Table of Contents
Journal of Hormones
Volume 2014 (2014), Article ID 190347, 17 pages
http://dx.doi.org/10.1155/2014/190347
Review Article

Systematic Literature Review of the Epidemiology of Nongenetic Forms of Hypogonadism in Adult Males

1Product Value Strategy Consulting, Optum, Eden Prairie, MN 55344, USA
2Global Health Outcomes, Merck & Co., Inc., West Point, PA 19486, USA
3School of Pharmacy, Temple University, Philadelphia, PA 19140, USA
4Epidemiology, Optum, Ann Arbor, MI 48108, USA
5Men’s Health Boston, Brookline, MA 02445, USA
6Harvard Medical School, Boston, MA 02115, USA
7Boolean Research Consulting, Westmount, QC, Canada
8Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley S752EP, UK
9Department of Human Metabolism, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield S10 2RX, UK

Received 20 May 2014; Accepted 23 June 2014; Published 22 July 2014

Academic Editor: Jack van Honk

Copyright © 2014 Victoria Zarotsky et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This study summarizes the literature on the prevalence, incidence, and proportion of patients receiving treatment for male hypogonadism and a systematic literature search was performed for articles published in the last 20 years. Of the 97 studies identified, 96 examined the prevalence, 2 examined the incidence, and 4 examined the proportion of males with hypogonadism patients receiving treatment. Based on studies conducted in Europe and USA, the prevalence of hypogonadism in the general population ranged from 2.1% to 12.8% of middle-aged to older men, with an estimated incidence of 12 new cases per 1,000 person-years. Prevalence was higher among patients with comorbid conditions, such as type 2 diabetes mellitus and obesity. Approximately 10–12% of men with hypogonadism were receiving testosterone treatment. This literature review suggests that there is potentially a significant burden of hypogonadism in the general population. Burden seems to increase with age and in the presence of certain disease conditions. Data suggests that many hypogonadal men who may benefit from testosterone replacement are not receiving treatment. This may be the result of underdiagnosis of the disease, lack of awareness by patients or physicians, irregularities surrounding the diagnostic criteria, and deficiency of long-term safety studies.

1. Introduction

Hypogonadism in men has been defined as a clinical syndrome resulting from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa, due to disruption of one or more levels of the hypothalamic-pituitary-testicular axis [1]. A diagnosis of hypogonadism is typically based on the signs and symptoms associated with low T, followed by biochemical confirmation of low testosterone (T) [1]. The most widely accepted parameter used to establish hypogonadism is the measurement of serum total testosterone (TT) [1]; however, cut-off values used to indicate hypogonadism have not been clearly defined and vary across studies. Recent clinical practice guidelines published by the Endocrine Society have reported that the average TT threshold, at which the likelihood of most symptoms associated with hypogonadism increases, corresponds to the lower limit of the normal range for young men, that is, approximately 300 ng/dL (10.4 nmol/liter) [1]. Correspondingly, a common threshold used in the literature to indicate hypogonadism is serum TT <300 ng/dL (<10.4 nmol/L); however, cut-off values of <200 ng/dL (6.94 nmol/L) to <350 ng/dL (<12 nmol/L) are not uncommon. These thresholds are sometimes combined with requisite signs and symptoms, but not always. The result is a range of operational definitions of hypogonadism used in the literature, varying in degree of stringency and potentially leading to variations in estimates of prevalence of the disease.

The literature on the epidemiology of hypogonadism is confounded by considerable heterogeneity across studies, varying not only by operational definition but also by patient populations, study design, time frame of study, and geography. Estimates of prevalence, incidence, and treatment rates are influenced by all of these factors. The aim of this systematic review of the epidemiology of hypogonadism was to determine the prevalence and incidence of hypogonadism, as well as the proportion of males with hypogonadism receiving treatment of hypogonadism, while accounting for differences in patient and study characteristics and operational definition of hypogonadism used.

2. Methods

2.1. Eligibility Criteria

Eligible studies were defined in this systematic review as original studies that assessed the prevalence, incidence, or treatment rates of adult males (≥18 years of age) with hypogonadism, acquired or idiopathic. Studies on genetic forms of hypogonadism (i.e., Klinefelter’s syndrome) and secondary publications of the same results were not included. Observational studies with sample sizes >30 were included in this review; treatment and intervention studies were excluded.

2.2. Search Methods for Identification of Studies

Three pharmacologic and biomedical literature databases were searched for this systematic literature review: PubMed/MEDLINE database, Cochrane Library Database, and EMBASE. Search strings composed of medical subject heading (MeSH) terms, from the controlled vocabulary indexing hierarchy and/or in-text terms in title and/or abstract fields, were used (Table 1). Citations were limited to English language articles, published during a 20-year period (January 01, 1992, to August 31, 2012). The reference list of included publications was searched for relevant articles.

tab1
Table 1: Search strategy executed in PubMed/MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials August 31, 2012, and incidence, prevalence, and treatment rates.
2.3. Data Extraction

We abstracted key data elements using a standardized abstraction tool, including type of research design, country, study period, sample size, operational definition of hypogonadism used, study population characteristics, and outcomes. One author screened the search results against the predefined inclusion and exclusion criteria. Titles were evaluated, abstracts were reviewed, and potentially relevant full-text articles were evaluated for relevance. A quality check was conducted on 20% of the abstracts by a second reviewer.

We categorized studies based on population of interest: population-based studies were those with large sample sizes (>1 thousand) and minimal age restrictions and conducted in a specific geographical location; community-based studies were those with relatively smaller sample sizes (i.e., hundreds) and more restricted age ranges and conducted in a specific geographical location; primary care-based studies were those that recruited patients from a general primary care or medical clinic seeking medical care; screening-based studies recruited healthy individuals from a general health screening clinic. Primary care-based studies and screening-based studies were classified together as they were conducted in the same setting. Finally, clinical condition-based studies were those that examined prevalence of hypogonadism in patient populations with specific clinical conditions. We also separately summarized prevalence of hypogonadism by age for studies that provided these data.

3. Results

3.1. Literature Search Results

The literature search identified 1,395 articles that were reviewed for inclusion. After review of titles and abstracts, we evaluated 175 full-text articles and identified 97 articles that met our eligibility criteria: 96 reported on the prevalence of hypogonadism, 2 on the incidence, and 4 on treatment proportions (not mutually exclusive). The PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow chart can be found in Figure 1.

