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This perspective provides an overview of issues needed to bring a testosterone‐progestogen combined transdermal male hormonal contraceptive to the market. Large‐scale phase 2b trials are near completion and a pivotal trial to confirm efficacy and safety has been designed. We believe we are close to accomplishing the steps necessary to bring the first male‐directed effective, safe, and reversible pharmaceutical contraceptive approach to the public. If successful, we believe it will provide a new option for couples to consider in their family planning. [ABSTRACT FROM AUTHOR]

Backgrounds: Despite a wide spectrum of contraceptive methods for women, the unintended pregnancy rate remains high (45% in the US), with 50% resulting in abortion. Currently, 20% of global contraceptive use is male‐directed, with a wide variation among countries due to limited availability and lack of efficacy. Worldwide studies indicate that >50% of men would opt to use a reversible method, and 90% of women would rely on their partner to use a contraceptive. Additional reasons for novel male contraceptive methods to be available include the increased life expectancy, sharing the reproductive risks among partners, social issues, the lack of pharma industry involvement and the lack of opinion makers advocating for male contraception. Aim: The present guidelines aim to review the status regarding male contraception, the current state of the art to support the clinical practice, recommend minimal requirements for new male contraceptive development and provide and grade updated, evidence‐based recommendations from the European Society of Andrology (EAA) and the American Society of Andrology (ASA). Methods: An expert panel of academicians appointed by the EAA and the ASA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results: Sixty evidence‐based and graded recommendations were produced on couple‐centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non‐hormonal methods, vaccines, and social and ethical considerations. Conclusion: As gender roles transform and gender equity is established in relationships, the male contribution to family planning must be facilitated. Efficient and safe male‐directed methods must be evaluated and introduced into clinical practice, preferably reversible, either hormonal or non‐hormonal. From a future perspective, identifying new hormonal combinations, suitable testicular targets, and emerging vas occlusion methods will produce novel molecules and products for male contraception. [ABSTRACT FROM AUTHOR]

Increasing survival rates of children following cancer treatment have resulted in a significant population of adult survivors with the common side effect of infertility. Additionally, the availability of genetic testing has identified Klinefelter syndrome (classic 47,XXY) as the cause of future male infertility for a significant number of prepubertal patients. This study explores new spermatogonia stem cell (SSC)-based fertility therapies to meet the needs of these patients. Testicular cells were isolated from cryopreserved human testes tissue stored from XY and XXY prepubertal patients and propagated in a two-dimensional culture. Cells were then incorporated into a 3D human testicular organoid (HTO) system. During a 3-week culture period, HTOs maintained their structure, viability, and metabolic activity. Cell-specific PCR and flow cytometry markers identified undifferentiated spermatogonia, Sertoli, Leydig, and peritubular cells within the HTOs. Testosterone was produced by the HTOs both with and without hCG stimulation. Upregulation of postmeiotic germ cell markers was detected after 23 days in culture. Fluorescence in situ hybridization (FISH) of chromosomes X, Y, and 18 identified haploid cells in the in vitro differentiated HTOs. Thus, 3D HTOs were successfully generated from isolated immature human testicular cells from both euploid (XY) and Klinefelter (XXY) patients, supporting androgen production and germ cell differentiation in vitro. [ABSTRACT FROM AUTHOR]

Context Male hypogonadism is associated with visceral obesity and the metabolic syndrome: factors important for the development of nonalcoholic fatty liver disease (NAFLD). The Testosterone Trials (The T Trials) showed testosterone (T) treatment compared with placebo in older hypogonadal men was associated with decreases in cholesterol and insulin levels suggesting that T treatment may improve NAFLD. Objective Compare effects of T vs placebo treatment on NAFLD scores and liver scans in elderly hypogonadal men. Methods Secondary data analyses from 479 older hypogonadal men with total T < 275 ng/dL from The T Trials were performed. Three clinical liver fat scores—lipid accumulation product index, hepatic steatosis index, nonalcoholic fatty liver disease-metabolic syndrome score—and liver computed tomography (CT) Hounsfield units and liver to spleen ratio were evaluated at baseline and 12 months after treatment. Results There were no statistically significant differences of change in lipid accumulation product index (P =.98), hepatic steatosis index (P =.67), and nonalcoholic fatty liver disease-metabolic syndrome (P =.52) in 246 men treated with T compared with 233 treated with placebo for 12 months. Liver CT showed no statistically significant difference of change in Hounsfield units (P =.24; n = 71 for T, n = 69 for placebo) and liver to spleen ratio (P =.74; n = 55 for T, n = 62 for placebo) between the 2 groups. Conclusions Our study did not show improvement of NAFLD in older hypogonadal men after 12 months of T vs placebo treatment, as assessed by 3 clinical scores and liver CT for hepatic steatosis. Future studies with longer treatment duration and additional NAFLD diagnostic modalities as primary outcome are warranted. [ABSTRACT FROM AUTHOR]

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Context: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. Objective: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). Methods: Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; =50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or = 50% reduction in UFC from baseline to study end. Results: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4±140.3 µg/24 hours at baseline to 131.3± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved = 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P=0.01) in patients who achieved = 48% UFC reduction. Three patients developed grade = 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liverrelated serious adverse events that resolved within 4 weeks of seliciclib discontinuation. Conclusion: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination. [ABSTRACT FROM AUTHOR]

