Single and multi-dose pharmacology of recombinant and urinary human chorionic gonadotrophin in men.

OBJECTIVE: Human choriogonadotrophin (hCG) treatment of gonadotrophin-deficient infertile men uses hCG of urinary (uhCG) or recombinant (rhCG) origin, but these treatments have not been compared nor are there studies defining rhCG dosing in men. DESIGN: hCG products were studied in randomized cross-over single-dose studies of standard (Study 1, 1500 IU and 62.5 µg, respectively) or high (Study 2, 5000 IU and 250 µg) dose and a multi-dose population pharmacology study of hCG use. PARTICIPANTS: Eight (Study 1) and seven (Study 2) volunteers in cross-over and 52 gonadotrophin-deficient men in the multi-dose study MEASUREMENTS: In cross-over studies, serum testosterone (T), dihydrotestosterone (DHT) and estradiol by liquid chromatography-mass spectrometry (LCMS) and serum hCG, LH, FSH, SHBG and T (observational study) by immunoassays. RESULTS: After standard and high-dose injection, serum hCG and testosterone responses had similar timing and peak concentrations except for a mildly lower early (<48 h) serum testosterone with uhCG. In the multi-dosing study, both hCGs had similar pharmacokinetics (pooled half-life 5.8 days, p < .001), while serum testosterone concentrations were stable after injection and did not differ between hCG products. Bench testing verified that 20% of pens from 4/10 individuals were used inappropriately. CONCLUSIONS: Although hCG pharmacokinetics are not formally bioequivalent, the similar pharmacodynamic effects on serum testosterone indicate that at the doses tested both hCGs provide comparable clinical effects. The starting dose of rhCG for treating gonadotrophin-deficient men should be 62.5 µg (6 clicks) of the rhCG pen.

The Potential of Edible Insects as a Safe, Palatable, and Sustainable Food Source in the European Union.

Entomophagy describes the practice of eating insects. Insects are considered extremely nutritious in many countries worldwide. However, there is a lethargic uptake of this practice in Europe where consuming insects and insect-based foodstuffs is often regarded with disgust. Such perceptions and concerns are often due to a lack of exposure to and availability of food-grade insects as a food source and are often driven by neophobia and cultural norms. In recent years, due to accelerating climate change, an urgency to develop alternate safe and sustainable food-sources has emerged. There are currently over 2000 species of insects approved by the World Health Organization as safe to eat and suitable for human consumption. This review article provides an updated overview of the potential of edible insects as a safe, palatable, and sustainable food source. Furthermore, legislation, food safety issues, and the nutritional composition of invertebrates including, but not limited, to crickets (Orthoptera) and mealworms (Coleoptera) are also explored within this review. This article also discusses insect farming methods and the potential upscaling of the industry with regard to future prospects for insects as a sustainable food source. Finally, the topics addressed in this article are areas of potential concern to current and future consumers of edible insects.

Sex steroids and androgen biomarkers in the healthy man study: within-person variability and impact of fasting.

OBJECTIVE: Serum testosterone measurements in clinical practice mostly utilize "direct" (non-extraction) immunoassays which have method-specific bias due to steroid cross-reactivity and nonspecific matrix artifacts. Although more accurate, sensitive, and specific liquid chromatography-mass spectrometry (LCMS) dominates in clinical research, the within-person variability of serum testosterone in healthy men using LCMS measurement is not reported. DESIGN: Longitudinal multi-sampling observational study of men in excellent health over 3 months. METHODS: Elite healthy men (n = 325) over 40 years of age in excellent, asymptomatic health provided 9 blood samples over 3 months with serum testosterone, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) measured by validated LCMS with conventional biochemical and anthropometric variables. RESULTS: Quantitative estimates of within-person variability within day and between day, week, month, and quarter were stable other than an increase due to fasting. The androgen biomarkers most sensitive to age and testosterone among widely used biochemical and anthropometric variables in middle-aged and older men were identified. CONCLUSIONS: This study provides estimates of variability in serum testosterone and the best androgen biomarkers that may prove useful for future studies of androgen action in male ageing.