190347.fig.001
Figure 1: Flow diagram.
3.2. Prevalence of Hypogonadism

Among the 96 identified prevalence studies, 7 were population- [25] or community- [68] based studies and 7 were primary care or health screening studies [915]. Ten examined age-related changes for hypogonadism [2, 3, 8, 9, 12, 13, 1619] and seventy-eight were clinical condition-based studies [2097]. Studies varied considerably in geographic location, patient characteristics, sample sizes, and operational definition for hypogonadism. These studies are described in Tables 2 and 3.

tab2
Table 2: Prevalence of hypogonadism in population-, community-, and primary care or screening-based populations.
tab3
Table 3: Prevalence of hypogonadism among patients with specific conditions.
3.2.1. Population-Based Studies

The prevalence of hypogonadism in the 4 population-based studies ranged from 2.1% to 12.8% [25] (Table 2). Sample sizes in these studies ranged from 1,490 to 2,966 participants and the mean (SD) ages of the study participants ranged from 47.3 (12.5) to 59.15 (10.8) years. Mean age was not reported in one of the studies [3]; however, the sample was equally divided among men in their 40s, 50s, and 60s [3]. The studies were conducted in Europe (Belgium, Estonia, Hungary, Italy, Poland, Spain, Sweden, and UK) and USA.

The operational definition of hypogonadism used across studies varied considerably: the Study of Health in Pomerania (SHIP, 1997–2001) (Germany) [5] used the most liberal definition of hypogonadism (TT < 300 ng/dL, no symptom criteria) and reported the highest prevalence at 12.8%; the European Male Aging Study (EMAS, 2003–2005) [4] used the most stringent definition of symptomatic hypogonadism (TT < 317 ng/dL plus 3 specific symptoms of decreased frequency of morning erections, sexual thoughts, and erectile dysfunction) and reported the lowest prevalence at 2.1%. The Boston Area Community Health Survey (BACH, 2002–2005) [3] and the Massachusetts Male Aging Study (MMAS, 1987–1989) [2], both USA based, used similar operational definitions of symptomatic hypogonadism (TT cut-offs of <300 ng/dL plus ≥1 specific symptom or ≥2 nonspecific symptoms (BACH) and either TT <200 ng/dL plus ≥3 symptoms or TT 200–400 ng/dL plus FT <8.91 ng/dL plus ≥3 symptoms (see Table 2)) with reported prevalence of 5.6% (BACH) and 6.0% (MMAS), respectively.

3.2.2. Community-Based Studies

The prevalence of hypogonadism among the 3 community-based studies ranged from 9.5% to 31.2% (Table 2) [68]. All studies were cross-sectional and were conducted in Austria, China (Hong Kong), and Malaysia. The sample sizes ranged from 247 to 351 men, and the mean (SD) ages of men varied from 54 (NR) to 75.8 (0.4) years. The operational definition of hypogonadism varied considerably, with TT cut-offs ranging from <200 to <400, with and without low FT, and with and without symptoms. The highest prevalence (31.2%) was reported in a study of men with a mean age of 75.8 years [6].

3.2.3. Primary Care/Screening-Based Studies

Seven cross-sectional studies, conducted in Brazil, Chile, India, Italy, Taiwan, and USA, examined the prevalence of hypogonadism in a primary care or screening-based settings [915] (Table 2). Prevalence was higher than that observed in the general population surveys, ranging from 12% [10, 12] to 38.7% [13], with the majority around 20% [11, 12, 14, 15]. The sample sizes ranged from 96 to 2,719 men and the mean (SD) age of the participants in the studies ranged from 53.1 (NR) to 61.9 (7.5) years. Six of the studies used low TT to define hypogonadism [1015] and one study used low bioavailable T and symptoms [9]. Using TT <300 ng/dL as a marker, prevalence was 19.3% [15], 19.8% [14], 24.1% [12], 24.2% [11], and 38.7% [13]. One study used a stricter TT threshold (TT < 230 ng/dL) with a lower resulting prevalence of 12% [10]. Adding symptoms as a criterion, the prevalence decreased from 24.1% to 12% [12] and from 24.2% to 20.4% [11].

3.2.4. Clinical Condition-Based Studies

A total of 78 studies were identified and assessed prevalence of hypogonadism among patients with specific medical conditions (Table 3). The prevalence varied considerably by medical condition. Hypogonadism occurred commonly among patients with type 2 diabetes mellitus (T2DM). Thirteen studies conducted in the UK, Australia, India, Italy, and USA showed the prevalence of hypogonadism in patients with T2DM ranging from 4.4% to above 45% [23, 25, 29, 36, 40, 45, 47, 48, 50, 56, 61, 71, 87] varying based on the definition of hypogonadism used: prevalence ranged from 4.4% to 36% using TT <8 mmol [23, 29, 45, 50, 56, 61, 71], from 24.5 to 43% using TT <10.4 mmol [36, 40, 47, 48], and from 34.7% to 45% using TT <12 mmol [25, 87]. Hypogonadism was also common among obese patients with prevalence ranging from 15% to 78.8% [22, 54, 74] and among patients with MetS, ranging from 30 to 35% [27, 62, 83]. When combined with obesity or metabolic syndrome (MetS), prevalence estimates among patients with T2DM were higher (51% [39] and 43% [70] for patients with T2DM and obesity and MetS, resp.).

Prevalence of hypogonadism in patients with cardiac disease [44, 55, 65, 67, 84, 94, 95], erectile dysfunction [24, 26, 3235, 37, 49, 52, 59, 66, 85, 88], HIV [31, 38, 58, 78, 92, 93, 96], respiratory disease [51, 57, 64], depression [53, 68], cancer [43, 46, 63, 75, 76, 79, 80, 82, 91], rheumatoid arthritis [89], osteoporosis [30, 42], chronic kidney disease [21, 28, 60, 97], sickle cell disease [86], myopathies [20, 41, 52, 73, 90], urological diseases [77, 81], Peyronie’s disease [69], and Alzheimer’s and Parkinson’s disease [72] is detailed in Table 3.

