Testosterone therapy in older men: clinical implications of recent landmark trials.

Testosterone therapy for men with hypogonadism due to identifiable hypothalamic-pituitary-testicular (HPT) pathology is uncontroversial. However, the risks and benefits of testosterone for men with clinical features of hypogonadism in the absence of identifiable HPT axis pathology have been uncertain. Recent landmark placebo-controlled trials assessed the benefits and risks of testosterone therapy (≤3 years) for middle-aged and older men with symptoms and possible signs of hypogonadism or end-organ androgen deficiency, low or low-normal serum testosterone concentrations, but no HPT pathology: Testosterone therapy (1) had modest-but clinically significant-benefits on average self-reported energy and mood, sexual function, and satisfaction; (2) in conjunction with a lifestyle programme, reversed or reduced incident type 2 diabetes mellitus (T2D) in men at high risk of or newly diagnosed with T2D; (3) modestly improved objectively assessed muscle strength and timed walking distance; (4) increased bone density and strength, but did not reduce falls or typical osteoporotic fractures and surprisingly increased the risk of fractures typically attributable to trauma; and (5) did not significantly increase the risk of myocardial infarction, stroke, or prostate cancer. These landmark trials help to inform clinical decision-making about testosterone therapy for men.

Aging and androgens: Physiology and clinical implications.

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

Epidemiology of Male Hypogonadism.

The epidemiology of male hypogonadism has been understudied. Of the known causes of endogenous androgen deficiency, only Klinefelter syndrome is common with a likely population prevalence of greater than 5:10,000 men (possibly as high as 10-25:10,000). Mild traumatic injury might also be a common cause of androgen deficiency (prevalence 5-10:10,000 men), but large, long-term studies must be completed to confirm this prevalence estimation that might be too high. The classic causes of male androgen deficiency-hyperprolactinemia, pituitary macroadenoma, endogenous Cushing syndrome, and iron overload syndrome-are rare (prevalence < 10,000 men).

Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men.

CONTEXT: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. OBJECTIVE: To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men. DESIGN, SETTING, AND PARTICIPANTS: The UK Biobank prospective cohort study of community-dwelling men aged 40-69 years old, followed for 11 years. MAIN OUTCOME MEASURES: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa. RESULTS: In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06-1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09-1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63-0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59-0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72-0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results. CONCLUSIONS: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.

Daily Oral Administration of the Novel Androgen 11ß-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men.

BACKGROUND: 11ß-methyl-19-nortestosterone (11ß-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11ß-MNT dodecylcarbonate (11ß-MNTDC), was well tolerated in healthy men. METHODS: We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18-50 years) were randomized to receive oral placebo or 11ß-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11ß-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires). RESULTS: There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11ß-MNTDC resulted in a dose-related increase in serum 11ß-MNTDC and 11ß-MNT concentrations sustained over 24 hours. Administration of 11ß-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P < 0.01). Adverse effects that may be related to 11ß-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11ß-MNTDC groups. CONCLUSION: Daily oral 11ß-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11ß-MNTDC as a potential male oral contraceptive.

High concentrations of LH cause virilization in a postmenopausal woman.

Some testosterone-producing adrenal tumors can be successfully treated with long-acting GnRH analogs and adrenal venous sampling can be useful to detect rare ectopic sex steroid-producing tumors or confirm bilateral adrenal androgen hyperproduction in female hyperandrogenism.

Testicular fine-needle aspiration for the assessment of intratesticular hormone concentrations.

Measurement of intratesticular sex steroid concentrations in men informs both the development of male hormonal contraceptives and the understanding of male infertility. Given the challenges of using invasive techniques to measure testicular hormone physiology, our group has used a minimally-invasive fine-needle aspiration technique to measure intratesticular hormones in normal healthy men. Herein, we present a post-hoc analysis of the safety and efficacy of testicular fine-needle aspiration (FNA) completed as part of six clinical trials. From 2001 through 2011, a total of 404 procedures were conducted among 163 research volunteers, 85.9% of which were successful in obtaining sufficient fluid for the measurement of intratesticular steroid concentrations. Pain was the most common side effect, with 36.8% of procedures associated with moderate procedural pain and 4.7% with severe procedural pain. Postprocedural pain was uncommon and abated within a few days. Mild local bruising occurred with 14.9% of procedures. Two serious adverse events (0.5%) required surgical intervention. The risk of an adverse event was not associated with age, body mass index, testicular size, or the volume of fluid aspirated. Testicular FNA to obtain fluid for measurement of intratesticular steroid concentrations frequently causes mild to moderate procedural pain, but serious adverse events occur rarely. Testicular FNA has been instrumental for defining human intratesticular hormone physiology and is a minimally-invasive, safe, effective method for obtaining fluid for research on testicular physiology and pathology.

