Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer

Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08–2.39, p = 0.018), but not PFS (HR = 1.04, 95% CI 0.74–1.46, p = 0.8) or PSA response (odds ratio = 1.14, 95% CI = 0.65–1.99, p = 0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR = 0.16, 95% CI = 0.06–0.46, p < 0.001) and PFS (HR = 0.31, 95% CI = 0.12–0.80, p = 0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR = 1.93, 95% CI = 1.19–3.12, p = 0.008) and a suggestion favoring docetaxel for AR-gained patients (HR = 0.53, 95% CI = 0.24–1.16, p = 0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial.

Candidates to salvage therapy after external-beam radiotherapy of prostate cancer: Predictors of local recurrence volume and metastasis-free survival

PurposeThe purpose of this study was to assess the predictors of metastasis-free survival (MFS) and of the volume of the local recurrence in patients with rising prostate-specific antigen (PSA) serum level after radiotherapy for prostate cancer and referred for prostate magnetic resonance imaging (MRI) and biopsy in view of salvage treatment.Materials and methodsA total of 132 consecutive men (median age, 70 years; IQR, 66–77 years) with rising PSA after prostate radiotherapy who underwent prostate MRI and biopsy in view of salvage treatment between January 2010 and July 2017 were retrospectively evaluated at a single center. MFS predictors were assessed with Cox models. Predictors of the volume of the local recurrence (number of invaded prostate sectors at biopsy) were assessed using Poisson regression among variables available at PSA relapse.ResultsAt multivariate analysis, an initial Gleason score ≥ 8 (OR = 7 [95% confidence interval (CI): 1.2–40]; P = 0.03), a recent radiotherapy (OR = 17 [95% CI: 3.9–72]; P < 0.0001), the use of androgen deprivation therapy at PSA relapse (OR = 12.5 [95% CI: 2.8–57]; P = 0.001) and the number of invaded prostate sectors (OR = 1.5 [95% CI: 1.1–2]; P = 0.007) and maximum cancer core length (OR = 0.7 [95%CI: 0.6–0.9]; P = 0.002) at biopsy performed at PSA relapse were significant MFS predictors. The PSA level at relapse was significant independent predictor of the volume of local recurrence only when used as a continuous variable (P = 0.0002) but not when dichotomized using the nadir + 2 threshold (P = 0.41).ConclusionPathological and clinical factors can help predict MFS in patients with rising PSA after prostate radiotherapy and candidates to salvage treatment. The PSA level at relapse has strong influence on the local recurrence volume when used as a continuous variable.     

Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

The addition of docetaxel and abiraterone to androgen deprivation therapy (ADT) heralded a new era in the first-line treatment of metastatic castration-sensitive prostate cancer (mCSPC). Following the success of these combination regimens, 3 new trials presented data on using enzalutamide or apalutamide in men with mCSPC, which showed similar success. These seminal trials collectively established the addition of docetaxel, enzalutamide, apalutamide, or abiraterone to ADT as standards in the upfront treatment of mCSPC. Notably, a subset of patients in these more recent trials were treated with a combination of docetaxel, ADT, and androgen receptor signaling inhibitors or maintenance androgen receptor signaling inhibitors after docetaxel and ADT that provided an initial glimpse into the efficacy of these triplet or maintenance strategies. We discuss the implications of these recent findings and place them in context of the current mCSPC treatment landscape.     

3,3 diindolylmethane leads to apoptosis,decreases sperm quality,affects blood estradiol 17 β and testosterone,oestrogen (α and β) and androgen receptor levels in the reproductive system in male rats

3,3 Diindolylmethane (DIM) is a major digestive product of indole‐3 carbinol, obtained from Brassica family vegetables such as broccoli, cabbage and Brussels sprouts. This study aimed to investigate the effects of DIM on sperm parameters, histological structures of testicular tissues, blood testosterone (T) and estradiol 17‐β (E2) in male rats. Thirty‐eight male Sprague Dawley rats were used. Rats were divided into four groups: Group I: referred as Control group, received corn oil only; Group II: as DIM‐10, rats received 10 mg kg^?1 DIM; Group III: as DIM‐50, rats received 50 mg kg^?1 DIM; Group IV: as DIM‐100, received 100 mg kg^?1 DIM during 53 days. Spermatological parameters, malondialdehyde (MDA) levels of testes and serum T and E2 levels were assayed. Histopathological examinations of tests were done. DIM caused an increase in MDA levels. It decreased motility and live sperm rates and increased degeneration of testicular tissues. While DIM‐10 did not affect abnormal sperm rate, higher concentrations increased the abnormalities. Sperm density was higher in DIM‐10 groups when compared to both other groups. Only DIM‐50 had an anti‐androgenic effect among all groups. Only, DIM‐10 showed anti‐estrogenic activity as compared to higher DIM groups. In conclusion, DIM (i) had side effect on some sperm characteristics, (ii) increased the MDA levels and (iii) led to histological degeneration of testicular tissues and apoptosis in a dose‐dependent manner.     