3.2.5. Prevalence of Hypogonadism by Age

A total of 10 studies, conducted in Chile, China, Europe, Italy, and USA, examined changes in prevalence of hypogonadism with age (Table 4) [2, 3, 8, 9, 12, 13, 1619]. Sample sizes ranged from 96 to 2,162 and mean (SD) ages ranged from 47.3 (12.5) to 61.9 (7.5) years. Five of the studies were population-based[2, 3, 1719], one was community-based [8], and 4 were primary care-/screening-based [9, 12, 13, 16]; one was longitudinal [17] and 9 were cross-sectional [2, 3, 8, 9, 12, 13, 16, 18, 19].

tab4
Table 4: Prevalence of hypogonadism by age.

The prevalence of hypogonadism increased with each increasing age category [2, 3, 8, 9, 12, 13, 1619], with the rare exception within certain age categories [3, 8] (Table 4). Three of the studies reported significant values for trend [2, 9, 12], 3 reported significant differences between older and younger age categories [3, 9, 18], 2 studies did not conduct statistical analysis for differences in prevalence by age [17, 19], and one study was nonsignificant [8]. One cross-sectional study [13] reported a 17% (95% CI, 1.08–1.27) increase in risk of hypogonadism, for every 10-year increase in age. Prevalence ranged from approximately 0.1% to 16.5% among men aged 40–49, from 0.6% to 31.8% among men aged 50–59, from 3.2% to 30.1% among men aged 60–69, up to 66.7% among men of age ≥70 years [2, 3, 12, 1719], and 49% in the study that assessed the 80+ age category [17] (not all studies used the same age cut-offs).

3.3. Incidence of Hypogonadism

In two population-based studies (SHIP [5] and BACH [2]), in which incidence was examined, the reported incidence was 12.3 cases per 1,000 person-years in the US and 11.7 cases per 1000 person-years in Germany.

3.4. Treatment Rates for Hypogonadism

The proportion of patients receiving treatment was defined as the percentage of men with hypogonadism who were receiving testosterone therapy. Only 4 studies were identified and reported treatment proportions: one population-based [98], one primary care-based [13], and 2 clinical condition-based studies [38, 79]. The population-based (BACH) and clinical-based studies (HIM) reported that 10% [98] and 12% [13] of patients were receiving treatment for hypogonadism, respectively. Among the clinical condition-based studies, 12.1% of 144 childhood cancer survivors [79] and 38% of 296 men with HIV were on treatment for hypogonadism [38].

4. Discussion

In this systematic review, we identified 97 studies that met our inclusion/exclusion criteria for assessing the epidemiology of hypogonadism. The prevalence of hypogonadism was high and varied according to the operational definition of hypogonadism used and the population studied. The prevalence of hypogonadism in the population-based, community-based, and primary care- or screening-based studies ranged from 2.1 to 12.8% [915], from 9.5 to 31.2% [918], and from 12 to 38.7% [915], respectively. The prevalence was higher among clinical-based populations with specific conditions. For example, among patients with T2DM, obesity, and MetS, the prevalence ranged from 4.4 to >50% [23, 25, 29, 36, 40, 45, 47, 48, 50, 56, 61, 71, 87], from 15 to 78.8% [22, 54, 74], and from 30 to 35% [27, 62, 83], respectively.

In most instances, studies showed a linear relationship between prevalence and the degree of liberalness in the operational definition of hypogonadism [4, 5, 7, 12]. For instance, Haring et al. [5] reported prevalence estimates below TT levels of 8.0, 8.7, 10.4, and 12.0 nmol/L, which were 3.4%, 4.5%, 12.8%, and 21.6%. The added criteria of symptoms typically ensued a lower prevalence due to increased stringency of diagnosis. Among the population- and community-based studies, those that used a more stringent definition of hypogonadism, which included symptoms and low T, reported the lowest prevalence, ranging from 2.1% to 9.52% [24, 7, 8], while those using a more liberal definition of hypogonadism (low T only) reported higher prevalence, ranging from 19.1% to 31.2% [57]. The association between definition of hypogonadism and prevalence was also apparent among the primary care-/health screening-based studies (12–39%).

Prevalence also varied by age. Hypogonadism was consistently found to increase with age for studies reporting data by age (REF), with one study citing an increase of 17% (95% CI, 1.08–1.27) in risk of hypogonadism, for every 10-year increase in age [13]. One study that had a considerably older cohort (mean age of 75.8 years) [6] reported the highest prevalence (31.2%) among community-based studies. It was estimated in a 2007 publication that there were 4.7 million American men aging 30–79 years with symptomatic androgen deficiency [3]. It was projected that there will be as many as 6.5 million American men aging 30–79 years with symptomatic hypogonadism by 2025, an increase of 38% from the year 2000 population estimates, due to an aging population [3].

Despite the significant prevalence of hypogonadism, data suggest that the vast majority of hypogonadal men are not receiving treatment for this condition [13, 98]. Reasons for this low treatment proportion have not been definitively determined; however, contributing factors may include inadequate knowledge base among physicians regarding hypogonadism and uncertainty regarding diagnostic criteria. The main indication for testosterone replacement therapy is sexual dysfunction with symptoms of reduced libido and/or erectile dysfunction. This may not be an issue to some men and therefore they are not treated or subjects may decline therapy. Also, individuals may not be able to afford therapy in countries where people have to pay for their prescriptions and healthcare. Furthermore, with the lack of long-term placebo-controlled safety studies, some clinicians may have concerns especially in the older man in regard to risks of prostate cancer and cardiovascular disease, even though there is limited evidence from current published studies or meta-analyses. The only study which did show a possible relationship between testosterone replacement therapy and cardiovascular events was the TOM trial [99]. However, this study involved the administration of larger testosterone doses than those used in normal clinical practice and was not sufficiently powered to detect an increase in cardiovascular events. A similar trial where routine doses of testosterone were used did not detect any increase in cardiovascular events [100].

Results of this review highlight the fact that there is no standardized definition used in the hypogonadism epidemiologic research. The hypogonadism literature reports wide-ranging prevalence based not only on the different populations or subpopulations studied, but also on the use of diverse biochemical cut points or varied choices of symptoms. The actual prevalence of disease that a clinician will treat in his or her office may in fact be higher than what we found in this review, as clinicians may use a more liberal definition of hypogonadism to base their treatment decisions on.

The studies in this review represented a wide geographic distribution with samples from USA, Europe, Asia, and South America. The prevalence of hypogonadism may vary by geographical location, as recently demonstrated in a large international cohort of older men (>65 years of age) showing important geographical differences in concentrations of T [101]. However, differences in patient populations and operational definitions used across studies made it difficult to interpret the findings based on geography in the current review.

