Recovery of Male Reproductive 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: To investigate rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections. 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 a further 12 months while remaining blinded to treatment. Sex steroids (T, DHT, E2, E1) by LCMS, LH, FSH and SHBG by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire (PDQ), International Index of Erectile Function (IIEF), SF-12) were measured at entry (three months after 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 to 12 weeks remaining stable thereafter with serum T and SHBG 11% and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carryover higher scores in T-treated men, but after weeks 18 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 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 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.

The Efficacy and Safety of Letrozole or Anastrozole in The Treatment of Specific Male Infertility Patients: Meta-Analysis and Systematic Review

Background: Letrozole (LE) or anastrozole (AZ) is clinically beneficial in male infertility patients with a low testosterone-estradiol ratio (T/E2). Many scholars believe it has the potential to become one of the effective drugs to treat male infertility. But some relevant research results are different or even the opposite. Study Question: The purpose of this report is to evaluate the efficacy and safety of letrozole or anastrozole in the treatment of specific male infertility patients. Data Sources: We performed a comprehensive literature search using PubMed, Embase, Cochrane, CNKI, VIP, CBM, and Wanfang Date through August 2021 for all studies.Study Design: We conducted a systematic review with meta- analysis of the all available literature reporting sperm conventional parameters, gonadotropin and testosterone levels, and/or the pregnancy rate. Results: The total of 10 studies involving 280 patients were included. LE or AZ administration increased significantly sperm concentration, total sperm count, and serum luteinizing hormone, follicle-stimulating hormone, testosterone levels and T / E2 compared with baseline values, but E2 levels were significantly reduced. In contrast, LE or AZ did not have any significant effect on sperm concentration and motility and pregnancy rate, but improved total sperm count, sperm morphology, compared to the control group, which included studies done with Selective estrogen receptor modulators (SEMR) or testosterone undecanoate (TU). Conclusion: LE or AZ may be effective in the treatment of low T / E2 male infertility, perhaps better than other anti-estrogen or exogenous testosterone supplementation. In addition, we should pay special attention to the changes of E2 during treatment.

Correction of Androgen Deficiency in Men with Type 2 Diabetes

Background: In men with low levels of testosterone in the blood, it is believed that the symptoms can be regarded as an association between testosterone deficiency syndrome and related comorbidities. Aim: to investigate the effectiveness of testosterone therapy in patients with type 2 diabetes (T2D) and androgen deficiency. Materials and methods: Testosterone replacement therapy was carried out in 26 men with T2D and clinically or laboratory-confirmed androgen deficiency. The age of the subjects ranged from 35 to 69 years old. Laboratory studies included determinations of the concentration of the hormones estradiol, luteinizing hormone (LH), and prostate-specific antigen (PSA). The observation period was 9 months. Results: The average level of total blood testosterone in the subjects before treatment was 9.4 mol/l and was likely lower than that of the control group (19.3 ± 1.6 nmol/l). The levels of total testosterone in the subjects ranged from 3.9 nmol/l to 10.7 nmol/l, and hormone levels measuring less than 8.0 nmol/l were observed in only 11 patients. After a course of testosterone replacement therapy, a stabilization in total testosterone levels at the level of reference values (as compared to the start of treatment) was observed in the blood of men with T2D after 9 months of observation and the administration of the fourth injection (16.83 ± 0.75 nmol/l). Conclusion: The use of long-acting injectable testosterone undecanoate leads to normalization of total testosterone levels in the blood of men with T2D and androgen deficiency, and LH levels in these patients are unlikely to change.

Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men

Background: Reliable biomarkers of androgen activity in humans are lacking. The aim of this study was, therefore, to identify new protein markers of biological androgen activity and test their predictive value in relation to low vs. normal testosterone values and some androgen deficiency linked pathologies.<br />Methods: Blood samples from 30 healthy GnRH-antagonist treated males were collected at three time points: a) before GnRH antagonist administration; b) 3 weeks later, just before testosterone undecanoate injection, and c) after additional 2 weeks. Subsequently they were analysed by mass spectrometry to identify potential protein biomarkers of testosterone activity. Levels of proteins most significantly associated with testosterone fluctuations were further tested in a cohort of 75 hypo- and eugonadal males suffering from infertility. Associations between levels of those markers and cardio-metabolic parameters, bone mineral density as well as androgen receptor CAG repeat lengths, were explored.<br />Results: Using ROC analysis, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6) and fructose-bisphosphate aldolase (ALDOB), as well as a Multi Marker Algorithm, based on levels of 4HPPD and IGFBP6, were shown to be best predictors of low (< 8 nmol/L) vs. normal (> 12 nmol/L) testosterone. They were also more strongly associated with metabolic syndrome and diabetes than testosterone levels. Levels of ALDOB and 4HPPD levels also showed association with AR CAG-repeat lengths.<br />Conclusions: We identified potential new protein biomarkers of testosterone action. Further investigations to eluciadate their clinical potential are warranted.<br />Funding: The work was supported by ReproUnion 2.0 (grant no 20201846), which is funded by the Interreg V EU program.

Improved glycaemic control and reduced incidence of myocardial infarctions, strokes, and mortality in men with hypogonadism and type 2 diabetes, with and without long-term testosterone therapy

Introduction Guidelines by the ESC and EASD state that patients with diabetes have a two-fold excess risk of vascular outcomes. An increasing number of studies suggests that testosterone therapy (TTh) has cardiometabolic benefits in men with hypogonadism and type 2 diabetes (T2DM). Methods In a registry of men with hypogonadism in a urological office, 361 men had T2DM and received standard diabetes treatment including lifestyle recommendations and coaching in a diabetes center. 183 men received TTh with testosterone undecanoate injections 1000 mg/12 weeks following an initial 6-week interval (T-group). 178 men opted against TTh and served as controls (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups. 12-year analyses of 3149 patient-years are reported. Results Mean (median) follow-up 8.2±3.2 (8) years in the T-group, 9.2±2.8 (10) years in CTRL, baseline age: 60.6±5.4 (T-group) and 63.5±5.0 (CTRL) years (p&lt;0.0001). All but 7 patients were overweight or obese. 70 patients (38.3%) in the T-group and 70 (39.3%) in CTRL had a history of cardiovascular disease (myocardial infarction MI, stroke, or coronary artery disease diagnosis) (p=0.8341). Baseline smoking prevalence was 41.0% (75 men) in the T-group and 38.2% (68 men) in CTRL (p=0.5161). The T-group had significantly worse baseline risk factor profile than CTRL: BMI (36.5±4.5 vs. 33.4±5.3 kg/m2), systolic blood pressure (163.0±13.5 vs. 145.6±14.6 mmHg), LDL (4.7±0.9 vs. 4.1±1.4 mmol/L), HbA1c 9.4±1.4 vs. 7.8±0.7% (p&lt;0.0001 for all). HbA1c progressively decreased by 3.7±0.2% at 12 years in the T-group and increased in CTRL by 3.2±0.2%, estimated adjusted difference between groups: −6.9% [95% CI: −7.4; −6.4] (p&lt;0.0001 for all). Fasting glucose decreased in the T-group by 1.9±0.1 and increased in CTRL by 1.8±0.1 mmol/L, estimated adjusted difference: −3.6 mmol/L [95% CI: −4.0; −3.3] (p&lt;0.0001 for all). Men in the T-group lost 19.7±0.4% weight, men in CTRL gained 9.1±0.4%, estimated adjusted difference: −28.8% [95% CI: −30.2; −27.4] (p&lt;0.0001 for all). During the observation period, 15 patients (8.2%) died in the T-group vs. 61 (34.3%) in CTRL (p&lt;0.0001). In the T-group, there were no cases of MI or stroke. In CTRL, there were 56 cases of MI (31.5%) and 56 cases of stroke (31.5%). 35 patients (19.7%) suffered a MI and a stroke. Medication adherence to testosterone was 100% as all injections were administered in the medical office and documented. Conclusions Long-term treatment with TU in men with hypogonadism and T2DM significantly reduces mortality, compared to untreated controls. Improved glycaemic control and weight loss may have contributed to these outcomes. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG, Berlin, Germany