and facilitating HPV integration thus contributing to an immunogenic phenotype, but also by cooperating with the epithelial growth factor receptor (EGFR) to promote resistance to therapy. Conclusion The expression of sex hormone receptors may be of prognostic value in specific tumour subgroups, but the use of hormonal therapies for HNSCC is still not in close sight.

Prostate cancer (PC) is a leading cause of cancer-related death in men in Western countries. Androgen receptor (AR) signaling is a major driver of PC; therefore, androgen deprivation by medical and surgical castration is the standard treatment for patients with PC. However, over time, most patients will progress to metastatic castration-resistant PC. Enzalutamide is the only AR antagonist approved by the Food and Drug Administration for the treatment of metastatic castration-resistant PC. However, resistance to enzalutamide also develops in most patients with castration-resistant PC. Thus, there is an urgent need to develop new AR antagonists with new structures. For this purpose, we conducted both in silico and natural product screenings. From the in silico screening, we obtained T5853872 and more potent compound, STK765173. From the natural product screening, the novel compound arabilin was isolated from Streptomyces sp. MK756-CF1. Unlike STK765173, arabilin could overcome resistance to enzalutamide. Furthermore, we also extracted a novel compound, antarlide A, and its geometric isomers from Streptomyces sp. BB47. Antarlides A-F have novel 22-membered-ring macrocyclic structures, while antarlides G and H have 20-membered-ring structures. Both antarlides B and G showed potent AR antagonist activity in prostate cancer cells and could overcome resistance to enzalutamide.

Background: Female pattern hair loss is also observed in women without increased androgen levels. Vitamin D is a factor that has recently been considered in dealing with these patients. Deficiency of Vitamin D might be correlated with diffuse hair loss. Objective: To determine the frequency of serum levels of Vitamin D3 in patients with female pattern of hair loss (FPHL) at tertiary care hospital Karachi. Methodology: This cross-sectional research was conducted upon a sample of 163 female patients (chosen via non-probability – consecutive sampling) presenting to the Dept. of Dermatology, Abbasi Shaheed Hospital, Karachi from 29th July 2018 to 28 th January 2019, with a clinical diagnosis of FPHL. Data was recorded onto a structured questionnaire containing inquiries pertaining to basic biodata, sociodemographic details, and inferences obtained from blood tests (CBC, serum ferritin, TSH level and vitamin D level). Serum 25 OH Vitamin D level < 20 was taken as deficient, 21-29 was insufficient and over 30 was sufficient. Data was analyzed using SPSS. v. 21.0. Results: The mean age was 30.39±6.36 years. Mean FPHL duration was 5.85±2.89 months. Total 63.2% patients were classified as mild, 26.45% patients were classified as moderate and 10.4% patients were classified as severe. Total 73% patients were found as vitamin D deficient, 22.1% as vitamin D insufficient and 4.9% as vitamin D sufficient. Significant association of vitamin D deficiency was observed with education status, vitamin D intake since past 6 months, and socio economic status. Conclusion: Results showed high vitamin D3 deficiency (73.0%) among patients with female pattern of hair loss (FPHL).

Targeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR-targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies blocking continued AR signaling. Here, we identify a novel AR/AR-V7 degrader (ARVib) and found that ARVib effectively degrades AR/AR-V7 protein and attenuates AR/AR-V7 downstream target gene expression in prostate cancer cells. Mechanistically, ARVib degrades AR/AR-V7 protein through the ubiquitin-proteasome pathway mediated by HSP70/STUB1 machinery modulation. ARVib suppresses HSP70 expression and promotes STUB1 nuclear translocation, where STUB1 binds to AR/AR-V7 and promotes its ubiquitination and degradation. ARVib significantly inhibits resistant prostate tumor growth and improves enzalutamide treatment in vitro and in vivo. These data suggest that ARVib has potential for development as an AR/AR-V7 degrader to treat resistant CRPC.

Dry eye disease (DED) is a multifactorial disorder of the ocular surface that results in ocular discomfort, visual disturbance and damage to the ocular surface. It is one of the most common complaints in daily ophthalmic practice. The greater prevalence of dry eye in women compared to men suggests that sex hormones may have a role in this condition. Sex hormones; estrogen and androgens influence production of all components of the tear film including aqueous layer, lipid layer, and mucin layer. Various mechanisms such as decrease in hormonal levels, shift in feedback mechanisms, and changes in receptor receptivity interplay to alter the ocular surface homeostasis and subsequently result in DED. The purpose of this review is to briefly outline current scientific evidence on the influence of androgen and estrogen on the lacrimal and meibomian glands as well as on the ocular surface epithelia including conjunctival goblet cells during reproductive and menopausal periods. This article also outlines the updates regarding role of gonadal hormones in the treatment of dry eye. Keywords: Dry Eye, Sex hormones, Estrogen, Androgen, Testosterone, Progesterone, Tear film, Meibomian gland, Lacrimal gland, Ocular surface, Menopause, HRT, Schirmer’s test.