We can expect approximately 12 new cases of hypogonadism per 1,000 person-years [2, 5] and approximately 481,000 new cases of hypogonadism per year in US men aged 40–69 years [2]. It has been projected that there will be as many as 6.5 million US men aging 30–79 years with symptomatic AD by 2025 [3], an increase of 38% from the year 2000 population estimates, due to an aging population. While there is no conclusive evidence from this review that the prevalence of hypogonadism in the general population is increasing over time, there is evidence that the prevalence of hypogonadism does increase with age and with certain comorbidities such as T2DM and obesity, all of which are increasing in the general population. It follows that there may well be an increasing proportion of older men who will benefit from treatment for hypogonadism. As the proportion of the world’s population in the older ages continues to increase, the importance of studying, diagnosing, and treating male hypogonadism will also rise.

The mainstay treatment of low testosterone is testosterone replacement therapy (TRT), although there is indication that modification of diet and exercise regimes have the ability to improve testosterone levels [99]. Despite the significant prevalence of hypogonadism, self-reported data suggest that the vast majority of hypogonadal men are not receiving TRT treatment for this condition [13, 98]. Reasons for this low treatment proportion have not been definitively determined; however, contributing factors may include inadequate knowledge base among physicians regarding hypogonadism and uncertainty regarding diagnostic criteria. The main indication for TRT is sexual dysfunction, which, for some men, may not affect their daily lives, and therefore they choose not to be treated. Also, individuals may not be able to afford therapy in countries where people have to pay for their prescriptions and healthcare.

Another impeding factor for prescribing TRT may be a concern over the potential risk of cardiovascular disease and prostate cancer. The safety of TRT lacks examination in large, prospective, and adequately powered controlled trials [100]. Smaller studies have been published, some suggesting an association between testosterone replacement therapy and cardiovascular adverse events [100]. The TOM trial was terminated early due to an increased frequency of cardiovascular events in the men treated with testosterone [102]. However, this study involved the administration of larger testosterone doses than those used in normal clinical practice and was not sufficiently powered to detect an increase in cardiovascular events. A similar trial, which used routine doses of testosterone, did not detect any increase in cardiovascular events [103]. To address the question of safety and in lieu of long term, prospective safety data, the Endocrine Society Task Force on Testosterone Use in Adult Men commissioned a meta-analysis of randomized and observational studies with long-term follow-up in testosterone therapy in 2010. The analyses of 51 studies found no significant effect of TRT on mortality, prostate, or cardiovascular outcomes [100]. More recently, a retrospective database study of 8709 male veterans who underwent coronary angiography between 2005 and 2011 reported an increased risk (absolute risk increase: 5.8% (95% CI: −1.4% to 13.1%)) of experiencing an adverse cardiovascular event (all-cause mortality, MI, or ischemic stroke) among TRT versus nontreated men at 3 years after coronary angiography [104]. Although this study garnered media attention, it is limited by serious methodological concerns which put the results in question.

4.1. Limitations

A general limitation in hypogonadism research is the lack of a standardized operational definition of hypogonadism. Recently, professional societies have proposed operational definitions which include criteria of specific signs and symptoms plus biochemical low TT, typically defined as TT <300 ng/dL (<10.4 nmol/L) [1]. However, the literature is confounded by numerous studies using a variety of different definitions: some include sign and symptom criteria and others do not; biochemical TT thresholds used range from <8 nmol/L to <12 nmol/L, others use an FT criterion and no TT (as men with normal TT may be quite symptomatic in clinical due to low FT), and others use a TT and FT criterion. The varying definitions used make comparisons between studies difficult.

The proportions of patients receiving T therapy in the population were obtained from one population-based study and one primary care-based study, both of which reported on the number of participants who were receiving T therapy. Medication use, including use of T therapy, was assessed by patient self-report in the studies. Self-report of medication use is subjective and is at risk of both reporting bias and measurement bias. A more accurate measurement of treatment proportions could be obtained from chart review or commercial claims database study and may be an interesting objective for a future study.

As with all systematic reviews, publication bias, which can lead to bias if only positive studies or studies with a statistically significant difference are published, is an issue in this review. Another limitation of this review is that a quality appraisal of the individual studies was not conducted. Although methodological aspects of the individual studies, which may have influenced outcomes or comparisons between studies, were considered and commented on during the assessment of the evidence, a systematic quality assessment of the studies was not carried out.

5. Conclusions

This literature review suggests that there is potentially a significant burden of hypogonadism in the general population. The burden of hypogonadism increases with age and in the presence of certain clinical conditions, such as T2DM and obesity. Data suggested that the vast majority of hypogonadal men in the general population are not receiving treatment. This may be the result of underdiagnosis of the disease, due to lack of awareness by patients and/or physicians and the irregularities surrounding the diagnostic criteria.

Disclosure

The authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors and are fully responsible for all content and editorial decisions and were involved in all stages of paper development. This original paper has not been previously presented in whole by the authors. A portion of the information has been presented as a poster entitled “The prevalence, incidence and treatment rates of hypogonadism in men across geographies: a systematic review of the literature” at the ISPOR, May 18–22, 2013, New Orleans, LA.

Conflict of Interests

Victoria Zarotsky and Wendy Carman are employees of Optum and were contracted by Merck & Co., Inc., to conduct this study. Donna Coffin is employee of Boolean Research Consulting Services who was contracted by Optum. Ming-Yi Huang is a Postdoctoral Fellow funded by Merck & Co., Inc. Puneet K. Singhal is employed by Merck & Co., Inc. T. Hugh Jones has received research grants from BayerHealthcare, UK, and honoraria for educational lectures and/or advisory boards from BayerHealthcare, Clarus, Lilly, Merck, and Prostrakan. T. Hugh Jones and Abraham Morgentaler have served as Consultants to Merck & Co., Inc., for this study.

Acknowledgments

This study was conducted by Optum located in Eden Prairie, Minnesota, USA, and was funded by Merck & Co., Inc., West Point, PA. This study was supported by Merck & Co., Inc.

