Aggressiveness of Localized Prostate Cancer: the Key Value of Testosterone Deficiency Evaluated by Both Total and Bioavailable Testosterone: AndroCan Study Results.

Failure rates after first-line treatment of localized prostate cancer (PCa) treatment remain high. Improvements to patient selection and identification of at-risk patients are central to reducing mortality. We aimed to determine if cancer aggressiveness correlates with androgen levels in patients undergoing radical prostatectomy for localized PCa. We performed a prospective, multicenter cohort study between June 2013 and June 2016, involving men with localized PCa scheduled to undergo radical prostatectomy. Clinical and hormonal patient data (testosterone deficiency, defined by total testosterone (TT) levels < 300 ng/dL and/or bioavailable testosterone (BT) levels < 80 ng/dL) were prospectively collected, along with pathological assessment of preoperative biopsy and subsequent radical prostatectomy specimens, using predominant Gleason pattern (prdGP) 3/4 grading. Of 1343 patients analyzed, 912 (68%) had prdGP3 PCa and 431 (32%) had high-grade (prdGP4, i.e., ISUP ≥ 3) disease on prostatectomy specimens. Only moderate concordance in prdGP scores between prostate biopsies and prostatectomy specimens was found. Compared with patients with prdGP3 tumors (i.e., ISUP ≤ 2), significantly more patients with prdGP4 cancers had demonstrable hypogonadism, characterized either by BT levels (17.4% vs. 10.7%, p < 0.001) or TT levels (14.2% vs. 9.7%, p = 0.020). BT levels were also lower in patients with prdGP4 tumors compared to those with prdGP3 disease. Testosterone deficiency (defined by TT and/or BT levels) was independently associated with higher PCa aggressiveness. BT is a predictive factor for prdGP4 disease, and evaluating both TT and BT to define hypogonadism is valuable in preoperative assessment of PCa (AndroCan Trial: NCT02235142).

Sex steroids in serum and prostatic tissue of human cancerous prostate (STERKPROSER trial).

BACKGROUND: Currently, there is no consensus regarding the expected concentration levels of intra-prostatic sex steroids in patients with Prostate Cancer (PCa). Our objective was to assess the concentration levels of sex steroids in prostatic tissue and serum, in two cohorts of patients with localized PCa or benign prostatic hyperplasia (BPH). METHODS: Between September 2014 and January 2017, men selected for radical cystectomy (for bladder cancer) or open prostatectomy (for BPH), and men selected for radical prostatectomy for localized PCa were included. Blood samples were collected at baseline before surgery, and steroid concentrations were assessed following the recommendations of the Endocrine Society. Intra-prostatic samples were collected from fresh surgical samples, and assessed by gas chromatography and mass spectrometry (GC/MS). Permanova analysis was performed. Analyses were adjusted for age, prostate weight, and prostate-specific antigen (PSA) level. RESULTS: A total of 73 patients (41 patients with PCa and 32 patients with BPH) were included in this study. Patients with PCa were younger, and had smaller prostate volumes with higher levels of PSA. The levels of Total Testosterone (TT), Di-Hydro-Testosterone (DHT), and Estradiol (E2) in the serum were not significantly different between PCa and BPH. In PCa tissue, TT concentrations were significantly lower (0.11 ng/g vs 0.47 ng/g, P = 0.0002), however its derivative E2 had significantly higher concentrations (31.0 ng/g vs 22.3 ng/g, P = 0.01). DHT tissue concentrations were not significantly different between the two groups (5.55 ng/g vs 5.42 ng/g, P = 0.70). Intra-prostatic TT concentrations were significantly lower in the peripheral zone than in the central zone for the CaP group (0.07 ng/g vs 0.15 ng/g, P = 0.004). CONCLUSIONS: Patients with PCa had lower intra-prostatic TT and higher E2 concentrations levels compared to the patients with BPH. PCa seem to consume more TT and produce more E2, especially in the peripheral zone.

Sexual steroids in serum and prostatic tissue of human non-cancerous prostate (STERPROSER trial).

