Testosterone therapy over 60 months improves aging male symptoms scores in all men with adult-onset testosterone deficiency.

OBJECTIVE: We evaluated change (Δ) in AMSS in men with adult-onset testosterone deficiency (TD) on/not on testosterone undecanoate (TU) by analysing a registry of men with adult-onset TD. METHODS: Analyses were performed using non-parametric statistics to determine ΔAMSS at 6-12 monthly intervals in men on/not on TU and movement in AMSS. Factors predicting ΔAMSS were established via linear/multiple regression. RESULTS: TU was significantly associated with lower AMSS values compared with that at baseline/prior assessment during the initial 42 months treatment; 259 of the 260 men showed improvement. In the 361 men not on TU, AMSS values increased during 60 months of follow-up compared with that at baseline/prior assessment; improvement after 60 months was evident in 1 man, whilst AMSS remained the same or worsened in 213 and 147 men, respectively. In men on TU, baseline AMSS was inversely associated with ΔAMSS (R2 = 0.97), with no other factors reaching significance. Baseline AMSS, age, serum total testosterone (TT), waist circumference (WC), and diastolic blood pressure (BP) were associated with ΔAMSS in men not on TU. DISCUSSION: We show that TU was associated with lower AMSS in men with adult-onset TD whilst non-treatment led to increased values. Baseline AMSS values inversely predicted ΔAMSS in both groups.

The effects of long-term testosterone treatment on endocrine parameters in hypogonadal men: 12-year data from a prospective controlled registry study.

Testosterone therapy (TTh) is the primary treatment for aging men with functional hypogonadism. Whilst the benefits of testosterone (T) replacement are well-evidenced, the long-term data for TTh on metabolic and endocrine parameters is limited. Here we present the effect of TTh on endocrine parameters in hypogonadal men at a 12-year follow-up. In this single-centre, cumulative, prospective, registry study, 321 hypogonadal men (mean age: 58.9 years) received testosterone undecanoate injections in 12-week intervals for up to 12 years. Blood samples were taken at every other visit to measure levels of total T (TT), calculated free T, sex hormone-binding globulin (SHBG), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone and prolactin. We observed an increase in TT of 15.5 nmol/L (p < 0.0001), a reduction in SHBG of 10.5 nmol/L (p < 0.0001) and an increase in calculated free T of 383.04 pmol/L (p < 0.0001) over the study period. This was accompanied by an increase in estradiol levels by 14.9 pmol/L (p < 0.0001), and decreases in progesterone (0.2 ng/mL, p < 0.0001), LH (10.4 U/L, p < 0.0001) and FSH (8.4 U/L, p < 0.0001) were demonstrated at 12-years. The levels of prolactin remained unchanged. Long-term TTh altered hormonal parameters to predictably modify the endocrine system. These effects were sustained during the entire observation time of 12 years.

Mechanisms underlying the metabolic actions of testosterone in humans: A narrative review.

The role of testosterone in improving sexual symptoms in men with hypogonadism is well known. However, recent studies indicate that testosterone plays an important role in several metabolic functions in males. Multiple PubMed searches were conducted with the use of the terms testosterone, insulin sensitivity, obesity, type 2 diabetes, anaemia, bone density, osteoporosis, fat mass, lean mass and body composition. This narrative review is focused on detailing the mechanisms that underlie the metabolic aspects of testosterone therapy in humans. Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids and suppressing inflammation. At a cellular level, testosterone increases the expression of insulin receptor ß subunit, insulin receptor substrate-1, protein kinase B and glucose transporter type 4 in adipose tissue and adenosine 5'-monophosphate-activated protein kinase expression and activity in skeletal muscle. Observational studies show that long-term therapy with testosterone prevents progression from prediabetes to diabetes and improves HbA1c. Testosterone increases skeletal muscle satellite cell activator, fibroblast growth factor-2 and decreases expression of the muscle growth suppressors, myostatin and myogenic regulatory factor 4. Testosterone increases haematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations. Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on bone. In conclusion, testosterone exerts a series of potent metabolic effects, which include insulin sensitization, maintenance and growth of the skeletal muscle, suppression of adipose tissue growth and maintenance of erythropoiesis and haematocrit.

Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study.

AIMS: To investigate whether testosterone therapy (TTh) in men with hypogonadism and type 2 diabetes mellitus (T2DM) improves glycaemic control and insulin sensitivity, and results in remission of T2DM. MATERIAL AND METHODS: A total of 356 men who had total testosterone levels ≤12.1 nmol/L (350 ng/dL) and symptoms of hypogonadism were included in the study and followed up for 11 years. All patients received standard diabetes treatment and 178 patients additionally received parenteral testosterone undecanoate 1000 mg every 12 weeks following an initial 6-week interval. A control group comprised 178 hypogonadal patients who opted not to receive TTh. RESULTS: Patients with hypogonadism and T2DM treated with testosterone had significant progressive and sustained reductions in fasting glucose, glycated haemoglobin (HbA1c) and fasting insulin over the treatment period. In the control group, fasting glucose, HbA1c and fasting insulin increased. Among the patients treated with testosterone 34.3% achieved remission of their diabetes and 46.6% of patients achieved normal glucose regulation. Of the testosterone-treated group, 83.1% reached the HbA1c target of 47.5 mmol/mol (6.5%) and 90% achieved the HbA1c target of 53.0 mmol/mol (7%). In contrast, no remission of diabetes or reductions in glucose or HbA1c levels were noted in the control group. There were fewer deaths, myocardial infarctions, strokes and diabetic complications in the testosterone-treated group. CONCLUSIONS: Long-term TTh in men with T2DM and hypogonadism improves glycaemic control and insulin resistance. Remission of diabetes occurred in one-third of the patients. TTh is potentially a novel additional therapy for men with T2DM and hypogonadism.

Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality.

Objective: The association between erectile dysfunction (ED), hypogonadism, cardiovascular disease, and type 2 diabetes is well documented, but long-term data are limited. The aim of this study is to investigate effects of long-term testosterone therapy (TTh) with testosterone undecanoate in men with hypogonadism and ED.Patients and methods: Observational, prospective registry of 805 hypogonadal men with different degrees of ED, evaluated by the International Index of Erectile Function - Erectile Function Domain. Four hundred and twelve patients underwent TTh, 393 patients served as controls, with an observation period up to 12 years.Results: TTh led to substantial and sustained reduction of ED; improvement in erectile function was significant for each successive year until year 9. This was accompanied by improvements in cardiometabolic risk factors and urinary function throughout the 12-year follow-up period. Benefits of TTh were stronger for patients with moderate/severe ED than for patients with no/minor ED. Incidence of prostate cancer, major adverse cardiovascular events, and mortality were significantly lower in men on TTh compared with untreated men.Conclusion: Long-term TTh for up to 12 years alleviates ED, improves cardiometabolic risk factors, and reduces prostate cancer. Patients must stay on TTh consistently for a long time to achieve maximum benefits of TTh.

Testosterone therapy may reduce prostate cancer risk due to testosterone deficiency at a young age via stabilizing serum testosterone levels.

Objectives: To investigate whether testosterone replacement therapy (TRT) reduces prostate cancer (PCa) risk via stabilizing serum testosterone (T) levels beyond simply elevating serum T levels and whether TRT reduces PCa risk due to low serum T levels at a young age.Methods: We analyzed data of 776 hypogonadal men from a urology center in Bremerhaven, Germany through 2004-2016 to investigate whether the TRT group has more stable T levels and whether TRT can reduce the risk of PCa due to low serum T levels at an early age. We derived an index, Maximum Decline of T Relative to Baseline (MDRB), to describe the magnitude of T declines and variations over time.Results: We found the TRT group has more stable serum T levels (e.g. smaller drop-offs) during the follow-up period as compared to the non-TRT group, and the mean of MDRB is significantly higher in the untreated group (1.553 nmol/L VS 0.013 nmol/L; p-value < .001). TRT significantly reduces the risk of PCa associated with T deficiency at a young age (p-value = .00087).Conclusions: TRT may reduce PCa risk via maintaining serum T levels within individual's normal range; T surveillance may be needed for males who have low serum T levels at a young age to monitor abnormal variations of T levels and ensure timely treatment when necessary to reduce PCa risk.

