The testis, eunuchs, and testosterone: a historical review over the ages and around the world.

INTRODUCTION: Testosterone therapy for men with testosterone deficiency is widely used, yet remains controversial. The rich and fascinating history of the testicles, including human castration, provides a valuable perspective on this important topic. OBJECTIVES: This study reviewed the history of testosterone from antiquity to the modern day. METHODS: Primary sources consisted of books and relevant articles, augmented by a MEDLINE search using the key words "testis," "testicles," "castration," "eunuchs," "testosterone," and "testicular function." RESULTS: An early scientific observation was that castration reduced sexual development and activity, originating with domestication of animals approximately 10 000 years ago. Human castration appears in ancient Egyptian mythology more than 4000 years ago, in Greek mythology from 8th century BCE, and in the Bible. The history of eunuchs in China spanned 2000 years, beginning with the Hsia dynasty (2205-1766 BCE). The concept that the testicles produced some factor responsible for male sexual development and behavior was thus known throughout the world since the beginning of recorded history. Testosterone was isolated and synthesized in 1935 and was soon available as a treatment. Multiple benefits of testosterone therapy were apparent by 1940. Recent large, controlled testosterone studies have conclusively demonstrated sexual and general health benefits, with a strong safety profile. CONCLUSION: Testosterone has been a known substance for <1% of the historical timeline, yet knowledge that the testes were responsible for male sexual development and behavior has been known since the beginning of recorded history. Today, modern evidence has demonstrated the importance of normal levels of testosterone for general health as well as sexual function and desire. Yet, testosterone therapy remains controversial. We believe this historical review provides a helpful perspective on this age-old issue.

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.

How the rise of testosterone therapy in men was inspired by lizard research with David Crews.

A chance encounter in 1975 with David Crews in Harvard Square led to 3 years of research in his lab, investigating the role of testosterone (T) in male sexual behavior of the lizard, Anolis carolinensis. In 1988 when I began my practice as a urologist and specialist in men's health, my research experience with lizards led me to offer testosterone therapy (TTh) to men suffering with symptoms of testosterone deficiency, despite the universal belief that TTh caused prostate cancer (PCa). My investigation of this topic over 30+ years has led to revolutionary changes in the diagnosis and treatment of men with testosterone deficiency and our understanding of the biology of testosterone and PCa. Today, it is routine for men successfully treated for PCa to receive TTh, a remarkable fact given that standard treatment for men with advanced PCa has been androgen deprivation for the last 80 years. Our research showed low T was not protective for PCa; TTh did not appear to worsen PCa for various cancer stages; and provided the theoretical framework for understanding why androgen deprivation shrinks PCa tumors, yet TTh appears to not cause PCa growth under most conditions. This is based on the Saturation Model, which recognizes there is a finite ability of androgens to stimulate PCa growth, which becomes maximal at low T concentrations. David Crews was an outstanding mentor-the lessons I learned from him inspired a lifetime of work, which in turn led to improved quality of life for millions of men.

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.

Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men.

The relative proportional increase of the elderly population within many countries will become one of the most significant social transformations of the twenty-first century and, for the first time in history, persons aged 65 or above outnumbered children under five years of age globally. One in four persons living in Europe and Northern America will be aged 65 or over. One of the goals of ISSAM is to raise awareness of the special health needs of older men. Since a significant number of aging men will eventually become testosterone deficient, the Hypogonadism panel of ISSAM updates its guidelines.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

BACKGROUND: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS & LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849-867.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with hypoactive sexual desire disorder (HSDD). METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS AND LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

Background: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). Aim: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. Methods: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. Outcomes: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. Results: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. Clinical Implications: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. Strengths & Limitations: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. Conclusion: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

Association of low testosterone with changes in non-cardiovascular biomarkers in adult men.

Testosterone has effects on many organs and systems. The purpose of this study was to test the hypothesis that low testosterone is associated with changes in various non-cardiovascular biomarkers in men older than 40 who were tested for possible hypogonadism. We extracted data from 9939 outpatient men who were over 40 years old (median age 56) and who also had concurrent laboratory measurements of total testosterone and one or more biomarkers of interest: estradiol, uric acid, prostate-specific antigen (PSA), sex-hormone binding globulin (SHBG), luteinizing hormone, creatinine, bone alkaline phosphatase (BAP), creatine kinase, hemoglobin A1c, and 25-hydroxy-vitamin D, and body mass index (BMI). In a smaller exploratory study of 19 otherwise healthy men presenting for evaluation of possible hypogonadism, pre-albumin (a.k.a.transthyretin, a marker of anabolism) and testosterone were measured. Men with lower levels of testosterone had significantly (p < 0.001) lower mean levels of PSA, SHBG, luteinizing hormone, and estradiol. Overall, men with low levels of testosterone also had significantly (p < 0.001) higher mean levels of LDH and BAP, but these associations varied between men who were younger or older than 56 years. There was a moderate but statistically significant positive correlation (r = 0.63, p < 0.05) between testosterone levels and pre-albumin. These results confirm our hypothesis that testosterone deficiency is associated with a broad range of systemic changes demonstrable in hormonal and non-hormonal serum assays in men over 40 years old being tested for possible hypogonadism.

