Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial.

Importance: The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown. Objective: To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism. Design, Setting, and Participants: This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023. Intervention: Participants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo. Main Outcomes and Measures: The primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model. Results: A total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men. Conclusions and Relevance: In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study's findings may facilitate a more informed appraisal of the potential risks of TRT. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.

Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study.

BACKGROUND: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial. METHODS: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. RESULTS: As of July 1, 2021, 5,076 subjects had been randomized. CONCLUSIONS: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.

Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial.

CONTEXT: Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated. DESIGN: Double-blinded, placebo-controlled trial. SETTING: Twelve US academic medical centers. PARTICIPANTS: Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded. INTERVENTIONS: Testosterone or placebo gel for 12 months. MAIN OUTCOMES: Percentile changes in PSA during testosterone treatment of 12 months. RESULTS: Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8. CONCLUSIONS: When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL.

Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline.

Objective: To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. Participants: The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. Conclusions: We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.

Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men.

OBJECTIVES: To evaluate the effects of testosterone-replacement therapy (TRT) on prostate health indicators in hypogonadal men, including rates of prostate cancer diagnoses, changes in prostate-specific antigen (PSA) levels and lower urinary tract symptoms (LUTS) over time. PATIENTS AND METHODS: The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry of treated and untreated, newly-diagnosed hypogonadal men (n = 999). Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer; PSA and testosterone levels were measured via local and central laboratory assays; and LUTS severity was assessed via the International Prostate Symptom Score (IPSS). Incidence rates per 100 000 person-years were calculated. Longitudinal mixed models were used to assess effects of testosterone on PSA levels and IPSS. RESULTS: Of the 999 men with clinically diagnosed hypogonadism (HG), 750 (75%) initiated TRT, contributing 23 900 person-months of exposure. The mean testosterone levels increased from 8.3 to 15.4 nmol/L in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. Overall, the proportion of positive biopsies was nearly identical in men on TRT (37.5%) compared to those not on TRT (37.0%) over the course of the study. There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score by TRT status. Lower IPSS irritative sub-scale scores were reported in treated compared to untreated men. CONCLUSIONS: Results support prostate safety of TRT in newly diagnosed men with HG.

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.).

Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the testosterone trials.

CONTEXT: The prevalence of sexual dysfunction, low vitality, and poor physical function increases with aging, as does the prevalence of low total and free testosterone (TT and FT) levels. However, the relationship between sex hormones and age-related alterations in older men is not clear. OBJECTIVE: To test the hypotheses that baseline serum TT, FT, estradiol (E2), and sex hormone-binding globulin (SHBG) levels are independently associated with sexual function, vitality, and physical function in older symptomatic men with low testosterone levels participating in the Testosterone Trials (TTrials). DESIGN: Cross-sectional study of baseline measures in the TTrials. SETTING: The study was conducted at 12 sites in the United States. PARTICIPANTS: The 788 TTrials participants were ≥ 65 years and had evidence of sexual dysfunction, diminished vitality, and/or mobility disability, and an average of two TT < 275 ng/dL. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Question 4 of Psychosocial Daily Questionnaire (PDQ-Q4), the FACIT-Fatigue Scale, and the 6-minute walk test. RESULTS: Baseline serum TT and FT, but not E2 or SHBG levels had small, but statistically significant associations with validated measures of sexual desire, erectile function, and sexual activity. None of these hormones was significantly associated within or across trials with FACIT-Fatigue, PHQ-9 Depression or Physical Function-10 scores, or gait speed. CONCLUSIONS: FT and TT levels were consistently, independently, and positively associated, albeit to a small degree, with measures of sexual desire, erectile function, and sexual activity, but not with measures of vitality or physical function in symptomatic older men with low T who qualified for the TTrials.

Pheochromocytoma-induced atrial tachycardia leading to cardiogenic shock and cardiac arrest: resolution with atrioventricular node ablation and pacemaker placement.