Long-term Outcomes of Testosterone Treatment in Men: A T4DM Postrandomization Observational Follow-up Study.

CONTEXT: The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with testosterone (T) treatment reducing diabetes diagnosis by 40%. BACKGROUND: The long-term effects on new diagnosis of diabetes, cardiovascular and prostate disease, sleep apnea, weight maintenance trajectory and androgen dependence were not yet described. METHODS: A follow-up email survey after a median of 5.1 years since last injection obtained 599 (59%) completed surveys (316 T, 283 P), with participants in the follow-up survey compared with nonparticipants in 23 anthropometric and demographic variables. RESULTS: Randomization to was TU associated with stronger belief in study benefits during (64% vs 49%, P < .001) but not after the study (44% vs 40%, P = .07); there is high interest in future studies. At T4DM entry, 25% had sleep apnea with a new diagnosis more frequent on TU (3.0% vs 0.4%, P = .03) during, but not after, the study. Poststudy, resuming prescribed T treatment was more frequent among TU-treated men (6% vs 2.8%, P = .03). Five years after cessation of TU treatment there was no difference in self-reported rates of new diagnosis of diabetes, and prostate or cardiovascular disease, nor change in weight maintenance or weight loss behaviors. CONCLUSION: We conclude that randomized T treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism was associated with higher levels of self-reported benefits and diagnosis of sleep apnea during, but not after, the study as well as more frequent prescribed poststudy T treatment consistent with androgen dependence in some men receiving prolonged injectable TU.

Evaluation of irish consumers' knowledge of salmonellosis and food-handling practices.

Salmonella is one of numerous food-borne pathogens that could possibly pose a major threat to global food safety. Salmonella is primarily associated with foods such as poultry, eggs, vegetables, and some dairy products. However, infected food handlers and faecal contaminated environments are also significant sources and reservoirs of this pathogen. This study comprehensively evaluated the Irish consumers' food safety knowledge by exploring their knowledge level, practices and attitudes regarding raw meat handling, cross-contamination while handling different types of food products, and knowledge of Salmonella risk and associated food-handling practices. The online SurveyMonkey tool was used to distribute a quantitative survey titled "Evaluation of Knowledge and Food-handling practices of Irish Consumers" from July to November 2020 and generated a total of 1916 responses. Results indicated that 79.9% of the studied Irish population had a good knowledge of salmonellosis and risk perception related to food handling practices. Knowledge of cross-contamination, hygienic practices and pathogens associated with poultry were also considered high. However, knowledge of meat handling was low at 44.9%. It was also observed that age, gender, marital status, gross annual income, and nationality were influential factors regarding the food safety knowledge of consumers, while age, marital status and gender indicated significant differences regarding awareness of correct food hygiene practices.

Recovery of male reproductive endocrine function after ceasing prolonged testosterone undecanoate injections.

CONTEXT: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known. OBJECTIVE: The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections. MATERIALS AND METHODS: Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later. RESULTS: In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant's own pre-treatment baseline over 12 months since the last injection. CONCLUSIONS: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

Optimal injection interval for testosterone undecanoate treatment of hypogonadal and transgender men.

OBJECTIVE: To define the optimized inter-injection interval of injectable testosterone undecanoate (TU) treatment for hypogonadal and transmen based on individual dose titration in routine clinical practice. DESIGN AND METHODS: A prolective observational study of consecutive TU injections in men undergoing testosterone replacement therapy for pathological hypogonadism or masculinization of female-to-male transgender (transmen) subject to individual dosing titration to achieve a stable replacement regimen. RESULTS: From 2006 to 2019, 6899 injections were given to 325 consecutive patients. After excluding the 6-week loading dose, 6300 injections were given to 297 patients who had at least three and a median of 14 injections. The optimal injection interval (mean of last three injection intervals) had a median of 12.0 weeks (interquartile range 10.4-12.7 weeks). The interval was significantly influenced by age and body size (body surface area, BSA) but not by diagnosis or trough serum LH, FSH, and SHBG. Longer (≥14 weeks; 68/297, 23%), but not shorter (≤10 weeks; 22/297, 7.4%), intervals were weakly correlated with age but not diagnosis or other covariables. Low blood hemoglobin increased with trough serum testosterone to reach plateau once testosterone was about 10 nmol/L or higher. CONCLUSION: Optimal intervals between TU injection after individual titration resulted in the approved 12-week interval in 70% of patients with only minor influence for clinical application of BSA and not of trough serum LH, FSH, and SHBG. Individually optimized inter-injection interval did not differ between men with primary or secondary hypogonadism or transmen.

Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial.

BACKGROUND: Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme. METHODS: T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50-74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8-11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. FINDINGS: Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was -0·95 mmol/L (SD 2·78) in the placebo group and -1·70 mmol/L (SD 2·47) in the testosterone group (mean difference -0·75 mmol/L, -1·10 to -0·40; p<0·0001). The treatment effect was independent of baseline serum testosterone. A safety trigger for haematocrit greater than 54% occurred in six (1%) of 484 participants in the placebo group and 106 (22%) of 491 participants in the testosterone group, and a trigger for an increase of 0·75 µg/mL or more in prostate-specific antigen occurred in 87 (19%) of 468 participants in the placebo group and 109 (23%) of 480 participants in the testosterone group. Prespecified serious adverse events occurred in 37 (7·4%, 95% CI 5·4 to 10·0) of 503 patients in the placebo group and 55 (10·9%, 8·5 to 13·9) of 504 patients in the testosterone group. There were two deaths in each group. INTERPRETATION: Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated. FUNDING: Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

Rate and Extent of Recovery from Reproductive and Cardiac Dysfunction Due to Androgen Abuse in Men.

CONTEXT: Androgen abuse impairs male reproductive and cardiac function, but the rate, extent, and determinants of recovery are not understood. OBJECTIVE: To investigate recovery of male reproductive and cardiac function after ceasing androgen intake in current and past androgen abusers compared with healthy non-users. METHODS: Cross-sectional, observational study recruited via social media 41 current and 31 past users (≥3 months since last use, median 300 days since last use) with 21 healthy, eugonadal non-users. Each provided a history, examination, and serum and semen sample and underwent testicular ultrasound, body composition analysis, and cardiac function evaluation. RESULTS: Current abusers had suppressed reproductive function and impaired cardiac systolic function and lipoprotein parameters compared with non- or past users. Past users did not differ from non-users, suggesting full recovery of suppressed reproductive and cardiac functions after ceasing androgen abuse, other than residual reduced testicular volume. Mean time to recovery was faster for reproductive hormones (anti-Mullerian hormone [AMH], 7.3 months; luteinizing hormone [LH], 10.7 months) than for sperm variables (output, 14.1 months) whereas spermatogenesis (serum follicle-stimulating hormone [FSH], inhibin B, inhibin) took longer. The duration of androgen abuse was the only other variable associated with slower recovery of sperm output (but not hormones). CONCLUSION: Suppressed testicular and cardiac function due to androgen abuse is effectively fully reversible (apart from testis volume and serum sex hormone binding globulin) with recovery taking between 6 to 18 months after ceasing androgen intake with possible cumulative effects on spermatogenesis. Suppressed serum AMH, LH, and FSH represent convenient, useful, and underutilized markers of recovery from androgen abuse.

Testosterone for Androgen Deficiency-Like Symptoms in Men Without Pathologic Hypogonadism: A Randomized, Placebo-Controlled Cross-over With Masked Choice Extension Clinical Trial.

BACKGROUND: Off-label testosterone prescribing for androgen deficiency (AD)-like sexual and energy symptoms of older men without pathologic hypogonadism has increased dramatically without convincing evidence of efficacy. METHODS: In a randomized, double-blind, placebo-controlled study with three phases, we entered 45 men aged at least 40 years without pathologic hypogonadism but with AD-like energy and/or sexual symptoms to either daily testosterone or placebo gel treatment for 6 weeks in a cross-over study design with a third, mandatory extension phase in which participants chose which previous treatment they preferred to repeat while remaining masked to their original treatment. Primary endpoints were energy and sexual symptoms as assessed by a visual analog scale (Lead Symptom Score [LSS]). RESULTS: Increasing serum testosterone to the healthy young male range produced no significant benefit more than placebo for energy or sexual LSS. Covariate effects of age, body mass index, and pretreatment baseline serum testosterone on quality-of-life scales were detected. Only 1 out of 22 indices from seven quality-of-life scales was significantly improved by testosterone treatment over placebo. Participants did not choose testosterone significantly more than placebo as their preferred treatment in the third phase. CONCLUSIONS: Six-week testosterone treatment does not improve energy or sexual symptoms more than placebo in symptomatic men without pathologic hypogonadism.