Pocket change: a simple educational intervention increases hospitalist documentation of comorbidities and improves hospital quality performance measures.

BACKGROUND: Complete documentation of patient comorbidities in the medical record is important for clinical care, hospital reimbursement, and quality performance measures. We designed a pocket card reminder and brief educational intervention aimed at hospitalists with the goal of improving documentation of 6 common comorbidities present on admission: coagulation abnormalities, metastatic cancer, anemia, fluid and electrolyte abnormalities, malnutrition, and obesity. METHODS: Two internal medicine inpatient teams led by 10 hospitalist physicians at an academic medical center received the educational intervention and pocket card reminder (n = 520 admissions). Two internal medicine teams led by nonhospitalist physicians served as a control group (n = 590 admissions). Levels of documentation of 6 common comorbidities, expected length of stay, and expected mortality were measured at baseline and during the 9-month study period. RESULTS: The intervention was associated with increased documentation of anemia, fluid and electrolyte abnormalities, malnutrition, and obesity in the intervention group, both compared to baseline and compared to the control group during the study period. The expected length of stay increased in the intervention group during the study period. CONCLUSIONS: A simple educational intervention and pocket card reminder were associated with improved documentation and hospital quality measures at an academic medical center.

Clinical practice patterns in the assessment and management of low testosterone in men: an international survey of endocrinologists.

OBJECTIVE: To document current practices in the approach to low testosterone in older men. Given that recommendations are based on low-level evidence, we hypothesized that there would be a wide variability in clinical practice patterns. DESIGN: Members of all major endocrine and andrological societies were invited to participate in a Web-based survey of the diagnostic work-up and management of a hypothetical index case of a 61-year old overweight man presenting with symptoms suggestive of androgen deficiency, without evidence of hypothalamic-pituitary-gonadal (HPT) axis disease. RESULTS: Nine hundred and forty-three respondents (91·2% adult endocrinologists) from Northern America (63·7%), Europe (12·7%), Oceania (8·2%), Latin America and Caribbean (7·6%), and the Middle East, Asia, or Africa (7·8%) completed the survey. Response rates among participating societies ranged from 4·1-20·0%. There was a wide variability in clinical practice patterns, especially regarding biochemical diagnosis of androgen deficiency, exclusion of HPT axis pathology, and monitoring for prostate cancer. In a man with suggestive symptoms, 42·4% of participants would offer testosterone treatment below a serum total testosterone of 10·4 nmol/l (300 ng/dl). A total of 46·0% of participants were, over the last five years, 'less inclined' to prescribe testosterone to men with nonspecific symptoms and borderline testosterone levels, compared to 'no change' (29·3%) or 'more inclined' (24·7%), P < 0·001. CONCLUSIONS: This large-scale international survey shows a wide variability in the management of lowered testosterone in older men, with deviations from current clinical practice guidelines, and a temporal trend towards increasing reluctance to prescribe testosterone to men without classical hypogonadism. These findings highlight the need for better evidence to guide clinicians regarding testosterone therapy.

Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: a randomized, controlled trial.

