Biochemical predictors of structural hypothalamus-pituitary abnormalities detected by magnetic resonance imaging in men with secondary hypogonadism.

PURPOSE: Organic conditions underlying secondary hypogonadism (SH) may be ascertained by magnetic resonance imaging (MRI) of the hypothalamic-pituitary region that could not be systematically proposed to each patient. Based upon limited evidence, the Endocrine Society (ES) guidelines suggest total testosterone (T) < 5.2 nmol/L to identify patients eligible for MRI. The study aims to identify markers and their best threshold value predicting pathological MRI findings in men with SH. METHODS: A consecutive series of 609 men seeking medical care for sexual dysfunction and with SH (total T < 10.5 nmol/L and LH ≤ 9.4 U/L) was retrospectively evaluated. An independent cohort of 50 men with SH was used as validation sample. 126 men in the exploratory sample and the whole validation sample underwent MRI. RESULTS: In the exploratory sample, patients with pathological MRI findings (n = 46) had significantly lower total T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate specific antigen (PSA) than men with normal MRI (n = 80). Receiver Operating Characteristics analysis showed that total T, LH, FSH and PSA are accurate in identifying men with pathologic MRI (accuracy: 0.62-0.68, all p < 0.05). The Youden index was used to detect the value with the best performance, corresponding to total T 6.1 nmol/L, LH 1.9 U/L, FSH 4.2 U/L and PSA 0.58 ng/mL. In the validation cohort, only total T ≤ 6.1 nmol/L and LH ≤ 1.9 U/L were confirmed as significant predictors of pathologic MRI. CONCLUSION: In men with SH, total T ≤ 6.1 nmol/L or LH ≤ 1.9 U/L should arise the suspect of hypothalamus/pituitary structural abnormalities, deserving MRI evaluation.

Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy.

BACKGROUND: Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH). OBJECTIVE: To review the mechanism by which TRT could damage the cardiovascular system. MATERIALS AND METHODS: Comprehensive literature search of recent clinical and experimental studies. RESULTS: The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via ß1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. DISCUSSION: The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. CONCLUSIONS: Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed.

Critical evaluation of different available guidelines for late-onset hypogonadism.

BACKGROUND: Late-onset hypogonadism (LOH) is a syndrome characterized by clinical and biochemical evidence of low testosterone levels with advancing age. In recent years, several guidelines, position statements and other recommendations have become available. It is unclear whether similar indications are reported in these documents. OBJECTIVE: To review similarities and differences among available documents on the management of hypogonadism, with a special focus on LOH. MATERIALS AND METHODS: PubMed, Google and international societies websites were searched on March 2020 for documents published in the last 10 years on the management of hypogonadism and LOH. RESULTS: Nine documents were found, each developed by: (a) the American Urological Association; (b) the British Society for Sexual Medicine; (c) the Canadian Medical Association; (d) the Endocrine Society; (e) the Endocrine Society of Australia; (f) the European Academy of Andrology; (g) the European Association of Urology; (h) the International Consultation for Sexual Medicine; and (i) the International Society for the Study of Aging Male. DISCUSSION: Despite similar principles, differences were found both for the diagnostic workup and follow-up. Particularly, discrepancies were reported both for total and free testosterone levels for diagnosis and for total testosterone for monitoring. CONCLUSION: Available documents differ in terms of specific recommendations for the management of hypogonadism and LOH. Given the relevant clinical implications of adequate management of these disorders, future guidelines should report more consistent measures to be adopted in clinical practice.

Testosterone replacement therapy.

