Endogenous Testosterone Research Articles

The Impact of Baseline Endogenous Testosterone Levels on Risk Stratification in Pathological Organ-Confined Prostate Cancer: Results in 460 Patients Treated with Robot-Assisted Radical Prostatectomy

The Impact of Baseline Endogenous Testosterone Levels on Risk Stratification in Pathological Organ-Confined Prostate Cancer: Results in 460 Patients Treated with Robot-Assisted Radical Prostatectomy

Bioavailable testosterone and androgen receptor activation, but not total testosterone, are associated with muscle mass and strength in females.

Testosterone, the major androgen, influences the reproductive and non-reproductive systems in males and females via binding to the androgen receptor (AR). Both circulating endogenous testosterone and muscle AR protein content are positively associated with muscle mass and strength in males, but there is no such evidence in females. Here, we tested whether circulating testosterone levels were associated with muscle mass, function, or the muscle anabolic response to resistance training in pre-menopausal females. Twenty-seven pre-menopausal, untrained females (aged 23.5 ± 4.8 years) underwent a 12-week resistance training programme. Muscle strength, size, power, and plasma and urine androgen hormone levels were measured. Skeletal muscle biopsies were collected before and after the training programme to quantify the effect of resistance training on AR content and nuclear localisation. Primary muscle cell lines were cultured from a subset (n=6) of the participants' biopsies and treated with testosterone to investigate its effect on myotube diameter, markers of muscle protein synthesis and AR cellular localisation. Physiological levels of total testosterone were not associated with muscle mass or strength at baseline or with the changes in muscle mass and strength that occurred in response to resistance training in our cohort of pre-menopausal females. In contrast, bioavailable testosterone and the proportion of nuclear-localised AR were positively associated with skeletal muscle mass and strength in pre-menopausal females. In vitro, supra-physiological doses of testosterone increased myocyte diameter, but this did not occur via the Akt/mTOR pathway as previously suggested. Instead, we show a marked increase in AR nuclear localisation with testosterone administration in vitro. KEY POINTS: Total circulating testosterone was not related to muscle mass or strength before or after resistance training in pre-menopausal females. Bioavailable testosterone was positively related to exercise-induced muscle hypertrophy in pre-menopausal females. In vivo nuclear localisation of the androgen receptor was positively related to muscle mass in pre-menopausal females at baseline, but not to resistance training-induced hypertrophy. Testosterone treatment induced androgen receptor nuclear translocation but did not induce mTOR signalling in primary skeletal myocytes cultured from pre-menopausal female muscle.

8462 Synergistic Outcomes Of hCG And GLP1-RA Combination Therapy: Improved Body Composition And Carbohydrate Metabolism

Abstract Disclosure: F. Comite: None. K. O'Malley: None. Objective: Precision medicine prevents and reverses diseases of aging by way of systematic analysis of body composition and extensive blood biomarkers. Andropause, the age-related reduction of free testosterone (FT) in males, elicits symptoms primarily of muscle loss, decreased libido, and diminished energy. Exogenous testosterone therapy (TTx) subsequently increases lean body mass (LBM) and improves both libido and energy levels in affected males. More recently, stimulation of endogenous testosterone from the testes, human Chorionic Gonadotropin (hCG) has emerged as a compelling physiologic alternative to TTx. Common comorbidities to andropause are DMII and/or obesity. Recent literature surrounds the use of GLP-1 receptor agonists to improve insulin sensitivity in these disorders of carbohydrate metabolism. A primary benefit secondary to GLP-1 use is reduction of fat mass; however, concerns of this monotherapy surround loss of muscle.[1] Remarkably, when treated adjunctly with GLP-1s, hCG therapy significantly mitigates muscle loss while maintaining optimal carbohydrate biomarkers. The efficacy and benefits of hormonal optimization through hCG therapy simultaneous to GLP-1 intervention were investigated. Methods: In this retrospective analysis, a cohort of 20 males ≥30 years of age were reviewed at baseline timepoints and 18 months post treatment-initiation. Participants underwent biweekly hCG and weekly GLP-1 subcutaneous injections. Exclusion criteria restricted use of alternative GLP-1/GIP combination medication. Paired T-Tests were used to determine a relationship between LBM, FT, percent body fat (PBF), fasting glucose (FG), fasting insulin (FI), and HbA1c at each timepoint. Results: Body composition analysis as shown via bioelectrical impedance proved baseline PBF (mean=24.60) significantly reduced post-treatment (p<0.05, mean=18.08) for all participants. In addition, relevant carbohydrate metabolic biomarkers FG, FI, and HbA1c provided significant reductions (p<0.05). Initial FT (mean=67.76) and LBM (mean=150.36) increased significantly at follow-up (p<0.05) with values of 167.55 and 154.91, respectively. Discussion: Using metrics of precision medicine, our interpretation reveals a promising combination therapy for males experiencing andropause. The novel use of hCG to optimize FT levels enhances muscle, while simultaneously, fat loss and reversal of harmful carbohydrate metabolic markers resultant from GLP-1 therapy are achieved. Muscle loss due to overall weight loss is thus ameliorated. Our findings merit further investigation of the magnitude of downstream improvements, particularly in energy and libido.

