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Background: Inter‐assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain. Design: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. Results: Evidence‐based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. Conclusions: This article aims to improve the quality of the interpretation of testosterone results by non‐specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems. [ABSTRACT FROM AUTHOR]

Background: Apo A‐I Leu75Pro amyloidosis is a rare systemic hereditary disease, whose hallmark and earliest involvement is testicular impairment, characterized by hypogonadism and macrorchidism; renal and hepatic involvement are the other characteristics. Objective: To evaluate for the first time the prevalence of osteopenia, osteoporosis and vertebral fractures (VFs) in men with this form of amyloidosis affected by hypogonadism and under long‐term testosterone replacement therapy (TRT). Materials and methods: Retrospective study on 50 men >50 years (median age 64.5) with dual‐energy X‐ray absorptiometry (DXA), hormonal, and biochemical data available at least 3 years after the start of TRT. Serum gonadal hormones and bone markers, lumbar and femoral DXA‐scan with morphometric assay for evaluation of VFs were assessed. Results: At 7.5 years from start of TRT, lumbar and/or femoral osteopenia and osteoporosis were found in 54% and 10% of patients, respectively. Of the men who had the morphometric assay performed, five of 34 (14.7%) had VFs. Compared to patients with normal bone mineral density, men with osteopenia and osteoporosis were older, had lower body mass index, higher sex hormone binding globulin and showed more frequently renal involvement. Multiorgan involvement, without different TRT dosage, was associated with lower testosterone levels. Discussion and conclusion: Men with hypogonadism because of Apo A‐I Leu75Pro amyloidosis under long‐term TRT had a high burden of low bone mass (64%) and VFs (almost 15%). Osteopenia‐osteoporosis was more frequently observed in older patients with multi‐organ disease, which might contribute to impair bone health beyond hypogonadism. [ABSTRACT FROM AUTHOR]

Background: Hypogonadism is a worldwide problem among men causing sexual, physical and mental problems. Testosterone therapy is the first‐choice treatment for male hypogonadism, with several side effects, that is, subfertility. Clomiphene citrate (CC) is an alternative off‐label therapy for a certain group of hypogonadal males, especially for those with an active or future child wish. There is scarce literature in usage of CC for men with hypogonadism. The aim of this retrospective study was to evaluate the effectiveness and safety of CC for hypogonadal males. Methods: In this single‐centre study, men treated with CC for hypogonadism were evaluated retrospectively. Primary outcome was hormonal evaluation including total testosterone (TT), free testosterone (FT), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Secondary outcomes were hypogonadal symptoms, metabolic and lipid parameters, haemoglobin (Hb), haematocrit (Ht), prostate specific antigen (PSA), side effects, the effect of a trial without medication and potential predictors for biochemical and clinical response. Results: In total, 153 hypogonadal men were treated with CC. Mean TT, FT, LH and FSH increased during treatment. TT increased from 9 to 16 nmol/L, with a biochemical increase in 89% of the patients. In patients who continued CC treatment, an increased level of TT persisted after 8 years of treatment. With CC treatment, 74% of the patients experienced hypogonadal symptom improvement. LH at the lower normal range before CC treatment was predictive for better TT response. During CC therapy, few side effects were reported and no clinical important changes in PSA, Hb and Ht were found. Conclusion: Clomiphene citrate is an effective therapy on short and long term, improving both clinical symptoms and biochemical markers of male hypogonadism with few side effects and good safety aspects. [ABSTRACT FROM AUTHOR]

Sexual dysfunction, which is defined as 'difficulty during any stage of the sexual encounter that prevents or impairs the individual or couple from enjoying sexual activity', is globally prevalent in males with prediabetes and diabetes. It is an early harbinger of cardiovascular diseases and has a profound impact on one's physical, mental, and social health. Among patients with either prediabetes or diabetes, the most common male sexual dysfunctions are hypogonadism, erectile dysfunction, and premature ejaculation. In Asia, although sexual health is an important factor of men's health, it is rarely discussed freely in real‐life practice. Addressing sexual health in Asian males has always been challenging with multiple barriers at the levels of patients and health care providers. Therefore, the assessment and management of sexual dysfunction in routine clinical practice should involve a holistic approach with effective patient–provider communication. In this review, we discuss the epidemiology, pathophysiology, and the management of hypogonadism, erectile dysfunction, and premature ejaculation among males with either prediabetes or diabetes (type 1 and type 2), as well as the evidence gaps across Asia. [ABSTRACT FROM AUTHOR]