Klinefelter Syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (47, XXY), and impaired fertility due to loss of spermatogonial stem cells (SSCs). Early testicular cryopreservation could be an option for future fertility treatments in these patients, including SSCs transplantation or in vitro spermatogenesis. It is critically essential to adapt current in vitro SSCs propagation systems as a fertility option for KS patients. KS human testicular samples (13,15- and 17-year-old non-mosaic KS boys) were donated by patients enrolled in an experimental testicular tissue banking program. Testicular cells were isolated from cryopreserved tissue and propagated in long-term culture for 110 days. Cell-specific gene expression confirmed the presence of all four main cell types found in testes: Spermatogonia, Sertoli, Leydig, and Peritubular cells. A population of ZBTB16+ undifferentiated spermatogonia was identified throughout the culture using digital PCR. Flow cytometric analysis also detected an HLA-/CD9+/CD49f+ population, indicating maintenance of a stem cell subpopulation among the spermatogonial cells. FISH staining for chromosomes X and Y showed most cells containing an XXY karyotype with a smaller number containing either XY or XX. Both XY and XX populations were able to be enriched by magnetic sorting for CD9 as a spermatogonia marker. Molecular karyotyping demonstrated genomic stability of the cultured cells, over time. Finally, single-cell RNAseq analysis confirmed transcription of ID4, TCN2, and NANOS 3 within a population of putative SSCs population. This is the first study showing successful isolation and long-term in vitro propagation of human KS testicular cells. These findings could inform the development of therapeutic fertility options for KS patients, either through in vitro spermatogenesis or transplantation of SSC, in vivo. [ABSTRACT FROM AUTHOR]

Context: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. Objective: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. Methods: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 μg if weight ≤ 60 kg, or 150 μg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. Results: After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. Conclusion: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18). [ABSTRACT FROM AUTHOR]

Background: Dimethandrolone (DMA) and 11β‐methyl‐19‐nortestosterone (11β‐MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. Objective: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. Materials/Methods: In two clinical trials of DMA undecanoate (DMAU) and 11β‐MNT dodecylcarbonate (11β‐MNTDC), oral prodrugs of DMA and 11β‐MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non‐parametric Kruskal‐Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. Results: Class effects were seen, with decrease in HDL‐C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA‐IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11β‐MNTDC. An increase in LDL‐C was seen with 11β‐MNTDC but not with DMAU. Discussion: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. Conclusion: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds. [ABSTRACT FROM AUTHOR]

Context: Dimethandrolone undecanoate (DMAU) is being developed as a male contraceptive. Daily oral administration of DMAU, a potent androgen that is not aromatized, markedly suppresses serum testosterone (T) and estradiol (E2) in healthy men. E2 deficiency can increase bone resorption in men.Objective: This work aimed to assess changes in bone turnover markers with DMAU administration in a 28-day study.Design: A randomized, double-blind, placebo-controlled study was conducted.Setting: This study took place at 2 academic medical centers.Participants: Healthy men, age 18 to50 years (n = 81), participated.Intervention: Men received 0, 100, 200, or 400 mg of oral DMAU for 28 days. Serum C-terminal telopeptide of type I collagen (CTX; bone resorption marker) and procollagen type I amino-terminal propeptide (P1NP; bone formation marker) were measured on days 1 and 28.Main Outcome Measures: Changes in bone turnover markers and serum hormones over the treatment period were measured.Results: On day 28, median serum T and E2 were markedly suppressed in all treatment groups vs placebo (P < .001 for both). Percentage change (%) in serum P1NP significantly differed across treatment groups (P = .007): Serum P1NP significantly increased in the 200 mg (5%, interquartile range [IQR] -7% to 27%) and 400 mg (22%, IQR -1% to 40%) groups relative to placebo (-8%, IQR -20% to 0%). Change (%) in serum CTX did not differ between groups (P = .09).Conclusions: DMAU administration for 28 days to healthy men leads to marked suppression of serum T and E2, yet increases P1NP, a serum marker of bone formation. Longer-term studies of the potent androgen DMAU are warranted to determine its impact on bone health in men. [ABSTRACT FROM AUTHOR]

Background: Repeat sports-related concussive/subconcussive injury (RC/SCI) is related to memory impairment. Objective & Methods: We sought to determine memory differences between persons with RC/SCI, moderate-to-severe single-impact traumatic brain injury (SI-TBI), and healthy controls. MRI scans from a subsample of participants with SI-TBI were used to identify the neuroanatomical correlates of observed memory process differences between the brain injury groups. Results: Both brain injury groups evidenced worse learning and recall in contrast to controls, although SI-TBI group had poorer memory than the RC/SCI group. Regarding memory process differences, in contrast to controls, the SI-TBI group evidenced difficulties with encoding, consolidation, and retrieval, while the RC/SCI group showed deficits in consolidation and retrieval. Delayed recall was predicted by encoding, with consolidation as a secondary predictor in the SI-TBI group. In the RC/SCI group, delayed recall was only predicted by consolidation. MRI data showed that the consolidation index we used mapped onto hippocampal atrophy. Conclusions: RC/SCI is primarily associated with consolidation deficits, which differs from SI-TBI. Given the role of the hippocampus in memory consolidation and the fact that hyperphosphorylated tau tends to accumulate in the medial temporal lobe in RC/SCI, consolidation deficits may be a cognitive marker of chronic traumatic encephalopathy in athletes. [ABSTRACT FROM AUTHOR]