BACKGROUND: The aim of testosterone replacement therapy (TRT) is to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, depressed mood, anaemia, loss of muscle and bone mass, by increasing serum testosterone levels to physiologic range. TRT has been used in the last 70 years, and overtime, numerous preparations and formulations have been developed to improve pharmacokinetics (PKs) and patient compliance. The routes of delivery approved for use in the Western world include buccal, nasal, subdermal, transdermal and intramuscular (IM). OBJECTIVES: The aim of this narrative review was to describe and compare all available and approved testosterone preparations according to pharmacology, PKs and adverse effects. MATERIALS AND METHODS: We have performed an extensive PubMed review of the literature on TRT in clinical practice. Contraindications and monitoring of TRT were analyzed by comparing available guidelines released in the last five years. We provide a review of advantages and disadvantages of different modalities of TRT and how to monitor treatment to minimize the risks. RESULTS: TRT is associated with multiple benefits highly relevant to the patient. However, the recommendations given in different guidelines on TRT are based on data from a limited number of randomized controlled trials (RCTs), as well as non-randomized clinical studies and observational studies. This is the case for the safety of a long-term TRT in late-onset hypogonadism (LOH). No evidence is provided indeed on the effects of TRT on endpoints such as deterioration of heart failure suggesting a cautious approach to T replacement in older men with a history of heart failure. CONCLUSION: Clinicians must consider the unique characteristics of each patient and make the necessary adjustments in the management of LOH in order to provide the safest and most beneficial results.

Late-onset hypogonadism: Prostate safety.

BACKGROUND: There have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers. OBJECTIVES: The aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer. MATERIALS AND METHODS: We have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety. RESULTS: Testosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits. There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late-onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non-high-risk disease. CONCLUSION: Testosterone replacement therapy could be considered for most men with late-onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.

Aromatase inhibitors and selective estrogen receptor modulators: Unconventional therapies for functional hypogonadism?

INTRODUCTION: Functional hypogonadism increases in prevalence due to aging as well as an overall increase of obesity. Aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) could be an alternative for testosterone replacement therapy (TRT), but have not yet been established as common clinical practice. METHODS: We conducted a thorough search of the literature published between 2009 and 2018. Only RCTs published in English were included. We assessed the impact of AIs and SERMs on gonadal steroids, sexual function and semen parameters, body composition and glucose homeostasis, physical function, bone mineral density (BMD), anemia, as well as potential adverse effects. RESULTS: Twelve RCTs were included, with a total number of 645 patients. A total of 145 men were included in RCTs comparing AIs versus placebo or TRT and 476 men in RCTs with SERMs versus placebo or TRT. One RCT compared AIs versus SERMs in 24 men. Inclusion criteria were heterogenic. Most studies only included a small number of patients (range 11-256) and follow-up time was relatively short (6 weeks to 12 months). AIs as well as SERMs increased serum testosterone levels. Overall, there was no effect on sexual symptoms nor on semen parameters. Following aromatase inhibition, only minimal improvement of body composition and physical function was observed in some of the trials, but spinal BMD decreased. SERMs only induced a small improvement in body composition. The effect of SERMs on physical function and on BMD was not assessed. No major adverse effects occurred. CONCLUSION: AIs are not recommended as treatment for functional hypogonadism because of insufficient efficacy as well as a decrease in BMD. SERMs might be an alternative for TRT, but more research is needed to evaluate their effect on hypogonadal signs and symptoms, as well as on their long-term safety profile.

Late-onset hypogonadism: a concept comes of age.

The term Late-onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as 'a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)'. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age-related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US-initiated 7 T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that 'in men >65 years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits'. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.

Clinical and biochemical correlates of male hypogonadism in type 2 diabetes.

The origin of hypogonadism, a condition including both symptoms and biochemical criteria of androgen deficiency, in type 2 diabetes is poorly known. In a cross-sectional study of 267 unselected patients, we analyzed the potential correlation of several clinical and biochemical variables as well as chronic micro- and macrovascular diabetic complications with hypogonadism. Hypogonadism was present in 46 patients (17.2%) using a cutoff of total testosterone 10.4 nmol/L and in 31 (11.6%) with a cutoff of 8 nmol/L. Among these patients, hypogonadotropic hypogonadism was the most prevalent form (82.6%). Compared to eugonadal subjects, hypogonadal men had significantly lower glomerular filtration rate (67.1 ± 23.4 vs. 78.4 ± 24.6 mL/min/1.73 m2 , p = 0.005) and higher prevalence of chronic kidney disease (43.5% vs. 20.4%, p = 0.002), abnormal liver function tests (26.7% vs. 12%, p = 0.019), and psychiatric treatment (23.9% vs. 10.4%, p = 0.025). Total testosterone levels correlated inversely with age (R = -0.164, p = 0.007), fasting blood glucose (R = -0.127, p = 0.037), and triglycerides (R = -0.134, p = 0.029) and directly with glomerular filtration rate (R = 0.148, p = 0.015). Calculated free testosterone and bioavailable testosterone correlated directly with hemoglobin (R = 0.171, p = 0.015 and R = 0.234, p = 0.001, respectively). Multivariate logistic regression analysis, after adjusting for relevant confounding variables, showed that age >60 years (OR = 3.58, CI 95% = 1.48-8.69, p = 0.005), body mass index >27 kg/m2 (OR = 2.85, CI 95% = 1.14-7.11, p = 0.025), hypertriglyceridemia (OR = 2.16, CI 95% = 1.05-4.41, p = 0.035), glomerular filtration rate <60 mL/min/1.73 m2 (OR = 2.51, CI 95% = 1.19-5.29, p = 0.015), and abnormal liver function tests (OR = 3.57, CI 95% = 1.48-8.60, p = 0.005) were independently associated with male hypogonadism. Although older age, body mass index, and hypertriglyceridemia have been previously related to hypogonadism, our results describe that chronic kidney disease and abnormal liver function tests are independently correlated with hypogonadism in type 2 diabetic men.