Clomiphene Citrate Treatment as an Alternative Therapeutic Approach for Male Hypogonadism: Mechanisms and Clinical Implications.

Male hypogonadism, which is characterized by low testosterone levels, has a significant impact on male sexual function, overall health, and fertility. Testosterone replacement therapy (TRT) is the conventional treatment for this condition, but it has potential adverse effects and is not suitable for men seeking to conceive. Testosterone plays an essential role in male sexual function, metabolism, mood, and overall well-being. Clomiphene citrate, a drug originally developed for female infertility, has recently gained attention as an off-label treatment for male hypogonadism. By blocking the negative feedback of estrogen on the hypothalamus and pituitary glands, clomiphene stimulates gonadotropin secretion, leading to increased endogenous testosterone production, which, in turn, improves sperm parameters and fertility and alleviates the symptoms of hypogonadism. Regarding the safety profile of clomiphene compared with TRT, clomiphene appears to confer a lower risk than TRT, which is associated with adverse effects such as polycythemia. Furthermore, combination therapy with clomiphene and anastrozole or human chorionic gonadotropin has been investigated as a potential approach to enhancing the effectiveness of treatments for improving hypogonadism symptoms. In conclusion, clomiphene citrate may offer a promising alternative to TRT for men with hypogonadism, particularly those desiring fertility preservations. However, its long-term efficacy and safety remain inadequately understood. Future research should focus on exploring the benefits of combination therapies and personalized treatment strategies based on individual patient characteristics.

New Insights into D-Aspartate Signaling in Testicular Activity.

D-aspartate (D-Asp) is an amino acid found in high concentrations in the testis and pituitary gland. Increasing evidence suggests that D-Asp promotes spermatogenesis by activating testosterone production in the Leydig cells via LH release from the pituitary gland. In vitro studies indicate that D-Asp may also influence steroidogenesis and spermatogenesis through autocrine and paracrine signals. D-Asp enhances StAR and steroidogenic enzyme expressions, facilitating testicular cell proliferation via the GluR/ERK1/2 pathway. Moreover, it supports spermatogenesis by enhancing the mitochondrial function in spermatocytes, aiding in the metabolic shift during meiosis. Enhanced mitochondrial function, along with improved MAM stability and reduced ER stress, has been observed in Leydig and Sertoli cells treated with D-Asp, indicating potential benefits in steroidogenesis and spermatogenesis efficiency. Conversely, D-Asp exerts a notable anti-apoptotic effect in the testis via the AMPAR/AKT pathway, potentially mediated by antioxidant enzyme modulation to mitigate testicular oxidative stress. This review lays the groundwork for future investigations into the molecules promoting spermatogenesis by stimulating endogenous testosterone biosynthesis, with D-amino acids emerging as promising candidates.

Testosterone and male contraception.