Background: This manuscript is a review and discussion of the published results of the T Trials. Objective: To re‐examine the efficacy of testosterone replacement of hypogonadal men >65 years of age in the T Trials. Materials and Methods: The T Trials were a complex collection of seven double blind, placebo‐controlled trials of the efficacy of testosterone as replacement therapy for older men with unequivocal hypogonadism. There were three main trials (sexual function; physical function; vitality) and four sub‐trials (cognition; bone; anemia; and cardiovascular). All subjects participated in the main trials while more selective inclusion/exclusion criteria existed for the sub‐trials. Subjects were excluded for perceived higher risk of prostate cancer and recent myocardial or cerebral vascular events. Results: The previously published results are reviewed here as seen in the context of this special issue on late‐onset hypogonadism. In the T Trials, positive benefits were seen in the sexual function, bone, and anemia trials with small but significant benefits in the vitality trial. No benefit was seen in the cognition trial, partial benefit in physical function, and a negative benefit outcome seen in the cardiovascular trial. The later trial was underpowered and the results were described as exploratory. Adverse events were relatively uncommon in the 12‐month treatment phase and additional 12‐month post‐treatment phase. The most frequent adverse effect ascribed to testosterone was erythrocytosis. Conclusions: The T Trials studied the efficacy of testosterone replacement therapy on 788 men with low testosterone and symptoms of hypogonadism. The studies demonstrated benefits in four trials (sexual function, vitality, bone, and anemia); partial benefit in the physical function trial; no effect in the cognition trial; and a negative effect in the exploratory cardiovascular trial. The T Trials were not designed to assess long‐term risks of testosterone in men. [ABSTRACT FROM AUTHOR]

Background: A novel formulation of oral testosterone undecanoate (TU) was studied in a long- and short-term phase III trial to evaluate safety and efficacy. Methods: Hypogonadal men (age 18-65 years; two morning serum testosterone (T) <300 ng/dl with signs/symptoms) were recruited into a 365 day (trial I) or 105 day (trial II), randomized, multicenter trial. Patients were randomized 1:1 to oral TU (n = 161) or T-gel (n = 160) in trial I, and 3:1 to oral TU, twice daily (BID) JATENZO® (n = 166) or a topical T product [Axiron® (n = 56)] in trial II. Dose adjustments were based on average T concentrations (Cavg). Efficacy was assessed based on T levels, body composition and bone density. Safety was assessed by standard clinical measures. Results: Oral TU efficacy (% of patients with eugonadal T Cavg) was 84% (serum Cavg = 628 ± 343 ng/dl) and 87% (serum T equivalent Cavg ≈ 489 ± 155 ng/dl) in trials I and II, respectively. Oral TU significantly (p <0.0001) improved all Psychosexual Daily Questionnaire parameters in trials I and II. In trial I, lean mass increased 3.2 ± 2.7 kg and fat decreased by 2.4 ± 3.6 kg (both p <0.0001) and bone density improved in hip (+0.012 ± 0.0225 g/cm²) and spine (+0.018 ± 0.0422 g/cm²) after 365 days (both p <0.0001). Oral TU-associated adverse effects were consistent with other T-replacement therapies but oral TU patients experienced a greater number of mild gastrointestinal adverse effects. Oral TU subjects in both studies exhibited an increase in mean systolic blood pressure of about 3-5 mmHg. Oral TU was not associated with liver toxicity nor did it cause an elevation in high-sensitivity C-reactive protein or lipoprotein-associated phospholipase A2 (cardiovascular safety biomarkers) after 365 days of therapy. Conclusion: A new oral TU formulation was safe and effective and represents a significant therapeutic advance for the treatment of appropriate hypogonadal men. [ABSTRACT FROM AUTHOR]

Summary: Objective: The purpose of this narrative review was to summarize available data on testosterone levels in normal, healthy adult males and females, to provide a physiologic reference framework to evaluate testosterone levels reported in males and females with conditions that elevate androgens, such as disorders of sex development (DSD), and to determine the separation or overlap of testosterone levels between normal and affected males and females. Methods: A literature review was conducted for published papers, from peer reviewed journals, reporting testosterone levels in healthy males and females, males with 46XY DSD, and females with hyperandrogenism due to polycystic ovary syndrome (PCOS). Papers were selected that had adequate characterization of participants, and description of the methodology for measurement of serum testosterone and reporting of results. Results: In the healthy, normal males and females, there was a clear bimodal distribution of testosterone levels, with the lower end of the male range being four‐ to fivefold higher than the upper end of the female range(males 8.8‐30.9 nmol/L, females 0.4‐2.0 nmol/L). Individuals with 46XY DSD, specifically those with 5‐alpha reductase deficiency, type 2 and androgen insensitivity syndrome testosterone levels that were within normal male range. Females with PCOS or congenital adrenal hyperplasia were above the normal female range but still below the normal male range. Conclusions: Existing studies strongly support a bimodal distribution of serum testosterone levels in females compared to males. These data should be considered in the discussion of female competition eligibility in individuals with possible DSD or hyperandrogenism. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the relationship between retired National Football League players executive functioning (EF) abilities on verbal memory performance and subprocesses. Method: Fifty-eight participants were divided into two groups: intact executive functioning (IEF) and deficit executive functioning (DEF). Participants completed the California Verbal Learning Test, Second Edition (CVLT-II) to evaluate verbal memory performance. Additionally, the Item Specific Deficit Approach (ISDA) was applied to the CVLT-II to quantify verbal memory subprocesses (i.e., encoding, consolidation, & retrieval). Next, we determined which ISDA indices predicted long-delayed free recall (LDFR) for both groups. We then computed hierarchal regressions to determine which ISDA indices were predictive of LDFR for each group. Next, we retained significant predictors from the ISDA and correlated them with measures of executive function in both groups with and without partialling out cognitive reserve (CR). Results: We found the IEF group outperformed the DEF group on the CVLT-II learning trials and LDFR, and demonstrated better encoding abilities. Hierarchical regression revealed that the ISDA was predictive of LDFR in both groups. The DEF group LDFR issues were only predicted by encoding problems. In contrast, LDFR deficits in the IEF were primarily driven by consolidation problems. The ISDA encoding index correlated with Trail Making Test part B and Phonemic Fluency Test. However, after partialling out the variance accounted for by CR, the associations between the encoding index and executive function were nonsignificant. Conclusions: Our results suggest that greater executive function results in better memory performances in retired football players. Lastly, improved executive function is related to greater CR. [ABSTRACT FROM AUTHOR]