The presence of symptoms of testosterone deficiency in the exercise-hypogonadal male condition and the role of nutrition.

PURPOSE: High volumes of aerobic exercise have been associated with reduced testosterone (T), known as the exercise-hypogonadal male condition (EHMC). Although the presence of low T has been identified, few studies have assessed the presence of androgen-deficient symptoms. The purpose of this investigation is to assess men exhibiting EHMC and evaluate their hypothalamic-pituitary-gonadal axis, the presence of hypogonadal symptoms, and also investigate a possible contribution of inadequate nutrition to the condition. METHODS: A cross-sectional design compared 9 long-distance runners exhibiting EHMC to 8 non-active controls. Comparisons included serum T, luteinizing hormone (LH), follicle-stimulating hormone, and cortisol, the Aging Male Symptoms (AMS) questionnaire score, bone mineral density (BMD), and a food frequency questionnaire. RESULTS: Mean T was significantly reduced in the EHMC group (EHMC 9.2 nmol L-1 vs. CONT 16.2 nmol L-1). The EHMC group demonstrated significantly higher AMS scores (EHMC 27.1 ± 7.3 vs. CONT 19.7 ± 2.5). There were no differences in bone density, although 3 cases of osteopenia were noted for EHMC in the lumbar spine, 1 in the right femur, and 1 in the radius. Energy availability was significantly reduced in EHMC (EHMC 27.2 ± 12.7 vs. CONT 45.4 ± 18.2 kcal d FFM-1). CONCLUSIONS: Men exhibiting EHMC do appear to present with symptoms associated with androgen deficiency. For the most part, these symptoms are limited to those reported on the AMS questionnaire, although there are also some cases of clinically low BMD. It is possible that inadequate energy intake is contributing to this condition.

European Association of Urology Position Statement on the Role of the Urologist in the Management of Male Hypogonadism and Testosterone Therapy.

Testosterone is a crucial sex hormone important for the health and development of men of all ages. It plays a role in the integrity and maintaining the function of several systems and organs. Testosterone deficiency is linked to a number of signs and symptoms potentially affecting every man in his complexity and masculinity, and is therefore of strong urological interest. For this reason, urologists should attach importance to the need for knowledge, vocational education, and training in this specific area.

The correlation between highly sensitive C-reactive protein levels and erectile function among men with late-onset hypogonadism.

We investigated the correlation between highly sensitive C-reactive protein (hs-CRP) levels and erectile function, and assessed the clinical role of hs-CRP levels in men with late-onset hypogonadism (LOH) syndrome. For 77 participants, we assessed Sexual Health Inventory for men (SHIM) score, Aging Male Symptoms (AMS) score and International Prostate Symptom Score (IPSS). We also evaluated free testosterone (FT), hs-CRP, total cholesterol, triglyceride levels, high density lipoprotein cholesterol, hemoglobin A1c, body mass index, waist size and blood pressure. We attempted to identify parameters correlated with SHIM score and to determine the factors affecting cardiovascular risk based on hs-CRP levels. A Spearman rank correlation test revealed that age, AMS score, IPSS and hs-CRP levels were significantly correlated with SHIM score. Age-adjusted analysis revealed that hs-CRP and IPSS were the independent factors affecting SHIM score (r= -0.304 and -0.322, respectively). Seventeen patients belonged to the moderate to high risk group for cardiovascular disease, whereas the remaining 60 belonged to the low risk group. Age, FT value and SHIM score showed significant differences between the two groups. A multivariate regression analysis demonstrated that SHIM score was an independent factor affecting cardiovascular risk (OR: 0.796; 95%CI: 0.637-0.995).

