The Effect of Testosterone Replacement Therapy on Nonalcoholic Fatty Liver Disease in Older Hypogonadal Men.

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.

Practice and development of male contraception: European Academy of Andrology and American Society of Andrology guidelines.

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.

Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone).

Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study's primary outcome is the rate of pregnancy in couples during the study's 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. IMPLICATIONS: The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive.

Treatment of Cushing Disease With Pituitary-Targeting Seliciclib.

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 liver-related 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.

Male contraception development: monitoring effective spermatogenesis suppression utilizing a user-controlled sperm concentration test compared with standard semen analysis.

OBJECTIVE: To determine whether a user-controlled sperm concentration test compared with standard semen analysis can effectively monitor spermatogenesis suppression for male contraception. DESIGN: Single center, prospective sub study of the ongoing clinical trial: "Study of daily application of Nestorone and testosterone combination gel for male contraception." SETTING: Research institute at an academic medical center. PARTICIPANT(S): Couples participating in the male contraceptive clinical trial. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): The ability by participants to monitor sperm suppression to a threshold compatible with contraceptive efficacy utilizing a user-controlled test verified by sperm concentration determined by standard laboratory methods. RESULT(S): Thirty-eight men participating in a hormonal male contraceptive clinical trial provided multiple samples during spermatogenesis suppression for this substudy. Participants, employing a user-controlled test, correctly identified the absence of sperm (a negative test) in 100% of their laboratory-confirmed azoospermic samples (n = 122). Participants also identified 100% of samples (n = 73) with sperm >0.2 million/mL as positive. Sperm counts between 0.01 and 0.2 million/mL were identified as negative in 96% of samples. Trial participants noted the overall ease of using the test with respect to sample preparation, test timing, and result interpretation, and that they could accurately use this test at home without difficulty. CONCLUSION(S): Participants undergoing spermatogenesis suppression in a hormonal male contraceptive trial performed user-controlled test to determine whether their semen sperm concentration was ≤ or >0.2 million/mL. Compared with standard semen analyses, participants correctly identified 100% of samples with sperm counts >0.2 million/mL as positive (Sensitivity 100%). A positive result when the couple is using a male contraceptive method triggers the need for semen analysis by a laboratory while the couple uses another method of contraception. Participants correctly diagnosed samples ≤0.2 million sperm/mL as negative in 99% of samples (specificity 99%). A negative result indicates a sperm concentration ≤0.2 million/mL, well below the threshold of ≤1 million/mL offering contraceptive efficacy demonstrated by prior studies. At-home sperm concentration test would minimize the need for users to return to the clinic to monitor suppression of spermatogenesis, decreasing cost and burden of male contraception trials and increasing practicality of the method. CLINICAL TRIAL REGISTRATION NUMBER: NCT: 03452111.

Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety.

BACKGROUND: Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AIM: To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. METHODS: Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OUTCOMES: The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. RESULTS: Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300-1,000 ng/dL [10-35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3-6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. CLINICAL IMPLICATIONS: Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. STRENGTHS & LIMITATIONS: These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. CONCLUSION: Oral TU offers a safe and effective long-term treatment option for men with hypogonadism. Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750-1758.

In vitro propagation of XXY human Klinefelter spermatogonial stem cells: A step towards new fertility opportunities.

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.

Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism.

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).

Testosterone Replacement Therapy in Hypogonadal Men.

All approved testosterone replacement methods, when used according to recommendations, can restore normal serum testosterone concentrations, and relieve symptoms in most hypogonadal men. Selection of the method depends on the patient's preference with advice from the physician. Dose adjustment is possible with most delivery methods but may not be necessary in all hypogonadal men. The use of hepatotoxic androgens must be avoided. Testosterone treatment induces reversible suppression of spermatogenesis; if fertility is desired in the near future, human chronic gonadotropin, selective estrogen receptor modulator, estrogen antagonist, or an aromatase inhibitor that stimulates endogenous testosterone production may be used.

The emerging role of mitochondrial derived peptide humanin in the testis.