Pheochromocytoma should be considered in young patients who have acute cardiac decompensation, even if they have no history of hypertension. Atrioventricular node ablation and pacemaker placement should be considered for stabilizing pheochromocytoma patients with cardiogenic shock due to atrial tachyarrhythmias. A 38-year-old black woman presented with cardiogenic shock (left ventricular ejection fraction, <0.15) that did not respond to the placement of an intra-aortic balloon pump. A TandemHeart(®) Percutaneous Ventricular Assist Device was inserted emergently. After atrioventricular node ablation and placement of a temporary pacemaker, the TandemHeart was removed. Computed tomography of the abdomen revealed a pheochromocytoma. After placement of a permanent pacemaker, the patient underwent a right adrenalectomy. This is, to our knowledge, the first reported case of pheochromocytoma-induced atrial tachyarrhythmia that led to cardiogenic shock and cardiac arrest unresolved by the placement of 2 different ventricular assist devices, but that was completely reversed by radiofrequency ablation of the atrioventricular node and the placement of a temporary pacemaker. We present the patient's clinical, laboratory, and imaging findings, and we review the relevant literature.

Reversible Adrenal Insufficiency in Three Patients With Post-Roux-en-Y Gastric Bypass Noninsulinoma Pancreatogenous Hypoglycemia Syndrome.

Objective. Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a disorder of endogenous hyperinsulinemia that is clinically distinguishable from insulinoma, with a greater preponderance after Roux-en-Y gastric bypass (RYBG). Hyperinsulinemic hypoglycemia can predispose to attenuation of counterregulatory hormone responses to hypoglycemia, and consequent suppression of the hypothalamic-pituitary-adrenal (HPA) axis. This case series describes 3 individuals who were diagnosed with adrenal insufficiency (AI) after undergoing RYGB, complicated by NIPHS. Methods. A retrospective chart review was performed for each individual. Chart review applied particular attention to the onset of hyperinsulinemic hypoglycemia following bariatric surgery and the dynamic testing leading to the diagnoses of NIPHS and AI. Results. In each case, reactive hypoglycemia ensued within months to years after RYGB. Cosyntropin stimulation testing confirmed the diagnosis of AI. Hydrocortisone therapy reduced the frequency and severity of hypoglycemia and was continued until successful medical and/or surgical management of hyperinsulinism occurred. Follow-up testing of the HPA axis demonstrated resolution of AI. In all cases, hydrocortisone therapy was finally discontinued without incident. Conclusion. We speculate that transient AI is a potential complication in patients who experience recurrent hyperinsulinemic hypoglycemia after RYGB. The putative mechanism for this observation may be attenuation of the HPA axis after prolonged exposure to severe, recurrent hypoglycemia. We conclude that biochemical screening for AI should be considered in individuals who develop post-RYGB hyperinsulinemic hypoglycemia. If AI is diagnosed, supportive treatment should be maintained until hyperinsulinemic hypoglycemia has been managed effectively.

Effects of glycemia on immediate complications following CABG.

OBJECTIVE: We investigated the relationship between postoperative glucose levels (days 1 through 3) and immediate outcomes in patients who underwent isolated coronary artery bypass grafting (CABG). METHODS: We conducted a retrospective study of 2,558 consecutive patients who had isolated CABG. Patients were stratified into 3 groups based on their pre-operative mortality risk (MR), using Society of Thoracic Surgeons' criteria. Average glucose levels for the first 3 days following surgery were determined. Glucose levels for each group were divided into quartiles and related to relevant outcomes. Odds ratios assessing changes in outcomes as functions of increased glucose exposure were determined for postoperative days 1, 2, and 3 and for postoperative days 1 and 2 and 1 through 3. RESULTS: The number of patients in each MR group (1 through 3; low, medium, and high) was 1,233, 852, and 473, respectively. Mean ± SD quartile glucose levels for days 1 and 2 were 133 ± 8.2, 150.4 ± 4.7, 167.2 ± 6.89, and 205.9 ± 24.9 mg/dL. The proportion of patients with a glucose level <70 mg/dL was 6.4%, <60 mg/dL was 2.7%, and <50 mg/dL was 1.1%. The most consistent and significant correlations between glucose quartiles and outcomes were observed for MR group 1, and they were most significant for the first 2 days following surgery. Glycemic control was not correlated with mortality, but it was correlated with total complications. CONCLUSION: Hyperglycemia during the first two days after CABG adversely affected total complications in patients who were in the low and medium MR groups, but it did not significantly affect hospital mortality.

Clinical review: Why is androgen replacement in males controversial?