Objective: Men with male hypogonadism (MH) experience sexual dysfunction, which improves with testosterone replacement therapy (TRT). However, randomised controlled trials provide little consensus on functional and behavioural symptoms in hypogonadal men; these are often better captured by qualitative information from individual patient experience. Methods: We systematically searched major electronic databases to identify qualitative data from men with hypogonadism, with or without TRT. Two independent authors performed the selection, extraction, and thematic analysis of data. Quality of eligible studies was assessed using the Critical Appraisals Skills Programme and Grading of Recommendations Assessment, Development and Evaluation‐Confidence in the Evidence from Reviews of Qualitative research tools. Results: We analysed data from five studies published in nine reports that assessed a total of 284 participants. Published data were only available within North America, with no ethnic minority or other underserved groups included. In addition to sexual dysfunction, men with MH experienced adverse changes in physical strength, perceptions of masculinity, cognitive function, and quality of life. The experience of MH appeared dependent on the source(s) of educational material. Discussion: We propose a patient‐centred approach to clinician interactions rather than focusing on discreet MH symptoms. Current evidence about the experience of MH is limited to North America and predominantly white ethnicity, which may not be broadly applicable to other geographic regions. Broadening our understanding of the MH experience may improve the targeting of information to patients. In addition, a multidisciplinary approach may better address symptoms neither attributable to MH nor alleviated by TRT. [ABSTRACT FROM AUTHOR]

Background: Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first‐choice therapy, with several side effects, including negative feedback of the hypothalamic–pituitary–gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism, clomiphene citrate is used as off‐label therapy. This systematic review and meta‐analysis aimed to evaluate the effectiveness and safety of clomiphene citrate therapy for men with hypogonadism. Methods: The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with clomiphene citrate. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument, was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic and lipid profile, side effects, safety aspects. Results: We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta‐analysis, with a total of 1279 patients. Therapy and follow‐up duration varied between one and a half and 52 months. Total testosterone increased with 2.60 (95% CI 1.82–3.38) during clomiphene citrate treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone‐binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males questionnaire, whose improved during treatment. Reported side effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported. Conclusion: Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. Clomiphene citrate has few reported side effects and good safety aspects. [ABSTRACT FROM AUTHOR]

Background: Obesity in men is also shown to be associated with reduced reproductive potential, and this particular subtype was described as male obesity‐associated secondary hypogonadism (MOSH). Recent studies showing the influence of sleep disorders on testosterone levels suggested a potential role of sleep disorders in determining the development of MOSH. Objectives: To assess the association between night‐time sleep duration and day napping and the prevalence of MOSH. Materials and methods: In this cross‐sectional study, 226 obese male participants aged 18–30 years were enrolled. Daytime napping and night‐time sleep duration data were collected using a standardized self‐reported Chinese‐language questionnaire. MOSH was defined as obese men (BMI ≥ 30 kg/m2) with hypogonadal symptoms and decreased total testosterone level and/or free testosterone level, excluding other causes of hypogonadism. Results: The overall prevalence of MOSH was 48.2% in this study. An inverse association was observed between night sleep duration and the risk of prevalent MOSH. Men who reported fewer than 6 h of night‐time sleep had reduced total testosterone and free testosterone levels and an increased risk of MOSH. Further regression analysis revealed that after adjustment for potential confounders, the odds ratio of MOSH for the short night‐time sleep group (<6 h vs. 6–8 h) was 6.17 (p = 0.040). No significant association was observed between day napping status and prevalence of MOSH. Discussion and conclusion: Short night sleep duration was associated with an increased risk of MOSH in the young obese Chinese population. Chronic sleep curtailment has a negative effect on obese men's health in terms of hypogonadism. [ABSTRACT FROM AUTHOR]

Background: Hypogonadism associated with cancer is reported to cause cachexia and a variety of physical and psychological symptoms. This study aims to evaluate whether androgen replacement therapy can improve cancer‐related symptoms in male advanced cancer patients. Methods: An investigator‐initiated, prospective, and randomized controlled study was conducted. Patients with low serum testosterone levels (total or free testosterone levels were <2.31 ng/mL or <11.8 pg/mL, respectively) were randomly assigned to the control or testosterone enanthate administration (testosterone group) groups. Testosterone enanthate was injected into the muscle tissue at a dose of 250 mg every 4 weeks (baseline, week 4, and week 8). Differences in quality of life questionnaires and cachexia‐related serum protein levels between groups were assessed. Results: This study enrolled and randomized 106 and 81 patients, respectively. Moreover, 41 and 40 patients were in the control and testosterone groups, respectively. Although no significant differences in the change of subscales and total scores in Functional Assessment of Anorexia/Cachexia Treatment were noted from the baseline between the two groups, the testosterone group showed a significantly better change in the 'unhappiness' item of the Edmonton Symptom Assessment System at week 12 compared with baseline versus the control group (−1.4 and 0.0 points, respectively; mean, P = 0.007). No significant differences exist in the change of serum interleukin‐6 and insulin‐like growth factor‐1 levels at week 12 from the baseline between the control and testosterone groups. Consequently, the testosterone group significantly inhibited the change in serum tumour necrotic factor‐α level at week 12 from the baseline compared with the control group (+0.4 and +0.1 pg/mL, respectively; mean, P = 0.005). Conclusions: Although testosterone enanthate did not improve most of the items in health‐related quality of life questionnaires, testosterone enanthate induced a significantly better change in the 'unhappiness' item at week 12 compared with the control. Testosterone enanthate may be a potential treatment option for male advanced cancer patients. [ABSTRACT FROM AUTHOR]