BACKGROUND: The specific involvement of the sex steroids in the growth of the prostatic tissue remains unclear. Sex steroid concentrations in plasma and in fresh surgical samples of benign central prostate were correlated to prostate volume. METHODS: Monocentric prospective study performed between September 2014 and January 2017. Age, obesity parameters, and both serum and intraprostatic concentrations of sex steroids were collected complying with the latest Endocrine Society guidelines and the steroids assessed by GC/MS. Statistical calculations were adjusted for age and body mass index (BMI). RESULTS: Thirty-two patients, equally divided between normal- and high-volume prostate groups, were included in the analysis. High-volume prostate patients were older, heavier and had higher BMI. Comparison adjusted for age and BMI showed higher DHT concentrations in high-volume prostate. Both normal- and high-volume prostate tissues concentrate sex steroids in a similar way. Comparison of enzymatic activity surrogate marker ratios within tissue highlighted similar TT/E1 and TT/E2 ratios, and higher DHT/E1 ratio and lower DHT/PSA ratio in the high-volume prostates. CONCLUSIONS: STERPROSER trial provides evidence for higher DHT concentration in highvolume prostates, that could reflect either higher 5-alpha reductase expression or lower expression of downstream metabolizing enzymes such as 3a-hydoxysteroid dehydrogenase.

Systemic compensatory response to neonatal estradiol exposure does not prevent depletion of the oocyte pool in the rat.

The formation of ovarian follicles is a finely tuned process that takes place within a narrow time-window in rodents. Multiple factors and pathways have been proposed to contribute to the mechanisms triggering this process but the role of endocrine factors, especially estrogens, remains elusive. It is currently hypothesized that removal from the maternal hormonal environment permits follicle formation at birth. However, experimentally-induced maintenance of high 17ß-estradiol (E2) levels leads to subtle, distinct, immediate effects on follicle formation and oocyte survival depending on the species and dose. In this study, we examined the immediate effects of neonatal E2 exposure from post-natal day (PND) 0 to PND2 on the whole organism and on ovarian follicle formation in rats. Measurements of plasma E2, estrone and their sulfate conjugates after E2 exposure showed that neonatal female rats rapidly acquire the capability to metabolize and clear excessive E2 levels. Concomitant modifications to the mRNA content of genes encoding selected E2 metabolism enzymes in the liver and the ovary in response to E2 exposure indicate that E2 may modify the neonatal maturation of these organs. In the liver, E2 treatment was associated with lower acquisition of the capability to metabolize E2. In the ovary, E2 depleted the oocyte pool in a dose dependent manner by PND3. In 10 µg/day E2-treated ovaries, apoptotic oocytes were observed in newly formed follicles in addition to areas of ovarian cord remodeling. At PND6, follicles without any visible oocyte were present and multi-oocyte follicles were not observed. Our study reveals a major species-difference. Indeed, neonatal exposure to E2 depletes the oocyte pool in the rat ovary, whereas in the mouse it is well known to increase oocyte survival.

Implication of the mineralocorticoid axis in rainbow trout osmoregulation during salinity acclimation.

Cortisol and glucocorticoid receptors (GRs) play an important role in fish osmoregulation, whereas the involvement of the mineralocorticoid receptor (MR) and its putative ligand 11-deoxycorticosterone (DOC) is poorly investigated. In this study, we assessed the implication of DOC and MR in rainbow trout (Oncorhynchus mykiss) osmoregulation during hypo- and hypersaline acclimation in parallel with the cortisol-GR system. A RIA for DOC was developed to measure plasma DOC levels, and a MR-specific antibody was developed to localize MR protein in the gill, intestine, and kidney. This is the first study to report DOC plasma levels during salinity change and MR localization in fish osmoregulatory tissue. Corticosteroid receptor mRNA abundance was investigated in osmoregulatory tissue during salinity acclimation, and the effect of cortisol and DOC on ionic transporters gene expression was assayed using an in vitro gill incubation method. Differential tissue-, salinity-, and time-dependent changes in MR mRNA levels during both hyper- and hyposaline acclimations and the ubiquitous localization of MR in osmoregulatory tissue suggest a role for the MR in osmoregulation. Presumably, DOC does not act as ligand for MR in osmoregulation because there were no changes in plasma DOC levels during either freshwater-seawater (FW-SW) or SW-FW acclimation or any effect of DOC on gill ionic transporter mRNA levels in the gill. Taken together, these results suggest a role for MR, but not for DOC, in osmoregulation and confirm the importance of cortisol as a major endocrine regulator of trout osmoregulation.