The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have a cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced cardiotoxicity, 80 adult male mice were randomly divided into 8 groups to receive the following treatments via intraperitoneal injection: saline daily, HNG (5 mg/kg) daily, DRZ (60 mg/kg) weekly, Dox (3 mg/kg) weekly, DRZ + HNG, Dox + HNG, Dox + DRZ, and Dox + HNG + DRZ. Echocardiograms were performed before and at 4, 8, and 9.5 wk after the beginning of treatment. All mice were euthanized at 10 wk. In the absence of Dox, HNG, DRZ, or DRZ + HNG had no adverse effect on the heart. Dox treatment caused decreases in ejection fraction and cardiac mass and increases in cardiomyocyte apoptosis and intracardiac fibrosis. HNG or DRZ alone blunted the Dox-induced decrease in left ventricle posterior wall thickness and modestly ameliorated the Dox-induced decrease in ejection fraction. HNG + DRZ significantly ameliorated Dox-induced decreases in ejection function, cardiac fibrosis, and cardiac mass. Using a targeted analysis for the mitochondrial gene array and protein expression in heart tissues, we demonstrated that HNG + DRZ reversed DOX-induced altered transcripts that were biomarkers of cardiac damage and uncoupling protein-2. We conclude that HNG enhances the cardiac protective effect of DRZ against Dox-induced cardiotoxicity. HNG + DRZ protects mitochondria from Dox-induced cardiac damage and blunts the onset of cardiac dysfunction. Thus, HNG may be an adjuvant to DRZ in preventing Doxinduced cardiotoxicity. [ABSTRACT FROM AUTHOR]

We previously showed that testosterone (T) deficiency enhanced high-fat/low-carbohydrate diet (HFD)-induced hepatic steatosis in rats independent of insulin resistance and that T replacement reduced hepatic macrovesicular fat accumulation and inflammation. The present report explores the mechanism of T's protective effects on HFD-induced steatohepatitis. Adult male rats were randomized into four treatment groups for 15 wk: intact rats on regular chow diet or HFD, and castrated rats on HFD with or without T replacement. Fatty acid β-oxidation and de novo synthesis were not changed by castration and T replacement, but expression of lipid export proteins ApoB100 and microsomal triglyceride transfer protein (MTP) was suppressed by HFD in both intact and castrated rats but restored by T replacement. Macrovesicular lipid droplet-related proteins perilipin 1 and fat-specific protein 27 were increased by HFD in castrated rats and suppressed by T replacement. Higher activation/expression of ER stress proteins (PERK, IRE-1α, JNK, NF-κB, and CHOP) was demonstrated in castrated rats fed HFD compared with intact animals, and T replacement suppressed these changes. We conclude that 1) HFD leads to ApoB100/MTP suppression reducing export of lipids; 2) castration promotes progression to steatohepatitis through activation of the ER stress pathway and enhancement of macrovesicular droplet protein expression; and 3) testosterone suppresses ER stress, inhibits the formation of macrovesicular lipid droplets, promotes lipid export, and ameliorates steatohepatitis induced by HFD and castration. [ABSTRACT FROM AUTHOR]

Purpose: Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing's disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course. Methods: The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after ('second round') an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: 'agreement' if no more than two responses were outside a 2 week window around the median response; 'disagreement' if more than two responses were outside a 2 week window around the median response. Recommendations were developed based on second round results. Results: Panel agreement was 65.9% before and 88.6% after the in-person discussion. The panel recommended follow-up within 8 weeks for patients in remission on glucocorticoid replacement and within 1 year of surgery; within 4 weeks for patients with uncontrolled persistent or recurrent disease; within 8-24 weeks in post-radiotherapy patients controlled on medical therapy; and within 24 weeks in asymptomatic patients with stable plasma ACTH concentrations after bilateral adrenalectomy. Conclusions: With a high level of consensus using the Delphi process, panelists recommended regular follow-up in most patient scenarios for this chronic condition. These recommendations may be useful for assessment of CD care both in research and clinical practice. [ABSTRACT FROM AUTHOR]

Importance: Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions.Objective: To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI).Design, Setting, and Participants: The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014.Interventions: Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year.Main Outcomes and Measures: The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months.Results: Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89).Conclusions and Relevance: Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions.Trial Registration: clinicaltrials.gov Identifier: NCT00799617. [ABSTRACT FROM AUTHOR]

Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.Trial Registration: clinicaltrials.gov Identifier: NCT00799617. [ABSTRACT FROM AUTHOR]

Objective: Various concussion characteristics and personal factors are associated with cognitive recovery in athletes. We developed an index based on concussion frequency, severity, and timeframe, as well as cognitive reserve (CR), and we assessed its predictive power regarding cognitive ability in retired professional football players.Method: Data from 40 retired professional American football players were used in the current study. On average, participants had been retired from football for 20 years. Current neuropsychological performances, indicators of CR, concussion history, and play data were used to create an index for predicting cognitive outcome.Results: The sample displayed a range of concussions, concussion severities, seasons played, CR, and cognitive ability. Many of the participants demonstrated cognitive deficits. The index strongly predicted global cognitive ability (R2= .31). The index also predicted the number of areas of neuropsychological deficit, which varied as a function of the deficit classification system used (Heaton:R2= .15; Wechsler:R2= .28).Conclusions: The current study demonstrated that a unique combination of CR, sports concussion, and game-related data can predict cognitive outcomes in participants who had been retired from professional American football for an average of 20 years. Such indices may prove to be useful for clinical decision making and research. [ABSTRACT FROM AUTHOR]