Rates of unintended pregnancy have remained relatively stagnant for many years, despite a broad array of female contraceptive options. Recent restrictions on access to abortion in some countries have increased the urgency for expanding contraceptive options. Increasing data suggest men are keen to utilize novel reversible male contraceptives. Despite decades of clinical research in male contraception, no reversible hormonal product currently exists. Nestorone/testosterone, among other novel androgens, shows promise to finally move to pivotal Phase 3 studies and introduction to the marketplace. Hormonal male contraception utilizes androgens or androgen-progestin combinations to exploit negative feedback that regulates the hypothalamic-pituitary-testicular axis. By suppressing release of gonadotropins, these agents markedly decrease endogenous testosterone production, lower intratesticular testosterone and suppress spermatogenesis. The addition of a progestin enhances the degree and speed of sperm suppression. The androgen component preserves a state of symptomatic eugonadism in the male. There is growing demand and acceptance of male contraceptive options in various forms. As these formulations progress through stages of drug development, regulatory oversight and communication with developers around safety and efficacy standards and garnering industry support for advancing the production of male contraceptives will be imperative.

The role of endogenous testosterone in relationship with low- and intermediate-risk prostate cancer: a systematic review.

An enduring debate in research revolves around the association between elevated endogenous testosterone levels and prostate cancer. This systematic review is intended to assess the present understanding of the role of endogenous testosterone in the diagnosis and treatment of low- and intermediate-risk prostate cancer. Our search strategy was the following: (endogenous testosterone) AND (((low risk) OR (intermediate risk)) AND ((diagnosis) OR (treatment))) AND (prostate cancer); that was applied to PubMed, Web of Science, and Scopus databases to identify pertinent articles. Two investigators performed an independent selection following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The preliminary investigation detected 105 records, and 81 records remained after eliminating duplicates. Following the review of titles and abstracts, 71 articles were excluded. A comprehensive examination of the full text was conducted for 10 articles, excluding 3 of them. After revising the references of eligible articles, other 3 articles were included. We finally identified 10 suitable studies, including three main topics: (1) association between endogenous testosterone and European Association of Urology (EAU) risk classes; (2) association between endogenous testosterone density and the tumor load; and (3) association of endogenous testosterone with tumor upgrading and tumor upstaging. Actual literature about the impact of endogenous testosterone on low- and intermediate-risk prostate cancer is not numerous, but appears to be still conflicting. More investigations are needed to increase the consistency of the literature's results.

High-temperature liquid chromatography-isotope ratio mass spectrometry methodology for carbon isotope ratio determination of anabolic steroids in urine

BackgroundGas Chromatography Isotope Ratio Mass Spectrometry (GC-C-IRMS) has long been used in routine laboratories to determine the δ13C values of anabolic steroids in urine, differentiating between, e.g., endogenous and synthetic testosterone (T) in sports doping control. Until now, liquid chromatography (LC-IRMS) has not been used. The LC-IRMS setup doesn't allow organic solvents or modifiers in the mobile phase for δ13C determinations. Mid-to non-polar analytes such as steroids can be analysed in water heated to High Temperatures (HT, up to 200 °C) because at 200 °C has a similar polarity as 80/20 methanol/water at ambient temperature. In this work, we developed a method for steroids in urine, extending the application of the LC-IRMS to non-polar analytes in complex matrices. ResultAn HT-LC-IRMS method capable of determining the δ13C values of four steroids (i.e., testosterone (T), 5α-androstane-3α,17β-diol (ααβ), 5β-androstane-3α,17β-diol (βαβ) and pregnanetriol (PT)) in urine was developed and validated. Accuracy ranged from 0.23 ‰ (ααβ and βαβ) to 0.49 ‰ (T), and the detection limit was set at 10 ng mL−1 (T, ααβ+βαβ). The validation data and a comparison of authentic urine samples analysed with HT-LC-IRMS and GC-C-IRMS indicated a comparable performance between HT-LC-IRMS and GC-C-IRMS. SignificanceHT-LC-IRMS can be used to determine δ13C values of anabolic steroids, extending the applicability of both HT-LC and LC-IRMS to non-polar substances determined in a complex matrix in routine laboratory practice.

Endocrine, gender dysphoria, and sexual function benefits of gender-affirming bilateral orchiectomy: patient outcomes and surgical technique.

