Intraprostatic hormone dosage: Validation of a novel prostate biopsy technique.

BACKGROUND: Advances in chromatography and mass spectrometry have allowed us to develop a novel technique for measuring intraprostatic hormone concentrations directly on prostate needle biopsies, rather than using traditional punch excision. This has significant clinical implications as intraprostatic dihydrotestosterone and testosterone levels could help monitor prostate growth, neoplasia and castration resistance. METHODS: Patients undergoing radical cystoprostatectomy for bladder cancer were prospectively included. Each prostate specimen received one 90mg punch excision and six needle biopsies. Intraprostatic hormones were dosed through gas chromatography-mass spectrometry. RESULTS: We included twenty patients, of which eleven were incidentally diagnosed with prostate cancer; four had ISUP 1 (20%) and seven had ISUP 2 (35%). The prostate biopsy technique was unable to obtain measures for testosterone, Delta-4-androsterone and androstenedione. Tissue concentrations of DHEA, DHT, E1 and E2 can be obtained with no significant difference from the reference established on a punch from a single biopsy core sample. CONCLUSIONS: Our study demonstrates that intraprostatic concentrations of DHEA, DHT, E1 and E2 can be measured without significant difference from the reference established on a single punch excision. This finding opens the way to research on the interactions between endocrinology and prostate oncogenesis and particularly on the mechanisms of resistance to hormone therapies in vivo.

Relationship of preoperative androgen levels and metabolic syndrome with quality of life and erectile function in patients who are to undergo radical prostatectomy.

This study aims to investigate whether clinical and biological preoperative characteristics of patients who were to undergo radical prostatectomy were associated with impairment in patient-reported quality of life (QoL) and erectile dysfunction immediately before intervention. We evaluated patient-reported outcomes among 1019 patients (out of 1343) of the AndroCan study, willing to score the Aging Male Symptom (AMS) and the International Index of Erectile Function 5-item (IIEF-5) auto-questionnaires. Univariate linear regression and robust multiple regression were used to ascertain the relationship between demographic, clinical, and hormonal parameters and global AMS or IIEF-5 scores. As a result, most patients (85.1') of the Androcan cohort agreed to complete questionnaires. Significantly higher IIEF-5 global scores were found in non-Caucasian and obese patients, with larger waist circumference, metabolic syndrome, diabetes mellitus, cardiovascular disease, hypertension, high blood sugar, concomitant medications, and hypogonadism, while the AMS global score was significantly higher in patients with larger waist circumference, metabolic syndrome, high blood pressure, raised glycemia, and concomitant medication. The IIEF-5 global score was correlated to age, dehydroepiandrosterone (DHEA), fat mass percentage, and androstenediol (D5). The AMS global score was significantly correlated to DHEA, D5, and DHEA sulfate. Finally, the multivariate models showed that QoL and erectile function were significantly affected, before surgery, by symptoms and signs that are usually considered as pertaining to the metabolic syndrome, while sexual hormones are essentially correlated to erectile dysfunction.

PSA and obesity among men with localized prostate cancer: results of the ANDROCAN study.

PURPOSE: PSA is known to be lowered in obese patients. There is a lack of data regarding patients with prostate cancer. Our objective was to prospectively assess the relationship PSA concentration, PSA mass and BMI in a cohort of patients with localized prostate cancer. METHODS: A prospective, multicenter cohort study was conducted including patients undergoing radical prostatectomy. Clinical and biological data were collected for each patient before surgery. RESULTS: A total of 1343 patients were analyzed. Mean age was 64.0 years. Mean weight was 82.2 kg and mean BMI was 26.8 kg/m2. Mean PSA concentration was 8.7 ng/mL and mean PSA mass 29.3 ng. On univariate analysis, an association was found between PSA mass and either BMI, weight and waist circumference. No association was found between PSA concentration and each weight parameters. On multivariate analysis, obesity was not an independent predictor of PSA concentration (p = 0.73). Independent predictors of PSA concentration were cardiovascular disease (negative association, p = 0.034), predominant Gleason 4 (positive association, p < 0.001) and pT3a (positive association, p < 0.001). BMI was an independent predictor of PSA mass (positive association, p = 0.009). PSA mass was negatively associated with TT (p = 0.015) and cardiovascular disease (p = 0.003), and positively associated with BT (p = 0.032), Gleason grade ≥ 4 + 3 (p < 0.001) and pT3a (p < 0.001). CONCLUSION: In this prospective study of patients with localized prostate cancer, higher BMI was associated with higher PSA mass but not with higher PSA concentration. Screening obese patients with a specific PSA method does not appear to be critical.

