Low Serum Testosterone Concentrations Research Articles

Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: a cross-sectional study of six international referral centres

Although some male patients with congenital hypogonadotropic hypogonadism (CHH) undergo spontaneous reversal following treatment, predictors of reversal remain elusive. We aimed to assemble the largest cohort of male patients with CHH reversal to date and identify distinct classes of reversal. This multicentre cross-sectional study was conducted in six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. Adult men with CHH (ie, absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic-pituitary-gonadal [HPG] axis dysfunction) were eligible for inclusion. CHH reversal was defined as spontaneous recovery of HPG axis function off treatment. Centres provided common data elements on patient phenotype, clinical assessment, and genetics using a structured, harmonised data collection form developed by COST Action BM1105. Latent class mixture modelling (LCMM) was applied to establish whether at least two distinct classes of reversal could be identified and differentially predicted, and results were compared with a cohort of patients without CHH reversal to identify potential predictors of reversal. The primary outcome was the presence of at least two distinct classes of reversal. A total of 87 male patients with CHH reversal and 108 without CHH reversal were included in the analyses. LCMM identified two distinct reversal classes (75 [86%] in class 1 and 12 [14%] in class 2) on the basis of mean testicular volume, micropenis, and serum follicle-stimulating hormone (FSH) concentration. Classification probabilities were robust (0·998 for class 1 and 0·838 for class 2) and modelling uncertainty was low (entropy 0·90). Compared with class 1, patients in class 2 had significantly larger testicular volume (p<0·0001), no micropenis, and higher serum FSH concentrations (p=0·041), consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH. Patients without CHH reversal were more likely to have anosmia (p=0·016), cryptorchidism (p=0·0012), complete absence of puberty (testicular volume <4 cm³; p=0·0016), and two or more rare genetic variants (ie, oligogenicity; p=0·0001). Among patients who underwent genetic testing, no patients (of 75) with CHH reversal had a rare pathogenic ANOS1 variant compared with ten (11%) of 95 patients without CHH reversal. Individuals with CHH reversal had a significantly higher rate of rare variants in GNRHR than did those without reversal (nine [12%] of 75 vs three [3%] of 95; p=0·025). Applying LCMM to a large cohort of male patients with CHH reversal uncovered two distinct classes of reversal. Genetic investigation combined with careful clinical phenotyping could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder. National Institutes of Health National Center for Advancing Translational Sciences; Ministry of Health, Rome, Italy; Ministry of University, Rome, Italy; National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Josiah Macy Jr Foundation. For the Italian translation of the abstract see Supplementary Materials section.

Effects of postnatal exposure to cadmium on male sexual incentive motivation and copulatory behavior: Estrogen and androgen receptors expression in adult brain rat

There are numerous evidence showing that cadmium (Cd) is an endocrine disruptor that exerts multiple toxic effects at different reproductive levels, including male sexual behavior (MSB). The effect of early exposure to Cd on sexual incentive motivation (SIM) and MSB in adult stage, and the immunoreactivity of receptors for hormones such as estrogens and androgens in brain regions that are relevant for the SIM and MSB display, have not been studied until now. The present study evaluated the effects of 0.5 and 1 mg/kg CdCl2 from day 1–56 of postnatal life on SIM and MSB in adults rats, as well as serum testosterone concentrations, Cd concentration in blood, testis, and brain areas, and the immunoreactivity in estrogen receptors (ER-α and -β), and androgen receptor (AR) in the olfactory bulbs (OB), medial preoptic area (mPOA), and medial amygdala (MeA). Our results showed that both doses of Cd decreased SIM and MSB, accompanied by low serum concentrations of testosterone. Also, there was a significant reduction in immunoreactivity of ER-α and AR in mPOA, and a significant reduction in AR in MeA on male rats treated with Cd 1 mg/kg. These results show that exposure to high doses of Cd in early postnatal life could alter the correct integration of hormonal signals in the brain areas that regulate and display SIM and MSB in adult male rats.

Testosterone and type 2 diabetes prevention: translational lessons from the T4DM study.