Gender-affirming bilateral orchiectomy (GABO) may be completed as either a standalone procedure (sGABO) or at the same time as gender-affirming vaginoplasty (vGABO). GABO is postulated to decrease gender-affirming hormone therapy (GAHT) dosages and reduce gender dysphoria, but these phenomena are not empirically described in the medical literature. The primary aim of this study was to describe changes in GAHT dosages after sGABO and vGABO. A secondary aim was to assess sGABO patients' preoperative decision-making priorities and postoperative satisfaction. A retrospective chart review identified 204 patients who completed GABO as either a standalone procedure (64% of patients) or at the same time as vaginoplasty (36%). Patient demographic data, surgical outcomes, and pre- and postoperative GAHT dosage data were recorded. Patients completed an opinion questionnaire to assessed decision-making priorities, as well as postoperative satisfaction and changes in quality-of-life measures. Primary outcomes included pre- and postoperative dosages of estradiol, progesterone, and spironolactone. Secondary outcomes included sGABO patient priorities, satisfaction with sGABO, changes in quality-of-life measures between sGABO and vGABO patients, and sGABO recommendations to future patients. The sGABO and vGABO patients experienced a statistically significant dosage reduction in all three GAHT assessed: estradiol, progesterone, and spironolactone (P < .05). All patients discontinued spironolactone postoperatively. Zero complications related to GABO were recorded for patients in either group. The patient questionnaire revealed that sGABO patients prioritize decreasing endogenous testosterone and reducing their GAHT as most important in their decision to undergo sGABO prior to vaginoplasty. A majority of sGABO patients reported improvement in all nine quality-of-life indices. None of the sGABO patients would recommend against sGABO to a friend who is waiting for vaginoplasty. For patients who are interested in vaginoplasty, sGABO may serve as a more immediate, low-risk, intermediary step that comes with the benefits of GABO, including significant GAHT medication reduction and gender dysphoria relief. This study offers a comprehensive evaluation of the impact of GABO on patients, combining empirical data with subjective patient feedback. Limitations include the retrospective design and the use of unvalidated survey questions. Prevaginoplasty GABO is a viable option to more immediately alleviate gender dysphoria and reduce GAHT medications for patients who are interested in gender-affirming vaginoplasty.

Modulation of the attentional response to baby schema by testosterone in pedohebephilic men and its relation to the nurturing system

Previous fMRI research found increased brain responses in men with pedophilic interest to non-sexual pictures of child and animal faces. This raised the question of whether an aberrant nurturing system could be linked to pedophilia. To further explore this hypothesis, 20 pedohebephilic and 23 teleiophilic men performed a target detection task with adult versus infant human and animal faces, which measured selective attention towards the baby schema by comparing reaction times to infant versus adult targets that were presented amongst distractors of the other category. Since the response to baby schema can be influenced by steroid hormones, saliva samples were additionally collected to determine endogenous testosterone, progesterone, estradiol and cortisol. Contrary to expectations, all men did not react faster to infant than adult faces. Yet, pedohebephilic men were more distracted by infant’s faces than teleiophilic men. Pedohebephilic men with higher testosterone were faster in orienting attention to infant targets in the context of adult distractors. This association was not observed in teleiophilic men. Our results support the idea of an overactive nurturing system in pedophilia, which may be influenced by the endogenous testosterone level.

Effects of endogenous testosterone on oscillatory activity during verbal working memory in youth.

Testosterone levels sharply rise during the transition from childhood to adolescence and these changes are known to be associated with changes in human brain structure. During this same developmental window, there are also robust changes in the neural oscillatory dynamics serving verbal working memory processing. Surprisingly, whereas many studies have investigated the effects of chronological age on the neural oscillations supporting verbal working memory, none have probed the impact of endogenous testosterone levels during this developmental period. Using a sample of 89 youth aged 6-14 years-old, we collected salivary testosterone samples and recorded magnetoencephalography during a modified Sternberg verbal working memory task. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting maps were subjected to whole-brain ANCOVAs examining the effects of testosterone and sex, controlling for age, during verbal working memory encoding and maintenance. Our primary results indicated robust testosterone-related effects in theta (4-7 Hz) and alpha (8-14 Hz) oscillatory activity, controlling for age. During encoding, females exhibited weaker theta oscillations than males in right cerebellar cortices and stronger alpha oscillations in left temporal cortices. During maintenance, youth with greater testosterone exhibited weaker alpha oscillations in right parahippocampal and cerebellar cortices, as well as regions across the left-lateralized language network. These results extend the existing literature on the development of verbal working memory processing by showing region and sex-specific effects of testosterone, and are the first results to link endogenous testosterone levels to the neural oscillatory activity serving verbal working memory, above and beyond the effects of chronological age.