Background: Polycystic ovary syndrome (PCOS) is a complex medical condition characterized by elevated androgen levels, menstrual irregularities, and small cysts on one or both ovaries. The prevalence of PCOS is 6 to 10% in women. C-reactive protein (CRP) is an acute-phase protein produced by the hepatic cells and it’s levels increased in inflammation that increases interleukin-6 by macrophages and T cells. Aims and Objective: A correlative study of role and usefulness of CRP in women with PCOS and its correlation with different biochemical parameters. Materials and Methods: This was hospital based case-control study carried out among PCOS was conducted in the Department of Obstetrics & Gynaecology, Index Medical College Hospital, Indore. This study was conducted from 1st January 2018 to 31st December 2019. A total of 260 subjects with age group between 15 to 45 years were divided into two group; cases (130) and controls (130). Results: Among a total of 260 cases, based on clinical and different biochemical parameters, 130 were diagnosis with PCOS and 130 were apparently healthy women. The mean ±SD of various parameters among PCOS cases were; body mass index (BMI) 32.97±8.466, P (

STUDY QUESTION Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood? SUMMARY ANSWER AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone replacement therapy. WHAT IS KNOWN ALREADY Animal studies have shown that AGD is a postnatal ‘read-out’ of foetal androgen action, and short AGD in male offspring is considered a sign of feminization caused by in utero disruption of the reproductive system. Likewise, measurement of AGD in human studies has suggested AGD to be part of the testicular dysgenesis syndrome hypothesis, which proposes that male reproductive disorders, such as hypospadias, cryptorchidism, some cases of impaired semen quality and TC, all share a common foetal origin. STUDY DESIGN, SIZE, DURATION The aim was to assess AGD in men with a history of TC and controls, and furthermore to examine AGD during testosterone replacement therapy in adulthood. Study participants were TC survivors with a mild Leydig cell insufficiency who participated in a randomized double-blind study of testosterone replacement therapy versus placebo for 52 weeks (N = 69). Men from the general population were prospectively included from a study on testicular function as controls (N = 67). PARTICIPANTS/MATERIALS, SETTING, METHODS We measured two variants of AGD; as our primary outcome the anoscrotal distance (AGDas) measured from the centre of the anus to the posterior base of the scrotum, and secondarily the anopenile distance (AGDap) measured from the anus to the cephalad insertion of the penis. Using multiple regression analysis, the mean difference in AGD between TC survivors and men from the general population was assessed, adjusted for height, BMI and examiner. Next, AGD was measured before and after 52 weeks of treatment with testosterone or placebo, and with covariance analysis differences between the two groups at follow-up was assessed after adjustment for baseline AGD, examiner, BMI and change in BMI during treatment. MAIN RESULTS AND THE ROLE OF CHANCE TC survivors had a shorter AGDas (−0.84 cm, 95% CI: −1.31; −0.37) compared to men from the general population, and AGDas did not differ between the testosterone and placebo treated group at follow-up (0.11 cm, 95% CI: −0.22; 0.44). In contrast, AGDap was not shorter in TC survivors after adjustment (0.05 cm, 95% CI: −0.30; 0.39), and was 0.48 cm longer (95% CI: 0.13; 0.82) at follow-up in the testosterone treated compared to the placebo-treated group. LIMITATIONS, REASONS FOR CAUTION A limitation of the study is that the number of included men was limited, and results need confirmation in a larger study. Furthermore, TC survivors were significantly older than controls. For the comparison of AGD in TC survivors and controls, it was not possible to conduct the examinations with the examiner being blinded to which group he was examining, and it cannot be excluded that this can cause a bias. WIDER IMPLICATIONS OF THE FINDINGS The shorter AGDas in TC survivors compared to controls, which did not change upon adult testosterone replacement therapy, supports the hypothesis that reduced AGD is part of the testicular dysgenesis syndrome and may be a marker of disrupted foetal testicular development. By contrast, AGDap was not shorter in TC survivors and might be modestly sensitive to adult testosterone treatment, and thus inferior to AGDas as a constant postnatal marker of the foetal androgen environment. STUDY FUNDING/COMPETING INTEREST(S) Expenses were paid by the Department of Oncology, Copenhagen University Hospital, Rigshospitalet. Kiowa Kirin International covered expenses for Tostran and placebo. The Danish Cancer Society, The Danish Cancer Research Foundation, the Preben & Anna Simonsen Foundation, and Rigshospitalet have supported the study. L.P. was financed by the Research Fund of the Capital Region of Denmark. The authors have no competing interests. TRIAL REGISTRATION NUMBER Part of the study is based on men participating in a randomized controlled trial registered at ClinicalTrials.gov, NCT02991209, 25 November 2016.

Managing social groups in zoos requires controlling reproduction in individuals that do not have a current breeding recommendation, while simultaneously maintaining social harmony and animal well-being. Contraceptives, such as gonadotropin releasing-hormone (GnRH) agonists, that suppress testosterone production, offer a potential solution. They achieve infertility by interrupting spermatogenesis and may ameliorate androgen-induced aggression. This study investigated the effects of two GnRH agonists, histrelin and deslorelin, on testosterone, testis size, body weight and sperm production in male lion-tailed macaques, along with subjective observations of aggressive behavior. Five trials at three institutions with 14 males demonstrated that 100 mg histrelin or 9 to 12 mg of deslorelin could at least temporarily reduce testosterone, but a lower 6 mg dose was ineffective. However, ability of deslorelin to produce azoospermia varied among males, even at the highest dose. In general, a higher dose was needed (1) to achieve than to maintain suppression of any measured parameter and (2) to suppress sperm production than testosterone concentration. Testosterone production was also more likely than sperm production to recover, suggesting possible damage to seminiferous tubules but not to Leydig cells. Aggressive behavior was reduced in all but the group receiving the lowest dose. This allowed social groups to be maintained for many years despite recovery of testosterone in some males, suggesting that new social roles had been learned and become independent of androgen influence.