Aging Male Questionnaire in normal and complaining men.

INTRODUCTION: Detection of androgen deficiency is at least, based on specific questionnaires, defined by sexual, psychological, and somatic variables. Their relationships with sexual hormone levels are poorly understood. AIM: To assess the Aging Male Symptoms (AMS) score and sex hormone levels in normal and complaining men in order to define the relationship between the key parameters related to androgen deficiency. METHODS: Nine hundred and three men were interviewed via phone by a trained interviewer who completed the questionnaire; 539 men consulting for a checkup in a health center and 471 complaining men, who completed the AMS scale in clinical setting, were selected, after excluding subjects with major and/or chronic diseases, endocrine disorders, psychological dysfunctions, and metabolic syndrome. MAIN OUTCOME MEASURES: Total AMS score and psychological, somatic and sexual subscores, as a function of age. RESULTS: The AMS questionnaires the were completed in a clinical setting or via calling-up line were comparable. In both cases, total AMS scores and subscores were significantly dependent of age and were correlated to income. In normal men, the only two parameters that significantly changed with age were the AMS sexual subscore and bioavailable testosterone (BT). Complaining men aged more than 50 years old had a significantly higher total AMS scores, subscores, and BT level than normal men up to 60 years old, and these differences weakened with increasing age. In normal and complaining men, whatever the AMS sexual subscore, any variation in testosterone (T) and BT levels was observed. CONCLUSIONS: The AMS scale could be defined as a screening test for androgen deficiency symptoms in men between 50 and 65 years of age. The sexual AMS subscore and BT level are the key variables to identify those symptoms; the severity of sexual symptoms can not be explained by a BT level decrease.

Plasma 11-deoxycorticosterone (DOC) and mineralocorticoid receptor testicular expression during rainbow trout Oncorhynchus mykiss spermiation: implication with 17alpha, 20beta-dihydroxyprogesterone on the milt fluidity?

BACKGROUND: In rainbow trout (Oncorhynchus mykiss), the endocrine control of spermiation is not fully understood. Besides 11ketotestosterone (11KT) and 17alpha, 20beta-dihydroxyprogesterone (MIS), the potential physiological ligand of the mineralocorticoid receptor (MR) 11-deoxycorticosterone (DOC), is a credible candidate in O. mykiss spermiation regulation as spermiation is accompanied with changes in aqueous and ionic flows. METHODS: In this study, we investigated potential roles of DOC during spermiation 1) by describing changes in blood plasma DOC level, MR mRNA abundance during the reproductive cycle and MR localization in the reproductive tract 2) by investigating and comparing the effects of DOC (10 mg/kg) and MIS (5 mg/kg) supplementations on sperm parameters 3) by measuring the in vitro effect of DOC on testis MIS production. RESULTS: The plasma concentration of DOC increased rapidly at the end of the reproductive cycle to reach levels that were 10-50 fold higher in mature males than in immature fish. MR mRNA relative abundance was lower in maturing testes when compared to immature testes, but increased rapidly during the spermiation period, immediately after the plasma rise in DOC. At this stage, immunohistochemistry localized MR protein to cells situated at the periphery of the seminiferous tubules and in the efferent ducts. Neither DOC nor MIS had significant effects on the mean sperm volume, although MIS treatment significantly increased the percentage of males producing milt. However, a significant reduction in the spermatocrit was observed when DOC and MIS were administrated together. Finally, we detected an inhibitory effect of DOC on testis MIS production in vitro. CONCLUSION: These results are in agreement with potential roles of DOC and MR during spermiation and support the hypothesis that DOC and MIS mechanisms of action are linked during this reproductive stage, maybe controlling milt fluidity. They also confirm that in O. mykiss MIS is involved in spermiation induction.