References

  1. S. Bhasin, G. R. Cunningham, F. J. Hayes et al., “Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline,” The Journal of Clinical Endocrinology & Metabolism, vol. 95, no. 6, pp. 2536–2559, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. A. B. Araujo, A. B. O'Donnell, D. J. Brambilla et al., “Prevalence and incidence of androgen deficiency in middle-aged and older men: Estimates from the Massachusetts male aging study,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 12, pp. 5920–5926, 2004. View at Publisher · View at Google Scholar · View at Scopus
  3. A. B. Araujo, G. R. Esche, V. Kupelian et al., “Prevalence of symptomatic androgen deficiency in men,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 11, pp. 4241–4247, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. A. Tajar, I. T. Huhtaniemi, T. W. O'Neill et al., “Characteristics of androgen deficiency in Late-onset hypogonadism: results from the European Male Aging study (EMAS),” Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 5, pp. 1508–1516, 2012. View at Publisher · View at Google Scholar · View at Scopus
  5. R. Haring, T. Ittermann, H. Völzke et al., “Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania,” Aging Male, vol. 13, no. 4, pp. 247–257, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. A. Ponholzer, S. Madersbacher, M. Rauchenwald, S. Jungwirth, P. Fischer, and K. Tragl, “Vascular risk factors and their association to serum androgen levels in a population-based cohort of 75-year-old men over 5 years: results of the VITA study,” World Journal of Urology, vol. 28, no. 2, pp. 209–214, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. E. M. Khoo, H. M. Tan, and W. Y. Low, “Erectile dysfunction and comorbidities in aging men: an urban cross-sectional study in Malaysia,” Journal of Sexual Medicine, vol. 5, no. 12, pp. 2925–2934, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. S. Y. S. Wong, D. C. C. Chan, A. Hong, and J. Woo, “Prevalence of and risk factors for androgen deficiency in middle-aged men in Hong Kong,” Metabolism: Clinical and Experimental, vol. 55, no. 11, pp. 1488–1494, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. J. E. Blümel, P. Chedraui, S. A. Gili, A. Navarro, K. Valenzuela, and S. Vallejo, “Is the Androgen Deficiency of Aging Men (ADAM) questionnaire useful for the screening of partial androgenic deficiency of aging men?” Maturitas, vol. 63, no. 4, pp. 365–368, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. L. di Luigi, P. Sgrò, V. Fierro et al., “Prevalence of undiagnosed testosterone deficiency in aging athletes: does exercise training influence the symptoms of male hypogonadism?” Journal of Sexual Medicine, vol. 7, no. 7, pp. 2591–2601, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. A. Goel, R. J. Sinha, D. Dalela, S. Sankhwar, and V. Singh, “Andropause in Indian men a preliminary cross-sectional study,” Urology Journal, vol. 6, no. 1, pp. 40–46, 2009. View at Google Scholar · View at Scopus
  12. C.-C. Liu, W.-J. Wu, Y.-C. Lee et al., “The prevalence of and risk factors for androgen deficiency in aging Taiwanese men,” Journal of Sexual Medicine, vol. 6, no. 4, pp. 936–946, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. T. Mulligan, M. F. Frick, Q. C. Zuraw, A. Stemhagen, and C. McWhirter, “Prevalence of hypogonadism in males aged at least 45 years: The HIM study,” International Journal of Clinical Practice, vol. 60, no. 7, pp. 762–769, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. A. N. Júnior, S. dos Santos Szelbracikowski, A. C. Nardi, and J. C. de Almeida, “Age-related testosterone decline in a Brazilian cohort of healthy military men,” International Brazilian Journal of Urology, vol. 37, no. 5, pp. 591–597, 2011. View at Publisher · View at Google Scholar · View at Scopus
  15. H. J. Schneider, C. Sievers, J. Klotsche et al., “Prevalence of low male testosterone levels in primary care in Germany: cross-sectional results from the DETECT study,” Clinical Endocrinology, vol. 70, no. 3, pp. 446–454, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. L. Di Luigi, P. Sgrò, V. Fierro et al., “Prevalence of undiagnosed testosterone deficiency in aging athletes: does exercise training influence the symptoms of male hypogonadism?” Journal of Sexual Medicine, vol. 7, no. 7, pp. 2591–2601, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. S. M. Harman, E. J. Metter, J. D. Tobin, J. Pearson, and M. R. Blackman, “Longitudinal effects of aging on serum total and free testosterone levels in healthy men,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 724–731, 2001. View at Publisher · View at Google Scholar · View at Scopus
  18. J.-Y. Li, X.-Y. Li, M. Li et al., “Decline of serum levels of free testosterone in aging healthy Chinese men,” Aging Male, vol. 8, no. 3-4, pp. 203–206, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. F. C. W. Wu, A. Tajar, J. M. Beynon et al., “Identification of late-onset hypogonadism in middle-aged and elderly men,” The New England Journal of Medicine, vol. 363, no. 2, pp. 123–135, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Abbasi, D. E. Mattson, M. Cuisinier et al., “Hyposomatomedinemia and hypogonadism in hemiplegic men who live in nursing homes,” Archives of Physical Medicine and Rehabilitation, vol. 75, no. 5, pp. 594–599, 1994. View at Google Scholar · View at Scopus
  21. F. Albaaj, M. Sivalingham, P. Haynes et al., “Prevalence of hypogonadism in male patients with renal failure,” Postgraduate Medical Journal, vol. 82, no. 972, pp. 693–696, 2006. View at Publisher · View at Google Scholar · View at Scopus
  22. C. A. Allan, B. J. Strauss, H. G. Burger, E. A. Forbes, and R. I. McLachlan, “The association between obesity and the diagnosis of androgen deficiency in symptomatic ageing men,” Medical Journal of Australia, vol. 185, no. 8, pp. 424–427, 2006. View at Google Scholar · View at Scopus
  23. S. G. Anderson, A. Heald, N. Younger et al., “Screening for hypogonadism in diabetes 2008/9: results from the Cheshire Primary Care cohort,” Primary Care Diabetes, vol. 6, no. 2, pp. 143–148, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Arafa, W. Zohdy, S. Aboulsoud, and R. Shamloul, “Prevalence of late-onset hypogonadism in men with type 2 diabetes mellitus,” Andrologia, vol. 44, no. 1, pp. 756–763, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Biswas, D. Hampton, R. G. Newcombe, and D. A. Rees, “Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life,” Clinical Endocrinology, vol. 76, no. 5, pp. 665–673, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. T. J. Bunch, D. Abraham, S. Wang, and A. W. Meikle, “Pituitary radiographic abnormalities and clinical correlates of hypogonadism in elderly males presenting with erectile dysfunction,” Aging Male, vol. 5, no. 1, pp. 38–46, 2002. View at Publisher · View at Google Scholar · View at Scopus