Metabolic syndrome, levels of androgens, and changes of erectile dysfunction and quality of life impairment 1 year after radical prostatectomy.

Robust data evaluating the association of preoperative parameters of the patients with quality of life after radical prostatectomy are lacking. We investigated whether clinical and biological preoperative characteristics of the patients were associated with impaired patient-reported quality of life (QoL) and sexual outcomes 1 year after radical prostatectomy. We evaluated patient-reported outcomes among the 1343 men participating in the AndroCan trial (NCT02235142). QoL and erectile dysfunction (ED) were assessed before and 1 year after radical prostatectomy using validated self-assessment questionnaires (Aging Male's Symptoms [AMS] and the 5-item abridged version of the International Index of Erectile Function [IIEF5]). At baseline, 1194 patients (88.9%) accepted to participate. A total of 750 (55.8%) patients answered the 1-year postoperative questionnaires. Out of them, only 378 (50.4% of responders) provided answers that could be used for calculations. One year after prostatectomy, ED had worsened by 8.0 (95% confidence interval [CI]: 7.3-8.7; P < 0.0001) out of a maximum of 20. The global AMS score has worsened by 2.8 (95% CI: 1.7-3.8; P < 0.0001). ED scores 1 year postsurgery were positively correlated with preoperative age and percentage of fat mass, and negatively correlated with total cholesterol, dehydroepiandrosterone (DHEA), and androstenediol (D5); AMS were poorly correlated with preoperative parameters. QoL and sexual symptoms significantly worsened after radical prostatectomy. Baseline bioavailable testosterone levels were significantly correlated with smaller changes on AMS somatic subscores postprostatectomy. These findings may be used to inform patients with newly diagnosed prostate cancer.

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.

Obesity and hypogonadism are associated with an increased risk of predominant Gleason 4 pattern on radical prostatectomy specimen.

PURPOSE: To compare histological features of prostate cancer according to both obesity, defined by a body mass index (BMI) ≥30 kg/m2, and androgenic status in patients who underwent radical prostatectomy. MATERIALS AND METHODS: Between March 2007 and September 2013, clinical, pathological and biological data were prospectively collected for patients referred for radical prostatectomy in a single European center. Preoperative total testosterone (TT) and bioavailable testosterone (bioT) serum determinations were performed. The threshold for hypogonadism was set at TT <3 ng/mL. The preoperative PSA value was registered. Gleason score (GS) and predominant Gleason pattern (PrdGP) were determined in prostate tissue specimens, and crosschecked by two uro-pathologists. Statistical analyzes were done for PrdGP4 risk assessment. RESULTS: A total of 937 consecutive patients were included. One hundred and thirty-five filled the criterion for obesity (14.4%), out of which 42 had TT <3 ng/mL (31.1%), while in non-obese patients, only 97 had TT <3 ng/mL (12.0%). In prostate specimens, mean GS was 6.8±0.5: 291 patients (31.1%) had a PrdGP4. The incidence of PrdGP4 was higher (p<0.001) in the 135 obese patients [50% when hypogonadal (p<0.02) or 42% when eugonadal (p<0.005)] than in non-obese patients (28.9% and 27.1%, respectively). In multivariable analyzis for PrdGP4 risk, obesity, TT <3 ng/mL, PSA, and age were independent risk factors. CONCLUSIONS: Both obesity and hypogonadism are independent risk factors for PrdGP4 in patients who underwent radical prostatectomy and should be taken into account in localized prostate cancer management, to improve the therapeutic choice, especially when prostate sparing approach is considered.

Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Hypogonadism affects an estimated 2-4 million men in the USA, but only 5% receive treatment. Testosterone replacement therapy reduces the effects of testosterone deficiency on sexual function, mood and energy in hypogonadal patients. Long-term hypogonadism management requires testosterone treatment to restore serum concentrations of testosterone and its active metabolites, within physiological ranges; a testosterone preparation that achieves physiological plasma concentrations without supra-physiological escape is a preferred option. A previous 1-year study European clinical study showed the efficacy and safety of a transdermal testosterone patch (Testopatch(®) ). The present study shows the long-term (6-year) safety and efficacy of Testopatch in patients with primary or secondary hypogonadism. We show that, over the long-term, Testopatch was associated with no relevant changes in PSA concentration and PSA velocity, or any significant prostate risks (there were no cases of prostate cancer). OBJECTIVE: To assess the change in prostate-specific antigen (PSA) concentrations in patients with primary or secondary hypogonadism, receiving transdermal testosterone. PATIENTS AND METHODS: This was an interventional, 6-year study, conducted in Urology and Endocrinology centres in Belgium, France, Germany, the Netherlands and Spain. Participants were primary (48%) or secondary (52%) hypogonadal patients who received two 60 cm(2) testosterone patches (Testopatch(®) ), delivering 4.8 mg of testosterone per day, applied every 2 days. During treatment, total testosterone (TT), dihydrotestosterone, oestradiol and, PSA concentrations were measured in a centralised laboratory every 3 months during the first year, and every 6 months thereafter. RESULTS: In all, 200 patients [mean (sd) age 41.0 (12.5) years, body weight 82.5 (13.7) kg, height 177.2 (9.3) cm, body mass index 26.2 (3.4) kg/m(2) ] were treated with transdermal testosterone patches. In all, 161 patients completed the 1-year study and 115 entered into a 5-year study extension; 51 patients completed the sixth year of the study. The mean baseline concentrations of TT and PSA were 1.4 ng/mL and 0.47 ng/mL, respectively; TT serum concentrations >3 ng/mL were achieved in 85% of patients and fluctuated between 4.4 and 6.0 ng/mL. At each successive 6-month time point, mean the PSA values were 0.60, 0.67, 0.76, 0.70, 0.61, 0.68, 0.64, 0.71, 0.75, 0.74, 1.01, 0.78, 0.80 ng/mL, respectively. The mean PSA velocity was negligible (0.00-0.03 ng/mL/year) from 30 months to the end of the trial, except for a value of 0.08 at 60 months. Seven patients had a PSA concentration of >4 ng/mL due to a sharp PSA increase. Six of these patients had prostatitis and PSA concentrations returned to previous levels with appropriate treatment. No prostate cancer was reported during the trial. CONCLUSION: These data support a strong safety profile for Testopatch, even at the highest registered dosage.

High incidence of predominant Gleason pattern 4 localized prostate cancer is associated with low serum testosterone.

PURPOSE: We characterized the aggressiveness of prostate cancer by Gleason score and predominant Gleason pattern in relation to preoperative serum testosterone. MATERIALS AND METHODS: In a prospective study serum total testosterone was measured preoperatively in patients referred to our department from January 2007 to January 2011 for radical prostatectomy. Gleason score and predominant Gleason pattern were determined in prostate biopsy and prostate tissue specimens. RESULTS: A total of 431 patients were enrolled in the study. In biopsies a predominant Gleason pattern 4 was observed in 72 patients (17%). In prostate specimens the predominant Gleason pattern 4 increased to 132 patients (31%). In the 132 patients total testosterone was lower than in the 299 with predominant Gleason pattern 3 (4.00 vs 4.50 ng/ml, p = 0.001), prostate specific antigen was higher (8.4 vs 6.6 ng/ml, p <0.00001), and extraprostatic extension and positive margins were noted more often (49% vs 20% and 23% vs 14%, p <0.000001 and 0.02, respectively). The 62 patients with total testosterone less than 3.0 ng/ml were larger (mean 7 kg, p = 0.0001) with a higher body mass index (mean 0.5 kg/m(2), p <0.000001). They had a higher percent of Gleason score with predominant Gleason pattern 4 (47% vs 28%, p = 0.002). CONCLUSIONS: Low total testosterone is associated with a higher percent of predominant Gleason pattern 4, a signature of prostate cancer aggressiveness. Tumor aggressiveness cannot be accurately estimated by biopsy Gleason score and predominant Gleason pattern. Preoperative total testosterone should be added to prostate specific antigen determination to improve management for prostate cancer.

Preoperative low serum testosterone levels are associated with tumor aggressiveness in radical prostatectomy treated cancer patients.