Keywords: androgen deficiency; male hypogonadism; testosterone EN androgen deficiency male hypogonadism testosterone 396 397 2 09/12/23 20231001 NES 231001 As for any other endocrine condition, the diagnosis of male hypogonadism follows a three-step process, starting with a clinical suspicion, followed by biochemical confirmation and then localisation of the disease (i.e., confirming the underlying aetiology). While the clinician may thus by these simple measures reduce the effects of biologic variability on serum testosterone measurements, variability due to assay methodology depends on the local availability of testosterone assays. Towards optimising diagnosis and management of male hypogonadism: Commentary on CEN-2023-000285 "Standardising the biochemical confirmation of adult male hypogonadism; a joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine". [Extracted from the article]

Background: The novel severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) disease 2019 (COVID‐19) seems to have a worse clinical course among infected men compared with women, thus highlighting concerns about gender predisposition to serious prognosis. Therefore, androgens, particularly testosterone (T), could be suspected as playing a critical role in driving this excess of risk. However, gonadal function in critically ill men is actually unknown, mainly because serum T concentration is not routinely measured in clinical practice, even more in this clinical context. Objective: To overview on possible mechanisms by which serum T levels could affect the progression of COVID‐19 in men. Methods: Authors searched PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library, Google, and institutional websites for medical subject headings terms and free text words referred to "SARS‐CoV‐2," "COVID‐19," "testosterone," "male hypogonadism," "gender" "immune system," "obesity," "thrombosis" until May 19th 2020. Results: T, co‐regulating the expression of angiotensin‐converting enzyme 2 and transmembrane protease serine 2 in host cells, may facilitate SARS‐CoV‐2 internalization. Instead, low serum T levels may predispose to endothelial dysfunction, thrombosis and defective immune response, leading to both impaired viral clearance and systemic inflammation. Obesity, one of the leading causes of severe prognosis in infected patients, is strictly associated with functional hypogonadism, and may consistently strengthen the aforementioned alterations, ultimately predisposing to serious respiratory and systemic consequences. Discussion and conclusion: T in comparison to estrogen may predispose men to a widespread COVID‐19 infection. Low serum levels of T, which should be supposed to characterize the hormonal milieu in seriously ill individuals, may predispose men, especially elderly men, to poor prognosis or death. Further studies are needed to confirm these pathophysiological assumptions and to promptly identify adequate therapeutic strategies. [ABSTRACT FROM AUTHOR]

In the past few years, Leydig cell (LC) transplantation has been regarded as an effective strategy for providing physiological patterns of testosterone in vivo. Recently, we have successfully converted human foreskin fibroblasts (HFFs) into functional Leydig‐like cells (iLCs) in vitro by using the CRISPR/dCas9 system, which shows promising potential for seed cells. However, it is not known whether the reprogrammed iLCs can survive or restore serum testosterone levels in vivo. Therefore, in this study, we evaluate whether reprogrammed iLCs can restore the serum testosterone levels of castrated rats when they are transplanted into the fibrous capsule. We first developed the castrated Sprague Dawley rat model through bilateral orchiectomy and subsequently injected extracellular matrix gel containing transplanted cells into the fibrous capsule of castrated rats. Finally, we evaluated dynamic serum levels of testosterone and luteinizing hormone (LH) in castrated rats, the survival of implanted iLCs, and the expression levels of Leydig steroidogenic enzymes by immunofluorescence staining and Western blotting. Our results demonstrated that implanted iLCs could partially restore the serum testosterone level of castrated rats, weakly mimic the role of adult Leydig cells in the hypothalamic‐pituitary‐gonadal axis for a short period, and survive and secrete testosterone, through 6 weeks after transplantation. Therefore, this study may be valuable for treating male hypogonadism in the future. [ABSTRACT FROM AUTHOR]

Aim: It is challenging to evaluate reproductive potential during childhood. These challenges necessitate the use of invasive dynamic tests. Although the anti-Mullerian hormone (AMH) is a reliable biomarker in evaluating testicular function, especially in the pre-pubertal period, there are uncertainties concerning its use in a clinical setting. This study is focused on comparing the AMH and human chorionic gonadotropin (hCG) test in boys with hypogonadism.Methods: A total of 160 boys aged between 0 and 18 years who presented with complaints associated with hypogonadism were prospectively enrolled in the study. All children were assigned to the following five groups: gonadal disorders (n = 34), androgen synthesis and end organ effect disorder (n = 48), isolated genital malformation disorders (n = 57), hypogonadotropic hypogonadism (n = 15) and constitutional delayed puberty (n = 6). All children underwent a short 3-day hCG test (1500 U/m2 /day). The concordance and correlation were evaluated between the hCG test and AMH.Results: All groups exhibited a strong correlation (r160 = 0.689) and strong concordance (Kappa coefficient160 = 0.7) between the AMH and hCG test. Values of AMH higher than 32.7 pmol/L and hCG responses higher than 86 pmol/L were significant as indicative markers of functional testicular tissue presence.Conclusions: This study has shown that there is a strong correlation between the AMH and short-term hCG test and that values of AMH higher than 32.7 pmol/L and stimulated testosterone higher than 86 pmol/L can be used as indicators of functionally sufficient testicular tissue. These results indicate that AMH value can be used as a reliable and useful biomarker in the evaluation of the testicular function in 46 XY hypogonadism. [ABSTRACT FROM AUTHOR]