Testosterone acting via the androgen receptor, and via aromatisation to oestradiol, an activator of the oestrogen receptor, plays key roles in adipose tissue, bone and skeletal muscle biology. This is reflected in epidemiological studies associating obesity and disordered glucose metabolism with lower serum testosterone concentrations and an increased risk of type 2 diabetes (T2D) in men. Testosterone also modulates erythrocytosis and vascular endothelial and smooth muscle cell function, with potential impacts on haematocrit and the cardiovascular system. The Testosterone for the Prevention of Type 2 Diabetes (T4DM) study enrolled men aged 50 years and over with a waist circumference of 95 cm or over, impaired glucose tolerance or newly diagnosed T2D, and a serum testosterone concentration (as measured by chemiluminescence immunoassay) <14.0 nmol/L. The study reported that a 2-year treatment with testosterone undecanoate 1000 mg, administered 3-monthly intramuscularly, on the background of a lifestyle program, reduced the likelihood of T2D diagnosis by 40% compared to placebo. This effect was accompanied by a decrease in fasting serum glucose and associated with favourable changes in body composition, hand grip strength, bone mineral density and skeletal microarchitecture but not in HbA1c, a red blood cell-dependent measure of glycaemic control. There was no signal for cardiovascular adverse events. With the objective of informing translational science and future directions, this article discusses mechanistic studies underpinning the rationale for T4DM and translational implications of the key outcomes relating to glycaemia, and body composition, together with effects on erythrocytosis, cardiovascular risk and slow recovery of the hypothalamo-pituitary-testicular axis.

Approach to the Patient: The Evaluation and Management of Men ≥50 Years With Low Serum Testosterone Concentration.

Although testosterone replacement in men with classic hypogonadism due to an identified pathology of the hypothalamic-pituitary-testicular axis is uncontroversial, the role of testosterone treatment for men with age-related declines in circulating testosterone is unclear. This is due to the lack of large, long-term testosterone therapy trials assessing definitive clinical endpoints. However, men ≥50 years of age, particularly those who have a body mass index >25 kg/m2 and multiple comorbidities, commonly present with clinical features of androgen deficiency and low serum testosterone concentrations. Clinicians are faced with the question whether to initiate testosterone therapy, a difficult dilemma that entails a benefit-risk analysis with limited evidence from clinical trials. Using a case scenario, we present a practical approach to the clinical assessment and management of such men.

The influence of testosterone on the risk of cardiovascular events after percutaneous coronary intervention.

Between 2015 and 2018, 580 men undergoing PCI at a tertiary referral hospital were divided into low (<3.25 ng/mL) and normal (≥3.25 ng/mL) testosterone groups. Major adverse cardiovascular event (MACE) was defined as the composite outcome of CV death, myocardial infarction, and target lesion revascularization/target vessel revascularization (TLR/TVR) during up to 48 months follow-up after PCI. There were 111 and 469 patients in the low and normal testosterone groups, respectively, with the overall MACE rate of the former being higher than the latter (26.13% vs. 13.01%, p = 0.0006). Moreover, the overall TLR/TVR (20.72% vs. 11.73%, p = 0.0125) and myocardial infarction (3.6% vs. 0.85%, p = 0.0255) rates were significantly higher in those with low serum testosterone who also had a shorter average event-free survival analysis of MACE (25.22 ± 0.88 months) than those with normal testosterone levels (35.09 ± 0.47 months, log-rank p = 0.0004). Multiple logistic regression demonstrated an association between low serum testosterone (<3.25 ng/mL) and a higher MACE rate [odds ratio: 2.06, 95% confidence interval (CI) 1.21-3.51, p = 0.0081]. After adjusting for variables in a Cox regression model, hazard ratios (HRs) for MACE (HR: 1.88, 95% CI: 1.20-2.95, p = 0.0058) and TLR/TVR (HR: 1.73, 95% CI: 1.06-2.83, p = 0.0290) rates were higher in the low testosterone group than those in the normal testosterone group. Low serum testosterone concentrations were associated with a higher risk of MACE and TLR/TVR after PCI than those with normal testosterone levels.