CONTEXT: Symptoms and signs consistent with androgen deficiency and low testosterone levels are recognized frequently in clinical practice. Recent population-based epidemiological studies indicate that low testosterone levels in men are associated with increased morbidity and mortality. The clinician must be able to counsel patients to help them determine whether testosterone replacement therapy is appropriate for them. EVIDENCE ACQUISITION: The authors have conducted a literature search in PubMed, and we have reviewed references in the multiple systematic reviews and meta-analyses that have been published on this topic. EVIDENCE SYNTHESIS: We have attempted to provide the reader with an appreciation of the evidence that can be used to support the diagnosis of androgen deficiency, the efficacy of treatment, the potential risks of treatment, the therapeutic options, and the recommendations for monitoring treatment. CONCLUSIONS: We think that published clinical experience justifies testosterone replacement therapy in males who have not initiated puberty by age 14 and in males with low testosterone levels due to classical diseases of the hypothalamic-pituitary-gonadal axis. The benefit:risk ratio is less certain in older men and in those with chronic diseases associated with low testosterone levels. The decision to treat in this setting is much more controversial because there are few large clinical trials that have demonstrated efficacy and no large clinical trials that have determined potential risks of increasing the incidence of clinical prostate cancers or cardiovascular events. We provide a critical review of the evidence that supports treatment and potential risks and ways to reduce the risks if the physician and patient elect testosterone replacement.

Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.

OBJECTIVE: Our objective was to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. CONCLUSIONS: We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and, in some men in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected by measurement of free or bioavailable testosterone level, using validated assays. We recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African-Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score above 19, or uncontrolled or poorly controlled heart failure. When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored using a standardized plan.

Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.

OBJECTIVE: The objective was to provide guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, five additional experts, a methodologist, and a professional writer. The Task Force received no corporate funding or remuneration. EVIDENCE: The Task Force used systematic reviews of available evidence to inform its key recommendations. The Task Force used consistent language and graphical descriptions of both the strength of recommendation and the quality of evidence, using the recommendations of the Grading of Recommendations, Assessment, Development, and Evaluation group. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during three group meetings, several conference calls, and e-mail communications. The drafts prepared by the panelists with the help of a professional writer were reviewed successively by The Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Committee, and Council. The version approved by the Council was placed on The Endocrine Society's web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and in some patients by measurement of free or bioavailable testosterone level, using accurate assays. We recommend testosterone therapy for symptomatic men with androgen deficiency, who have low testosterone levels, to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 3 ng/ml without further urological evaluation, erythrocytosis (hematocrit > 50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) greater than 19, or class III or IV heart failure. When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored using a standardized plan.

Hypogonadism in male patients with cancer.

BACKGROUND: Patients with cancer often develop anorexia, fatigue, and decreased muscle mass. These signs and symptoms are nonspecific, and they frequently occur in other conditions, including hypogonadism. METHODS: The objectives of this study were 1) to measure testosterone levels in patients with cancer and 2) to examine the correlations between testosterone, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), ghrelin levels, and appetite in patients with cancer patients and in a noncancer control group. This was designed as a cross-sectional study in the setting of a university-affiliated Veterans Affairs Medical Center. The study population included 31 male patients with cancer and 25 gender-matched noncancer controls of similar age. The variables total testosterone (TT), calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), TNF-alpha, IL-6, IGF-1, and active ghrelin were measured in fasting morning plasma samples. Appetite was measured according to a visual analog scale. The main outcome measures were cFT and cBT. RESULTS: Cancer patients had mean TT levels similar to levels in the noncancer control group but significantly lower levels of cFT, cBT, IGF-1, and appetite. SHBG, LH, TNF-alpha, IL-6, and ghrelin levels were increased in patients with cancer compared with the control group. cFT and cBT levels were correlated inversely with IL-6 and ghrelin levels and were correlated directly with IGF-1 levels and appetite. CONCLUSIONS: Patients with cancer had lower levels of biologically active testosterone. TT was not adequate for the evaluation of hypogonadism, because SHBG levels were increased. A reliable measurement of FT and/or BT should be used. LH was elevated in the patients with cancer, indicating that low FT levels were caused by primary testicular dysfunction. The authors postulated that high IL-6 or ghrelin levels inhibit testosterone synthesis, although a secondary effect at the hypothalamic-pituitary levels cannot be excluded.

Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia.

Anorexia and weight loss are negative prognostic factors in patients with cancer. Although total ghrelin levels are increased in energy-negative states, levels of the biologically active octanoylated ghrelin and the anorexigenic peptide YY (PYY) have not been reported in patients with cancer-induced cachexia. We hypothesized that abnormal ghrelin and/or PYY levels contribute to cancer-induced cachexia. We evaluated 21 patients with cancer-induced cachexia; 24 cancer patients without cachexia; and 23 age-, sex-, race-, and BMI-matched subjects without cancer. Active ghrelin levels and the active to total ghrelin ratio were significantly increased in subjects with cancer-induced cachexia, compared with cancer and noncancer controls. PYY levels were similar among groups. Appetite measured by a visual analog scale was not increased in subjects with cachexia. The increase in active ghrelin levels is likely to be a compensatory response to weight loss. Cachexia may be a state of ghrelin resistance because appetite does not correlate with ghrelin levels. Changes in the active to total ghrelin ratio suggest that a mechanism other than increased secretion must be responsible for the increase in active ghrelin levels. PYY is unlikely to play an important role in cancer-induced cachexia.

Andropause: is androgen replacement therapy indicated for the aging male?

The number of men in the United States > or =65 years of age is projected to increase from 14,452,000 in 2000 to 31,343,000 in 2030. Approximately 30% of men 60-70 years of age and 70% of men 70-80 years of age have low bioavailable or free testosterone levels. Symptoms and findings of testosterone deficiency are similar to those associated with aging. They include loss of energy, depressed mood, decreased libido, erectile dysfunction, decreased muscle mass and strength, increased fat mass, frailty, osteopenia, and osteoporosis. Several small clinical trials indicate that testosterone replacement therapy can improve many of these findings; however, the studies have not been powered to assess potential risks, such as the need for invasive treatment of benign prostatic hyperplasia, development of a clinical prostate cancer, or cardiovascular events. Thus, the benefit/risk ratio of testosterone replacement therapy in aging men is not known.

Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor.

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.

Familial aggregation of prostate cancer in African-Americans and white Americans.

BACKGROUND: We compared the incidence of prostate cancer in first-degree family members of African-Americans with that in white Americans. METHODS: A historical cohort design was used to enroll 330 incident cases <80 years of age that were diagnosed at the Houston VA Medical Center between June 9, 1993 and June 8, 1996. We compared incidence rates in the probands' families with the incidence rates found in contemporaneous data from the national and regional Surveillance, Epidemiology, and End-Results (SEER) program. RESULTS: Three-hundred five probands (41% African-American) had evaluable first-degree relatives (394 African-American, 527 non-African-American). The standardized incidence ratio was 1.61 overall (95% confidence interval (CI): 1.22-2.13) and did not differ between African-American and non-African-American families: 1.58 (1.05-2.29) and 1.65 (1.06-2.45) in African-Americans and non-African-Americans, respectively. CONCLUSIONS: The similar level of familial aggregation is evidence that the higher incidence of prostate cancer in African-Americans is not attributable to a higher prevalence of germline mutations predisposing to the disease.

In vivo preservation of steroid specificity in CWR22 xenografts having a mutated androgen receptor.

BACKGROUND: In vitro studies of CWR22 tumor cells lack steroid specificity. We sought to determine if CWR22 xenografts also lack steroid specificity. METHODS: We injected castrated nude mice with CWR22 tumor cells (6 x 10(6) cells) and implanted Alzet osmotic pumps that delivered approximately 1 mg steroid/kg body weight/day. RESULTS: Serum PSA levels were detectable in intact mice and castrated mice treated with testosterone (T), but not in those treated with estradiol (E(2)), progesterone (P), or flutamide (F). T maintained mean tumor weight similar to that in intact mice (P = NS). We observed no tumors in castrated mice or mice treated with E(2), P, or F, and tumor histology was consistent with weights. CONCLUSIONS: The mutation of the androgen receptor (H874Y) that occurs in the CWR22 xenograft model of human prostate cancer does not significantly affect in vivo steroid specificity for E(2), P, or F.