The influence of correction of carbohydrate metabolism and body weight on endogenous testosterone production in men with type 2 diabetes mellitus, obesity and hypogonadism

Male hypogonadism and type 2 diabetes mellitus (T2DM) are often combined and aggravate each other. Considering the pathogenetic relationship with the components of the metabolic syndrome (hyperglycemia, insulin resistance, obesity) and the potential reversibility of testosterone deficiency, as well as the wariness of doctors and patients regarding testosterone replacement therapy, it is interesting to study the effect of various methods for correcting carbohydrate metabolism and obesity on endogenous testosterone production. When analyzing the effect of lifestyle correction, drug therapy for T2DM and obesity, as well as metabolic surgery on testosterone production, encouraging results were obtained with regard to methods that provide, first of all, significant reduction in body weight (medications from the group of glucagon-like peptide-1 receptor agonists and bariatric surgery). As for other classes of new antidiabetic drugs, it is likely that all of them may have direct or indirect beneficial effects on male sexual function, mainly by reducing glucotoxicity and inflammation. However, this hypothesis requires studies on large samples of patients. In addition, there is still no convincing data on the significance of correction of carbohydrate metabolism, regardless of weight loss, in relation to endogenous testosterone production, and there is also no data on the degree of improvement in glycemic control required for a clinically significant increase in serum testosterone levels.

(008) VAGINAL TESTOSTERONE ABSORBANCE AFTER SEXUAL AROUSAL

Abstract Introduction While topical (exogenous) estrogens have been a focus of treatment for vaginal pain, recent work has shown testosterone may also revitalize weakened vaginal tissue. This research has documented that vaginal tissue responds well to exogenous testosterone treatment, supporting the hypothesis that endogenous testosterone may play a significant role in vaginal health. However, is it not known how the dynamics of vaginal arousal may contribute to activity of endogenous testosterone within the vaginal environment. Specifically, there is reason to expect that vaginal sexual arousal may activate mechanisms within the vaginal tissue that increase absorption of testosterone from the mucosal layer into the tissue beneath. Objective This project aims to characterize the influence of vaginal arousal on the presence of testosterone in the vaginal mucosa both pre- and post-arousal, and the within-person stability of these effects over time (3 weeks). Methods Analyses are drawn from an ongoing clinical trial in which participants complete 3 in-lab sessions spaced 3 weeks apart, in which they provided samples of cervicovaginal fluid before and after watching an erotic video (~7 minutes). For each fluid sample, participants insert a disposable menstrual cup, which sits loosely around the cervix, for about 10 minutes. After the post-arousal menstrual cup is removed, participants complete a survey battery that includes demographics and measures of sexual function and sexual desire. Results For the present analysis, data were drawn from 68 participants that had pre- and post-arousal samples for at least one study session. Preliminary tests revealed that, controlling for changes in fluid volume, testosterone in the vaginal mucosa decreased significantly between pre- and post-vaginal sexual arousal (F(1, 197.26) = 67.29, p &amp;lt; .0001). Additional data regarding the association between absorption of testosterone during arousal and self-reported sexual functioning will also be presented. Conclusions Though further work is needed to confirm testosterone is absorbed into the surrounding vaginal tissue, our findings suggest a significant movement of testosterone out of cervicovaginal fluid during sexual arousal. Likely, the increased blood flow that accompanies vaginal sexual arousal allows for greater absorption of testosterone originally present in the mucosa into the vaginal tissue. If vaginal sexual arousal allows for greater testosterone absorption, it may provide a unique window of time during which application of exogenous testosterone may be most advantageous. Further, if endogenous testosterone absorption happens during masturbation or sexual activity, this may function over the longer term as a protective factor for tissue integrity. Disclosure No.