OBJECTIVE: To study the potential role for using serum biomarkers, including insulin-like factor 3 (INSL3), 17α-hydroxyprogesterone, antimüllerian hormone, and inhibin B, as correlates of intratesticular T (IT-T) concentrations in men. DESIGN: Prospective, randomized, controlled trial. SETTING: University-based medical center. PATIENT(S): Thirty-seven healthy men aged 18-50 years. INTERVENTION(S): All men received the GnRH antagonist acyline, plus very low doses of hCG (0 IU, 15 IU, 60 IU, or 125 IU) SC every other day or 7.5 g T gel daily (75 mg delivered). The IT-T concentrations obtained by percutaneous testicular aspiration with simultaneous serum protein and steroid concentrations were measured at baseline and after 10 days of treatment. MAIN OUTCOME MEASURE(S): Intratesticular and serum hormone and gonadotropin concentrations. RESULT(S): After 10 days of gonadotropin suppression, serum INSL3 decreased by more than 90% and correlated highly with IT-T concentrations. In contrast, serum inhibin B, antimüllerian hormone, and 17α-hydroxyprogesterone did not correlate with IT-T. Serum INSL3 increased with the dose of hCG administered and returned to baseline after treatment. CONCLUSION(S): Serum INSL3 correlates highly with IT-T and serum T concentrations during acute gonadotropin suppression in men. Human chorionic gonadotropin stimulates dose-dependent increases in INSL3 and IT-T in healthy men and might be a useful biomarker of IT-T concentration in some clinical settings. CLINICAL TRIAL REGISTRATION NUMBER: NCT# 00839319.

Testosterone treatment and mortality in men with low testosterone levels.

CONTEXT: Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known. OBJECTIVE: The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels. DESIGN: This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time-varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori. SETTING: The study was conducted with a clinical database that included seven Northwest Veterans Affairs medical centers. PATIENTS: Patients included a cohort of 1031 male veterans, aged older than 40 yr, with low total testosterone [≤250 ng/dl (8.7 nmol/liter)] and no history of prostate cancer, assessed between January 2001 and December 2002 and followed up through the end of 2005. MAIN OUTCOME MEASURE: Total mortality in testosterone-treated compared with untreated men was measured. RESULTS: Testosterone treatment was initiated in 398 men (39%) during routine clinical care. The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men (P<0.0001) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone. After multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease, testosterone treatment was associated with decreased risk of death (hazard ratio 0.61; 95% confidence interval 0.42-0.88; P = 0.008). No significant effect modification was found by age, diabetes, or coronary heart disease. CONCLUSIONS: In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment. These results should be interpreted cautiously because residual confounding may still be a source of bias. Large, randomized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels.

Assessment and management of low bone density in inflammatory bowel disease and performance of professional society guidelines.

BACKGROUND: Inflammatory bowel disease (IBD) patients have increased prevalence of osteoporosis, leading to guideline recommendations for bone mineral density (BMD) testing. The study aim was to identify predictors of BMD testing and treatment and assess guideline effectiveness to identify IBD patients with osteoporosis. METHODS: Records of all IBD patients at seven medical facilities were reviewed for clinical data and BMD testing from January 1996 through October 2006. RESULTS: A total of 2035 patients had 317 bone density tests performed. Osteopenia was found in 48% of patients, osteoporosis in 26%. Among patients meeting guideline criteria for BMD testing and ≥1 year of follow-up, 23.3% underwent testing. The strongest predictors of testing were menopause (adjusted hazard ratio [AHR] 3.02) and receiving care at a tertiary center (AHR 2.56). Testing rates were low in patients with age ≥60 years, ulcerative colitis, and a history of inpatient IBD treatment. Osteoporotic patients received calcium/vitamin D and bisphosphonates in 59% and 75% of cases, respectively. Osteoporotic males had a 37% rate of hypogonadism. Guideline criteria do not distinguish patients with osteoporosis. The criteria had a sensitivity, specificity, positive predictive value, and negative predictive value of 84%, 23%, 27%, and 81% for osteoporosis in the tested population, respectively. CONCLUSIONS: Osteoporosis is highly prevalent in the IBD population, but BMD testing and osteoporosis treatments are underutilized. Male hypogonadism is common in osteoporotic IBD patients. Guidelines do not identify IBD patients with osteoporosis.

The effect of 5alpha-reductase inhibition with dutasteride and finasteride on bone mineral density, serum lipoproteins, hemoglobin, prostate specific antigen and sexual function in healthy young men.