Aging and androgens: Physiology and clinical implications.

In men > ~35years, aging is associated with perturbations in the hypothalamus-pituitary-testicular axis and declining serum testosterone concentrations. The major changes are decreased gonadotropin-releasing hormone (GnRH) outflow and decreased Leydig cell responsivity to stimulation by luteinizing hormone (LH). These physiologic changes increase the prevalence of biochemical secondary hypogonadism-a low serum testosterone concentration without an elevated serum LH concentration. Obesity, medications such as opioids or corticosteroids, and systemic disease further reduce GnRH and LH secretion and might result in biochemical or clinical secondary hypogonadism. Biochemical secondary hypogonadism related to aging often remits with weight reduction and avoidance or treatment of other factors that suppress GnRH and LH secretion. Starting at age ~65-70, progressive Leydig cell dysfunction increases the prevalence of biochemical primary hypogonadism-a low serum testosterone concentration with an elevated serum LH concentration. Unlike biochemical secondary hypogonadism in older men, biochemical primary hypogonadism is generally irreversible. The evaluation of low serum testosterone concentrations in older men requires a careful assessment for symptoms, signs and causes of male hypogonadism. In older men with a body mass index (BMI) ≥ 30, biochemical secondary hypogonadism and without an identifiable cause of hypothalamus or pituitary pathology, weight reduction and improvement of overall health might reverse biochemical hypogonadism. For older men with biochemical primary hypogonadism, testosterone replacement therapy might be beneficial. Because aging is associated with decreased metabolism of testosterone and increased tissue-specific androgen sensitivity, lower dosages of testosterone replacement therapy are often effective and safer in older men.

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations.

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in people with diabetes with no available treatment. AIMTo explore the effect of testosterone treatment on liver. Testosterone therapy improves insulin resistance and reduces total body fat, but its impact on the liver remains poorly studied.METHODSThis secondary analysis of a 40 wk, randomised, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging (MRI).RESULTSOf 88 patients enrolled in the index study, 39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo. All patients had > 5% hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD. Median liver fat at baseline was 15.0% (IQR 11.5%-21.1%) in the testosterone and 18.4% (15.0%-28.9%) in the placebo group. Median ALT was 34units/L (26-38) in the testosterone and 32units/L (25-52) in the placebo group. At week 40, patients receiving testosterone had a median reduction in absolute liver fat of 3.5% (IQR 2.9%-6.4%) compared with an increase of 1.2% in the placebo arm (between-group difference 4.7% P < 0.001). After controlling for baseline liver fat, testosterone therapy was associated with a relative reduction in liver fat of 38.3% (95% confidence interval 25.4%-49.0%, P < 0.001). CONCLUSIONTestosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone. Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified.

Definition of Castrate Resistant Prostate Cancer: New Insights.

The term castrate resistant prostate cancer (CRPC) was initially proposed by the Prostate Cancer Working Group 2 in 2008 to define the state of clinical and/or biochemical progression of prostate cancer (PCa) in an environment with very low serum testosterone concentration. Clinical progression is based on the radiological imaging proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) adapted to PCa. Biochemical progression is defined as an over 25% increase in serum prostate-specific antigen within two consecutive measurements separated by at least one week, and an absolute value above 2.0 ng/mL. Finally, the castrate environment is usually defined as a serum testosterone concentration maintained below 50 ng/dL or 1.7 nmol/dL. This definition does not incorporate the new and more accurate imaging modalities to assess clinical progression and the capability of the new biochemical measurements to assess the true castration environment. Ga-68-PSMA-11 PET CT/MRI and whole-body MRI are the new imaging modalities that should replace the classic thoracic CT scan, abdomino-pelvic CT scan, and technetium 99-m bone scintigraphy. In addition, Ga-68-PSMA-11 PET is the current basis for the new therapies targeting metastatic sites. Moreover, the current methods for measuring the very low serum testosterone concentrations in clinical laboratories are the widespread chemiluminescent assays, which are inappropriate, while LC-MSMS is the only method recommended to assess the castrate environment. In addition, recent research shows that serum luteinising hormone concentration associates better than serum testosterone with the castration environment, even when it is measured with LC-MSMS. In summary, the current definition of CRPC seems outdated. An extensive update to diagnose true CRPC is also needed to differentiate CRPC men with M0 (non-metastatic) from those with M1 (metastatic) CRPC. WC: 277.