Objectives Whether endogenous sex hormones play a role in cardiovascular disease ( CVD) risk in men is unclear. Few studies have examined associations of sex hormones with atherosclerosis measured by coronary artery calcium score ( CACS) and carotid intima-media thickness ( cIMT). We evaluated the association of testosterone (T) and other sex hormones with CACS and cIMT. Methods Using the large multi-ethnic cohort of 3164 men without known CVD in the Multi-Ethnic Study of Atherosclerosis ( MESA), cross-sectional associations of tertiles of endogenous sex hormones with CACS and cIMT were analysed. Results In regard to CAC, there was a significant negative trend (P-trend = 0·02) for CACS>0 over tertiles of free T ( FT) with RRs (95% CI) for the lowest to highest tertiles. There was also a marginally significant positive trend (P-trend = 0·06) for CACS>0 over tertiles of sex hormone-binding globulin ( SHBG) with RRs for the lowest to highest tertiles. There were no significant associations with CACS >0 for tertiles of TT (Total T), bioavailable T ( BT), oestradiol (E2) and dehydroepiandrosterone ( DHEA). There was significantly higher log CACS after adjustment for CVD risk factors for lower TT levels, compared to higher levels, using 9·54 and 10·4 nmol/l as cut-off points. In regard to cIMT, there was a significant positive trend ( P = 0·003) in mean cIMT over the tertiles of BT, but not for TT, FT, E2, DHEA and SHBG. There was significantly lower cIMT after adjustment for CVD risk factors for lower TT levels compared to higher levels. Conclusion In a population of male subjects with no known CVD, lower FT is associated with higher RR of CACS>0 and lower TT is associated with higher log CACS. Lower BT and TT are associated with lower cIMT. While these findings support the positive correlation between low T and coronary atherosclerosis, the opposite findings on cIMT warrant further evaluation. [ABSTRACT FROM AUTHOR]

Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study-XO, XX, XY and XXY-to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males ('forebrain cholinergic' and 'cerebelo-pontine-thalamo-cortical'), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA. [ABSTRACT FROM AUTHOR]

Background: We describe the recruitment of men for The Testosterone (T) Trials, which were designed to determine the efficacy of T treatment.Methods: Men were eligible if they were ≥65 years, had an average of two morning total T values <275 ng/dL with neither value >300 ng/mL, and had symptoms and objective evidence of mobility limitation, sexual dysfunction, and/or low vitality. Men had to be eligible for and enroll in at least one of these three main trials (physical function, sexual function, vitality).Results: Men were recruited primarily through mass mailings in 12 U.S. communities: 82% of men who contacted the sites did so in response to mailings. Men who responded were screened by telephone to ascertain eligibility. Of 51,085 telephone screens, 53.5% were eligible for further screening. Of 23,889 initial screening visits (SV1), 2,781 (11.6%) men were eligible for the second screening visit (SV2), which 2,261 (81.3%) completed. At SV2, 931 (41.2%) men met the criteria for one or more trials, the T level criterion and had no other exclusions. Of these, 790 (84.6%) were randomized; 99 (12.5%) in all three trials and 348 (44%) in two trials. Their mean age was 72 years and mean body mass index (BMI) was 31.0 kg/m(2). Mean (standard deviation) total T (ng/dL) was 212.0 (40.0).Conclusion: Despite the telephone screening to enrollment ratio of 65 to 1, we met the recruitment goals for each trial. Recruitment of symptomatic older men with low testosterone levels is difficult but feasible. [ABSTRACT FROM AUTHOR]

Human (HN) prevents stress-induced apoptosis in many cells/tissues. In this study we showed that HN ameliorated chemotherapy [cyclophosphamide (CP) and Doxorubicin (DOX)]-induced male germ cell apoptosis both ex vivo in seminiferous tubule cultures and in vivo in the testis. HN acts by several putative mechanisms via binding to: an IL-12 like trimeric membrane receptor; BAX; or insulin-like growth factor binding protein-3 (IGFBP-3, a proapoptotic factor). To understand the mechanisms of HN on male germ cell apoptosis, we studied five HN analogues including: HNG (HN-S14G, a potent agonist), HNG-F6A (no binding to IGFBP-3), HN-S7A (no self-dimerization), HN-C8P (no binding to BAX), and HN-L12A (a HN antagonist) on CP-induced male germ cell apoptosis in mice. CP-induced germ cell apoptosis was inhibited by HN, HNG, HNG-F6A, HN-S7A, and HN-C8P (less effective); but not by HN-L12A. HN-L12A, but not HN-S7A or HN-C8P, blocked the protective effect of HN against CP-induced male germ cell apoptosis. HN, HN-S7A, and HN-C8P restored CP-suppressed STAT3 phosphorylation. These results suggest that HN: (1) decreases DOX (ex vivo) and CP (in vivo ) induced male germ cell apoptosis; (2) action is mediated by the membrane receptor/STAT3 with minor contribution by BAX-binding pathway; (3) self-dimerization or binding to IGFBP-3 may not be involved in HN's effect in testis. HN is an important molecule in the regulation of germ cell homeostasis after injury and agonistic analogues may be developed for treating male infertility or protection against chemotherapy side effects. [ABSTRACT FROM AUTHOR]