Recently, Leydig cell (LC) transplantation has been revealed as a promising strategy for treating male hypogonadism; however, the key problem restricting the application of LC transplantation is a severe lack of seed cells. It seems that targeted activation of endogenous genes may provide a potential alternative. Therefore, the aim of this study was to determine whether targeted activation of Nr5a1, Gata4 and Dmrt1 (NGD) via the CRISPR/dCas9 synergistic activation mediator system could convert human foreskin fibroblasts (HFFs) into functional Leydig‐like cells. We first constructed the stable Hsd3b‐dCas9‐MPH‐HFF cell line using the Hsd3b‐EGFP, dCas9‐VP64 and MS2‐P65‐HSF1 lentiviral vectors and then infected it with single guide RNAs. Next, we evaluated the reprogrammed cells for their reprogramming efficiency, testosterone production characteristics and expression levels of Leydig steroidogenic markers by quantitative real‐time polymerase chain reaction or Western blotting. Our results showed that the reprogramming efficiency was close to 10% and that the reprogrammed Leydig‐like cells secreted testosterone rapidly and, more importantly, responded effectively to stimulation with human chorionic gonadotropin and expressed Leydig steroidogenic markers. Our findings demonstrate that simultaneous targeted activation of the endogenous NGD genes directly reprograms HFFs into functional Leydig‐like cells, providing an innovative technology that may have promising potential for the treatment of male androgen deficiency diseases. [ABSTRACT FROM AUTHOR]

US Endocrine Society (ES) published a clinical practice guideline on testosterone therapy in men with hypogonadism, and Endocrine Society of Australia (ESA) a position statement on management of male hypogonadism. Both emphasize the importance of diagnosing men who are androgen deficient due to organic (classical or pathological) hypogonadism arising from disorders of the hypothalamus, pituitary or testes, who assuredly benefit from testosterone therapy. Both recognize that men with an intact gonadal axis may have low testosterone concentrations, for instance older men or men with obesity or other medical comorbidities. ES guidelines classify such symptomatic men as having organic (advanced age) or functional (obesity, medical comorbidities) hypogonadism, giving an option for testosterone therapy as a shared decision between clinicians and individual patients. ESA did not recommend testosterone therapy in these men. ES offers a reference range for total testosterone established in young men, while ESA cites age‐standardized reference ranges. ES recommends using free testosterone as well as total testosterone to identify men with hypogonadism in conditions where sex hormone‐binding globulin (SHBG) is altered, or when total testosterone is borderline. ESA recommends confirmatory biochemical testing with total testosterone, recognizing that this may be lower than expected if SHBG concentrations are low. Both emphasize the importance of identifying pre‐existing prostate and cardiovascular disease prior to initiating testosterone therapy, with ES providing specific recommendations for PSA measurement, deferring testosterone therapy after major cardiovascular events and indications for pituitary imaging. These contrasting approaches highlight gaps in the evidence base where individualized patient management is required. [ABSTRACT FROM AUTHOR]

The purpose of the study was to evaluate whether testosterone replacement therapy improves muscle mechanical and physical function in addition to increasing lean leg mass and total lean body mass in aging men with type 2 diabetes and lowered bio-available testosterone (BioT) levels. Thirty-nine men aged 50-70 years with type 2 diabetes and BioT levels <7.3 nmol/L were included from an academic tertiary-care medical center. Patients were randomized to testosterone gel (testosterone replacement therapy, n = 20) or placebo ( n = 19) for 24 weeks, applying a double-blinded design. Muscle mechanical function was assessed by Nottingham Leg Rig (leg extension power) and isokinetic dynamometry (knee extensor maximal isometric contraction, rate of force development (RFD100), maximal dynamic contraction (Dyn180)). Physical function was assessed by gait speed. Body composition was assessed by whole body dual-energy X-ray absorptiometry (total lean body mass, lean leg mass, total fat mass, leg fat mass). Levels of total testosterone (TotalT), BioT, free testosterone (FreeT), and sex hormone-binding globulin were measured from fasting blood samples. Coefficients ( b) represent the placebo-controlled mean effect of intervention. Maximal isometric contraction ( b = 18.4 Nm, p = 0.039), RFD100 ( b = 195.0 Nm/s, p = 0.017) and Dyn180 ( b = 10.2 Nm, p = 0.019) increased during testosterone replacement therapy compared with placebo. No changes were observed in leg power or gait speed. Total lean body mass ( b = 1.9 kg, p = 0.001) and lean leg mass ( b = 0.5 kg, p < 0.001) increased, while total fat mass ( b = −1.3 kg, p = 0.009) and leg fat mass ( b = −0.7 kg, p = 0.025) decreased during testosterone replacement therapy compared with placebo. Total T ( b = 14.5 nmol/L, p = 0.056), BioT ( b = 7.6 nmol/L, p = 0.046), and FreeT ( b = 0.32 nmol/L, p = 0.046) increased during testosterone replacement therapy compared with placebo, while sex hormone-binding globulin ( n = −2 nmol/L, p = 0.030) decreased. Knee extensor muscle mechanical function was preserved, and body composition improved substantially during testosterone replacement therapy for 24 weeks compared with placebo, whereas physical function (gait speed) was unchanged in aging men with type 2 diabetes and lowered BioT levels. [ABSTRACT FROM AUTHOR]