Recent testosterone drop-off and risk of cardiovascular events.

Low baseline testosterone level has been associated with the development of risk factors for cardiovascular disease such as insulin resistance and obesity. In addition to the absolute testosterone level, remarkable changes in testosterone level may have an acute effect on cardiovascular disease development and progression, which has been rarely investigated. In this study, we used a clinical dataset of 376 hypogonadal men whose testosterone levels were measured every six months for up to 11 years from a registry study in Germany, and conducted survival analyses to investigate the effect of testosterone changes since the last visit (time-varying) on the risk of cardiovascular events. Given the potential discrepancies in comorbidity conditions among patients with prior cardiovascular events and those without, all the analyses were stratified by patients' prior cardiovascular event status. We found the effects were not different among patients with prior cardiovascular events and those without. Regardless of patients' prior cardiovascular event status, patients with larger testosterone declines (≥3.12 nmol/L, 90th percentile) since the last visit were more likely to experience myocardial infarction. In conclusion, recent pronounced testosterone drop-offs may affect the risk of cardiovascular events among hypogonadal men. Future longitudinal studies are needed to confirm our exploratory study findings.

Long-term testosterone therapy improves liver parameters and steatosis in hypogonadal men: a prospective controlled registry study.

Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD) and both are prevalent in men with testosterone deficiency. Long-term effects of testosterone therapy (TTh) on NAFLD are not well studied. This observational, prospective, cumulative registry study assesses long-term effects of testosterone undecanoate (TU) on hepatic physiology and function in 505 hypogonadal men (T levels ≤350 ng/dL). Three hundred and twenty one men received TU 1000 mg/12 weeks for up to 12 years following an initial 6-week interval (T-group), while 184 who opted against TTh served as controls (C-group). T-group patients exhibited decreased fatty liver index (FLI, calculated according to Mayo Clinic guidelines) (83.6 ± 12.08 to 66.91 ± 19.38), γ-GT (39.31 ± 11.62 to 28.95 ± 7.57 U/L), bilirubin (1.64 ± 4.13 to 1.21 ± 1.89 mg/dL) and triglycerides (252.35 ± 90.99 to 213 ± 65.91 mg/dL) over 12 years. Waist circumference and body mass index were also reduced in the T-group (107.17 ± 9.64 to 100.34 ± 9.03 cm and 31.51 ± 4.32 to 29.03 ± 3.77 kg/m2). There were 25 deaths (7.8%) in the T-group of which 11 (44%) were cardiovascular related. In contrast, 28 patients (15.2%) died in C-group, and all deaths (100%) were attributed to CVD. These data suggest that long-term TTh improves hepatic steatosis and liver function in hypogonadal men. Improvements in liver function may have contributed to reduced CVD-related mortality.

Clinically occult prostate cancer cases may distort the effect of testosterone replacement therapy on risk of PCa.

BACKGROUND: Although prostate cancer (PCa) screening is conducted before testosterone replacement therapy (TRT), clinically occult PCa cases may exist. METHODS: To evaluate whether the possible inclusion of occult PCa cases distorts the effect of TRT on risk of PCa, we followed 776 hypogonadal males (TRT = 400, non-TRT = 376) from a urology center in Germany from 2004 to 2016, with a mean follow-up period of 7 years. We assumed occult cases might take 1-2 years (latency period) to become clinically detectable after receiving TRT. We selected several latency periods (12/18/24 months) and compared the risk of PCa in the TRT and non-TRT group over the latency period, from the end of latency period till the end of follow-up, and over the whole follow-up time. RESULTS: Overall, 26 PCa cases occurred in the non-TRT group vs 9 cases in the TRT group. Within 18 months of follow-up, 9 cases occurred in the TRT group vs 0 cases in the non-TRT group; from the end of 18 months till the end of follow-up, 26 cases occurred in the non-TRT group vs 0 cases in the TRT group. The adjusted table showed seemingly adverse effects of TRT on PCa development within 18 months (p = 0.0301) and beneficial effects from the end of 18 months till the end of follow-up (p = 0.0069). Similar patterns were observed for 12 or 24 months as the latency period. CONCLUSIONS: TRT may make occult PCa cases detectable within early phase of treatment and present a beneficial effect in the long run. Future longitudinal studies are needed to confirm findings from our exploratory analyses.