A high-volume, low-cost approach to participant screening and enrolment: Experiences from the T4DM diabetes prevention trial.

BACKGROUND/AIMS: Participant recruitment to diabetes prevention randomised controlled trials is challenging and expensive. The T4DM study, a multicentre, Australia-based, Phase IIIb randomised controlled trial of testosterone to prevent Type 2 diabetes in men aged 50-74 years, faced the challenge of screening a large number of prospective participants at a small number of sites, with few staff, and a limited budget for screening activities. This article evaluates a high-volume, low-cost, semi-automated approach to screen and enrol T4DM study participants. METHODS: We developed a sequential multi-step screening process: (1) web-based pre-screening, (2) laboratory screening through a network of third-party pathology centres, and (3) final on-site screening, using online data collection, computer-driven eligibility checking, and automated, email-based communication with prospective participants. Phone- and mail-based data collection and communication options were available to participants at their request. The screening process was administered by the central coordinating centre through a central data management system. RESULTS: Screening activities required staffing of approximately 1.6 full-time equivalents over 4 years. Of 19,022 participants pre-screened, 13,108 attended a third-party pathology collection centre for laboratory screening, 1217 received final, on-site screening, and 1007 were randomised. In total, 95% of the participants opted for online pre-screening over phone-based pre-screening. Screening costs, including both direct and staffing costs, totalled AUD1,420,909 (AUD75 per subject screened and AUD1411 per randomised participant). CONCLUSION: A multi-step, semi-automated screening process with web-based pre-screening facilitated low-cost, high-volume participant enrolment to this large, multicentre randomised controlled trial. Centralisation and automation of screening activities resulted in substantial savings compared to previous, similar studies. Our screening approach could be adapted to other randomised controlled trial settings to minimise the cost of screening large numbers of participants.

Pharmacokinetics and Acceptability of Subcutaneous Injection of Testosterone Undecanoate.

CONTEXT: Can injectable testosterone undecanoate (TU) be administered effectively and acceptably by the subcutaneous (SC) route? OBJECTIVE: To investigate the acceptability and pharmacokinetics (PK) of SC injection of TU. DESIGN: Randomized sequence, crossover clinical study of SC vs IM TU injections. SETTING: Ambulatory clinic of an academic andrology center. PARTICIPANTS: Twenty men (11 hypogonadal, 9 transgender men) who were long-term users of TU. injections. Intervention: Injection of 1000 mg TU (in 4 mL castor oil vehicle) by SC or IM route. Main Outcome Measures: Patient-reported pain, acceptability, and preference scales. PK by measurement of serum testosterone, dihydrotestosterone (DHT), and estradiol (E2) concentrations with application of population PK methods and dried blood spot (DBS) sampling. RESULTS: Pain was greater after SC compared with IM injection 24 hours (but not immediately) after injection but both routes were equally acceptable. Ultimately 11 preferred IM, 6 preferred SC, and 3 had no preference. The DBS-based PK analysis of serum testosterone revealed a later time of peak testosterone concentration after SC vs IM injection (8.0 vs 3.3 days) but no significant route differences in model-predicted peak testosterone concentration (8.4 vs 9.6 ng/mL) or mean resident time (183 vs 110 days). The PK of venous serum testosterone, DHT, and E2 did not differ according to route of injection. CONCLUSIONS: We conclude that SC TU injection is acceptable but produces greater pain 24 hours after injection that may contribute to the overall majority preference for the IM injection. The PK of testosterone, DHT, or E2 did not differ substantially between SC and IM routes. Hence whereas further studies are required, the SC route represents an alternative to IM injections without a need to change dose for men for whom IM injection is not desired or recommended.