  27. A. D. A. Caldas, A. L. Porto, L. D. C. D. Motta, and L. A. Casulari, “Relationship between insulin and hypogonadism in men with metabolic syndrome,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 53, no. 8, pp. 1005–1011, 2009. View at Google Scholar · View at Scopus
  28. J. J. Carrero, A. R. Qureshi, A. Nakashima et al., “Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease,” Nephrology Dialysis Transplantation, vol. 26, no. 1, pp. 184–190, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. R. Y. T. Chen, G. A. Wittert, and G. R. Andrews, “Relative androgen deficiency in relation to obesity and metabolic status in older men,” Diabetes, Obesity and Metabolism, vol. 8, no. 4, pp. 429–435, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. R. Clapauch, D. J. D. C. Braga, L. P. Marinheiro, S. Buksman, and Y. Schrank, “Risk of late-onset hypogonadism (Andropause) in Brazilian men over 50 years of age with osteoporosis: usefulness of screening questionnaires,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 52, no. 9, pp. 1439–1447, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. J. Collazos and M. Esteban, “Has prolactin a role in the hypogonadal status of HIV-infected patients?” Journal of the International Association of Physicians in AIDS Care, vol. 8, no. 1, pp. 43–46, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. G. Corona, V. Boddi, F. Lotti et al., “The Relationship of testosterone to prostate-specific antigen in men with sexual dysfunction,” Journal of Sexual Medicine, vol. 7, no. 1, part 1, pp. 284–292, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Corona, E. Mannucci, F. Lotti et al., “Impairment of couple relationship in male patients with sexual dysfunction is associated with overt hypogonadism,” Journal of Sexual Medicine, vol. 6, no. 9, pp. 2591–2600, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. G. Corona, E. Mannucci, F. Lotti et al., “Pulse pressure, an index of arterial stiffness, is associated with androgen deficiency and impaired penile blood flow in men with ED,” Journal of Sexual Medicine, vol. 6, no. 1, pp. 285–293, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. G. Corona, E. Mannucci, L. Petrone et al., “NCEP-ATPIII-defined metabolic syndrome, type 2 diabetes mellitus, and prevalence of hypogonadism in male patients with sexual dysfunction,” Journal of Sexual Medicine, vol. 4, no. 4, part 1, pp. 1038–1045, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. G. Corona, E. Mannucci, L. Petrone et al., “Association of hypogonadism and type II diabetes in men attending an outpatient erectile dysfunction clinic,” International Journal of Impotence Research, vol. 18, no. 2, pp. 190–197, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. G. Corona, M. Monami, V. Boddi et al., “Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction,” Journal of Sexual Medicine, vol. 7, no. 4, pp. 1557–1564, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. N. F. Crum-Cianflone, M. Bavaro, B. Hale et al., “Erectile dysfunction and hypogonadism among men with HIV,” AIDS Patient Care and STDs, vol. 21, no. 1, pp. 9–19, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Dhindsa, M. G. Miller, C. L. McWhirter et al., “Testosterone concentrations in diabetic and nondiabetic obese men,” Diabetes Care, vol. 33, no. 6, pp. 1186–1192, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Dhindsa, S. Prabhakar, M. Sethi, A. Bandyopadhyay, A. Chaudhuri, and P. Dandona, “Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 11, pp. 5462–5468, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. A. Durga, F. Sepahpanah, M. Regozzi, J. Hastings, and D. A. Crane, “Prevalence of testosterone deficiency after spinal cord injury,” PM & R, vol. 3, no. 10, pp. 929–932, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. H. A. Fink, S. K. Ewing, K. E. Ensrud et al., “Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 10, pp. 3908–3915, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. S. B. Fleishman, H. Khan, P. Homel et al., “Testosterone levels and quality of life in diverse male patients with cancers unrelated to androgens,” Journal of Clinical Oncology, vol. 28, no. 34, pp. 5054–5060, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Florvaag, V. Oberle, M. Fritzenwanger et al., “Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells,” Aging Male, vol. 15, no. 3, pp. 180–186, 2012. View at Publisher · View at Google Scholar · View at Scopus
  45. H. K. Ganesh, H. A. V. Sarathi, J. George et al., “Prevalence of hypogonadism in patients with type 2 diabetes mellitus in an Asian Indian study group,” Endocrine Practice, vol. 15, no. 6, pp. 513–520, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. D. M. Greenfield, S. J. Walters, R. E. Coleman et al., “Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 9, pp. 3476–3482, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Grossmann, S. Panagiotopolous, K. Sharpe et al., “Low testosterone and anaemia in men with type 2 diabetes,” Clinical Endocrinology, vol. 70, no. 4, pp. 547–553, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Grossmann, M. C. Thomas, S. Panagiotopoulos et al., “Low testosterone levels are common and associated with insulin resistance in men with diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 5, pp. 1834–1840, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. A. Guay, A. D. Seftel, and A. Traish, “Hypogonadism in men with erectile dysfunction may be related to a host of chronic illnesses,” International Journal of Impotence Research, vol. 22, no. 1, pp. 9–19, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. G. I. Hackett, N. S. Cole, A. A. Deshpande, M. D. Popple, D. Kennedy, and P. Wilkinson, “Biochemical hypogonadism in men with type 2 diabetes in primary care practice,” British Journal of Diabetes and Vascular Disease, vol. 9, no. 5, pp. 226–231, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Halabi, E. G. Collins, N. Thorevska, M. J. Tobin, and F. Laghi, “Relationship between depressive symptoms and hypogonadism in men with COPD,” COPD: Journal of Chronic Obstructive Pulmonary Disease, vol. 8, no. 5, pp. 346–353, 2011. View at Publisher · View at Google Scholar · View at Scopus