Absent Diurnal Variation in Serum Testosterone in Young Men with Testosterone Deficiency.

PURPOSE: Although healthy young men demonstrate a diurnal pattern of serum testosterone, minimal information is available on diurnal variation in young men with testosterone deficiency. MATERIALS AND METHODS: Blood samples were obtained during a 24-hour period at 8 and 11 a.m., 2, 5 and 8 p.m., and 8 a.m. the following morning. Men were categorized with normal or low testosterone if serum testosterone was greater than 300 ng/dl or less than 300 ng/dl at 8 a.m., respectively. RESULTS: We studied 21 volunteers with a mean age of 31.7 years (range 18 to 49). Testosterone was normal in 11 men and low in 10 and all had a normal luteinizing hormone concentration. The low testosterone group was older (mean age 33.4 vs 30.1 years) with a higher body mass index (mean 32.6 vs 27.5 kg/m2) but the differences were not significant. The highest and lowest overall mean testosterone concentrations were observed at 8 a.m. and 2 p.m., respectively. Mean testosterone levels in the normal group declined between 8 a.m. and 2 p.m. from 423 to 358 ng/dl, representing a 15% decrease (p=0.0003). Mean testosterone in the low testosterone group was 228 ng/dl at 8 a.m. and 218 ng/dl at 2 p.m., representing a 4% decline (p=0.54). Calculated free testosterone paralleled total testosterone with a 14% decrease in the normal testosterone group (p <0.001) and a 5% decrease in the low testosterone group (p=0.52). Two of 11 men in the normal group showed no diurnal variation. No subject with baseline testosterone greater than 400 ng/dl had testosterone less than 300 ng/dl at any time point. CONCLUSIONS: Men with low testosterone failed to show diurnal variation on 24-hour blood sampling. We speculate that similar central mechanisms may be involved in the pathophysiology leading to secondary testosterone deficiency as well as the loss of circadian rhythms.

Successful treatment of Post-orgasmic illness syndrome with human chorionic gonadotropin.

Post-orgasmic illness syndrome (POIS) is an uncommon condition in which men experience debilitating symptoms following orgasm, including anxiety, weakness, and lassitude. The etiology is unknown, and treatment challenging. We present a 25y man with POIS since puberty. He dreaded ejaculation due to his subsequent symptoms. Multiple prior treatments had failed. Blood tests revealed testosterone (T) deficiency. hCG was prescribed. At 6 weeks T levels normalized with near-complete resolution of symptoms. This successful result argues for hormonal investigation in men with POIS, and a trial of hCG or T therapy if total or free T is low or borderline.

The History of Testosterone and the Evolution of its Therapeutic Potential.

INTRODUCTION: Testosterone therapy has been controversial since its synthesis in the 1930s to the present day. Testosterone's history provides depth and context for current controversies. AIM: To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern day. METHODS: Expert review of the literature. MAIN OUTCOME MEASURES: Impactful events in the history of testosterone. RESULTS: By the 1940s there was already a fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293-297) in 1941 that testosterone activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations-the saturation model-provided the theoretical framework for understanding the relation between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940. CONCLUSIONS: If the past has any lessons for the future, it is likely that research will continue to demonstrate health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine. Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev 2020;8:286-296.

Safety of testosterone therapy in men with prostate cancer.

Introduction: The use of testosterone therapy (TTh) in men with prostate cancer (PCa) is relatively new, and controversial, due to the longstanding maxim that TTh is contraindicated in men with PCa. Scientific advances have prompted a reevaluation of the potential role for TTh in men with PCa, particularly as TTh has been shown to provide important symptomatic and general health benefits to men with testosterone deficiency (TD), including many men with PCa who may expect to live 30-50 years after diagnosis. Areas covered: This review outlines the historical underpinnings of the historical belief that TTh 'fuels' PCa and the experimental and clinical studies that have radically altered this view, including description of the saturation model. The authors review studies of TTh in men with PCa following radical prostatectomy and radiation therapy, in men on active surveillance, and in men with advanced or metastatic PCa. Expert opinion: TTh provides important symptomatic and overall health benefits for men with PCa who have TD. Although more safety studies are needed, TTh is a reasonable therapeutic option for men with low-risk PCa after surgery or radiation. Data in men on active surveillance are limited, but initial reports are reassuring.

Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine.

INTRODUCTION: The International Consultation for Sexual Medicine met in Lisbon in 2018 to review updated recommendations regarding testosterone deficiency (TD) and its treatment. AIM: To provide updated clinical recommendations regarding TD and its treatment. METHODS: A Medline search was performed for testosterone (T) articles published since the 2015 International Consultation for Sexual Medicine report. Recommendations were presented at the Lisbon meeting, and feedback was incorporated into final recommendations. MAIN OUTCOME MEASURES: Selected topics for these updates included terminology, clinical diagnosis, sexual function, prostate, cardiovascular, metabolic conditions, anemia, bone health, and therapeutic options. RESULTS: The terms "testosterone deficiency" (TD) and "testosterone therapy" (TTh) were endorsed over numerous competing terms. The wide interindividual variability of sex hormone binding globulin concentrations influences the interpretation of total T concentrations. Symptoms of T deficiency more closely follow free T than total T concentrations. Symptomatic men with total T <350 ng/dL or free T <65-100 pg/mL may reasonably undergo a trial of T therapy. An empirical 6-month trial of TTh may be considered in men with strongly suggestive symptoms and values above these thresholds. Morning blood testing is indicated in men <40 years of age. Men >40 years may undergo initial afternoon testing, as long as confirmatory morning blood tests are later obtained. High-level evidence demonstrates TTh in men with TD improves sexual desire and erectile function. The weight of evidence indicates that TTh is not associated with increased risk of prostate cancer, cardiovascular events, or worsening lower urinary tract symptoms. Bone density and anemia are improved with TTh. Obesity and type 2 diabetes are associated with TD, and TTh provides consistent improvement in metabolic parameters. Multiple safe and effective therapeutic options are available to treat men with TD. CONCLUSIONS: Treatment of TD offers multiple benefits for sexual symptoms as well as for general health, without compelling evidence for increased risk of prostate cancer or cardiovascular events. Morgentaler A, Traish A, Hackett G, et al. Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine. Sex Med Rev 2019;7:636-649.

Serum Concentrations of Sex Hormone-binding Globulin Vary Widely in Younger and Older Men: Clinical Data from a Men's Health Practice.

BACKGROUND: The testosterone (T) status of a man is influenced by serum concentrations of sex hormone-binding globulin (SHBG). Specifically, tight binding of T to SHBG is believed to render the SHBG-bound T fraction biologically unavailable, meaning that interpretation of T levels in the clinical setting depends in part on knowledge of SHBG concentrations. Although SHBG levels have been reported in population studies, there is scant information for men presenting with clinical symptoms. OBJECTIVE: To report SHBG values for a large cohort of men presenting to a men's health center. DESIGN, SETTING, AND PARTICIPANTS: Medical records were reviewed for 1000 consecutive patients seen at our center with a reported SHBG value. SHBG concentrations were measured by a national clinical laboratory using an immunoassay run on a Beckman Coulter DXi system. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were age-stratified and data were plotted in the form of comparative histograms. RESULTS AND LIMITATIONS: The mean age (±standard deviation) of the total cohort was 53.5±13.5 yr (range 17-91). The mean SHBG was 31.8±15.2nmol/l (range 6-109), with a nearly 20-fold difference from the lowest to the highest values. SHBG was >60nmol/l in 5.6% of the men. Patients were stratified according to age. A total of 535 patients were ≤54 yr old. In this younger cohort, the mean age was 40.52±7.9 yr (range 17-54) and mean SHBG was 27.7±13.3nmol/l (range 6-88), and 2.2% of patients had SHBG >60nmol/l. A total of 465 patients were ≥55 yr old. In this older cohort, the mean age was 64.8±7.23 yr (range 55-91) and mean SHBG was 36.6±15.8 nmol/l (range 11-109), and 9% of patients had SHBG >60 nmol/l. Mean SHBG was significantly higher in the older group (p<0.001). CONCLUSIONS: A remarkably wide distribution of SHBG concentrations was observed in a clinical population of men presenting to a men's health center, among both younger and older men. Since SHBG concentrations greatly influence test results for hormones that bind to SHBG, recognition of this large interindividual variability should be considered in the clinical interpretation of these hormone results, particularly for T. Routine SHBG testing should be considered for men suspected of T deficiency. PATIENT SUMMARY: Sex hormone-binding globulin (SHBG) levels vary widely among both older and younger men. This may impact the interpretation of test results for hormones that bind to SHBG, such as testosterone, since the portion that binds to SHBG is believed to not be biologically available.