Aims To evaluate the effect of testosterone replacement therapy (TRT) on body composition, insulin sensitivity, oxidative metabolism and glycaemic control in aging men with lowered bioavailable testosterone (BioT) levels and type 2 diabetes mellitus (T2D) controlled on metformin monotherapy. Materials and methods We conducted a randomized, double-blind, placebo-controlled study in 39 men aged 50-70 years with BioT levels <7.3 nmol/L and T2D treated with metformin monotherapy. Patients were randomized to testosterone gel (TRT, n = 20) or placebo (n = 19) for 24 weeks. Lean body mass (LBM), total and regional fat mass were measured using whole-body dual-energy X-ray absorptiometry scans. Whole-body peripheral insulin sensitivity, endogenous glucose production (EGP) and substrate oxidation were assessed by euglycaemic-hyperinsulinaemic clamp with glucose tracer and combined with indirect calorimetry. Coefficients (β) represent the placebo-controlled mean effect of intervention. Results LBM (β = 1.9 kg, p = 0.001) increased after TRT, while total fat mass (β = −1.3 kg, p = 0.009), fat mass trunk (β = −0.7 kg, p = 0.043), fat mass legs (β = −0.7 kg, p = 0.025), fat mass arms (β = −0.3 kg, p = 0.001), and HDL cholesterol (β = −0.11 mmol/L, p = 0.009) decreased after TRT compared with placebo. Insulin-stimulated glucose disposal rates did not change in response to TRT compared with placebo (p = 0.18). Moreover, glycated haemoglobin, and basal and insulin-stimulated rates of EGP, lipid- and glucose-oxidation were unaltered after TRT. Conclusion TRT in aging men with lowered BioT levels and T2D controlled on metformin monotherapy improved body composition; however, glycaemic control, peripheral insulin sensitivity, EGP and substrate metabolism were unchanged. [ABSTRACT FROM AUTHOR]

Pharmacokinetics, pharmacodynamics and safety of a novel hydroalcoholic testosterone gel 2% ( TG) were evaluated in phase II sequential dose escalation studies using 3 application sites (thigh, abdomen and shoulder/upper arm) and 2 application methods. Hypogonadal men ( n = 40), 18-75 years, with serum testosterone <300 ng dl−1 were included in both studies. Study 1 evaluated hand-applied multiple doses of TG 1.25, 2.50 and 3.75 ml (23, 46 and 70 mg of testosterone, respectively), once daily for 10 days to shoulder/upper arm. Study 2 evaluated applicator-applied ( TG 1.25, 2.50 and 3.75 ml) versus hand-applied ( TG 2.5 ml) doses, once daily for 7 days to shoulder/upper arm. Primary endpoint for both studies was responder rate (Cave testosterone levels between 298 and 1050 ng dl−1). In Study 1 following multiple applications, >70% participants in each group were responders. Dose-dependent increase was observed in PK values for total testosterone, free testosterone and DHT. In Study 2, responder rate was dose proportional: 16.7%, 50.0% and 77.8% responders in TG 1.25, 2.50 and 3.75 ml groups respectively. The bioavailability was highest for the shoulder application. There was a significant improvement in almost all the domains of sexual functioning. Applicator-application was preferred over hand-application by majority of the participants. TG was found to be safe and well tolerated in hypogonadal men. [ABSTRACT FROM AUTHOR]

To study the prevalence of male obesity-secondary hypogonadism ( MOSH) in patients with moderate to severe obesity, we performed a prospective prevalence study including 100 male patients with moderate to severe obesity at a university tertiary hospital. Total testosterone ( TT) and sex hormone-binding globulin ( SHBG) concentrations among others were assayed in all patients. Serum-free testosterone ( FT) concentration was calculated from TT and SHBG levels. Semen analysis was conducted in 31 patients. We found a prevalence of 45% (95% CI: 35-55%) when considering decreased TT and/or FT concentrations. Serum concentrations of TT were correlated negatively with glucose ( r = −0.328, p < 0.001) and insulin resistance ( r = −0.261, p = 0.011). The same occurred with FT and glucose ( r = −0.340, p < 0.001) and insulin resistance ( r = −0.246, p = 0.016). Sixty-two percent (95% CI: 39-85%) of the patients with seminogram also presented abnormal results in semen analysis. The frequencies of low TT or low FT values were similar in patients with abnormal or normal semen analysis ( p = 0.646 and p = 0.346, respectively). Ejaculate volume inversely correlated with BMI (ρ = −0.400, p = 0.029) and with excess body weight (ρ = −0.464, p = 0.010). Our data show the prevalence of MOSH in patients with moderate to severe obesity is high. Low circulating testosterone is associated with insulin resistance and low ejaculate volume with higher BMI and excess body weight. Semen analysis must be performed in these patients when considering fertility whether or not presenting low circulating testosterone. [ABSTRACT FROM AUTHOR]