  52. M. A. Hamidi, A. Heidarzadeh, P. N. Akbari, D. F. Khosravi, and M. Z. Hamidi, “A survey on relative frequency of metabolic syndrome and testosterone deficiency in men with erectile dysfunction,” International Urology and Nephrology, vol. 44, no. 3, pp. 667–672, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. J. Hintikka, L. Niskanen, H. Koivumaa-Honkanen et al., “Hypogonadism, decreased sexual desire, and long-term depression in middle-aged men,” Journal of Sexual Medicine, vol. 6, no. 7, pp. 2049–2057, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Hofstra, S. Loves, B. van Wageningen, J. Ruinemans-Koerts, I. Janssen, and H. de Boer, “High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment,” Netherlands Journal of Medicine, vol. 66, no. 3, pp. 103–109, 2008. View at Google Scholar · View at Scopus
  55. E. A. Jankowska, B. Biel, J. Majda et al., “Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival,” Circulation, vol. 114, no. 17, pp. 1829–1837, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. D. Kapoor, H. Aldred, S. Clark, K. S. Channer, and T. H. Jones, “Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: Correlations with bioavailable testosterone and visceral adiposity,” Diabetes Care, vol. 30, no. 4, pp. 911–917, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. G. Kirbas, A. Abakay, F. Topcu, A. Kaplan, M. Unlu, and Y. Peker, “Obstructive sleep apnoea, cigarette smoking and serum testosterone levels in a male sleep clinic cohort,” Journal of International Medical Research, vol. 35, no. 1, pp. 38–45, 2007. View at Google Scholar
  58. R. S. Klein, Y. Lo, N. Santoro, and A. S. Dobs, “Androgen levels in older men who have or who are at risk of acquiring HIV infection,” Clinical Infectious Diseases, vol. 41, no. 12, pp. 1794–1803, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. T. S. Köhler, J. Kim, K. Feia et al., “Prevalence of androgen deficiency in men with erectile dysfunction,” Urology, vol. 71, no. 4, pp. 693–697, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. J. Kyriazis, I. Tzanakis, K. Stylianou et al., “Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients,” Nephrology Dialysis Transplantation, vol. 26, no. 9, pp. 2971–2977, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. S. la Vignera, A. E. Calogero, R. Condorelli, F. Lanzafame, B. Giammusso, and E. Vicari, “Andrological characterization of the patient with diabetes mellitus,” Minerva Endocrinologica, vol. 34, no. 1, pp. 1–9, 2009. View at Google Scholar · View at Scopus
  62. D. E. Laaksonen, L. Niskanen, K. Punnonen et al., “The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 2, pp. 712–719, 2005. View at Publisher · View at Google Scholar · View at Scopus
  63. J. E. Lackner, I. Märk, G. Schatzl, M. Marberger, and C. Kratzik, “Hypogonadism and androgen deficiency symptoms in testicular cancer survivors,” Urology, vol. 69, no. 4, pp. 754–758, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. F. Laghi, A. Antonescu-Turcu, E. Collins et al., “Hypogonadism in men with chronic obstructive pulmonary disease: prevalence and quality of life,” The American Journal of Respiratory and Critical Care Medicine, vol. 171, no. 7, pp. 728–733, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. E. Lerchbaum, S. Pilz, B. O. Boehm, T. B. Grammer, B. Obermayer-Pietsch, and W. März, “Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography,” Clinical Endocrinology, vol. 77, no. 3, pp. 475–483, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. A. A. Makhlouf, M. A. Mohamed, A. D. Seftel, and C. Neiderberger, “Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction,” International Journal of Impotence Research, vol. 20, no. 2, pp. 157–161, 2008. View at Publisher · View at Google Scholar · View at Scopus
  67. C. J. Malkin, P. J. Pugh, P. D. Morris, S. Asif, T. H. Jones, and K. S. Channer, “Low serum testosterone and increased mortality in men with coronary heart disease,” Heart, vol. 96, no. 22, pp. 1821–1825, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. R. S. McIntyre, D. Mancini, B. S. Eisfeld et al., “Calculated bioavailable testosterone levels and depression in middle-aged men,” Psychoneuroendocrinology, vol. 31, no. 9, pp. 1029–1035, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. S. A. Moreno and A. Morgentaler, “Testosterone deficiency and Peyronie's disease: pilot data suggesting a significant relationship,” Journal of Sexual Medicine, vol. 6, no. 6, pp. 1729–1735, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. A. O. Ogbera, “Relationship between serum testosterone levels and features of the metabolic syndrome defining criteria in patients with type 2 diabetes mellitus,” West African Journal of Medicine, vol. 30, no. 4, pp. 277–281, 2011. View at Google Scholar · View at Scopus
  71. O. A. Ogbera, C. Sonny, F. Olufemi, and A. Wale, “Hypogonadism and subnormal total testosterone levels in men with type 2 diabetes mellitus,” Journal of the College of Physicians and Surgeons Pakistan, vol. 21, no. 9, pp. 517–521, 2011. View at Google Scholar · View at Scopus
  72. M. S. Okun, M. R. DeLong, J. Hanfelt, M. Gearing, and A. Levey, “Plasma testosterone levels in Alzheimer and Parkinson diseases,” Neurology, vol. 62, no. 3, pp. 411–413, 2004. View at Publisher · View at Google Scholar · View at Scopus
  73. M. S. Okun, W. M. McDonald, and M. R. Delong, “Refractory nonmotor symptoms in male patients with Parkinson disease due to testosterone deficiency: a common unrecognized comorbidity,” Archives of Neurology, vol. 59, no. 5, pp. 807–811, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Pellitero, I. Olaizola, A. Alastrue et al., “Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery,” Obesity Surgery, vol. 22, no. 12, pp. 1835–1842, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. G. Pühse, A. Secker, S. Kemper, L. Hertle, and S. Kliesch, “Testosterone deficiency in testicular germ-cell cancer patients is not influenced by oncological treatment,” International Journal of Andrology, vol. 34, no. 5, part 2, pp. e351–e357, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. A. Rajagopal, R. Vassilopoulou-Sellin, J. L. Palmer, G. Kaur, and E. Bruera, “Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids,” Cancer, vol. 100, no. 4, pp. 851–858, 2004. View at Publisher · View at Google Scholar · View at Scopus
  77. E. L. Rhoden, E. P. Ribeiro, C. Teloken, and C. A. V. Souto, “Diabetes mellitus is associated with subnormal serum levels of free testosterone in men,” BJU International, vol. 96, no. 6, pp. 867–870, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. P. Rietschel, C. Corcoran, T. Stanley, N. Basgoz, A. Klibanski, and S. Grinspoon, “Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy,” Clinical Infectious Diseases, vol. 31, no. 5, pp. 1240–1244, 2000. View at Publisher · View at Google Scholar · View at Scopus