Dynamic Patterns of Testosterone Levels in Individuals and Risk of Prostate Cancer among Hypogonadal Men: A Longitudinal Study.

PURPOSE: We investigated whether dynamic patterns of testosterone levels contribute to risk of prostate cancer. MATERIALS AND METHODS: We used data on 376 untreated men with hypogonadism (testosterone 12.1 nmol/l or less) recruited from a urology office in Germany. Age at study entry served as a surrogate for age at the first detection of testosterone below 12.1 nmol/l. We derived 3 indicators, including the coefficient of variation, the ratio of the largest decline relative to the mean and the median of maximum declines, to measure the dynamic patterns of testosterone in an individual. RESULTS: Our findings suggest that the later that testosterone dropped below 12.1 nmol/l in a man, the less the lifetime risk of prostate cancer in that individual (HR 0.68, 95% CI 0.57-0.82). Further declines or dynamic variations of testosterone were associated with increased risk of prostate cancer (high vs low coefficient of variation HR 4.88, 95% CI 1.97-12.08, high vs low ratio of largest decline relative to mean HR 8.45, 95% CI 2.82-25.37 and high vs low median of maximum declines HR 2.70, 95% CI 1.15-6.35). CONCLUSIONS: To our knowledge this study is the first to provide evidence of the association between dynamic patterns of testosterone and prostate cancer development. This may have substantial clinical impacts on prostate cancer prevention.

Testosterone Deficiency and Testosterone Treatment in Older Men.

Frailty is a clinical condition related to changes in metabolism, to sarcopenia, and to decline in muscle mass and strength, bone mineral density, and physical function with aging. The pathophysiology of frailty is multifactorial and associated with comorbidities. Testosterone is implicated in regulating metabolic functions, maintenance of muscle and bone, and inhibition of adipogenesis. In older individuals, reduced testosterone is thought to contribute to an altered state of metabolism, loss of muscle and bone, and increased fat, leading to sarcopenia, sarcopenic obesity, and frailty. While no direct relationship between testosterone deficiency (commonly known as hypogonadism) and frailty has been established (due to the multifactorial nature of frailty), clinical evidence suggests that testosterone deficiency is associated with increased sarcopenia and obesity. Testosterone treatment in frail older men with limited mobility and with testosterone deficiency improved insulin resistance, glucose metabolism, and body composition. These changes contribute to better physical function and improved quality of life. Because frailty increases disability, comorbidities, and the risk of hospitalization, institutionalization, and mortality in older men, it is warranted to explore the potential usefulness of testosterone treatment in frail men with hypogonadism in order to attenuate the progression of sarcopenia and frailty. In this paper, we will discuss the impact of testosterone deficiency on frailty and the potential role of testosterone treatment in ameliorating and reducing the progression of frailty. Such an approach may reduce disability and the risk of hospitalization and increase functional independence and quality of life.

Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism).