BACKGROUND: The aim of this study was to characterize the aggressiveness of prostate cancer as assessed by the Gleason score (GS), the predominant Gleason pattern (pGP), and testosterone (T) serum concentration. METHODS: A total of 247 patients, referred to our Department (from January 2007 to December 2009) for a radical prostatectomy, underwent preoperative T and bioavailable testosterone (samplings between 07:00 and 10:00 h). Serum determinations (radioimmunoassayed in a central laboratory). GS and pGP were determined in prostate biopsies and prostate tissue specimens. RESULTS: In biopsy specimens, a GS7 was observed in 105 (43%) patients; 25 (10%) had pGP4. In prostate specimens, 163 (66%) had a GS7; 60 (24%) had pGP4. For prostate specimens, comparing the 75 patients with pGP4 (GS 4+3, 4+4 and 4+5) to the 172 with pGP3 (GS 3+3 and 3+4), T was lower (4.03 vs. 4.75 ng/mL, p=0.003) and prostrate-specific antigen (PSA) higher (11.1 vs. 7.3 ng/mL, p<0.00001). Extra prostatic extension and positive margins were observed more frequently (52% vs. 18%, p<0.000001 and 29% vs. 15%, p=0.009, respectively). The 40 patients with T <3.0 ng/mL were larger (+5 kg, body mass index: +1.7 kg/m2), PSA was higher (9.9 vs. 8.2 ng/mL, p=0.07). They had a higher percent of GS with pGP4: 53% vs. 25% (p=0.0008). CONCLUSIONS: Aggressiveness of the tumor cannot be properly estimated by the GS and pGP found in biopsies. The pGP in prostate specimens is of paramount importance, particularly in the case of a Gleason 7, to appreciate the outcomes and to choose the treatment. Preoperative testosterone should be added to PSA determination to improve prediction of treatment outcomes.

Comparison of oral versus transdermal testosterone supplementation in hypogonadal men.

OBJECTIVE: To compare mean serum total testosterone, bioavailable-testosterone, and dihydrotestosterone levels between transdermal testosterone and oral testosterone undecanoate treatment. METHODS: Multicentre, randomized, cross-over study; 44 men >18 years, testosterone ≤2.5 ng/mL. Two patches (Testopatch®) every other day in the morning or two capsules Pantestone® 40 mg bid in each 22-day period. Hormone serum levels of four blood samples over the first and last 48 h of each treatment period. RESULTS: Mean age 49 years. Mean testosterone before inclusion 1.99 ng/mL. Mean testosterone serum levels over the last 48 h of Testopatch treatment were superior to Pantestone (4.64 vs. 2.58 ng/mL, p<0.001). Testosterone trough levels at the end of each treatment period were significantly higher for Testopatch (3.15 vs. 2.45 ng/mL, p<0.01). Bioavailable-testosterone levels over the first and last 48 h of treatment were significantly greater with Testopatch than with Pantestone (p=0.001 and p<0.01). Dihydrotestosterone levels over the first and last 48 h of treatment (0.71 vs. 1.05 ng/mL and 0.68 vs. 0.89 ng/mL) as well as at trough (0.59 vs. 0.96 ng/mL) were significantly lower with Testopatch than with Pantestone (p<0.001, p<0.05, and p<0.001). SHBG levels decreased by Pantestone but not by Testopatch (p<0.001). CONCLUSIONS: Testopatch was superior to Pantestone to increase testosterone and bioavailable-testosterone levels in hypogonadal men from the first days and throughout the three weeks of treatment. Pantestone increased dihydrotestosterone to a larger extent and decreased SHBG.

Adhesiveness of a new testosterone-in-adhesive matrix patch after extreme conditions.

The objective of the study was to evaluate the adhesiveness of a new thin, transparent and comfortable testosterone-in-adhesive matrix patch, Testopatch, after extreme conditions. The study was a single-centre, open-label with randomization of sites (upper arms, lower back, thighs) and sides (left, right) of two 45 cm(2) patches, in 24 healthy subjects. Patches were symmetrically applied on one of the three sites. One patch was removed after 2.0 h, under resting conditions and the other patch was removed at 3.5 h, after extreme conditions (physical exercise, sauna, whirl bath). Adhesiveness was assessed of the area stuck and the measure of the forces necessary for patch removal using a Peel Patch Tester. Local safety was assessed at 2.0 and 3.5 h. After physical exercise and after sauna, patch adhesiveness was excellent (95%) when applied on the thigh and very good (90%) on the upper arm. Forces of patch removal were significantly lower at 3.5 h than 2.0 h, and at the lower back compared to the other application sites. There were no adverse effects. Slight erythema was observed that was considered to be clinically insignificant. Testopatch was safe and displayed adhesiveness, compatible with physical activities.