We compared a novel 5% testosterone (T) cream (AndroForte 5, Lawley Pharmaceuticals, Australia) with a 1% T gel (Testogel, Besins Healthcare, Australia). Using an open-label crossover design, subjects were randomized to one of two treatment sequences using either the T gel or T cream first in a 1 : 1 ratio. Each treatment period was 30 days with a 7-14 days washout period between them. On Days 1 and 30 of each treatment period blood was sampled at −15, −5 min, 0, 2, 4, 5, 6, 7, 8, 9, 10, 12 and 16 h post study drug administration. Sixteen men with established androgen deficiency aged between 29 and 73 years, who had undertaken a washout from prior testosterone therapy participated in the study. One subject failed to complete both arms and another was excluded post-completion because of a major protocol violation. Bioequivalence was established based on key pharmacokinetic ( PK) variables: AUC, Cavg, Cmax, Tmax, % fluctuation (with and without baseline correction) for the two formulations of testosterone on Day 1 and Day 30. The ratio and 90% CI of AUC 0.99 (0.86-1.14), Cmax 1.02 (0.84-1.24) and Cavg 0.99 (0.86-1.14) for T cream/T gel were within the predetermined bio-equivalence criteria of 80% to 125% at Day 30. There were no statistically significant differences between secondary biochemical markers: serum dihydrotestosterone ( DHT), oestradiol (E2), sex hormone-binding globulin ( SHBG), luteinizing hormone ( LH) and ( FSH). The two testosterone formulations were shown to be bioequivalent. [ABSTRACT FROM AUTHOR]

The role of androgens in cardiovascular disease is still controversial in men. In this study, we investigated metabolic disorders in Tunisian hypogonadal men compared with healthy controls. Forty hypogonadal men and 80 control subjects were enrolled. Patients with a history of pre-existing panhypopituitarism, thyroid dysfunction or inflammatory disease were excluded. Glycaemia, glycated haemoglobin (HbA1c), high-sensitive C-reactive protein (hs CRP), lipid profile, insulin, testosterone and gonadotrophins were measured. Insulin resistance was assessed by homoeostasis model assessment of insulin resistance (Homa IR). Waist circumference, body mass index and blood pressure were significantly higher in patients compared with controls. Glycemia, HbA1c, fasting serum insulin and Homa IR were significantly increased among hypogonadal men. In univariate analysis, testosterone levels were inversely correlated with body mass index, waist circumference, blood pressure, glycaemia, HbA1C, insulin, Homa IR and hs CRP. In multivariate analysis including all significant variables, initial testosterone level was the only independent risk factor for developing dyslipidaemia. With logistic regression, male hypogonadism was an independent risk factor for MS ( P < 0.001). We conclude that low testosterone level plays a central role in the development of metabolic syndrome. Further prospective data are required to establish the causative link. [ABSTRACT FROM AUTHOR]

Men with human immunodeficiency virus ( HIV) infection are often hypogonadal and develop several HIV-associated non-acquired immunodeficiency syndrome ( AIDS) ( HANA) conditions that impair overall health status. No studies explored the relationship between health status and serum testosterone (T) in HIV-infected men. This study aims to investigate the association between total serum T and HANA, multimorbidity, and frailty in a large cohort of 1359 HIV-infected men and to explore the relationship between patients' overall health status and serum T. Among biochemical and hormonal measurement performed the main are serum total T, free triiodothyronine (fT3), and luteinizing hormone. Other outcome measurements include anthropometry, assessment of comorbidities and disabilities, overall health status defined as the number of HANA and by the 38-item multimorbidity frailty index, anthropometry, and bone mineral density. The cumulative relative risk of comorbidities is increased in HIV-infected men with hypogonadism ( p < 0.001) and hypogonadism is associated with several comorbidities. The prevalence of hypogonadism increases progressively with the increase of the number of comorbidities. Frailty index is inversely related to serum total T (age-adjusted r = 0.298, r2 = 0.089, p < 0.0001). Serum fT3 levels are significantly lower in hypogonadal than eugonadal men ( p = 0.022). This suggests that low serum T could be considered a sensitive marker of frailty and poor health status and that the latter might induce hypogonadism. The more HIV-infected men are frail the more they are hypogonadal. This suggests that hypogonadism might be a naturally occurring condition in unhealthy HIV-infected men and raises concern about the safety of T treatment. In conclusion, low serum T is associated with multimorbidity, HANA, and frailty in HIV-infected men and this association seems to be bidirectional. Given the wide attitude to offer T treatment to HIV-infected men, caution is needed when prescribing T to HIV-infected male patients, especially if the patient is unhealthy or frail. [ABSTRACT FROM AUTHOR]