Enclomiphene citrate for the treatment of secondary male hypogonadism.

INTRODUCTION: Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone have led physicians to seek alternative treatment approaches. AREAS COVERED: Enclomiphene citrate is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist that is FDA-approved for the treatment of ovarian dysfunction in women. Clomiphene citrate has also been used off-label for many years to treat secondary male hypogonadism, particularly in the setting of male infertility. Here we review the literature examining the efficacy and safety of enclomiphene citrate in the setting of androgen deficiency. EXPERT OPINION: Initial results support the conclusion that enclomiphene citrate increases serum testosterone levels by raising luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, without negatively impacting semen parameters. The ability to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option.

Risk Factors for Hypogonadism in Male Patients with Type 2 Diabetes.

BACKGROUND: Male hypogonadism is an endocrine disease characterized by low levels of serum testosterone and is closely related to the development of diabetes. The purpose of the present study was to observe the risk factors for hypogonadism in male patients with type 2 diabetes. METHODS: A total of 213 patients with type 2 diabetes were enrolled and divided into a low total testosterone (TT) group (=75) and a normal TT group (=138). The patients' blood glucose, blood lipids, serum insulin, and sex hormones were measured. The correlations between the patients' metabolic index and sex hormone levels were analyzed. RESULTS: Compared with the normal TT group, body mass index (BMI), fasting insulin (FINS), and HOMA insulin resistance index (HOMA-IR) levels were significantly higher, but the luteinizing hormone (LH) levels were significantly lower in the low TT group (p < 0.05). Correlation analyses found that TT was negatively correlated with BMI, waist circumference (WC), FINS, and HOMA-IR. TT was positively correlated with LH and follicle-stimulating hormone (FSH). CONCLUSIONS: Several risk factors of diabetes associated closely with hypogonadism. BMI, metabolic syndrome (MS), HOMA-IR, and LH are independent risk factors for hypogonadism in male patients with type 2 diabetes.

Gonadal steroid-dependent effects on bone turnover and bone mineral density in men.

BACKGROUND: Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain. METHODS: One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS: As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS: Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00114114. FUNDING: AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Evidence of male hypogonadism at an early age as a familial risk of type 2 diabetes.

OBJECTIVE: Previous investigations provide evidence of an association of hypogonadism with type 2 diabetes in men, and low testosterone levels have been regarded a risk factor for the disease. Since a strong genetic predisposition to type 2 diabetes has been demonstrated, here we investigate a possible tendency towards hypogonadism in young male offspring of diabetic parents. MATERIAL AND METHODS: The study compares 32 male offspring of diabetic parents with 31 male offspring of nondiabetic parents matched by age. The subjects comprised boys (9-17 years) and young adults (19-25 years). Anthropomorphic measurements were made in all subjects. Fasting blood samples were analyzed for glucose and serum concentrations of testosterone (T), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), insulin and leptin were measured by ELISA. Free testosterone (FT) was calculated using T and SHBG levels. RESULTS: Serum T, FT and bioavailable T (BAT) levels in offspring of diabetic parents were significantly lower than those of offspring of nondiabetic parents across all age groups. Mean serum LH levels were also lower in offspring of diabetic parents compared to the controls. Although LH levels in young adults with diabetic parents, tended to be lower than those of age-matched controls but the difference was not statistically significant. Serum insulin and leptin, and insulin resistance measured by HOMA-IR were significantly raised in older offspring of diabetic parents but were within the normal range. CONCLUSION: Whereas hypogonadism was the only indicator of a possible predisposition to metabolic dysfunction in peripubertal children of diabetic parents, a significant change in other metabolic markers becomes apparent at a more advanced age.