The discovery of mitochondrial derive peptides (MDPs) has spotlighted mitochondria as central hubs in control and regulation of cell viability and metabolism in the testis in response to intracellular and extracellular stresses. MDPs (Humanin, MOTS-c and SHLP-2) are present in testes. Humanin, the first MDP, is predominantly expressed in Leydig cells, and moderately in germ cells and seminal plasma. The administration of synthetic humanin peptide agonist HNG protects male germ cells against apoptosis induced by intratesticular hormonal deprivation, testicular hyperthermia, and chemotherapeutic agents in rodent testes. Humanin interacting with IGFBP-3 and/or Bax (pro-apoptotic proteins) prevents the activation of germ cell apoptosis. Humanin participates in the network of IL-12/IL-27 family of cytokines to exert the immune-modulation of the testicular environment. Humanin and other MDPs may be important in the amelioration of testicular stress and prevention of cell injury with possible implications for male infertility, fertility preservation and contraceptive development.

Acceptability of the oral hormonal male contraceptive prototype, 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC), in a 28-day placebo-controlled trial.

OBJECTIVE: To determine men's satisfaction with and the potential acceptability of 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC). STUDY DESIGN: We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11ß-MNTDC for male contraception. RESULTS: Of 42 trial participants, 40 (30 11ß-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11ß-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel. CONCLUSION: A majority of participants in this short-term trial of daily oral 11ß-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects. IMPLICATIONS: Oral 11ß-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11ß-MNTDC.

Relation between Retinopathy and Progression of Coronary Artery Calcium in Individuals with Versus Without Diabetes Mellitus (From the Multi-Ethnic Study of Atherosclerosis).

Retinopathy is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. The microvascular diseases may play a prominent role in coronary heart disease (CHD) development in individuals with DM. We performed the study to evaluate the relation between non-DM retinopathy and CHD and also the association between baseline retinopathy and incidence and progression of CHD in individuals with and without DM. We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis, who had retinal photos and coronary artery calcium score (CACS) available. We studied the association between baseline retinopathy and incidence and progression of coronary artery calcification (CAC) in subjects with and without DM. In DM group, the presence of retinopathy was significantly associated with an increased rate of CAC (RR 1.3 (95% CI [1.02, 1.66]) after adjusting for age, sex, race, follow-up time, and CHD risk factors. In non-DM group, the presence of retinopathy was not significantly associated with increased risk of CAC, however, the interaction between presence of retinopathy and DM status was not statistically significant. Within the DM group with CAC present at baseline, the presence of retinopathy was significantly associated with greater CAC progression (113 Agatson units (AU) greater, (95% CI [51-174]). In the non-DM group with present CAC at baseline; the presence of retinopathy was associated with 24 (95% CI [-0.69, 48.76]) AU higher CAC progression. All findings were adjusted for CHD risk factors. In conclusion, after adjustment for major CHD risk factors, retinopathy was associated with progression of CAC in both DM and non-DM individuals. However, the association was stronger in those with DM.

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11ß-MNTDC in healthy men.

BACKGROUND: Dimethandrolone (DMA) and 11ß-methyl-19-nortestosterone (11ß-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 11ß-MNT dodecylcarbonate (11ß-MNTDC), oral prodrugs of DMA and 11ß-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 11ß-MNTDC. An increase in LDL-C was seen with 11ß-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.

In Vitro Propagation of XXY Undifferentiated Mouse Spermatogonia: Model for Fertility Preservation in Klinefelter Syndrome Patients.

Klinefelter syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (usually XXY), and spermatogonial stem cell (SSC) loss in their early life. Affecting 1 out of every 650 males born, KS is the most common genetic cause of male infertility, and new fertility preservation strategies are critically important for these patients. In this study, testes from 41, XXY prepubertal (3-day-old) mice were frozen-thawed. Isolated testicular cells were cultured and characterized by qPCR, digital PCR, and flow cytometry analyses. We demonstrated that SSCs survived and were able to be propagated with testicular somatic cells in culture for up to 120 days. DNA fluorescent in situ hybridization (FISH) showed the presence of XXY spermatogonia at the beginning of the culture and a variety of propagated XY, XX, and XXY spermatogonia at the end of the culture. These data provide the first evidence that an extra sex chromosome was lost during innate SSC culture, a crucial finding in treating KS patients for preserving and propagating SSCs for future sperm production, either in vitro or in vivo. This in vitro propagation system can be translated to clinical fertility preservation for KS patients.