Testosterone deficiency syndrome: treatment and cancer risk.

Testosterone deficiency syndrome (TDS) can be linked to premature mortality and to a number of co-morbidities (such as sexual disorders, diabetes, metabolic syndrome, ...). Testosterone deficiency occurs mainly in ageing men, at a time when prostate disease (benign or malign) start to emerge. New testosterone preparations via different route of administration appeared during the last decade allowing optimized treatment to these patients. One potential complication of this treatment is the increased risk of prostate and breast cancer. Consequently, the guidelines from the agencies and the institutions, the recommendations of the scientific expert committees and the attitude of the clinicians to who, when and how to treat hypogonadal patients, is very conservative, not to say, highly restrictive. To date, as documented in many reviews on the subject, nothing has been found to support the evidence that restoring testosterone levels within normal range increases the incidence of prostate cancer. In our experience, during a long-term clinical study including 200 hypogonadal patients receiving a patch of testosterone, 50 patients ended 5 years of treatment and no prostate cancer have been reported. In fact, the incidence of prostate cancer in primary or secondary testosterone treated hypogonadal men is lower than the incidence observed in the untreated eugonadal population. However, even if the number of patients treated in well-conducted clinical trials for whom cancer of the prostate has been reported is insignificant (a very few), the observed population is still too small to raise definite conclusions. Low testosterone levels have been reported in patients undergoing radical prostatectomy and the outcomes are of worse diagnostic in this population; at a later stage, testosterone deficiency can be induced by anti hormonal manipulation of patient with a prostate cancer, leading to the symptoms of hypogonadism. The question is to know whether it is justified, in case of profound symptoms, to supplement those patients with testosterone. Some attempts have been made and the results are encouraging: so it is time to re-examine our position and to question about the definite recommendation that patients with prostate cancer should never receive testosterone supplementation therapy; this is already the situation when intermittent androgen blockade is initiated if the biological response is satisfactory. Furthermore, it has been advocated that, under a rigorous surveillance, patients cured of prostate cancer can be treated with testosterone supplementation with beneficial results.

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.

Estrone sulfate (E1S), a prognosis marker for tumor aggressiveness in prostate cancer (PCa).

Seeking insight into the possible role of estrogens in prostate cancer (PCa) evolution, we assayed serum E2, estrone (E1), and estrone sulfate (E1S) in 349 PCa and 100 benign prostatic hyperplasia (BPH) patients, and in 208 control subjects in the same age range (50-74 years). E1 (pmol/L+/-S.D.) and E1S (nmol/L+/-S.D.) in the PCa and BPH patients (respectively 126.1+/-66.1 and 2.82+/-1.78, and 127.8+/-56.4 and 2.78+/-2.12) were significantly higher than in the controls (113.8+/-47.6 and 2.11+/-0.96). E2 was not significantly different among the PCa, BPH, and control groups. These assays were also carried out in PCa patients after partition by prognosis (PSA, Gleason score (GS), histological stage, and surgical margins (SM)). Significantly higher E1S levels were found in PCa with: PSA>10 ng/L (3.05+/-1.92) versus PSAor=4+3 (109.5+/-43.8) versus GS

Efficacy and safety of a new testosterone-in-adhesive matrix patch applied every 2 days for 1 year to hypogonadal men.