Outcomes of Prostate Biopsy in Men with Hypogonadism Prior or During Testosterone Replacement Therapy

Introduction: The relationship between Testosterone Replacement Therapy (TRT) and prostate cancer remains controversial. Most TRT studies show no change in prostate specific antigen (PSA) but some men do have PSA rise or develop an abnormal digital rectal exam (aDRE). Our objective was to examine the biopsy results of men with symptomatic hypogonadism before or during therapy. Materials and Methods: Data was extracted from our medical record on men with hypogonadism who had a prostate biopsy within the past 4 years done by 3 Urologists with guideline driven practice patterns. Results: 96 men were identified. Mean age at biopsy was 63 (range 40–85) and median PSA was 3.78ng/dL (0.5–662). Of the 61 men not on TRT, median PSA was 4.34 (0.5 to 662) and mean total testosterone 254 (191–341). There were 29 (47.5%) prostate cancers found (6 Gleason score 6, 13 Gleason score 7, 10 Gleason score 8 or 9). Of the 35 men on TRT, median PSA was 3.27 (0.5 to 13.7). The %PSA increase ranged from 2 to 251% (mean 93.5%). Mean total testosterone was 383 (146–792). Of the 14 men treated < 2 years, none had cancer. Of the 21 men treated 2 or more years 5 had cancer (2 Gleason score 6, 3 Gleason score 7). Conclusions: Men with hypogonadism and a clinical indication for biopsy often have prostate cancer, many high grade. No men with an initial PSA rise on TRT had cancer. Men on long term TRT should be monitored with PSA and DRE per guidelines.

Hypogonadism and Mortality in Aged Hospitalized Male Patients: A 5-Year Prospective Observational Study.

OBJECTIVE: To investigate the relationship between hypogonadism and mortality in aged hospitalized male patients. DESIGN: A 5-year prospective observational study was conducted. Gonadal function was assessed at hospital admission and mortality was registered in the follow-up period. PATIENTS AND METHODS: We studied all patients≥65 years admitted for any reason during 2010 and 2011. Serum T concentrations were quantified in all patients. Hypogonadism was defined by the presence of serum T levels<200 ng/dl. Number of deaths and all-cause and cardiovascular (CV) mortality were registered until December 31(st), 2014. RESULTS: During the study 150 patients were admitted and 103 (68.7%) of them died during follow-up. Hypogonadism was positively associated with mortality (P=0.036). The percentage of hypogonadal patients was significantly (P=0.02) higher in the group of patients who died in hospital compared with those who died after hospital discharge and those who survived. CV disease was the main cause of death in 52 patients (50.5%). Kaplan-Meier analysis showed a median survival time for all-cause mortality of 2.0 (0-16.5) months and 21.0 (5.0-33.2) months for patients with and without hypogonadism, respectively (P<0.001). Similar findings were found when analyzing mortality due to CV disease (P=0.009). Hypogonadism was a strong independent predictor for all-cause (adjusted multivariate analysis, HR 3.35; 1.55-7.23, P=0.002) and CV mortality (HR 2.14; 1.18-3.86, P=0.012). CONCLUSIONS: Hypogonadism discovered during hospitalization is associated with in-hospital and long-term mortality in elderly male patients and predicts both all-cause mortality and CV mortality in this population.

The Effect of Metformin and Metformin-Testosterone Combination on Cardiometabolic Risk Factors in Men with Late-onset Hypogonadism and Impaired Glucose Tolerance.

No previous study has investigated the effect of metformin, administered alone or together with testosterone, on cardiometabolic risk factors in men with hypogonadism. The study included 30 men with late-onset hypogonadism (LOH) and impaired glucose tolerance (IGT) who had been complying with lifestyle intervention. After 12 weeks of metformin treatment (1.7 g daily), the participants were allocated to one of 2 groups treated for the following 12 weeks with oral testosterone undecanoate (120 mg daily, n=15) or not receiving androgen therapy (n=15). Plasma lipids, glucose homeostasis markers, as well as plasma levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine and fibrinogen were determined before and after 12 and 24 weeks of therapy with the final dose of metformin. Patients with LOH and IGT had higher levels of hsCRP, homocysteine and fibrinogen than subjects with only LOH (n=12) or only IGT (n=15). Metformin administered alone improved insulin sensitivity, as well as reduced 2-h postchallenge plasma glucose and triglycerides. Testosterone-metformin combination therapy decreased also total and LDL cholesterol, uric acid, hsCRP, homocysteine and fibrinogen, as well as increased plasma testosterone. The effect of this combination therapy on testosterone, insulin sensitivity, hsCRP, homocysteine and fibrinogen was stronger than that of metformin alone. The obtained results indicate that IGT men with LOH receiving metformin may gain extra benefits if they are concomitantly treated with oral testosterone.

