Shehzad Basaria

Metabolic Syndrome in Men With Prostate Cancer Undergoing Long-Term Androgen-Deprivation Therapy

PURPOSE Prostate cancer (PCa) is one of the most common cancers in men. Men with recurrent or metastatic PCa are treated with androgen-deprivation therapy (ADT), resulting in profound hypogonadism. Because male hypogonadism is a risk factor for metabolic syndrome and men with PCa have high cardiovascular mortality, we evaluated the prevalence of metabolic syndrome in men undergoing long-term ADT. PATIENTS AND METHODS This was a cross-sectional study. We evaluated 58 men, including 20 with PCa undergoing ADT for at least 12 months (ADT group), 18 age-matched men with nonmetastatic PCa who had received local treatment and were recently found to have an increasing prostate-specific antigen (non-ADT group), and 20 age-matched controls (control group). Men in the non-ADT and control groups were eugonadal. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. RESULTS Mean age was similar among the groups. Men on ADT had significantly higher body mass index and lower total and free testosterone levels. The prevalence of metabolic syndrome was higher in the ADT group compared with the non-ADT (P < .01) and control (P = .03) groups. Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity and hyperglycemia. Androgen-deprived men also had elevated triglycerides compared with controls (P = .02). The prevalence of hypertension and low high-density lipoprotein levels were similar. CONCLUSION These data suggest that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk. Abdominal obesity and hyperglycemia were responsible for this higher prevalence. We recommend prospective studies to further delineate this association.

Long-term effects of androgen deprivation therapy in prostate cancer patients

background Prostate cancer (PCa) is one of the most common cancers in men and has an increasing incidence. In 1999, 37 000 men died from PCa in the USA. Androgen deprivation therapy (ADT) with GnRH agonists is frequently employed in the treatment of recurrent and metastatic PCa by inducing medical castration, rendering these men hypogonadal. Because hypogonadism in men is associated with a wide range of complications, we attempted to determine the effects of long‐term ADT in men with PCa.

Androgens and Diabetes in Men: Results from the Third National Health and Nutrition Examination Survey (NHANES III)

OBJECTIVE—Low levels of androgens in men may play a role in the development of diabetes; however, few studies have examined the association between androgen concentration and diabetes in men in the general population. The objective of this study is to test the hypothesis that low normal levels of total, free, and bioavailable testosterone are associated with prevalent diabetes in men. RESEARCH DESIGN AND METHODS—The study sample included 1,413 adult men aged ≥20 years who participated in the morning session of the first phase of the Third National Health and Nutrition Examination Survey, a cross-sectional survey of the civilian, noninstitutionalized population of the U.S. Bioavailable and free testosterone levels were calculated from serum total testosterone, sex hormone–binding globulin, and albumin concentrations. RESULTS—In multivariable models adjusted for age, race/ethnicity, and adiposity, men in the first tertile (lowest) of free testosterone level were four times more likely to have prevalent diabetes compared with men in the third tertile (odds ratio 4.12 [95% CI 1.25–13.55]). Similarly, men in the first tertile of bioavailable testosterone also were approximately four times as likely to have prevalent diabetes compared wth men in the third tertile (3.93 [1.39–11.13]). These associations persisted even after excluding men with clinically abnormal testosterone concentrations defined as total testosterone <3.25 ng/ml or free testosterone <0.07 ng/ml. No clear association was observed for total testosterone after multivariable adjustment (P for trend across tertiles = 0.27). CONCLUSIONS—Low free and bioavailable testosterone concentrations in the normal range were associated with diabetes, independent of adiposity. These data suggest that low androgen levels may be a risk factor for diabetes in men.

Effects of Testosterone Treatment in Older Men

BACKGROUND Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. METHODS We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. RESULTS Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. CONCLUSIONS In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).

Adverse Effects of Androgen Deprivation Therapy and Strategies to Mitigate Them

CONTEXT Androgen-deprivation therapy (ADT) is a key component of treatment for aggressive and advanced prostate cancer, but it has also been associated with adverse effects on bone, metabolic, cardiovascular, sexual, and cognitive health as well as body composition. OBJECTIVE To review the current literature on the adverse effects of ADT and strategies for ameliorating harm from ADT. EVIDENCE ACQUISITION The Medline database (through PubMed) was searched from inception to August 1, 2013, for studies documenting the side effects of ADT and for randomized and prospective trials of interventions to mitigate those side effects. EVIDENCE SYNTHESIS Adverse effects of ADT include decreases in bone mineral density; metabolic changes such as weight gain, decreased muscle mass, and increased insulin resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced testicle size; anemia; and fatigue. Several observational studies suggest an increased risk of diabetes and cardiovascular events, although most published studies report that ADT is not linked to greater cardiovascular mortality. Randomized trials have found value in treatments for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia (tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and hot flashes (venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin). CONCLUSIONS ADT is often a necessary component of the treatment of aggressive prostate cancer, yet it has known harms that can impair health and quality of life. Clinicians should be aware of interventions that can help mitigate these adverse effects. PATIENT SUMMARY Androgen deprivation therapy is a critical component of the management of aggressive and advanced prostate cancer, but it causes adverse effects including bone loss, metabolic changes, gynecomastia, muscle loss, hot flashes, and possibly increased cardiovascular events. Clinicians should be aware of interventions that can help mitigate these adverse effects.