Recruitment of men to a multi-centre diabetes prevention trial: an evaluation of traditional and online promotional strategies.

BACKGROUND: Effective interventions are required to prevent the current rapid increase in the prevalence of Type 2 diabetes. Clinical trials of large-scale interventions to prevent Type 2 diabetes are essential but recruitment is challenging and expensive, and there are limited data regarding the most cost-effective and efficient approaches to recruitment. This paper aims to evaluate the cost and effectiveness of a range of promotional strategies used to recruit men to a large Type 2 diabetes prevention trial. METHODS: An observational study was conducted nested within the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, a large, multi-centre randomised controlled trial (RCT) of testosterone treatment for the prevention of Type 2 diabetes in men aged 50-74 years at high risk of developing diabetes. Study participation was promoted via mainstream media-television, newspaper and radio; direct marketing using mass mail-outs, publicly displayed posters and attendance at local events; digital platforms, including Facebook and Google; and online promotions by community organisations and businesses. For each strategy, the resulting number of participants and the direct cost involved were recorded. The staff effort required for each strategy was estimated based on feedback from staff. RESULTS: Of 19,022 men screened for the study, 1007 (5%) were enrolled. The most effective recruitment strategies were targeted radio advertising (accounting for 42% of participants), television news coverage (20%) and mass mail-outs (17%). Other strategies, including radio news, publicly displayed posters, attendance at local events, newspaper advertising, online promotions and Google and Facebook advertising, each accounted for no more than 4% of enrolled participants. Recruitment promotions cost an average of AU$594 per randomised participant. The most cost-effective paid strategy was mass mail-outs by a government health agency (AU$745 per participant). Other paid strategies were more expensive: mail-out by general practitioners (GPs) (AU$1104 per participant), radio advertising (AU$1081) and newspaper advertising (AU$1941). CONCLUSION: Radio advertising, television news coverage and mass mail-outs by a government health agency were the most effective recruitment strategies. Close monitoring of recruitment outcomes and ongoing enhancement of recruitment activities played a central role in recruitment to this RCT. TRIAL REGISTRATION: ANZCTR, ID: ACTRN12612000287831 . Registered on 12 March 2012.

Telephone call reminders did not increase screening uptake more than SMS reminders: a recruitment study within a trial.

OBJECTIVES: The aim of the study was to compare the response rates and costs of phone call vs. short message service (SMS) screening reminders to prospective randomized controlled trial (RCT) participants. STUDY DESIGN AND SETTING: This study was a randomized evaluation within a large Australian diabetes prevention RCT. Participants were men aged 50-74 years, overweight or obese, without a previous type 2 diabetes diagnosis. Those eligible on a prescreening questionnaire who did not attend a further screening assessment within 4 weeks were randomized to receive an SMS or phone call reminder (N = 709). The primary outcome was attendance for further screening assessment within 8 weeks of prescreening. RESULTS: Attendance was 18% (62/354) in the SMS reminder group, and 23% (80/355) in the phone reminder group, with no statistically significant difference in response according to reminder type (relative risk = 1.29, 95% confidence interval [CI]: 0.96-1.73, P = 0.09). The lower confidence limits for response to SMS (95% CI: 14-22%) and phone reminders (95% CI: 18-27%) did not include the 8-week attendance rate before this evaluation, 12%. Phone reminders cost substantially more than SMS reminders (AU$6.21 vs. AU$0.53 per reminder). CONCLUSION: SMS reminders were as adequate a method as phone reminders to boost RCT screening uptake and were considerably more affordable.

Sperm cryopreservation prior to gonadotoxic treatment: experience of a single academic centre over 4 decades.