PURPOSE: Dutasteride and finasteride are 5alpha-reductase inhibitors that dramatically decrease serum levels of dihydrotestosterone. Because androgens affect bone, lipids, hematopoiesis, prostate and sexual function, we determined the impact of 5alpha-reductase inhibitors on these end points. MATERIALS AND METHODS: We conducted a randomized, double-blinded, placebo controlled trial of 99 men 18 to 55 years old randomly assigned to receive 0.5 mg dutasteride (33), 5 mg finasteride (34) or placebo (32) daily for 1 year. Bone mineral density was measured at baseline, after 1 year of treatment and 6 months after drug discontinuation. In addition, markers of bone turnover, fasting serum lipoprotein concentrations, hemoglobin and prostate specific antigen were measured at baseline, after 26 and 52 weeks of treatment, and again 24 weeks after drug discontinuation. Sexual function was assessed at these points by a validated questionnaire. RESULTS: Significant suppression of circulating dihydrotestosterone levels with the administration of dutasteride or finasteride did not significantly affect bone mineral density or markers of bone metabolism. Similarly serum lipoproteins and hemoglobin were unaffected. Serum prostate specific antigen and self-assessed sexual function decreased slightly during treatment with both 5alpha-reductase inhibitors but returned to baseline during followup. CONCLUSIONS: Profound suppression of circulating serum dihydrotestosterone induced by 5alpha-reductase inhibitors during 1 year does not adversely impact bone, serum lipoproteins or hemoglobin, and has a minimal, reversible effect on serum prostate specific antigen and sexual function in normal men. Circulating dihydrotestosterone does not appear to have a clinically significant role in modulating bone mass, hematopoiesis or lipid metabolism in normal men.

Serum 17-hydroxyprogesterone strongly correlates with intratesticular testosterone in gonadotropin-suppressed normal men receiving various dosages of human chorionic gonadotropin.

OBJECTIVE: To determine if serum concentrations of testosterone precursors would correlate with intratesticular testosterone (ITT) concentration measured directly by testicular aspiration and allow for a less invasive means of inferring ITT. DESIGN: Controlled clinical study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Twenty-nine normal men. INTERVENTION(S): We determined ITT concentration by testicular aspiration before and after treatment in men receiving exogenous T to block endogenous gonadotropin production and randomly assigned to one of four doses of hCG (0, 125 IU, 250 IU, or 500 IU every other day) for 3 weeks. MAIN OUTCOME MEASURE(S): The association between serum 17-hydroxyprogesterone (17OH-P), androstenedione, and DHEA and ITT. RESULT(S): With T administration alone, serum 17OH-P decreased significantly and increased significantly when 500 IU hCG was administered. End-of-treatment ITT strongly correlated with serum 17OH-P. Moreover, serum 17OH-P, but not androstenedione or DHEA, was independently associated with end-of-treatment ITT by multivariate linear regression. CONCLUSION(S): Serum 17OH-P is highly correlated with ITT in gonadotropin-suppressed normal men receiving T and stimulated with hCG. Serum 17OH-P is a surrogate biomarker of ITT and may be useful in research and in men receiving gonadotropin therapy for infertility.

Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist.

INTRODUCTION: Exogenous androgens plus progestins can be used to suppress spermatogenesis, resulting in effective male hormonal contraception; however, induction of azoospermia can require 3-6 months, and these methods require injectable or implantable androgens. We hypothesized that testosterone (T) transdermal gel (T gel) could be combined with a depot formulation of the progestin, depomedroxyprogesterone acetate (DMPA), with or without the potent GnRH antagonist, acyline, to suppress spermatogenesis conveniently, rapidly, and reversibly. OBJECTIVES: The objectives of the study were: 1) to determine the rate of severe oligospermia (< or = 1 million sperm/ml) using T gel+DMPA; and 2) to determine whether the addition of acyline to T gel+DMPA during the first 12 wk of the regimen would accelerate and improve suppression of spermatogenesis. METHODS: Forty-four healthy men, ages 18-55 yr, were randomized to T gel (100 mg daily)+DMPA (300 mg/3 months) or acyline (300 microg/kg.2 wk x 12 wk)+T gel+DMPA. Thirty-eight men completed the 24-wk treatment protocol. RESULTS: All men had dramatic suppression of spermatogenesis; 90% of the subjects became severely oligospermic, a rate comparable to implantable and injectable T+progestin combinations. The addition of acyline did not significantly accelerate spermatogenic suppression or improve rates of severe oligospermia. There were no serious adverse events, and there were minimal changes in weight, serum lipids, and prostate-specific antigen. CONCLUSIONS: The combination of T gel+DMPA is a promising new regimen in male contraception. The addition of the GnRH antagonist acyline, as part of an induction phase in a male contraception regimen, has limited clinical utility. Additional studies using T gel for male contraception are warranted.