Since the early 1990s, it has been recognized that testosterone (T) levels are lower in men with type 2 diabetes mellitus (T2DM) compared with nondiabetic men (controls). Hypogonadism has been reported in approximately 50% of men with T2DM with robust correlations with measures of obesity, such as waist circumference and body mass index (BMI). In longitudinal studies, hypogonadism has been identified as a predictor of incident T2DM. Experimental withdrawal of T led to acute decreased insulin sensitivity, which can be reversed by normalization of T concentrations. Androgen deprivation therapy, commonly used in men with advanced prostate cancer, increases the risk of incident T2DM significantly.While short-term studies of T therapy in hypogonadal men with T2DM show only minor effects, long-term administration of T leads to meaningful and sustained improvements of glycemic control with parallel reductions in body weight and waist circumference. The more insulin-resistant and obese a patient is at the time of initiation of T therapy, the more improvements are noted. The observed effects are likely mediated by the increase in lean body mass invariably achieved by T therapy, as well as the improvement in energy and motivation, referred to as the psychotropic effects of T. As recommended by various guidelines, measuring T levels and, if indicated, restoring men's T levels into the normal physiological range can have a substantial impact on ameliorating T2DM in hypogonadal men.

Effects of intermission and resumption of long-term testosterone replacement therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men.

OBJECTIVE: In addition to primary and secondary ('classical') hypogonadism, hypogonadism occurring in middle-aged and elderly men has been recognized. There is evidence that restoring T levels to normal improves body weight, serum lipids and glucose levels. DESIGN: Observational registry study. PATIENTS: Two hundred and sixty-two hypogonadal, middle-aged and elderly, men received testosterone replacement treatment (TRT). After having been on TRT for a mean duration of 65·5 months, TRT was temporarily intermitted in 147 patients for a mean of 16·9 months (Group I) due to cost reimbursement issues and in seven men due to prostate cancer. All these men resumed TRT for a mean period of 14·5 months. Of the cohort, 115 men were treated continuously (designated as Group C). To compare on-treatment to off-treatment periods, three periods of equal duration were defined: pre-intermission (on TRT), during intermission (off TRT) and post-intermission (on TRT after resumption of TRT). For proper comparison, the same periods were analysed for those patients who continued TRT throughout (Group C). MEASUREMENTS: Variables of body weight, glucose metabolism, lipids, blood pressure and C-reactive protein (CRP). RESULTS: In Group C there was a continuous improvement of body weight, serum lipids, glucose, HbA1c , blood pressure and CRP. In Group I there was a similar initial improvement which was reversed upon intermission of T administration but which appeared again when T treatment was reinstated. CONCLUSIONS: Our observation indicates that T administration improves body weight and metabolic factors in men with hypogonadism but withdrawal of T reverses these beneficial effects to appear again when TRT is resumed.

Effects of long-term testosterone replacement therapy, with a temporary intermission, on glycemic control of nine hypogonadal men with type 1 diabetes mellitus - a series of case reports.

Type 2 diabetes mellitus (T2DM) is often associated with obesity and subnormal serum testosterone (T) levels. Until 5 years ago there was no indication that men with type 1 diabetes mellitus (T1DM) had subnormal serum T. But recent studies indicate that about 10% of men with T1DM suffer from hypogonadism, as a rule aged men and men with obesity. While hypogonadal men with T2DM benefit from normalization of their serum T, this has not been investigated in men with T1DM. Nine men with T1DM, erectile dysfunction and hypogonadism (total testosterone ≤ 12 nmol/L) received testosterone replacement therapy (TRT). In seven men TRT was intermitted: one man with prostate malignancy and six men because of problems of reimbursement. Incidentally, this provided an opportunity to monitor the effects of withdrawal and of the reinstatement of TRT. In all men, glycemic control (serum glucose and HbA1c), weight, waist circumference, lipid profiles and erectile function improved upon TRT. The seven men whose TRT was intermitted showed a deterioration which improved again upon reinstatement of TRT. The data suggest that aging and obese men with T1DM might have subnormal T levels and that their glycemic control, lipid profiles and erectile function might benefit from TRT.

Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease?