STUDY QUESTION: What is the natural history of outcomes of sperm cryostorage at an Australian tertiary academic centre? SUMMARY ANSWER: Cryostorage is feasible in virtually all men facing gonadotoxic therapy but the timing of sperm disposal varies according to the reason for it. WHAT IS KNOWN ALREADY: Gonadotoxic treatment for cancer or non-cancer diseases damages spermatogenesis and impairs male fertility. Sperm cryopreservation is an established technique to preserve male fertility prior to gonadotoxic treatment. STUDY DESIGN, SIZE, DURATION: A retrospective review of clinical, anthropometric, semen analysis and hormonal data from 1978 to 2017 involving 2717 men comprising 2085 men with cancer, 234 non-cancer disease and 398 healthy controls, in a single tertiary academic centre with the same clinic and laboratory staff. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Sperm output was analysed according to diseases, the feasibility of sperm cryostorage notably for adolescents, regional access to an urban cryostorage facility, the determinants of sperm output and time-dependent disposal of cryostored sperm. Semen samples were assessed by contemporaneous WHO methods. MAIN RESULTS AND THE ROLE OF CHANCE: Of 2085 men with cancer, 904 (43%) had haematological malignancies, 680 (33%) testicular cancers and 136 (6.5%) were adolescents. Most men (89%) and adolescents (80%) could collect sperm. Sperm output for all cancers and non-cancer diseases was lower than controls. Sperm output correlated positively with total testicular volume (r = 0.44, P < 0.0001) and negatively with serum FSH and LH (r = -0.24, -0.12, respectively, both P < 0.0001) but not testosterone. For all stored samples, the median time in cryostorage was 8.5 years, 7% were transferred for use to induce pregnancy (median time 2.5 years) and 62.2% were discarded as no longer needed (return of fertility, 35.9% median 3.5 years; death, 26.3%, median 6.5 years), the high disposal rate reflecting regular annual follow-up to establish ongoing need for continued cryostorage. Cryostorage facilities are not available in remote and rural areas of the State and the proportion of outer regional and remote area residents cryostoring sperm was only about half that compared with urban residents. LIMITATIONS, REASONS FOR CAUTION: This study does not report the pregnancy outcomes of the patients who used the cryostored sperm, due to recent limitations on health data privacy. WIDER IMPLICATIONS OF THE FINDINGS: Sperm cryostorage is feasible for virtually all men, including sufficiently mature adolescents, who can collect semen to insure future paternity as well as making positive psychological preparation for the patient's survival. Disposal of cryostored material when no longer required is efficient with regular follow-up. Sperm cryopreservation should be an integral part of comprehensive treatment plan in men receiving gonadotoxic treatment but remains underutilized. STUDY FUNDING/COMPETING INTEREST(S): There was no external funding for this study and there were no relevant conflicts of interest.

Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double-blind randomized controlled trial.

BACKGROUND: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT). AIMS: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years. STUDY POPULATION: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT). SETTING, DRUG AND PROTOCOL: Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments. SECONDARY ENDPOINTS: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilization and costs. SAFETY: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end.

Urine and Serum Sex Steroid Profile in Testosterone-Treated Transgender and Hypogonadal and Healthy Control Men.

Background: The impact of testosterone (T) treatment on antidoping detection tests in female-to-male (F2M) transgender men is unknown. We investigated urine and serum sex steroid and luteinizing hormone (LH) profiles in T-treated F2M men to determine whether and, if so, how they differed from hypogonadal and healthy control men. Method: Healthy transgender (n = 23) and hypogonadal (n = 24) men aged 18 to 50 years treated with 1000 mg injectable T undecanoate provided trough urine and blood samples and an additional earlier postinjection sample (n = 21). Healthy control men (n = 20) provided a single blood and urine sample. Steroids were measured by mass spectrometry-based methods in urine and serum, LH by immunoassay, and uridine 5'-diphospho-glucuronosyltransferase 2B17 genotype by polymerase chain reaction. Results: Urine LH, human chorionic gonadotropin, T, epitestosterone (EpiT), androsterone (A), etiocholanolone (Etio), A/Etio ratio, dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and 5α,3α- and 5ß,3α-androstanediols did not differ between groups or by time since last T injection. Urine T/EpiT ratio was <4 in all controls and 12/68 (18%) samples from T-treated men, but there was no difference between T-treated groups. Serum estradiol, estrone, and DHEA were higher in transgender men, and serum T and DHT were higher in earlier compared with trough blood samples, but serum LH, follicle-stimulating hormone, and 3α- and 3ß,5α-diols did not differ between groups. Conclusion: Urine antidoping detection tests in T-treated transgender men can be interpreted like those of T-treated hypogonadal men and are unaffected by time since last T dose. Serum steroids are more sensitive to detect exogenous T administration early but not later after the last T dose.