Synthetic progestins such as levonorgestrel (LNG) are used in combination with testosterone (T) in male contraceptive clinical trials to suppress gonadotropins secretion, but whether progestins have additional direct effects on the testis are not known. This study aimed to examine the effect of a potent progestin, (LNG), alone or in combination with testosterone (T) on spermatogenesis in adult rats, and to evaluate the functional role of the progesterone receptors (PRs) in the testis. In comparison with a low dose of LNG treatment in adult rats for 4 weeks, T and T + LNG treatment decreased testicular sperm count to 64.1 and 40.2% of control levels respectively. LNG induced germ cell apoptosis at stages I-IV and XII-XTV; T increased apoptosis at stages VII-VIII; LNG + T treatment induced greater germ cell apoptosis at a wider range of seminiferous epithelial stages. RT-PCR and Western Blots showed that PR was present in testes and up-regulated during suppression of spermatogenesis induced by testicular hormonal deprivation. PR knockout (PRKO) mice had larger testes, greater sperm production, increased numbers of Sertoli and Leydig cells. Suppression of gonadotropin and intratesticular T by GnRH-antagonist treatment induced PR promoter driven LacZ expression in Leydig cells of PRKO mice. This suggests that GnRH-antagonist treatment while inducing germ cell apoptosis also up-regulates PR. We conclude that (i) LNG + T induced greater suppression of spermatogenesis through increase in germ cell apoptosis involving a wider range of seminiferous epithelial stages than either treatment alone, (ii) up-regulation of PR was associated with inhibition of spermatogenesis, (iii) PR knockout mice showed increased sperm production suggesting that testicular PR activated events play a physiological and pharmacological inhibitory role in the testis. These data support the hypothesis that in addition to its known suppressive effects on gonadotropins, progestins may have direct inhibitory actions on the testis. [ABSTRACT FROM AUTHOR]

Study Question: Do exogenous male hormonal contraceptives that suppress intratesticular testosterone and spermatogenesis interfere with the blood-testis barrier integrity in men?Summary Answer: When spermatogenesis was suppressed by testosterone alone or combined with levonorgestrel (LNG) treatment in men, the structural appearance of Sertoli cell tight junctions remained intact in the human testis.What Is Already Known: Testosterone promotes the integrity of the blood-testis barrier. Intratesticular androgen deprivation induced by exogenous testosterone plus a progestin to suppress spermatogenesis in a contraceptive regimen may disturb the structural and functional integrity of the blood-testis barrier.Study Design, Size and Duration: Testicular biopsies were obtained from a sub-study of a randomized clinical trial of 36 healthy Chinese men who were treated for 18 weeks and followed for at least a 12-week recovery period.Participants/material, Setting, Methods: Healthy Chinese male volunteers (27-48 years) were randomized to two treatment groups (n = 18/group) for 18 weeks: (1) testosterone undecanoate (TU) 1000 mg i.m. injection followed by a 500 mg injection every 6 weeks and (2) TU + LNG 250 μg orally daily. Blood samples were obtained from all participants before and during treatment and at the end of the recovery phase. Open testicular biopsies for this study were obtained from four men before treatment and from four men in each of the TU and TU + LNG groups at 2 and 9 weeks of treatment. The presence of antisperm antibodies was checked in the archived serum samples of the subjects at baseline, during treatment and at the end of the recovery period. Stored testicular biopsy samples from cynomolgus monkeys treated with either sub-cutaneous testosterone or placebo for 12 weeks were used for additional protein expression studies.Main Results and Role Of the Chance: Expression of blood-testis barrier associated proteins quantified by immunohistochemistry (claudin 3, claudin 11, junctional adhesion molecule-A, zonula occludens-1) remained unchanged despite a significant decrease in the numbers of pachytene spermatocytes and round spermatids in the seminiferous tubules at 9 weeks in the TU + LNG group. This was confirmed by immunoblots showing a lack of quantitative change in these tight junction proteins in monkeys after testosterone treatment. There were no increases in serum antisperm antibodies in the volunteers during the study.Limitations/reasons For Caution: The duration of the study was short and the long-term effects of male hormonal contraceptive treatments on the integrity of the blood-testis barrier remain to be determined.Wider Implications Of the Findings: This study supports the safety of male hormonal contraceptive treatment and does not corroborate the previous findings of disturbed immunological integrity of the blood-testis barrier from animal studies such as androgen receptor knockout mice and exogenous hormonal treatment in rats.Study Funding/competing Interest: The study was supported by grants from the Contraceptive Research and Development Program and the Mellon Foundation (MFG-02-64, MFG-03-67), Endocrine, Metabolism and Nutrition Training Grant (T32 DK007571), the Clinical and Translational Science Institute at Los Angeles Biomedical and Harbor-UCLA Medical Center (UL1RR033176 and UL1TR000124) and the Los Angeles Biomedical Research Institute Summer High School Student Program. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do exogenous male hormonal contraceptives that suppress intratesticular testosterone and spermatogenesis interfere with the blood–testis barrier integrity in men? SUMMARY ANSWER When spermatogenesis was suppressed by testosterone alone or combined with levonorgestrel (LNG) treatment in men, the structural appearance of Sertoli cell tight junctions remained intact in the human testis. WHAT IS ALREADY KNOWN Testosterone promotes the integrity of the blood–testis barrier. Intratesticular androgen deprivation induced by exogenous testosterone plus a progestin to suppress spermatogenesis in a contraceptive regimen may disturb the structural and functional integrity of the blood–testis barrier. STUDY DESIGN, SIZE AND DURATION Testicular biopsies were obtained from a sub-study of a randomized clinical trial of 36 healthy Chinese men who were treated for 18 weeks and followed for at least a 12-week recovery period. PARTICIPANTS/MATERIAL, SETTING, METHODS Healthy Chinese male volunteers (27–48 years) were randomized to two treatment groups (n = 18/group) for 18 weeks: (1) testosterone undecanoate (TU) 1000 mg i.m. injection followed by a 500 mg injection every 6 weeks and (2) TU + LNG 250 μg orally daily. Blood samples were obtained from all participants before and during treatment and at the end of the recovery phase. Open testicular biopsies for this study were obtained from four men before treatment and from four men in each of the TU and TU + LNG groups at 2 and 9 weeks of treatment. The presence of antisperm antibodies was checked in the archived serum samples of the subjects at baseline, during treatment and at the end of the recovery period. Stored testicular biopsy samples from cynomolgus monkeys treated with either sub-cutaneous testosterone or placebo for 12 weeks were used for additional protein expression studies. MAIN RESULTS AND ROLE OF THE CHANCE Expression of blood–testis barrier associated proteins quantified by immunohistochemistry (claudin 3, claudin 11, junctional adhesion molecule-A, zonula occludens-1) remained unchanged despite a significant decrease in the numbers of pachytene spermatocytes and round spermatids in the seminiferous tubules at 9 weeks in the TU + LNG group. This was confirmed by immunoblots showing a lack of quantitative change in these tight junction proteins in monkeys after testosterone treatment. There were no increases in serum antisperm antibodies in the volunteers during the study. LIMITATIONS/REASONS FOR CAUTION The duration of the study was short and the long-term effects of male hormonal contraceptive treatments on the integrity of the blood–testis barrier remain to be determined. WIDER IMPLICATIONS OF THE FINDINGS This study supports the safety of male hormonal contraceptive treatment and does not corroborate the previous findings of disturbed immunological integrity of the blood–testis barrier from animal studies such as androgen receptor knockout mice and exogenous hormonal treatment in rats. STUDY FUNDING/COMPETING INTEREST The study was supported by grants from the Contraceptive Research and Development Program and the Mellon Foundation (MFG-02-64, MFG-03-67), Endocrine, Metabolism and Nutrition Training Grant (T32 DK007571), the Clinical and Translational Science Institute at Los Angeles Biomedical and Harbor-UCLA Medical Center (UL1RR033176 and UL1TR000124) and the Los Angeles Biomedical Research Institute Summer High School Student Program. [ABSTRACT FROM AUTHOR]