Comparison of Patterns of Use and Clinical Outcomes Between Injections of Testosterone Undecanoate and Testosterone Cypionate: An Electronic Health Record Cohort Study

Background: Hypogonadism is characterized by low serum testosterone concentrations and the associated clinical manifestations (e.g., reduced libido, erectile dysfunction, and fatigue); testosterone therapy (TTh) is the primary treatment. This study compared treatment patterns and health outcomes in men using injection TTh with long-acting testosterone undecanoate (TU) injection versus short-acting testosterone cypionate (TC) injection. Methods: A U.S. electronic health records (EHR) database was retrospectively reviewed to identify adult men who had TTh of TU or TC (index treatment) between January 1, 2014, and December 31, 2018, and ≥1 EHR within the 12 months before and 6 months after index treatment. Results: There were 948 patients in the TU cohort and 121,852 in the TC cohort, of whom 419 and 86,219, respectively, were TTh-naive at index treatment. Hypogonadism diagnosis was documented in 81.1% and 58.8% of patients in the overall TU and TC cohorts, respectively. During the 1-year postindex period, higher adherence rates were observed in the TU versus TC cohort during months 7 through 12 (82.0% vs. 40.8%; p < 0.001), and a greater percentage of patients continued to receive TU (41.9%) versus TC (8.2%) for 12 months (p < 0.001). Variability in total testosterone levels was lower for TU versus TC in the TTh-naive population. Conclusions: In this retrospective EHR study, men who received TU demonstrated a two-fold higher adherence, a five-fold improved maintenance on index TTh, and more stable testosterone levels at 1-year follow-up versus men who received TC. More consistent TTh use observed with TU may result in improved health outcomes for men with hypogonadism.

Lower serum testosterone concentrations are associated with a higher incidence of dementia in men: The UK Biobank prospective cohort study.

The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone-binding globulin (SHBG) with incidence of dementia and Alzheimer's disease. Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables. In 159,411 community-dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P=.001, lowest vs highest quintile: hazard ratio [HR]=1.43, 95% confidence interval [CI]=1.13-1.81), and AD (P=.017, HR=1.80, CI=1.21-2.66). Lower SHBG was associated with a lower incidence of dementia (P<.001, HR=0.66, CI=0.51-0.85) and AD (P=.012, HR=0.53, CI=0.34-0.84). Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older men. Additional research is needed to determine causality.

International Prostate Symptom Score and Quality of Life Index for Lower Urinary Tract Symptoms Are Associated with Aging Males Symptoms Rating Scale for Late-Onset Hypogonadism Symptoms.

Although patients with late-onset hypogonadism (LOH) often experience lower urinary tract symptoms (LUTS), LUTS are not generally included in LOH symptoms. No study has examined the direct relation of the Aging Males Symptoms rating scale (AMS) and the International Prostate Symptom Score (IPSS) with the quality of life (QOL) index. We analyzed the relation between the IPSS and QOL index and various factors including the AMS in patients with LOH syndromes. This study comprised 1,688 men with LOH symptoms who visited our hospital or affiliated clinic. Factors associated with the IPSS were assessed in terms of age, scores of several questionnaires including the AMS, endocrinological variables, and serum concentration of PSA. Among these same factors, those associated with the QOL index were also evaluated. Finally, the same analyses were repeated in 187 patients with low serum testosterone concentration (<3.0 ng/mL). In a multivariate analysis using the significant items from the univariate analysis, AMS, age, and Erection Hardness Score correlated significantly with the IPSS. A trend analysis using items other than the AMS as adjustment factors also confirmed the relationship between an increase in QOL index and an increase in AMS. Similar results were obtained in the analysis of patients with low serum testosterone concentration. We revealed that the relation of IPSS with the QOL index for LUTS is closely associated with the AMS for LOH, regardless of testosterone level. When patients complain of LOH symptoms, a careful, detailed inquiry into LUTS is required.