Clomiphene citrate and optional human chorionic gonadotropin for treating male hypogonadism arising from long-term anabolic-androgenic steroid use—A pilot study

IntroductionLong-term anabolic-androgenic steroid (AAS) use poses several health risks, including secondary hypogonadism. There is a knowledge gap on treatment targeting the hypothalamic-pituitary-gonadal (HPG) axis among men with anabolic steroid-induced hypogonadism (ASIH). This study aims to gain insights into the potential utility of endocrine therapy to restore endogenous testosterone levels and alleviate ASIH symptoms in AAS dependent men. MethodsIn this proof-of-concept, single-site, open longitudinal pilot study, AAS dependent men with continuous AAS use and a desire to permanently discontinue use, were given endocrine therapy. The treatment included 25 mg clomiphene citrate (CC) every second day for 16 weeks, transdermal testosterone daily during the first four weeks, and if indicated, human chorionic gonadotropin (hCG) injections for a maximum of eight weeks. Physical exams including blood collection and online questionnaires were completed every four and two weeks, respectively. ResultsTen participants, with median age 32 years (interquartile range 30–45), with mean ± standard deviation AAS use of 11 ± 4 years, completed the CC intervention. Seven participants received hCG as part of their treatment protocol. Mild adverse events included headaches, dizziness, and mood swings, and no serious adverse events occurred. During the intervention, there was a decrease in levels of hematocrit, hemoglobin and ALT (alanine aminotransferase), as well as an increase in serum FSH (follicle stimulating hormone), LH (luteinizing hormone) and SHBG (sex hormone binding globulin). Five of ten participants reached a total testosterone level within normal range (9–30 nmol/l). The HPG axis response varied greatly among participants, and was not aligned with the severity of ASIH related withdrawal symptoms. ConclusionsThe findings from this proof-of-concept study may guide future randomized controlled trials aiming to investigate potential endocrine therapeutic approaches to ASIH.

Testosterone and the risk of incident atrial fibrillation in older men: further analysis of the ASPREE study

A cardiovascular safety trial of testosterone in men with cardiovascular risk factors or disease found no difference in rates of major adverse cardiovascular events (MACE) or death but noted more atrial fibrillation (AF) events in testosterone-treated men. We investigated the relationship between endogenous testosterone concentrations with risk of developing AF in healthy older men. Post-hoc analysis of 4570 male participants in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Men were aged ≥ 70 years, had no history of cardiovascular disease (including AF), thyroid disease, prostate cancer, dementia, or life-threatening illnesses. Risk of AF was modelled using Cox proportional hazards regression. Median (IQR) age was 73.7 (71.6-77.1) years and median (IQR) follow-up 4.4 (3.3-5.5) years, during which 286 men developed AF (15.3 per 1000 participant-years). Baseline testosterone was higher in men who developed incident AF compared men who did not [17.0 (12.4-21.2) vs 15.7 (12.2-20.0) nmol/L]. There was a non-linear association of baseline testosterone with incident AF. The risk for AF was higher in men with testosterone in quintiles (Q) 4&5 (Q4:Q3, HR=1.91; 95%CI=1.29-2.83 and Q5:Q3HR=1.98; 95%CI=1.33-2.94). Results were similar after excluding men who experienced MACE or heart failure during follow-up. Circulating testosterone concentrations within the high-normal range are independently associated with an increased risk of incident AF amongst healthy older men. This suggests that AF may be an adverse consequence of high-normal total testosterone concentrations. National Institute on Aging and National Cancer Institute at the National Institutes of Health; Australian Government (NHMRC, CSIRO); Monash University; and AlfredHealth.

Hormonal Basis of Biological Sex Differences in Human Athletic Performance.

Biological sex is a primary determinant of athletic human performance involving strength, power, speed, and aerobic endurance and is more predictive of athletic performance than gender. This perspective article highlights 3 key medical and physiological insights related to recent evolving research into the sex differences in human physical performance: (1) sex and gender are not the same; (2) males and females exhibit profound differences in physical performance with males outperforming females in events and sports involving strength, power, speed, and aerobic endurance; (3) endogenous testosterone underpins sex differences in human physical performance with questions remaining on the roles of minipuberty in the sex differences in performance in prepubescent youth and the presence of the Y chromosome (SRY gene expression) in males, on athletic performance across all ages. Last, females are underrepresented as participants in biomedical research, which has led to a historical dearth of information on the mechanisms for sex differences in human physical performance and the capabilities of the female body. Collectively, greater effort and resources are needed to address the hormonal mechanisms for biological sex differences in human athletic performance before and after puberty.