The complex pathophysiology of traumatic brain injury (TBI) involves not only the primary mechanical event but also secondary insults such as hypotension, hypoxia, raised intracranial pressure and changes in cerebral blood flow and metabolism. It is increasingly evident that these initial insults as well as transient events and treatments during the early injury phase can impact hypothalamic-pituitary function both acutely and chronically after injury. In turn, untreated pituitary hormonal dysfunction itself can further hinder recovery from brain injury. Secondary adrenal insufficiency, although typically reversible, occurs in up to 50% of intubated TBI victims and is associated with lower systemic blood pressure. Chronic anterior hypopituitarism, although reversible in some patients, persists in 25-40% of moderate and severe TBI survivors and likely contributes to long-term neurobehavioral and quality of life impairment. While the rates and risk factors of acute and chronic pituitary dysfunction have been documented for moderate and severe TBI victims in numerous recent studies, the pathophysiology remains ill-defined. Herein we discuss the hypotheses and available data concerning hypothalamic-pituitary vulnerability in the setting of head injury. Four possible pathophysiological mechanisms are considered: (1) the primary brain injury event, (2) secondary brain insults, (3) the stress of critical illness and (4) medication effects. Although each of these factors appears to be important in determining which hormonal axes are affected, the severity of dysfunction, their time course and possible reversibility, this process remains incompletely understood. [ABSTRACT FROM AUTHOR]

Hypogonadism in older men is a syndrome characterized by low serum testosterone levels and clinical symptoms often seen in hypogonadal men of younger age. These symptoms include decreased libido, erectile dysfunction, decreased vitality, decreased muscle mass, increased adiposity, depressed mood, osteopenia, and osteoporosis. Hypogonadism is a common disorder in aging men with a significant percentage ofmen over 60 years of age having serumtestosterone levels below the lower limits of young male adults. There are a variety of testosterone formulations available for treatment of hypogonadism. Data from many small studies indicate that testosterone therapy offers several potential benefits to older hypogonadal men. A large multicenter NIH supported double blind, placebo controlled study is ongoing, and this study should greatly enhance the information available on efficacy and side effects of treatment. While safety data is available across many age groups, there are still unresolved concerns associated with testosterone therapy. We have reviewed the diagnostic methods as well as benefits and risks of testosterone replacement therapy for hypogonadism in aging men. [ABSTRACT FROM AUTHOR]

The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy. [ABSTRACT FROM AUTHOR]

The article explains the connection of obesity-based testosterone drop and metabolic syndrome to sexual dysfunction and risks of contracting heart diseases (CVDs) in men who have Type 2 diabetes. The issue was addressed based on the data gathered from a U.S. national survey, an observational research on 253 Sri Lankan men with type 2 diabetes. Results of the studies show that obesity can change insulin reaction in internal organs, and reduce testosterone levels.