Low Serum Testosterone Concentrations Are Associated With Poor Cognitive Performance in Older Men but Not Women.

Objective: Current evidence on the association between serum testosterone and cognitive performance has been inconsistent, especially in older adults. To investigate the associations between serum testosterone and cognitive performance in a nationally representative sample of older men and women.Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014. 1,303 men and 1,349 women aged 60 years or older were included in the study. Serum total testosterone was preformed via isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) method. Free testosterone was calculated by Vermeulen’s formula. Cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test, Animal Fluency test, and Digit Symbol Substitution Test (DSST). Binary logistic regression and restricted cubic spline models were applied to evaluate the association of testosterone and cognitive performance.Results: In men, higher concentrations of total testosterone were associated with better performance on CERAD test (OR = 0.51; 95%CI = 0.27–0.95) and DSST (OR = 0.54; 95%CI = 0.30–0.99) in adjusted group. Similarly, higher concentrations of free testosterone were associated with better performance on CERAD test (OR = 0.32; 95%CI = 0.17–0.61) and DSST (OR = 0.41; 95%CI = 0.17–0.96) in men. These associations were not seen in women.Conclusion: Serum testosterone concentrations were inversely associated with cognitive performance in older men but not women in the United States.

Reproductive suppression of giraffe (Giraffa camelopardalis) under managed care using a GnRH immunological product.

Giraffe present unique contraception challenges as males persistently pursue females during estrus. Year-round pursuit during frequent recurring estrus can pose significant risk under slippery conditions. Complete ovarian suppression is a useful tool in giraffe because it eliminates estrous behavior, interest from the male, and controls reproduction. Effective reproduction control in giraffes has been achieved with porcine zona pellucida, oral melengestrol acetate, and depot medroxy-progesterone acetate. However, these methods allow some degree of folliculogenesis and estrous behavior. Improvest® is a gonadotropin releasing hormone (GnRH) immunological product that elicits antibodies against GnRH and abrogates the effects of endogenous GnRH. This study evaluated the efficacy of Improvest® for gonadal suppression in seven females and one male giraffe by monitoring steroid hormones. Seven female giraffe were treated intramuscularly with an initial dose, a booster at 4 weeks and maintenance boosters at 3-month intervals (600 µg/dose) for 12 months. Six females were on supplemental contraception during the induction phase because separation from males was not possible. In the male (treated with 400 µg), testosterone concentrations decreased after the second injection. However, even with low serum testosterone concentrations, mounting (of nontreated females) behavior was still observed occasionally. Ovarian activity was suppressed in all treated females and interest by the males stopped; supplemental contraceptives (during the induction phase) did not impede the effect of Improvest®. After 15.3 months (seven doses), Improvest® was discontinued in three females which no longer needed contraception. In these females, ovarian activity was noted approximately 90 days after the last dose.

Age-related cognitive impairment is associated with low serum concentrations of testosterone and CSF levels of amyloid beta 42 in male cynomolgus monkeys (Macaca fascicularis).

Aged memory-impaired cynomolgus monkeys had significantly lower levels of cerebrospinal amyloid (Aβ42 ) and serum testosterone compared with young animals and non-memory-impaired controls. Our findings confirm similar findings in the human and substantiate the usefulness of the cynomolgus monkey as a spontaneous model for aging-associated senile dementia of the Alzheimer type.

Obstructive Sleep Apnea Is Associated With Low Testosterone Levels in Severely Obese Men.