There is a wide variability in the clinical presentation of Klinefelter's syndrome. We report the case of a 45-year-old man who was incidentally diagnosed a 47, XXY/46, XY karyotype in a bone marrow aspiration (case 1). He presented hypogonadic features with undetectable testosterone levels and a height in accordance with mid-parental height. He had a monozygous sibling (case 2) who did not show clinical signs of hypogonadism and whose height exceeded mid-parental height. Both patients had presented language disorders since childhood. The karyotype of lymphocytes in peripheral blood of both subjects was compatible with mosaic Klinefelter's syndrome (46, XY/47, XXY). Testosterone replacement was initiated in case 1. Lack of testicular involvement due to mosaicism and the overexpression of the SHOX gene in case 2 could explain the marked differences in phenotype in these homozygous twins. [ABSTRACT FROM AUTHOR]

The objective of this review was to summarize the literature on the risk factors, comorbidities, and consequences of male hypogonadism, which is defined as a syndrome complex that includes biochemical confirmation of low testosterone (T) and the consistent symptoms and signs associated with low T. A systematic literature search was performed in PubMed/ MEDLINE, EMBASE, Cochrane Library for articles published in the last 10 years on risk factors, comorbidities, and consequences of male hypogonadism. Of the 53 relevant studies identified, nine examined potential risk factors, 14 examined potential comorbidities, and 30 examined potential consequences of male hypogonadism. Based on studies conducted in Asia, Australia, Europe, and North & South America, the important factors that predicted and correlated with hypogonadism were advanced age, obesity, a diagnosis of metabolic syndrome (MetS), and a poor general health status. Diabetes mellitus was correlated with hypogonadism in most studies, but was not established as a risk factor. Although diseases, such as coronary heart disease, hypertension, stroke, and peripheral arterial disease did not predict hypogonadism, they did correlate with incident low T. The data reviewed on potential consequences suggest that low T levels may be linked to earlier all-cause and cardiovascular related mortality among men. This literature review suggests that men with certain factors, such as advanced age, obesity, MetS, and poor general health, are more likely to have and develop hypogonadism. Low levels of T may have important long-term negative health consequences. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2012; 42 (11): 1205-1212 Abstract Background The effect of male hypogonadism on the immune response is poorly understood, even though testosterone has both immunosuppressive and anti-inflammatory effects in men. Design In this study, we compared the distribution and functional status of peripheral blood (PB) monocytes, dendritic cells (DCs) [CD16+ (monocytoid), CD33+ (myeloid) and CD33− (plasmacytoid)] and CD4+ CD25+ CD127−/lo regulatory T cells from hypogonadic men and control subjects. Immunophenotypic studies were performed both on resting and in vitro-stimulated cells. Results Overall, no significant differences were detected on the number of monocytes, DCs and CD4+ CD25+ CD127−/lo regulatory T cells between both groups of subjects. However, hypogonadic men showed slightly higher numbers of circulating CD16+ cells expressing the CD107b activation/degranulation-associated marker than controls, such differences reaching statistical significance after in vitro stimulation with CpG oligodeoxynucleotides. Interestingly, antigen-stimulated expression of CD107b on CD16+ cells inversely correlated with the serum concentrations of total testosterone ( r2 = −0·45; P = 0·01), free testosterone ( r2 = −0·48; P = 0·005), calculated free testosterone ( r2 = −0·44; P = 0·01) and bioavailable testosterone ( r2 = −0·46; P = 0·008) among all cases studied, as well as with both the LH ( r2 = −0·53, P = 0·04) and FSH ( r2 = −0·54, P = 0·04) serum levels among hypogonadic men. Conclusions These findings show an enhanced immunological response of circulating (activated) CD16+ DCs to antigen stimulation, which was inversely related to testosterone and gonadotropin serum levels. Such findings suggest a modulation by the hypothalamic-hypophyseal-gonadal axis of the immune response and may have clinical implications for hypogonadic men, as regards susceptibility to autoimmune diseases and increased responses to antigenic stimuli. [ABSTRACT FROM AUTHOR]

Differences in endothelin-1 (ET-1) blood plasma levels were established between healthy men and women. Little is known about vascular effects of testosterone and the interactions between sex hormones and endothelin. In order to study the relationship between ET-1 and testosterone in more detail, we have investigated 33 male patients with various forms of hypogonadism (13 with hypergonadotropic hypogonadism and 20 with hypogonadotropic hypogonadism). Fourteen age-matched healthy males served as controls. The basal ET-1 levels in patients with hypogonadism (0.96 ± 0.12 fmol/mL) (mean ± SEM) were significantly higher in comparison with the controls (0.44 ± 0.04 fmol/mL), p < 0.01. Fifteen individuals of these patients were studied during the therapy with testosterone depot 250 mg i.m. The ET-1 levels decreased in this group from 0.99 ± 0.22 to 0.78 ± 0.14 fmol/mL at the third and to 0.76 ± 0.25 fmol/mL at the sixth month of the medication, respectively. The differences were not significant compared with the initial levels, but the concentrations at the sixth month of the treatment were not statistically different in comparison with the ET-1 levels of the controls. There was no significant difference in lipid data between patients before and during testosterone medication, except for the high-density lipoprotein cholesterol, which decreased at the third month of the treatment. Our results show that plasma ET-1 levels in males with hypogonadism are elevated with a tendency to decrease after testosterone administration. The optimum testosterone is not associated with enhanced cardiovascular risk as far as ET-1 plasma levels and lipids are concerned. [ABSTRACT FROM AUTHOR]