(192) Evaluating Effect of hCG and hCG+rFSH Therapy on Ejaculation Disorders in Middle-Aged Men: A Case Study

Abstract Introduction The prevalence of various ejaculation disorders affecting middle-aged and older men has gained increasing attention due to their significant impact on quality of life. One of them, Late-Onset Hypogonadism (LOH) syndrome, can result in a decline in overall well-being. Testosterone replacement therapy (TRT) is commonly used to address LOH; however, it presents challenges such as diminishing endogenous testosterone secretion and incomplete symptom relief. Objective This study aimed to investigate the effects of human chorionic gonadotropin (hCG) or hCG plus recombinant follicle-stimulating hormone (rFSH) therapy in patients experiencing ejaculation disorders characterized by low semen volume and decreased pleasure during ejaculation. Methods Four male patients, aged 55 to 59 years, complaining of decreased ejaculatory pleasure and low semen volume, were enrolled in the study. One patient received hCG+rFSH therapy, while three patients received hCG alone. The initial dose of hCG was 5,000 units administered twice a week, and if deemed insufficient, it was increased to three times a week. rFSH was administered at a dosage of 150 units three times a week. Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and estradiol (E2) were measured monthly. Anastrozole (1 mg) was added for patients exhibiting elevated E2 levels. Results Case 1: A 58-year-old male. Prior to treatment, testosterone and E2 levels were 4.84 ng/mL and 34.2 pg/mL, respectively. hCG+rFSH therapy resulted in increased testosterone levels (10.2 ng/mL) and elevated E2 levels (109.0 pg/mL) after three months of treatment. Addition of anastrozole resulted in testosterone levels of 10.90 ng/mL and E2 levels of 57.9 pg/mL in the following month. The patient experienced improved sexual desire, increased semen volume, and hair loss as a side effect. Treatment was discontinued after six months. Case 2: A 57-year-old male with diabetes mellitus. Pre-treatment testosterone and E2 levels were 2.19 ng-mL and 21.9 pg/mL, respectively. After changing the hCG dosage to 5,000 units three times a week, testosterone levels reached 5.33 ng/mL and E2 levels increased to 72.8 pg/mL after two months. With the addition of anastrozole four months into treatment, E2 levels were 44.4 pg/mL after five months. The patient reported improved morning erections, increased libido, increased semen volume, and improved glycemic control (HbA1c decreased from 9.0 to 7.0). Case 3: A 55-year-old male. Pre-treatment testosterone and E2 levels were 4.99 ng/mL and 32.3 pg/mL, respectively. In the first month of hCG therapy, testosterone levels increased to 13.6 ng/mL, while E2 levels rose to 75.5 pg/mL. Then, despite testosterone remaining in the 9.0–10.0 ng/mL range, E2 levels increased to 100 pg/mL. With the addition of anastrozole in the fifth month, the patient reported increased semen volume thereafter. Case 4: A 59-year-old male with a history of bipolar disorder. Prior to treatment, testosterone and E2 levels were 2.45 ng/mL and 23.0 pg/mL, respectively. hCG therapy resulted in testosterone levels of 6.71 ng/ml and E2 levels of 51.0 pg/mL after two months. Conclusions This case study highlights the outcomes of hCG or hCG+rFSH therapy in middle-aged men experiencing ejaculation disorders. Disclosure No.

Association of Endogenous Testosterone with Physical Fitness Measures during Firefighter Occupational Health Evaluations.

Firefighting is a physically demanding profession associated with unacceptably high on-duty cardiovascular mortality. Low endogenous total testosterone (TT) is an emerging cardiometabolic (CM) risk factor in men, but limited data exists on its interactions with physical fitness (PF). Data from occupational health and fitness assessments of 301 male career firefighters (FFs) were analyzed. TT was categorized as low (<264 ng/dL), borderline (264-399 ng/dL), and reference (400-916 ng/dL). PF tests included cardiorespiratory fitness (submaximal treadmill), body fat percentage (BF%), push-ups, plank, and handgrip strength assessments. In the crude analyses, FFs in the low TT group had worse muscular and cardiorespiratory fitness measures compared to the referent group. However, after adjusting for age and BF%, none of the PF differences remained statistically significant. Similarly, the odds of less-fit FFs (PF performance below median values) having low TT were higher compared to the fitter ones only before adjusting for age and BF%. Therefore, in the final adjusted model, there was no significant association between TT and PF. Our data suggest that age and body fat confound the association between PF and TT. Low TT and poor PF are important components of FFs' CM risk profile, and there is potential benefit to considering TT screening as part of a comprehensive occupational health program that manages performing medical evaluations and provides education and preventative programming.