Obesity, hypertension, insulin resistance (IR), dyslipidaemia, impaired coagulation profile and chronic inflammation characterize cardiovascular risk factors in men. Adipose tissue is an active endocrine organ producing substances that suppress testosterone (T) production and visceral fat plays a key role in this process. Low T leads to further accumulation of fat mass, thus perpetuating a vicious circle. In this review, we discuss reduced levels of T and increased cardiovascular disease (CVD) risk factors by focusing on evidence derived from three different approaches. (i) epidemiological/ observational studies (without intervention); (ii) androgen deprivation therapy (ADT) studies (standard treatment in advanced prostate cancer); and (iii) T replacement therapy (TRT) in men with T deficiency (TD). In epidemiological studies, low T is associated with obesity, inflammation, atherosclerosis and the progression of atherosclerosis. Longitudinal epidemiological studies showed that low T is associated with an increased cardiovascular mortality. ADT brings about unfavourable changes in body composition, IR and dyslipidaemia. Increases in fibrinogen, plasminogen activator inhibitor 1 and C-reactive protein have also been observed. TRT in men with TD has consistently shown a decrease in fat mass and simultaneous increase in lean mass. T is a vasodilator and in long-term studies, it was shown to reduce blood pressure. There is increasing evidence that T treatment improves insulin sensitivity and lipid profiles. T may possess anti-inflammatory and anti-coagulatory properties and therefore TRT contributes to reduction of carotid intima media thickness. We suggest that T may have the potential to decrease CVD risk in men with androgen deficiency.

Recognizing the True Value of Testosterone Therapy in Health Care.

There has been little recognition within the medical community of the health impact of testosterone (T) deficiency (TD), also known as hypogonadism, and the substantial benefits of testosterone therapy (TTh) on health and quality of life despite high-level clinical evidence. In a roundtable symposium, investigators summarized the contemporary evidence in several key clinical areas. TD negatively impacts human health and quality of life and is associated with increased mortality. Several studies have demonstrated that TTh in men with TD reduced all-cause and cardiovascular mortality. The longstanding belief that TTh is associated with increased prostate cancer (PCa) risk is contradicted by recent evidence, including multiple studies showing that TTh is associated with reduced PCa risk. Similarly, the weight of current evidence indicates the purported concern that TTh is associated with increased cardiovascular risk is incorrect. Normalization of physiological T reduces myocardial infarction, stroke, and deaths compared with men whose testosterone levels failed to normalize. In diabetic men TTh improves insulin resistance, and a large 2-year controlled study in men with abnormal glucose tolerance showed a substantially reduced rate of diabetes among men treated with TTh compared with untreated controls. Long-term TTh in diabetic men resulted in progressive improvements in obesity and insulin requirements, including a substantial number who experienced complete remission of diabetes. Finally, TTh has been shown to reduce severe outcomes with Covid-19 infection. These lines of evidence argue strongly for the need for greater awareness in the medical community of the impact of TD on health, and of the health benefits of TTh.

Examining Male Predominance of Severe COVID-19 Outcomes: A Systematic Review.

Although not universal, many epidemiological data sources signal that a higher proportion of males than females with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections have adverse outcomes, such as intensive care unit (ICU) admission and death. Though likely multifactorial, the various hypotheses that have been proposed as underlying factors behind this trend are related to greater smoking prevalence among males, testosterone (T) deficiency causing an inflammatory storm, androgen-driven pathogenesis of SARS-CoV-2, a protective effect of estrogen in females, and inborn errors of cytokine immunity. This review aims at examining the evidence and at assessing the likelihood that the factors being investigated are contributory to the reported trend of male predominance of severe COVID-19 cases. Sources were obtained using the PubMed database and were selected based on their relevance to one of the primary hypotheses attempting to explain the strong male sex bias of severe SARS-CoV-2 infections. Emphasis was placed on meta-analyses and population-based studies. Sources are current through February 22, 2022. A severe COVID-19 case or outcome is defined in this review as a progression of the SARS-CoV-2 virus that results in either admission to an ICU for management of symptoms and clinical stabilization or which leads to death. Although the trend of male predominance of severe COVID-19 cases is likely multifactorial, the hypothesis of T deficiency causing an inflammatory storm has support from many studies with limited conflicting evidence. An inborn error in cytokine immunity is also well supported, but it needs more studies to add support to the hypothesis. The immunologic protective effect of estrogen is supported by multiple studies, but it also has conflicting evidence. It appears less likely that the trend is caused solely by an increased prevalence of smoking among males or an androgen-driven pathogenesis, based on the extent of conflicting evidence.

