The Changes of Prostatic Microvessel Density in Sprague-Dawleyrats After Castration Under the Effect of Estrogen/ Androgen at Different Concentrations

Background: Currently, there are relatively few studies on the effects of changes in estrogen and androgen levels on prostatic MVD.This article aimed to study the changes of prostatic MVD in SD rats after castration under the effect of estrogen/androgen at different concentrations.Methods: Male Sprague-Dawley(SD) rats aged 3-4 months were randomly divided into the control group, castration group, and different concentrations of estrogen/ androgen treatment after castration. Dihydrotestosterone(DHT) and estradiol(E) were administered daily by subcutaneous injection for one month. All the rats were sacrificed by cervical dislocation after one month, and the serum DHT and E concentrations of the rats in each group were measured by ELISA assay. Prostate tissues specimens were immunohistochemically stained with monoclonal antibodies against CD-34 and factor VIII for the MVD.Results: Compared with the control group, the MVD decreased significantly in the castration group (P<0.05). When the exogenous E concentration was constant, in general, the MVD of rats in all the groups increased with the increase of exogenous DHT concentration; Among them, compared with the castration group, the MVD increased significantly in the E0.05+DHT0.015 mg/kg group, E0.05+DHT0.05 mg/kg group, E0.05+DHT0.15 mg/kg group, E0.05+DHT0.5 mg/kg group, and E0.05+DHT1.5 mg/kg group (P<0.05). In addition, when the exogenous DHT concentration was constant, the MVD increased with the increase of exogenous E concentration in all the groups; Among them, compared with the control and castration group, the MVD increased significantly in the DHT0.15+E0.015 mg/kg group, DHT0.15+E0.15 mg/kg group, and DHT0.15+E0.5 mg/kg group (P<0.05).Conclusions: Androgens carried an important role in the regulation of prostatic MVD in SD rats, and the decrease of DHT concentration can induce a decrease in prostatic MVD. In contrast, prostatic MVD can be increased with the increase of DHT concentration. In addition, prostatic MVD can be increased gradually with the increase of estrogen concentration.

Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer

The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression (P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.

Management of endocrine disease: Optimal feminizing hormone treatment in transgender people

Transgender women are assigned male at birth, but identify as women. The incidence of gender dysphoria is estimated to be around 1% of the population. Gender dysphoria may be associated with depression and low quality of life, which in most cases improves during gender affirming hormonal treatment (GAHT). Feminizing hormonal treatment for transgender women or gender non-binary people typically includes natural estrogen (estradiol). Additional testosterone-blocking treatment is often needed to ensure suppression of the pituitary gonadal axis and may include cyproterone acetate, a gonadotropin releasing hormone agonist (GnRH-a) or spironolactone. The health risks of cyproterone acetate as anti-androgen treatment are debated and randomized protocols with other anti-androgen treatments are requested. Orchiectomy is performed in some transgender women after various duration of GAHT. Currently, natural progesterone is not recommended as part of GAHT due to limited knowledge on the balance between risks and benefits. In the present article we discuss evidence regarding established and upcoming feminizing treatment for adult transgender women or for gender non-binary people seeking feminization. Data on study populations with transgender women are put into a wider context of literature regarding effects of sex steroid hormones in cisgender study populations. Relevant follow up and monitoring during feminizing treatment is debated. The review has special focus on the pharmacotherapy of feminizing hormonal therapy.

Recovery of Male Reproductive Endocrine Function Following Prolonged Injectable Testosterone Undecanoate Treatment

Background: Exogenous androgen treatment suppresses the hypothalamo-pituitary testicular (HPT) axis causing reduced serum LH, FSH and testosterone (T). Recovery of male reproductive endocrine function in past androgen abusers takes 9-18 months with persistent mild lowering of serum T. The natural history of recovery of HPT axis following prolonged injectable testosterone undecanoate (TU) treatment at standard dose is not known. Therefore, the Runoff Study investigated the rate and extent of reproductive hormone recovery over 12 months following cessation of 2 years of TU treatment in the Testosterone for Diabetes Mellitus (T4DM) Study, while men remain blinded to treatment allocation. Methods: T4DM participants without pathological hypogonadism (n=1007) were randomised to TU or Placebo (P) injections every 3 months for 2 years with 303 subsequently volunteering to enter the Runoff study at 12 weeks after last injection. Before T4DM study unblinding, they provided blood samples and validated sexual function questionnaires (PDQ, IIEF-15) at entry (3 months after last injection), 6, 12, 18, 24, 40 and 52 weeks later. Serum steroid profile (T, DHT, E2, E1) was measured batchwise by LCMS and serum LH, FSH and SHBG by immunoassays. Results: Runoff study participants in both groups were similar and did not differ from all T4DM participants. As expected, at entry to Runoff serum T was higher in TU-treated men but at all timepoints from 12 weeks onwards serum T and SHBG remained consistently 11% and 13%, respectively, lower in TU-treated than in P-treated men. Similarly, at entry sexual function scores were higher in TU-treated men but subsequently no different from P-treated men. Serum LH and FSH recovered slowly with the median time to reach their own pre-treatment baseline of serum LH was 51.1 weeks [95% CI 50.4 – 53.0 weeks] and for serum FSH was 52.7 weeks [51.0 – 60.9 weeks]. Conclusion: After stopping 2 years of standard dose injectable TU treatment in men without pathological hypogonadism, recovery of testicular endocrine function is eventually complete but slow with serum gonadotropin recovery taking on 12 months since the last dose. Persistent mild, proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than signifying androgen deficiency. This suggests that recovery from androgen-induced HPT axis suppression depends primarily on time since cessation rather than dose or duration of androgen exposure.