Endocrine Society of Australia position statement on male hypogonadism (part 2): treatment and therapeutic considerations.

INTRODUCTION: Part 1 of this position statement dealt with the assessment of male hypogonadism, including the indications for testosterone therapy. This article, Part 2, focuses on treatment and therapeutic considerations for male hypogonadism and identifies key questions for future research. MAIN RECOMMENDATIONS: Key points and recommendations are:Excess cardiovascular events have been reported in some but not all studies of older men without pathological hypogonadism who were given testosterone treatment. Additional studies are needed to clarify whether testosterone therapy influences cardiovascular risk.Testosterone is the native hormone that should be replaced in men being treated for pathological hypogonadism. Convenient and cost-effective treatment modalities include depot intramuscular injection and transdermal administration (gel, cream or liquid formulations).Monitoring of testosterone therapy is recommended for efficacy and safety, focusing on ameliorating symptoms, restoring virilisation, avoiding polycythaemia and maintaining or improving bone mineral density.Treatment aims to relieve an individual's symptoms and signs of androgen deficiency by administering standard doses and maintaining circulating testosterone levels within the reference interval for eugonadal men.Evaluation for cardiovascular disease and prostate cancer risks should be undertaken as appropriate for eugonadal men of similar age. Nevertheless, when there is a reasonable possibility of substantive pre-existing prostate disease, digital rectal examination and prostate-specific antigen testing should be performed before commencing testosterone treatment.Changes in management as result of the position statement: Treatment aims to relieve symptoms and signs of androgen deficiency, using convenient and effective formulations of testosterone. Therapy should be monitored for efficacy and safety.

Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy.

INTRODUCTION: This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) MAIN RECOMMENDATIONS: Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings.

Detection and effects on serum and urine steroid and LH of repeated GnRH analog (leuprolide) stimulation.

Non-steroidal drugs that increase endogenous testosterone (T) may be used to exploit ergogenic effects of androgens in power sports. While superactive GnRH analog use is suspected, neither screening nor detection tests are developed. This study aimed to determine if (a) stimulation for 5 days by leuprolide (a superactive GnRH analog) of serum and urine steroids and urine LH is reproducible at a 2 week interval, (b) nandrolone decanoate (ND) co-administration masks responses to leuprolide administration, (c) performance of urine measurement of leuprolide and M1, its major metabolite, as a detection test. Healthy men were randomized into a 4 week parallel group, open label clinical study in which all men had daily sc injections of leuprolide (1mg) for 4 days in the 1st and 3rd weeks with hormone-free 2nd and 4th weeks. In the 3rd week, men were randomized to either ND injections or no extra treatment. Serum steroids were determined by liquid chromatography, tandem mass spectrometry (LC-MS), urine steroids by gas chromatography, mass spectrometry (GC-MS), urine leuprolide and M1 by high resolution LC-MS and urine LH by immunoassay. Leuprolide stimulated striking, reproducible increases in serum and urine LH and steroids (serum T, dihydroT (DHT), 3α diol; urine T, epitestosterone (E) and androsterone (A). ND suppressed basal serum T, E2, 3α diol, and urinary E but did not mask or change the magnitude of responses to leuprolide. Urine leuprolide and M1 measurement had 100% sensitivity and specificity in detecting leuprolide administration up to one day after cessation of injections with the detection window between 1 and 3 days after last dose. Screening using urine steroid and LH measurements, optimally by urinary log10(LHxT), correctly classified 82% of urine samples. It is concluded that leuprolide stimulation of endogenous testosterone is reproducible after a 10-day interval, is not masked by ND and is reliably detected by urine leuprolide or M1 measurement for at least 1 day after administration.