Higher testosterone is associated with higher HDL-cholesterol and lower triglyceride concentrations in older women: an observational study

Objective This study aimed to determine whether concentrations of testosterone and its main precursor after menopause, dehydroepiandrosterone (DHEA), are associated with lipoproteins and other lipids in community-dwelling older women. Methods The Sex Hormones in Older Women (SHOW) study was an observational study of 6358 Australian women, aged at least 70 years, with no prior major adverse cardiovascular event who had sex hormones measured by liquid chromatography–tandem mass spectrometry. Associations between hormones and lipids were examined using multilinear regression adjusted for potential confounders. Results The cross-sectional analyses included 3231 participants, median age 74.0 (interquartile range 71.7–77.9) years. Compared with concentrations in the lowest quartile (Q1), testosterone concentrations in the highest quartiles (Q3 and Q4) were positively associated with high-density lipoprotein cholesterol (HDL-C) (p = 0.002 and p < 0.001, respectively) while Q4 testosterone concentrations were positively associated with total cholesterol (p = 0.038). Q2, Q3 and Q4 testosterone concentrations were significantly inversely associated with triglycerides (TG) (p = 0.024, p = 0.003 and p < 0.001, respectively). For DHEA, Q4 concentrations was positively associated with non-HDL-C (p = 0.024). Conclusions In older women, higher endogenous testosterone concentrations are significantly associated with higher HDL-C and lower TG, indicating a less atherogenic profile. These findings suggest a neutral, or potentially protective, cardiovascular disease effect of testosterone in older women.

The injectable contraceptives depot medroxyprogesterone acetate and norethisterone enanthate substantially and differentially decrease testosterone and sex hormone binding globulin levels: A secondary study from the WHICH randomized clinical trial.

HIV acquisition risk with norethisterone (NET) enanthate (NET-EN) is reportedly less than for depo-medroxyprogesterone acetate intramuscular (DMPA-IM). We investigated the effects of these progestin-only injectable contraceptives on serum testosterone and sex hormone binding globulin (SHBG) levels, since these may play a role in sexual behavior and HIV acquisition. The open-label WHICH clinical trial, conducted at two sites in South Africa from 2018-2019, randomized HIV-negative women aged 18-40 years to 150 mg DMPA-IM 12-weekly (n = 262) or 200 mg NET-EN 8-weekly (n = 259). We measured testosterone by UHPLC-MS/MS and SHBG by immunoassay in matched pairs of serum samples collected at baseline (D0) and at peak serum progestin levels at 25 weeks post initiation (25W) (n = 214-218 pairs). Both contraceptives substantially decreased, from D0 to 25W, the total testosterone [DMPA-IM D0 0.560, 25W 0.423 nmol/L, -24.3% (p < 0.0001); NET-EN D0 0.551, 25W 0.253 nmol/L, -54.1%, (p < 0.0001)], SHBG [DMPA-IM D0 45.0, 25W 32.7 nmol/L, -29.8% (p < 0.0001); NET-EN D0 50.2, 25W 17.6 nmol/L, -65.1% (p < 0.0001)], and calculated free testosterone levels [DMPA-IM D0 6.87, 25W 5.38 pmol/L, -17.2% (p = 0.0371); NET-EN D0 6.00, 25W 3.70, -40.0% (p < 0.0001)]. After adjusting for change from D0, the total testosterone, SHBG and calculated free testosterone levels were significantly higher for DMPA-IM than NET-EN (64.9%, p < 0.0001; 101.2%, p < 0.0001; and 38.0%, p = 0.0120, respectively). The substantial and differential decrease in testosterone and SHBG levels does not explain our previous finding of no detected decrease in risky sexual behavior or sexual function for DMPA-IM or NET-EN users from D0 to 25W. Medroxyprogesterone (MPA) and NET are androgenic and are both present in molar excess over testosterone and SHBG concentrations at 25W. Any within or between contraceptive group androgenic effects on behavior in the brain are likely dominated by the androgenic activities of MPA and NET and not by the decreased endogenous testosterone levels. The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976).