  79. P. Romerius, O. Ståhl, C. Moëll et al., “Hypogonadism risk in men treated for childhood cancer,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 11, pp. 4180–4186, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. A. Salonia, A. Gallina, A. Briganti et al., “Preoperative hypogonadism is not an independent predictor of high-risk disease in patients undergoing radical prostatectomy,” Cancer, vol. 117, no. 17, pp. 3953–3962, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. G. Schatzl, C. Brössner, S. Schmid et al., “Endocrine status in elderly men with lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary tract function,” Urology, vol. 55, no. 3, pp. 397–402, 2000. View at Publisher · View at Google Scholar · View at Scopus
  82. G. Schatzl, S. Madersbacher, T. Thurridl et al., “High-grade prostate cancer is associated with low serum testosterone levels,” Prostate, vol. 47, no. 1, pp. 52–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  83. S. K. Singh, R. Goyal, and D. D. Pratyush, “Is hypoandrogenemia a component of metabolic syndrome in males?” Experimental and Clinical Endocrinology & Diabetes, vol. 119, no. 1, pp. 30–35, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. E. Serra, M. Porcu, L. Minerba et al., “High prevalence of male hypogonadism and sexual dysfunction in long-term clinically stable heart transplantation recipients,” International Journal of Cardiology, vol. 155, no. 3, pp. 476–477, 2012. View at Publisher · View at Google Scholar · View at Scopus
  85. B. Somani, S. Khan, and R. Donat, “Screening for metabolic syndrome and testosterone deficiency in patients with erectile dysfunction: results from the first UK prospective study,” BJU International, vol. 106, no. 5, pp. 688–690, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. A. Taddesse, I. L. Woldie, P. Khana et al., “Hypogonadism in patients with sickle cell disease: central or peripheral?” Acta Haematologica, vol. 128, no. 2, pp. 65–68, 2012. View at Publisher · View at Google Scholar · View at Scopus
  87. S. K. Talukder, F. Afsana, and S. J. Khan, “Metabolic syndrome in men with sexual dysfunction,” Diabetes and Metabolic Syndrome: Clinical Research and Reviews, vol. 4, no. 3, pp. 143–149, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. W. S. Tan, C. J. Ng, E. M. Khoo, W. Low, and H. M. Tan, “The triad of erectile dysfunction, testosterone deficiency syndrome and metabolic syndrome: findings from a multi-ethnic Asian men study (The Subang Men's Health Study),” The Aging Male, vol. 14, no. 4, pp. 231–236, 2011. View at Google Scholar · View at Scopus
  89. B. Tengstrand, K. Carlström, and I. Hafström, “Bioavailable testosterone in men with rheumatoid arthritis—high frequency of hypogonadism,” Rheumatology, vol. 41, no. 3, pp. 285–289, 2002. View at Publisher · View at Google Scholar · View at Scopus
  90. T. G. Travison, R. Shackelton, A. B. Araujo et al., “The natural history of symptomatic androgen deficiency in men: onset, progression, and spontaneous remission,” Journal of the American Geriatrics Society, vol. 56, no. 5, pp. 831–839, 2008. View at Publisher · View at Google Scholar · View at Scopus
  91. K. Tromp, J. J. M. Claessens, S. L. Knijnenburg et al., “Reproductive status in adult male long-term survivors of childhood cancer,” Human Reproduction, vol. 26, no. 7, pp. 1775–1783, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. G. Wagner, J. G. Rabkin, and R. Rabkin, “Illness stage, concurrent medications, and other correlates of low testosterone in men with HIV illness,” Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, vol. 8, no. 2, pp. 204–207, 1995. View at Google Scholar · View at Scopus
  93. J. T. Wahlstrom, A. Tang, J. Cofrancesco, N. Shah Jr., and A. S. Dobs, “Gonadal hormone levels in injection drug users,” Drug and Alcohol Dependence, vol. 60, no. 3, pp. 311–313, 2000. View at Publisher · View at Google Scholar · View at Scopus
  94. X.-F. Wang, J.-H. Wang, and J.-Y. Li, “Androgen deficiency in elderly men with systolic chronic heart failure,” Journal of Geriatric Cardiology, vol. 7, no. 3-4, pp. 138–142, 2010. View at Google Scholar · View at Scopus
  95. E. Wehr, S. Pilz, B. O. Boehm, W. März, and B. Obermayer-Pietsch, “Association of vitamin D status with serum androgen levels in men,” Clinical Endocrinology, vol. 73, no. 2, pp. 243–248, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. D. M. Wunder, N. A. Bersinger, C. A. Fux et al., “Hypogonadism in HIV-1-infected men is common and does not resolve during antiretroviral therapy,” Antiviral Therapy, vol. 12, no. 2, pp. 261–265, 2007. View at Google Scholar · View at Scopus
  97. M. I. Yilmaz, A. Sonmez, A. R. Qureshi et al., “Endogenous testosterone, endothelial dysfunction, and cardiovascular events in men with nondialysis chronic kidney disease,” Clinical Journal of the American Society of Nephrology, vol. 6, no. 7, pp. 1617–1625, 2011. View at Publisher · View at Google Scholar · View at Scopus
  98. S. A. Hall, A. B. Araujo, G. R. Esche et al., “Treatment of symptomatic androgen deficiency: results from the Boston Area Community Health Survey,” Archives of Internal Medicine, vol. 168, no. 10, pp. 1070–1076, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. P. Dandona and M. T. Rosenberg, “A practical guide to male hypogonadism in the primary care setting,” International Journal of Clinical Practice, vol. 64, no. 6, pp. 682–696, 2010. View at Publisher · View at Google Scholar · View at Scopus
  100. M. Fernández-Balsells, M. Murad, M. Lane et al., “Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 6, pp. 2560–2575, 2010. View at Publisher · View at Google Scholar
  101. E. S. Orwoll, C. M. Nielson, F. Labrie et al., “Evidence for geographical and racial variation in serum sex steroid levels in older men,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 10, pp. E151–E160, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. S. Basaria, A. D. Coviello, T. G. Travison et al., “Adverse events associated with testosterone administration,” The New England Journal of Medicine, vol. 363, no. 2, pp. 109–122, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. U. Srinivas-Shankar, S. A. Roberts, M. J. Connolly et al., “Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 2, pp. 639–650, 2010. View at Publisher · View at Google Scholar · View at Scopus
  104. R. Vigen, C. O'Donnell, A. Barón et al., “Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels,” The Journal of the American Medical Association, vol. 310, no. 17, pp. 1829–1836, 2013. View at Google Scholar