OBJECTIVES: To study long-term efficacy and safety of a testosterone-in-adhesive matrix patch, delivering 4.8 mg of testosterone daily. METHODS: Randomized, open label, multicenter 1-year study. 224 hypogonadal patients were included. 188 received 2 patches of 60 cm2 every 48 h and 36 patients had IM testosterone enanthate injection every 3 weeks. T, bioavailable T (BT), DHT, E2, LH, FSH and SHBG and clinical symptom scores (AMS and MSF-4) were assessed at 3, 6 and 12 months. RESULTS: In the patch group, T serum levels were above 3 ng/mL in 85% of patients and remained stable over time. BT, DHT and E2 levels were restored within physiological range. BT/T ratio varied from 20 to 70%. In the IM group, the percentages of "normalized" patients appeared to be lower, although the two groups cannot be adequately compared due to the kinetic profile of T following IM administration, resulting in greater variations of serum T levels, blood samplings occurring randomly at time of peak, trough, or in between. A significant correlation was found between T, BT and the MSF-4 changes. BT levels were significantly related to total AMS score. PSA values showed a mean (S.D.) increase of 0.13 (0.38), 0.23 (0.79) and 0.30 (1.47)ng/mL at weeks 14, 27 and 53, respectively. The patch was well tolerated with no negative impact either on lipid profile, or red blood cells. Administration site reactions occurred in 35 patients (18.8%). Adhesiveness was good (>or=75%) in >90% patients over the 1 year application period. CONCLUSION: Two 60 cm2 patches, allowed constant physiological levels of sexual hormones over time. This new patch was well tolerated, easy to use, well accepted by the patients and displayed a very good adhesiveness. Clinical efficacy was more related to BT than to T.

Pharmacokinetic study of a new testosterone-in-adhesive matrix patch applied every 2 days to hypogonadal men.

The present study assessed pharmacokinetic testosterone time profile and dose proportionality after application of a new matrix testosterone patch (30, 45, and 60 cm2 containing 0.5mg of testosterone per cm2). This open study was a single dose, three-period, crossover trial with a randomised treatment sequence in 24 hypogonadal men, consisting in a single 48-h application of two patches of 2x 30 cm2, 2x 45 cm2, 2x 60 cm2, separated by a 5-day wash-out. Testosterone concentrations were determined during patch application and after patch removal. Dose proportionality was assessed on baseline corrected, dose normalised parameters for C av,corr/D, C max,corr/D and AUC(0-48),corr/D. Testosterone concentrations rose during the first 9h following patch application, remained relatively sustained until 48 h and then decreased abruptly after patch removal, with a half-life of 1.3h. Testosterone levels were maintained above 3 ng/mL for 42-45 h with all patches. C av were 3.39, 4.03 and 4.58 ng/mL and Cmax were 4.33, 5.29 and 6.18 ng/mL according to the doses. AUC 0-48), C av and Cmax were dose dependent with mean ratios within the acceptance range (0.70-1.43). In conclusion, dose linearity was demonstrated between the different strengths of testosterone patches. Application resulted in dose proportional increases in serum T levels in hypogonadal men into the low to mid-normal range within the first hours and achieved steady state for 48 h. During this short term study with three consecutive patch applications, this patch was shown to be efficient, convenient and safe with excellent adhesiveness and skin tolerability, and with no cross-contamination to partner or to environment.

Determination of bioavailable testosterone [non sex hormone binding globulin (SHBG)-bound testosterone] in a population of healthy French men: influence of androstenediol on testosterone binding to SHBG.

BACKGROUND: Bioavailable testosterone (BT) is measured [assayed BT (aBT)] or calculated (cBT) in the diagnosis of hypogonadism in men. The cBT depends, however, on the values of the association constants of total testosterone (TT) for sex hormone-binding globulin (SHBG; K(s)) and albumin (K(a)), and its use therefore remains controversial. METHODS: In 503 selected, untreated healthy men, 20-74 years old, we measured TT, dihydrotestosterone (DHT), and androstenediol (5-diol) by GC-MS, SHBG by RIA, and BT after ammonium sulfate precipitation or by calculation according to the law of mass action. RESULTS: A slight decrease in TT, significant decreases in BT and 5-diol, no variation in DHT, and an increase in SHBG were observed with age. In young males (< or = 39 years), the lower normal limits were between 2.30 and 2.72 nmol/L for aBT and 8.50 nmol/L for TT. For K(s) = 1 x 10(9) L/mol and K(a) = 3.6 x 10(4) L/mol, the lower cBT limit was found to be 2-fold higher than for aBT. With optimized K(s) = 1.9 x 10(9) L/mol and K(a) = 2.45 x 10(4) L/mol, cBT values close to aBT were obtained. When 5-diol was included in the model as a competitive SHBG inhibitor, the correlation between cBT and aBT was better and the cBT:aBT ratios vs 5-diol were less biased. CONCLUSION: Lower normal serum aBT concentration in normal men appears to be between 2.30 and 2.72 nmol/L. Much higher serum cBT concentrations are associated with use of different association constants that may be inappropriate. When using the optimized binding constants, taking age-related 5-diol values into consideration slightly improves prediction of cBT.