High prevalence of subnormal testosterone in obese adolescent males: reversal with bariatric surgery.

OBJECTIVE: Obesity in adolescent males is associated with the lowering of total and free testosterone concentrations. Weight loss may increase testosterone concentrations. DESIGN AND METHODS: We evaluated the changes in sex hormones following bariatric surgery in 34 males (age range: 14.6-19.8 years) with obesity. These participants were part of a prospective multicenter study, Teen-Longitudinal Assessment of Bariatric Surgery. The participants were followed up for 5 years after surgery. Total testosterone, total estradiol, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, C-reactive protein, insulin and glucose were measured at baseline, 6 months and annually thereafter. Free testosterone, free estradiol and HOMA2-IR were calculated. RESULTS: Study participants lost one-third of their body weight after bariatric surgery, with maximum weight loss achieved at 24 months for most participants. Free testosterone increased from 0.17 (95% CI: 0.13 to 0.20) at baseline to 0.34 (95% CI: 0.30 to 0.38) and 0.27 nmol/L (95% CI: 0.23 to 0.32) at 2 and 5 years (P < 0.001 for both), respectively. Total testosterone increased from 6.7 (95% CI: 4.7 to 8.8) at baseline to 17.6 (95% CI: 15.3 to 19.9) and 13.8 (95% CI: 11.0 to 16.5) nmol/L at 2 and 5 years (P < 0.001), respectively. Prior to surgery, 73% of the participants had subnormal free testosterone (<0.23 nmol/L). After 2 and 5 years, only 20 and 33%, respectively, had subnormal free testosterone concentrations. Weight regain was related to a fall in free testosterone concentrations. CONCLUSIONS: Bariatric surgery led to a robust increase in testosterone concentrations in adolescent males with severe obesity. Participants who regained weight had a decline in their testosterone concentrations.

Dehydroepiandrosterone (DHEA)--a precursor steroid or an active hormone in human physiology.

INTRODUCTION: The circulation of large amounts of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEA-S) suggests a physiological role in human physiology. In the central nervous system, DHEA is considered a neurosteroid with a wide range of functions. AIM: The goal of this review is to discuss metabolism, biochemical, and physiological mechanism of DHEA action and the potential role of DHEA in aging and in ameliorating a host of pathological conditions, associated with aging. METHODS: We examined preclinical and clinical data reported in various studies from the available literature concerning the effects of DHEA in normal and pathological conditions. MAIN OUTCOME MEASURES: Data reported in the literature were analyzed, reviewed, and discussed. RESULTS: DHEA mediates its action via multiple signaling pathways involving specific membrane receptors and via transformation into androgen and estrogen derivatives (e.g., androgens, estrogens, 7α and 7ß DHEA, and 7α and 7ß epiandrosterone derivatives) acting through their specific receptors. These pathways include: nitric oxide synthase activation, modulation of γ-amino butyric acid receptors, N-methyl D-aspartate, receptors sigma receptors (Sigma-1), differential expression of inflammatory factors, adhesion molecules and reactive oxygen species, among others. Clinical and epidemiological studies suggested that low DHEA levels might be associated with ischemic heart disease, endothelial dysfunction, atherosclerosis, bone loss, inflammatory diseases, and sexual dysfunction. Most importantly, no significant adverse or negative side effects of DHEA were reported in clinical studies of men and women. CONCLUSIONS: DHEA modulates endothelial function, reduces inflammation, improves insulin sensitivity, blood flow, cellular immunity, body composition, bone metabolism, sexual function, and physical strength in frailty and provides neuroprotection, improves cognitive function, and memory enhancement. DHEA possesses pleiotropic effects and reduced levels of DHEA and DHEA-S may be associated with a host of pathologies; however, the clinical efficacy of DHEA supplementation in ameliorating patho-physiological symptoms remains to be evaluated.