Androgen Deprivation Therapy in Prostate Cancer and Metabolic Risk for Atherosclerosis

CONTEXT Prostate cancer (PCa) is the most common cancer in men. Androgen-deprivation therapy (ADT) is generally employed in the treatment of locally advanced and metastatic PCa. Although its use as an adjuvant therapy has resulted in improved survival in some patients, ADT has negative consequences. Complications like osteoporosis, sexual dysfunction, gynecomastia, and adverse body composition are well known. Recently, metabolic complications like insulin resistance, diabetes, dyslipidemia, and metabolic syndrome have emerged, which may be responsible for the increased cardiovascular mortality in this population. EVIDENCE ACQUISITION A MEDLINE search was conducted for articles published over the last 20 yr based on the key words androgen deprivation therapy AND insulin resistance, hyperglycemia, diabetes, dyslipidemia, metabolic syndrome, and cardiovascular disease. Relevant studies in non-PCa populations evaluating the association between testosterone and metabolism were also reviewed and briefly mentioned where relevant. EVIDENCE SYNTHESIS Prospective studies evaluating early (3-6 months) metabolic changes of ADT show development of hyperinsulinemia; however, glucose levels remain normal. Cross-sectional studies of men undergoing long-term (> or =12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. Furthermore, men undergoing ADT also experience higher cardiovascular mortality. CONCLUSION Long-term prospective studies of ADT are needed to determine the timing of onset of these metabolic complications and to investigate the mechanism behind them. In the meantime, we recommend baseline and serial screening for fasting glucose, lipids, and other cardiovascular risk factors in men receiving ADT. Glucose tolerance tests and cardiac evaluation may be required in selected cases.

Hypogonadism and androgen replacement therapy in elderly men

The decrease in testosterone levels with age is both central (pituitary) and peripheral (testicular) origin. Because serum levels of sex-hormone-binding globulin increase with aging, the decrease in free testosterone is of even greater magnitude. Recent long-term studies of testosterone therapy in hypogonadal elderly men have shown beneficial effects on bone density, body composition, and muscle strength without any substantial adverse effects on lipids and the prostate. Total testosterone level is the test of choice for initial screening of elderly men who present with signs and symptoms of hypogonadism. If the level is below 300 ng/dL, replacement therapy should be initiated. If the level is normal in a symptomatic patient, free or bioavailable testosterone should be determined. The pros and cons of testosterone therapy should be discussed in depth with every patient, and decisions should be made on an individual basis. This review summarizes the trials of testosterone replacement therapy in elderly men and outlines a diagnostic approach to these patients.

Testosterone Suppresses Hepcidin in Men: A Potential Mechanism for Testosterone-Induced Erythrocytosis

CONTEXT The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown. OBJECTIVE The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin. PARTICIPANTS Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied. METHODS Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders. RESULTS High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels. CONCLUSION Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.

Androgen Abuse in Athletes: Detection and Consequences

CONTEXT Doping with anabolic androgenic steroids (AAS) both in sports (especially power sports) and among specific subsets of the population is rampant. With increasing availability of designer androgens, significant efforts are needed by antidoping authorities to develop sensitive methods to detect their use. EVIDENCE ACQUISITION The PubMed and Google Scholar search engines were used to identify publications addressing various forms of doping, methods employed in their detection, and adverse effects associated with their use. EVIDENCE SYNTHESIS The list of drugs prohibited by the World Anti-Doping Agency (WADA) has grown in the last decade. The newer entries into this list include gonadotropins, estrogen antagonists, aromatase inhibitors, androgen precursors, and selective androgen receptor modulators. The use of mass spectrometry has revolutionized the detection of various compounds; however, challenges remain in identifying newer designer androgens because their chemical signature is unknown. Development of high throughput bioassays may be an answer to this problem. It appears that the use of AAS continues to be associated with premature mortality (especially cardiovascular) in addition to suppressed spermatogenesis, gynecomastia, and virilization. CONCLUSION The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. The development of sensitive detection techniques may help discourage (at least to some extent) the abuse of these compounds. Investigations are needed to identify ways to hasten the recovery of the gonadal axis in AAS users and to determine the mechanism of cardiac damage by these compounds.

Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point

BACKGROUND The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. METHODS We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. RESULTS The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. CONCLUSIONS Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.