BackgroundDisrupted sleep affects cardio-metabolic and reproductive health. Obstructive sleep apnea syndrome represents a major complication of obesity and has been associated with gonadal axis activity changes and lower serum testosterone concentration in men. However, there is no consistent opinion on the effect of obstructive sleep apnea on testosterone levels in men.ObjectiveThe aim of this study was to determine the influence of obstructive sleep apnea on total and free testosterone levels in severely obese men.Materials and methodsThe study included 104 severely obese (Body Mass Index (BMI) ≥ 35 kg/m2) men, aged 20 to 60, who underwent anthropometric, blood pressure, fasting plasma glucose, lipid profile, and sex hormone measurements. All participants were subjected to polysomnography. According to apnea-hypopnea index (AHI) patients were divided into 3 groups: <15 (n = 20), 15 - 29.9 (n = 17) and ≥ 30 (n = 67).ResultsThere was a significant difference between AHI groups in age (29.1 ± 7.2, 43.2 ± 13.2, 45.2 ± 10.2 years; p < 0.001), BMI (42.8 ± 5.9, 43.2 ± 5.9, 47.1 ± 7.8 kg/m2; p = 0.023), the prevalence of metabolic syndrome (MetS) (55%, 82.4%, 83.6%, p = 0.017), continuous metabolic syndrome score (siMS) (4.01 ± 1.21, 3.42 ± 0.80, 3.94 ± 1.81, 4.20 ± 1.07; p = 0.038), total testosterone (TT) (16.6 ± 6.1, 15.2 ± 5.3, 11.3 ± 4.44 nmol/l; p < 0.001) and free testosterone (FT) levels (440.4 ± 160.8, 389.6 ± 162.5, 294.5 ± 107.0 pmol/l; p < 0.001). TT level was in a significant negative correlation with AHI, oxygen desaturation index (ODI), BMI, MetS and siMS. Also, FT was in a significant negative correlation with AHI, ODI, BMI, age, MetS and siMS. The multiple regression analysis revealed that both AHI and ODI were in significant correlation with TT and FT after adjustment for age, BMI, siMS score and MetS components.ConclusionObstructive sleep apnea is associated with low TT and FT levels in severely obese men.

Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit.

Although gonadal axis dysregulation from energy deficit is well recognized in women, the effects of energy deficit on the male gonadal axis have received much less attention. To identify relevant articles, we conducted PubMed searches from inception to May 2021. Case series and mechanistic studies demonstrate that energy deficit (both acutely over days or chronically over months) either from inadequate energy intake and/or excessive energy expenditure can lower serum testosterone concentration as a result of hypothalamic-pituitary-testicular (HPT) axis dysregulation in men. The extent to which this has clinical consequences that can be disentangled from the effects of nutritional insufficiency, concomitant endocrine dysregulation (eg, adrenal and thyroid axis), and coexisting comorbidities (eg, depression and substance abuse) is uncertain. HPT axis dysfunction is primarily the result of loss of GnRH pulsatility resulting from a failure of leptin to induce kisspeptin signaling. The roles of neuroendocrine consequences of depression, hypothalamic-pituitary-adrenal axis activation, proinflammatory cytokines, Ghrelin, and genetic susceptibility remain unclear. In contrast to hypogonadism from organic pathology of the HPT axis, energy deficit-associated HPT dysregulation is functional, and generally reversible by restoring energy balance. The clinical management of such men should aim to restore adequate nutrition and achieve and maintain a healthy body weight. Psychosocial comorbidities must be identified and addressed. There is no evidence that testosterone treatment is beneficial. Many knowledge gaps regarding epidemiology, pathophysiology, and treatment remain and we highlight several areas that require future research.

Testosterone Therapy for the Treatment of Age-Related Hypogonadism: Risks with Uncertain Benefits.

Testosterone replacement therapy has been approved in the United States since the 1950s for men with “classical” hypogonadism. These men have specific and well-recognized hypothalamic, pituitary, or testicular conditions leading to deficient or absent endogenous testosterone. A more controversial treatment population is aging men, many with comorbidities, who have low serum testosterone concentrations compared with young healthy men and who do not have the well-recognized medical conditions that cause “classical” hypogonadism. Testosterone continues to be widely used in these men with “age-related hypogonadism” even though the benefits of testosterone for this use are uncertain and there are important risks, including a potential risk of major adverse cardiac events for the testosterone class, and two testosterone products with increases in blood pressure that can increase the risk of myocardial infarction and stroke. Given the uncertain clinical benefit of testosterone in men with “age-related hypogonadism” in the face of known and potential adverse outcomes, none of the testosterone products is FDA approved for such use.