Dimethandrolone Undecanoate, a Novel, Nonaromatizable Androgen, Increases P1NP in Healthy Men Over 28 Days.

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.

The IL-27 component EBI-3 and its receptor subunit IL-27Rα are essential for the cytoprotective action of humanin on male germ cells†.

Humanin (HN) is a mitochondrial-derived peptide that protects many cells/tissues from damage. We previously demonstrated that HN reduces stress-induced male germ cell apoptosis in rodents. HN action in neuronal cells is mediated through its binding to a trimeric cell membrane receptor composed of glycoprotein 130 (gp130), IL-27 receptor subunit (IL-27R, also known as WSX-1/TCCR), and ciliary neurotrophic factor receptor subunit (CNTFR). The mechanisms of HN action in testis remain unclear. We demonstrated in ex-vivo seminiferous tubules culture that HN prevented heat-induced germ cell apoptosis was blocked by specific anti-IL-27R, anti-gp130, and anti-EBI-3, but not by anti-CNTFR antibodies significantly. The cytoprotective action of HN was studied by using groups of il-27r-/- or ebi-3-/- mice administered the following treatment: (1) vehicle; (2) a single intraperitoneal (IP) injection of HN peptide; (3) testicular hyperthermia; and (4) testicular hyperthermia plus HN. We demonstrated that HN inhibited heat-induced germ cell apoptosis in wildtype but not in il-27r-/- or ebi-3-/- mice. HN restored heat-suppressed STAT3 phosphorylation in wildtype but not il-27r-/- or ebi-3-/- mice. Dot blot analyses showed the direct interaction of HN with IL-27R or EBI-3 peptide. Immunofluorescence staining showed the co-localization of IL-27R with HN and gp130 in Leydig cells and germ cells. We conclude that the anti-apoptotic effects of HN in mouse testes are mediated through interaction with EBI-3, IL-27R, and activation of gp130, whereas the role of CNTFR needs further studies. This suggests a multicomponent tissue-specific receptor for HN in the testis and links HN action with the IL-12/IL-27 family of cytokines.

Sensitivity and specificity of the macimorelin test for diagnosis of AGHD.

OBJECTIVE: The macimorelin test is approved for the diagnosis of adult growth hormone deficiency (AGHD) based on its efficacy vs the insulin tolerance test (ITT). Macimorelin has a significant advantage over ITT in avoiding hypoglycemia. Analyses were conducted to determine whether macimorelin performance is affected by age, BMI, or sex, and evaluate its performance vs ITT over a range of GH cutpoints. DESIGN: Post hoc analyses of data from a previous randomized phase 3 study included participants aged 18-66 years with BMI <37 kg/m2 and high (Group A), intermediate (Group B), or low (Group C) likelihood for AGHD based on pituitary history, and matched controls (Group D). METHODS: Probability of AGHD was estimated using unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted logistic models. Area under the curve (AUC) of the estimated receiver operating characteristic (ROC) curve (range, 0-1; 1 = perfect) was compared for adjusted vs unadjusted models. Separate analyses evaluated agreement, sensitivity, and specificity for macimorelin and ITT using cutpoints of 2.8, 4.0, 5.1, and 6.5 ng/mL. RESULTS: For participants in Group A (n = 41) and Group D (n = 29), unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted models had ROC AUCs (95% CIs) of 0.9924 (0.9807-1), 0.9924 (0.9807-1), 0.9916 (0.9786-1), and 0.9950 (0.9861-1), respectively. CONCLUSIONS: Macimorelin performance was not meaningfully affected by age, BMI, or sex, indicating robustness for AGHD diagnosis. Of the 4 GH cutpoints evaluated, the cutpoint of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutpoint (87%).

Reflections on the T Trials.

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.

Memory in repeat sports-related concussive injury and single-impact traumatic brain injury.

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.