Molecular action of norgestimate: new developments

Abstract

Background: Acne occurs because the sebaceous glands are overstimulated by high levels of androgens or are hypersensitive to normal levels of testosterone. In women with mild or moderate acne, the association of norgestimate (NG), and ethinyl estradiol (EE) is an effective treatment. This is related to the effect of oral contraceptives on androgen production and transport and the antiandrogenic properties of NG itself.

Design: The present work was undertaken to find out whether NG and its derivative, 17-deacetylnorgestimate(dNG), present steroid activities other than antiandrogen activities, using human progesterone receptor(PR), estrogen receptor α(ERα) and β(ERβ), glucocorticoid receptor(GR) and mineralocorticoid receptor(MR)-responsive cell lines.

Results: We confirmed that NG and its metabolite were progestogen partial agonists (EC₅₀ of 13 and 11.1?nM) and ERα selective agonists (EC₅₀ of 30.4 and 43.4?nM), as well as full antagonists of low affinity for GR (IC₅₀ of 325 and 255?nM) and moderate affinity for MR (IC₅₀ of 81.2 and 83.7).

Conclusion: We demonstrated that NG and dNG have full progestogen and weak estrogenic (through ERα) properties, which could explain in part the efficacy of NG in association with EE for the treatment of moderate acne in women. Moreover, their antagonist MR activity might have a favorable impact on cardiovascular risk, atherosclerosis and lipid profiles.     

围绝经期女性体内雄激素水平与脂肪分布的关联性研究

目的观察围绝经期女性的雄激素水平与身体脂肪含量的分布,探讨身体脂肪分布与雄激素水平变化的关系。方法选取423例40~60岁的健康女性作为研究对象,记录其基本资料、月经情况、绝经史及既往病史,测量身高、体重、脂肪分布,并计算体质指数、全身脂肪含量、总脂肪含量比例、男性脂肪比例、女性脂肪比例和躯干/下肢脂肪含量比值。采用ELISA法测定DHEA、SHBG,电化学发光法测定TT,计算游离雄激素指数FAI。结果绝经过渡期及绝经后早期女性全身脂肪含量及总脂肪比例升高,差异有统计学意义(P<0.05);各组脂肪分布差异无统计学意义(P>0.05);不同生殖衰老期女性的DHEA、TT及FAI水平差异无统计学意义(P>0.05)。DHEA水平与总脂肪含量比例及男性脂肪比例呈正相关,但与全身脂肪含量、女性脂肪比例及TL比值无相关性;TT、FAI水平与全身脂肪含量及总脂肪含量比例呈正相关,但与男性脂肪比例、女性脂肪比例及TL比值无相关性。结论围绝经期女性雄激素水平的变化,可能影响其身体脂肪组织含量及分布,但相关机制仍有待于进一步研究。     

Association between 25(OH)-vitamin D and testosterone levels: Evidence from men with chronic spinal cord injury

Objective: As an independent linear association between 25-hydroxyvitamin D (25(OH)D) and testosterone levels is controversial, this study aimed to explore this topic in men with chronic spinal cord injury (SCI), who exhibit a high prevalence of both androgen and vitamin D deficiency.

Design: Forty-nine men with chronic SCI consecutively admitted to a rehabilitation program underwent clinical/biochemical evaluations.

Results: Deficiency of 25(OH)D (<20?ng/mL) was found in 36 patients (73.5%). They exhibited significantly lower total testosterone and free testosterone levels, higher parathyroid hormone (PTH) and HOMA-IR, a poorer functional independence degree, and were engaged in poorer weekly leisure time physical activity (LTPA). Significant correlates of 25(OH)D levels were: total testosterone, free testosterone, PTH, functional independence degree and weekly LTPA. At the linear regression models, lower 25(OH)D levels were associated with both lower total and free testosterone after adjustment for age, smoking, alcohol consumption, comorbidities and HOMA-IR. However, after full adjustment, also including functional independence degree, BMI and LTPA, only the association of lower 25(OH)D with lower free testosterone was still significant.

Conclusion: In men with SCI, 25(OH)D correlates with total and free testosterone and exhibits an independent linear association with free testosterone. Regardless of this independent link, hypovitaminosis D and androgen deficiency are markers of poor health, sharing common risk factors to take into account in the rehabilitative approach to patients with SCI.