Predictors of testicular sperm retrieval in patients with non-obstructive azoospermia: a review.

Azoospermia is divided into two categories of obstructive azoospermia and non-obstructive azoospermia. Before 1995, couples with a male partner diagnosed with non-obstructive azoospermia had to choose sperm donation or adoption to have a child. Currently, testicular sperm aspiration or micro-dissection testicular sperm extraction combined with intracytoplasmic sperm injection allows patients with non-obstructive azoospermia to have biological offspring. The sperm retrieval rate is significantly higher in micro-dissection testicular sperm extraction compared with testicular sperm aspiration. Additionally, micro-dissection testicular sperm extraction has the advantages of minimal invasion, safety, limited disruption of testicular function, a low risk of postoperative intratesticular bleeding, and low serum testosterone concentrations. Failed micro-dissection testicular sperm extraction has significant emotional and financial implications on the involved couples. Testicular sperm aspiration and micro-dissection testicular sperm extraction have the possibility of failure. Therefore, predicting the sperm retrieval rate before surgery is important. This narrative review summarizes the existing data on testicular sperm aspiration and micro-dissection testicular sperm extraction to identify the possible factor(s) that can predict the presence of sperm to guide clinical practice. The predictors of surgical sperm retrieval in patients with non-obstructive azoospermia have been widely studied, but there is no consensus.

Preliminary Evaluation of an Order Template to Improve Diagnosis and Testosterone Therapy of Hypogonadism in Veterans.

Testosterone therapy is indicated for the treatment of hypogonadism. Evidence-based guidelines recommend testosterone treatment only for men with symptoms and signs of testosterone deficiency and consistently low serum testosterone concentrations; luteinizing hormone (LH) and follicle-stimulating hormone (FSH) measurements and discussion of risks and benefits of testosterone prior to therapy. However, the US Department of Veterans Affairs (VA) Office of the Inspector General (OIG) report found that health care providers were adhering poorly to guideline recommendations for the diagnosis and treatment of men with hypogonadism. A prior authorization drug request (PADR) testosterone order template was implemented at VA Puget Sound Health Care System. A retrospective chart review was conducted in veterans who were prescribed testosterone and had no previous prescription in the prior year. Eligible veterans were evaluated 6 months before (pretemplate) and after (posttemplate) implementation of the template, and 3 months after removal of alternative testosterone ordering pathways (posttemplate/no alternative ordering pathways) that were discovered after PADR template implementation. We assessed the proportion of eligible veterans with documented symptoms of testosterone deficiency; appropriate diagnosis and evaluation of hypogonadism with ≥ 2 low serum testosterone and LH and FSH levels; and discussion of risks and benefits of testosterone treatment. In the pretemplate period, only 20 of 80 eligible veterans (25%) had a completed PADR for testosterone. In the posttemplate period, 18 of 45 (44%) eligible veterans had a completed PADR but only 7 (17%) had the testosterone order template completed. In the posttemplate/no alternative ordering pathways period, 13 (68%) and 11 (58%) of 19 eligible veterans had a completed PADR and testosterone order template, respectively. In all 3 periods, documentation of clinical symptoms and a discussion of risks and benefits were similar. In contrast, the proportion of veterans who had ≥ 2 low testosterone levels with LH and FSH levels measured in the posttemplate and posttemplate/no alternative ordering pathways periods were higher (41% and 37%, respectively) vs the pretemplate period (23%). Veterans with documented clinical symptoms, discussion of risks and benefits, and ≥ 2 low testosterone with gonadotropin measurements were 100%, 57%, and 71%, respectively, in the posttemplate/no alternative ordering pathways period. Implementation of a PADR order template may be a promising approach to improve the diagnosis of hypogonadism and appropriate testosterone therapy in accordance with established evidence-based clinical practice guidelines, particularly in veterans who are receiving new prescriptions.

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

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