The pineal gland, through the rhythmic production of melatonin, seems to play an important role in the control of the reproductive function of many vertebrate species. In contrast, the effects of the pineal gland in humans and the relationship between gonadotropins and melatonin secretion are not yet clarified. On the basis of these considerations, the aim of the present study was to clarify whether melatonin serum concentrations were altered in males with different hypothalamo-pituitary–gonadal disturbances, in comparison to normal individuals. We have studied 36 individuals divided into three groups according to their gonadotropin status: normals, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. They were submitted to blood sample withdrawal at 03.00, 11.00 and 19.00 h for melatonin determination according to a radioimmunological method, without extraction of the sample. The results obtained in the present study suggest the existence of an interaction between the pituitary and the pineal gland. In fact, in the case of hypersecretion of gonadotropins, nocturnal melatonin release is reduced, while night melatonin secretion is increased in the opposite situation (hypogonadotropic hypogonadism). Both these endocrine pathologies are characterized by a reduced sexual steroid secretion; for that reason, this reduction cannot be regarded as responsible for the two opposite dysfunctions of melatonin release. In conclusion, our study shows that darkness-dependent release of melatonin in males with hypogonadotropic hypogonadism is significantly higher in comparison with the healthy men, while it is significantly reduced in patients with hypergonadotropic hypogonadism. A strong significant negative correlation is also found between gonadotropins and melatonin release. [ABSTRACT FROM AUTHOR]

Summary. Endothelin has various paracrine and endocrine effects on the male reproductive system. Testosterone is probably responsible for the higher endothelin levels in males. In addition, there is much ambiguity about the relationship between gonadotrophic hormones and endothelin. In order to study in more detail the relationship of endothelin with the hypothalamo-pituitary-gonadal axis in the male, we investigated 18 male patients with various forms of hypogonadism (seven with hypergonadotrophic hypogonadism and 11 with hypogonadotrophic hypogonadism). Eight age-matched healthy males served as controls. The basal endothelin levels in patients with hypogonadism (0.95 ± 0.53 fmol ml-1 ) were significantly higher than those of the controls (0.54 ± 0.06 fmol ml-1 ; P < 0.05). Males with hypergonadotrophic hypogonadism had significantly increased endothelin concentrations (1.05 ± 0.57 fmol ml-1 ; P < 0.05), whereas those with hypogonadotrophic hypogonadism (0.89 ± 0.53 fmol ml-1 ) had nonsignificantly (P > 0.05) elevated levels. No significant correlation was found between plasma endothelin levels and gonadotrophin, prolactin and testosterone concentrations. The results of this study suggest that plasma endothelin levels are increased in males with hypogonadism. [ABSTRACT FROM AUTHOR]

Summary. Hypogonadism is one of the crucial risk factors for male osteopenia and osteoporosis. There are few studies on the effects of long-term and consistently administered testosterone substitutive therapy on bone mineral density in men with gonadal androgen deficiency, and their results have been susceptible to various interpretations. The aim of our study was an evaluation of bone mineral content in 26 men, aged 18–57 years, with hypergonadotrophic hypogonadism who underwent long-lasting androgen re-placement therapy with testosterone esters (Omnadren 250), which conditioned proper psychosomatic androgenization. The control group comprised 405 healthy men, aged 20–60 years, a representative sample of the local male population. Among all examined men and in the control group, trabecular, cortical and total bone mineral content at the distal radius of the nondominant hand were assessed by peripheral quantitative computed tomography using the Stratec 960 apparatus. In 11 hypogonadal men (42.3%), the trabecular bone mineral content was found to be within normal ranges; in 15 patients (57.7%) its values were below -1 standard deviation (SD) (osteopenia). In six patients (23.1%), the cortical bone mineral content was between +1 SD and the arithmetic mean, X; in 13 examined men (50%), the cortical bone mineral content was below X and above -1 SD. Osteopenia was diagnosed in six hypogonadal males, whereas osteoporosis was found in one man (cortical bone mineral content below -2.5 SD). Only in seven of the examined men (26.9%) was the total bone mineral content found within normal ranges, whereas in 19 men (73.1%) the total bone mineral content was below -1 SD (osteopenia). Despite the testosterone replacement in hypogonadal men, the greatest reduction of bone mineral content was found in its trabecular and total values. Among all the men examined, the trabecular and total bone mineral contents were below the mean of our own reference values. The... [ABSTRACT FROM AUTHOR]