n effective, safe, reversible, and acceptable method of contraception is an important component of reproductive health and provides the opportunity of shared responsibility for family planning for both partners. Female hormonal contraceptives have been proven to be safe, reversible, available and widely acceptable by different populations. In contrast, male hormonal contraception, despite significant progress showing contraceptive efficacy comparable to female hormonal methods during last three decades, has not yet led to an approved product. Safety of a pharmaceutical product is an appropriate concern but the majority of male hormonal contraceptive clinical trials have not reported significant short term safety concerns. While the absence of serious adverse effects is encouraging, the studies have been designed for efficacy endpoints not long term safety. In this review we summarize potential risks and benefits of putative male hormonal contraceptives on reproductive and non-reproductive organs. While the review covers what we believe will be the likely class of drugs used for male hormonal contraception a true assessment of long term risks and benefits cannot be achieved without an available product. [ABSTRACT FROM AUTHOR]

41XXY mouse models share many characteristics of the human 47XXY Klinefelter syndrome (KS). This manuscript discusses the relative role of androgen deficiency and X chromosome genes resulting in the XXY mouse phenotype. The similarities in phenotype between 47XXY men and 41XXY mice suggest that the clinical manifestations in XXY men may be because of gene-dosage effect from genes that escape X inactivation in mouse. The 41XXY mouse is an excellent model for KS. [ABSTRACT FROM AUTHOR]

The article discusses a study on the bone architecture, volume and turnover in intact, castrated and simultaneously castrated and testosterone-replaced XXY mice via static and dynamic histomorphometry, micro-computed tomography and dual-energy X-ray absorptiometry (DXA). XXY mice and the XY mice were produced from a breeding colony while two groups of intact and castrated mice were generated and euthanized at 12 to 15 months. It concludes that osteopenia in Klinefelter syndrome (KS) is due to androgen deficiency and additional effect of genotype.

Background As reference laboratory methods for measuring free testosterone (FT) by equilibrium dialysis (ED) are laborious, costly and nonautomatable, FT levels are often calculated (cFT) rather than measured. However, the predictive accuracy of such estimates in routine use relative to laboratory measurements is not well defined. We provide a large-scale evaluation of the predictive accuracy for different FT formulae compared with laboratory ED measurement and an analysis of clinical factors that may influence accuracy. Methods The accuracy of five different cFT formulae (two equilibrium binding, three empirical) based on immunoassays of total testosterone (TT) and SHBG was evaluated by comparing those estimates with FT measurement by ED in 2159 serum samples from men at a single research laboratory over several years. Results cFT formulae show systematic discrepancies from the two equilibrium-binding formulae. One empirical formula overestimated FT relative to ED measurements, whereas two newer empirical cFT formulae were more concordant. These discrepancies persisted after correction for serum albumin and were not influenced by obesity, ethnicity or gonadal status. Conclusions Commonly used cFT formulae significantly overestimate FT relative to laboratory measurement by ED in male serum samples. The accuracy of the formulae is not influenced by correction for serum albumin, obesity, ethnicity or gonadal status. Such inaccuracy relative to the reference method renders some cFT estimates unreliable for evaluating androgen deficiency as recommended by clinical best practice guidelines. [ABSTRACT FROM AUTHOR]

Objective Giant pituitary adenomas (≥40 mm) pose a major management challenge. We describe the experience of a single surgeon and a dedicated neuro-endocrine team with multimodality treatment of these tumours in three specialized institutions. Design Retrospective data set analyses. Patients Fifty-one consecutive patients with a giant adenoma (39 endocrine-inactive, 12 endocrine-active; mean tumour diameter 45 mm) treated over 10 years by an endonasal transsphenoidal approach were included. All patients had surgical resection followed by radiotherapy and/or medical therapy as judged necessary. Measurements Hormonal and visual status, extent of resection, tumour control rates, complications and use of medical and radiotherapy were evaluated. Results Surgery resulted in gross total, near total and subtotal removal in21 (41%), 10 (20%) and 20 (39%) patients respectively. Complete tumour removal was associated with absence of cavernous sinus invasion ( P < 0·001). Long-term endocrine function improved in 49% of patients and new endocrinopathy occurred in 14·6%; 76% required long-term hormone replacement therapy. Vision improved in 81·5% of the patients and there was no visual worsening. At the last follow up (median 30 months), tumour control was achieved in 96% of patients: 59% with surgery alone, 20% with surgery plus focussed radiotherapy, 18% with surgery and medical therapy and two with all three modalities. Conclusions Endonasal surgery provides effective initial treatment for patients with giant adenomas. Multimodality therapy was needed in almost 50% of patients and this rate will likely increase with longer follow up. Close collaboration of neurosurgeons with endocrinologists and radiation oncologists is essential for optimal treatment of patients with these challenging tumours. [ABSTRACT FROM AUTHOR]

How do human beings decide when to be selfish or selfless? In this study, we gave testosterone to 25 men to establish its impact on prosocial behaviors in a double-blind within-subjects design. We also confirmed participants' testosterone levels before and after treatment through blood draws. Using the Ultimatum Game from behavioral economics, we find that men with artificially raised T, compared to themselves on placebo, were 27% less generous towards strangers with money they controlled (95% CI placebo: (1.70, 2.72); 95% CI T: (.98, 2.30)). This effect scales with a man's level of total-, free-, and dihydrotestosterone (DHT). Men in the lowest decile of DHT were 560% more generous than men in the highest decile of DHT. We also found that men with elevated testosterone were more likely to use their own money punish those who were ungenerous toward them. Our results continue to hold after controlling for altruism. We conclude that elevated testosterone causes men to behave antisocially. [ABSTRACT FROM AUTHOR]