Identification of BXDC2 as a Key Downstream Effector of the Androgen Receptor in Modulating Cisplatin Sensitivity in Bladder Cancer

Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.

Cortical bone mass is low in boys with Klinefelter Syndrome and improves with oxandrolone

Introduction Klinefelter syndrome (KS) is the most common sex aneuploidy in men. Affected males have hypogonadism, and as a result, face an increased risk for osteoporosis and fractures. Androgen therapy is standard in adolescents and adults with KS but has not been used earlier in childhood. Objective To determine the effects of androgen treatment on bone mass in children with KS. Study design Randomized, double-blind, placebo-controlled clinical trial of oxandrolone (OX; 0.06 mg/kg daily; n= 38) versus placebo (PL; n= 40) for 2 years in boys with KS (ages 4- 12 years). Changes in bone mass were examined by digital x-ray radiogrammetry, which determines the Bone Health Index (BHI) and standard deviation scores (BHI SDS). Results BHI SDS was similar between groups at baseline (-0.46±1.1 vs. -0.34±1.0 OX vs. PL, p&gt;0.05) and higher in the OX group at 2 years (-0.1 + 1.3 vs. -0.53 + 0.9, OX vs. PL, p&lt; 0.01). At baseline, BHI SDS values of all subjects were not normally distributed with 25.7% of subjects plotted below -1 SDS (p&lt;0.001), suggesting a deficit in bone mass. 13.5% of subjects had sustained a fracture and their BHI SDS was lower than those with no fractures (-1.6 + 1.3 vs. -0.3 + 1.0, p= 0.004). Conclusions Bone mass using BHI SDS is reduced in some children with KS and improves with OX. Since these individuals are at risk for osteoporosis, age-appropriate androgen replacement and future studies on bone health in children with KS should be further explored.

Proxalutamide (GT0918) Reduces the Rate of Hospitalization and Death in COVID-19 Male Patients: A Randomized Double-Blinded Placebo-Controlled Trial.

Importance: Previously, we have reported a retrospective cohort analysis demonstrating the protective effect of anti-androgens (5-alpha-reductase inhibitors) in COVID-19. Objective: To determine if the anti-androgen proxalutimide is an effective treatment for men with ambulatory mild COVID-19 disease.Design: A double-blinded, randomized, prospective, investigational study of proxalutamide for the treatment men with ambulatory mild COVID-19 disease.Setting: Outpatient centers (Brasilia, Brazil) from July 15 to December 1, 2020. Participants: Men with ambulatory mild COVID-19 disease (WHO ordinal scale ≤3).Interventions: Proxalutimide 200mg/day, or standard of care for 30 days or until full COVID-19 remission. Main Outcome and Measures: Percentage of subjects hospitalized due to COVID-19 [Time Frame: 30 days].Results: A total of 214 men were included and completed the trial; 114 men were randomized to the proxalutamide group, and 100 men were randomized to the control group. A statistically significant reduction in the percentage of subjects hospitalized due to COVID-19 was observed in men taking proxalutamide (0%) compared to the standard of care (27%), (p<0.001). The percentage of men requiring mechanical ventilation was reduced in the proxalutamide group (0%) compared to control (9%), (p<0.001). Zero fatalities occurred in the proxalutamide group, versus 2 in the control group.Conclusions and Relevance: Men with ambulatory mild COVID-19 disease (WHO ordinal scale ≤3) receiving anti-androgen treatment with proxalutamide, had significantly reduced rate of hospitalization compared to men not receiving anti-androgen treatment. Trial Registration: NCT04446429

Androgen Reduces Mitochondrial Respiration in Mouse Brown Adipocytes: A Model for Disordered Energy Balance in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including reduced postprandial thermogenesis. Although abnormalities in adipose tissue function have been widely reported in women with PCOS, less is known about direct effects of androgen on white and, particularly, brown adipocytes. The purpose of this study was to investigate the effect of the nonaromatizable androgen dihydrotestosterone (DHT) on (1) lipid accumulation and expression of adipogenic markers in immortalized mouse brown adipose cell lines (IMBATs), (2) mitochondrial respiration in IMBATs, (3) mitochondrial DNA content and gene expression, (4) expression of brown adipose tissue (BAT) markers and thermogenic activation. In addition, we profiled the relative levels of 38 adipokines secreted from BAT explants and looked at androgen effects on adipokine gene expression in both IMBATs and immortalized mouse white adipose (IMWATs) cell lines. Androgen treatment inhibited IMBAT differentiation in a dose-dependent manner, reduced markers of adipogenesis, and attenuated the β-adrenoceptor-stimulated increase in uncoupling protein-1 (UCP1) expression. In explants of mouse interscapular BAT, androgen reduced expression of UCP1, peroxisome proliferator-activated receptor-γ coactivator-1 (PCG-1) and Cidea. Significantly, as well as affecting genes involved in thermogenesis in BAT, androgen treatment reduced mitochondrial respiration in IMBATs, as measured by the Seahorse XF method. The results of this study suggest a role for excess androgen in inhibiting brown adipogenesis, attenuating the activation of thermogenesis and reducing mitochondrial respiration in BAT. Together, these data provide a plausible molecular mechanism that may contribute to reduced postprandial thermogenesis and the tendency to obesity in women with PCOS.