Use of Hormone Testing for the Diagnosis and Evaluation of Male Hypogonadism and Monitoring of Testosterone Therapy: Application of Hormone Testing Guideline Recommendations in Clinical Practice.

INTRODUCTION: Clinical practice guidelines recommend that testosterone (T) levels be measured on ≥2 occasions to confirm a diagnosis of hypogonadism, gonadotropins be measured to determine whether hypogonadism is primary or secondary, and T levels be measured to monitor the adequacy of T therapy. However, it is not known whether hormone testing as recommended by guidelines is routinely performed in real-world clinical practice. AIM: The aim of this study was to assess the use of hormone testing for the diagnosis and evaluation of hypogonadism and monitoring of T therapy in clinical practice. METHODS: In this retrospective cohort study of the Truven Health Marketscan(®) Commercial and Medicare Supplemental Insurance Databases during 2010-2012, 63,534 men over 18 years old who received T therapy and had continuous medical benefit enrollment for 1 year prior to and 6 months after T therapy initiation were included in this analysis. MAIN OUTCOME MEASURES: Proportion of patients who received ≥2, 1, or no T-level determinations prior to or following T therapy initiation. RESULTS: Seventy-one percent of hypogonadal men had T measured at least once and 40% had ≥ 2 tests, but only 12% of men had luteinizing hormone and/or follicle-stimulating hormone levels measured prior to T therapy initiation. Following T therapy initiation, 46% had ≥1 follow-up T measurements. CONCLUSIONS: Appropriate use of T and gonadotropin levels in clinical practice as recommended by guidelines is suboptimal, increasing the possibility of overdiagnosis of male hypogonadism, underdiagnosis of secondary hypogonadism, and inappropriate T therapy use and management. Further investigation is needed into reasons for nonadherence to guidelines for appropriate hormone testing to inform future quality improvement efforts.

Testosterone Replacement in Androgen-Deficient Men With Ejaculatory Dysfunction: A Randomized Controlled Trial.

CONTEXT: Low T levels have been associated with ejaculatory dysfunction (EjD) in cross-sectional studies; however, the efficacy of T replacement in improving EjD has not been studied in a randomized controlled trial. OBJECTIVE: To evaluate the efficacy of T replacement in androgen-deficient men with EjD. DESIGN: A multicenter, double-blind, randomized, placebo-controlled, 16-week trial with T solution 2% versus placebo. SETTING: Medical centers in the United States, Canada, and Mexico. PATIENTS OR OTHER PARTICIPANTS: Seventy-six men with one or more EjD symptoms, including delayed ejaculation, anejaculation, reduced ejaculate volume, and/or reduced force of ejaculation, and two total T levels <300 ng/dL (<10.41 nmol/L) measured with liquid chromatography tandem mass spectrometry. INTERVENTIONS: Sixty milligrams of T solution 2% or placebo applied to the axillae for 16 weeks. MAIN OUTCOME MEASURES: The primary outcome was a change in the score of the three-item Male Sexual Health Questionnaire-Ejaculatory Dysfunction-Short Form (MSHQ-EjD-SF); secondary outcomes included measured ejaculate volume, scores of the bother/satisfaction item of the MSHQ-EjD-SF, the orgasmic function domain of the International Index of Erectile Function Questionnaire, and the sexual activity log. RESULTS: Seventy-six participants were randomized; 66 completed the study. Baseline demographic and clinical characteristics were comparable between the treatment arms. T replacement improved the MSHQ-EjD-SF score (mean score change, +3.1); however, this effect was not statistically different from placebo (mean score change, +2.5; P = .596). No differences were seen in any of the secondary outcomes or frequency of adverse events. CONCLUSION: T replacement was not associated with significant improvement in EjD in androgen-deficient men.