Male hypogonadism : an update on diagnosis and treatment.

Male hypogonadism is one of the most common endocrinologic syndromes. The diagnosis is based on clinical signs and symptoms plus laboratory confirmation via the measurement of low morning testosterone levels on two different occasions. Serum luteinizing hormone and follicle-stimulating hormone levels distinguish between primary (hypergonadotropic) and secondary (hypogonadotropic) hypogonadism. Hypogonadism associated with aging (andropause) may present a mixed picture, with low testosterone levels and low to low-normal gonadotropin levels. Androgen replacement therapy in hypogonadal men has many potential benefits: improved sexual function, an enhanced sense of well-being, increased lean body mass, decreased body fat, and increased bone density. However, it also carries potential risks, including the possibility of stimulating the growth of an occult prostate cancer. The benefits of androgen therapy outweigh the risks in men with classic hypogonadism. However, for men with mild hypogonadism or andropause, the balance between benefits and risks is not always clear. Unfortunately, studies to date have included too small a number of patients and have been too short in duration to provide meaningful data on the long-term risks versus the benefits of androgen replacement therapy in these populations. Several products are currently marketed for the treatment of male hypogonadism. Weekly-to-biweekly injections of testosterone cypionate (cipionate) or testosterone enanthate (enantate) are widely used, as they are economical and generally well tolerated. However, once-daily transdermal therapies have become increasingly popular and now include both patch and gel systems. Intramuscular injection of testosterone undecanoate is an attractive new therapy that can be administered quarterly. To confirm an adequate replacement dosage, assessment of clinical responses and measurement of serum testosterone levels generally suffice. For selected men, serial measurement of bone mineral density during androgen therapy might be helpful to confirm end-organ effects. For men aged >50 years, we advocate measurement of hematocrit for detection of polycythemia and a digital rectal examination with a serum prostate-specific antigen level measurement for prostate cancer screening during the first few months of androgen therapy. Subsequently, a hematocrit should be obtained yearly or after changes in therapy, and annual prostate cancer screening can be offered to the patient after a discussion of its risks and benefits.

Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression.

In previous studies of testicular biopsy tissue from healthy men, intratesticular testosterone (ITT) has been shown to be much higher than serum testosterone (T), suggesting that high ITT is needed relative to serum T for normal spermatogenesis in men. However, the quantitative relationship between ITT and spermatogenesis is not known. To begin to address this issue experimentally, we determined the dose-response relationship between human chorionic gonadotropin (hCG) and ITT to ascertain the minimum dose needed to maintain ITT in the normal range. Twenty-nine men with normal reproductive physiology were randomized to receive 200 mg T enanthate weekly in combination with either saline placebo or 125, 250, or 500 IU hCG every other day for 3 wk. ITT was assessed in testicular fluid obtained by percutaneous fine needle aspiration at baseline and at the end of treatment. Baseline serum T (14.1 nmol/liter) was 1.2% of ITT (1174 nmol/liter). LH and FSH were profoundly suppressed to 5% and 3% of baseline, respectively, and ITT was suppressed by 94% (1234 to 72 nmol/liter) in the T enanthate/placebo group. ITT increased linearly with increasing hCG dose (P < 0.001). Posttreatment ITT was 25% less than baseline in the 125 IU hCG group, 7% less than baseline in the 250 IU hCG group, and 26% greater than baseline in the 500 IU hCG group. These results demonstrate that relatively low dose hCG maintains ITT within the normal range in healthy men with gonadotropin suppression. Extensions of this study will allow determination of the ITT concentration threshold required to maintain spermatogenesis in man.