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Volume 55, issue 1, pages 1-260, January 2009

Guidelines

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Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Males: ISA, ISSAM, EAU, EAA, and ASA Recommendations

Christina Wang a lowast , Eberhard Nieschlag b, Ronald Swerdloff a, Hermann M. Behre c, Wayne J. Hellstrom d, Louis J. Gooren e, Jean M. Kaufman f, Jean-Jacques Legros g, Bruno Lunenfeld h, Alvaro Morales i, John E. Morley j, Claude Schulman k, Ian M. Thompson l, Wolfgang Weidner m, Frederick C.W. Wu n.

Accepted 7 August 2008, Published online 30 August 2008, pages 121 - 130

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Take Home Message

The new ISA, ISSAM, EAU, EAA and ASA recommendations on the investigation, treatment and monitoring of late-onset hypogonadism in males provide updated evidence-based information for clinicians who diagnose and treat patients with adult onset, age related testosterone deficiency.

Article Outline

1. Introduction

Demographic data clearly demonstrate that the percent of population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that testosterone falls progressively with age and that a significant percentage of men over the age of 60 yr have serum testosterone levels that are below the lower limits of young adult (age 20–30 yr) men [1], [2], [3], and [4]. The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention.

The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs, and recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in “Testosterone and Aging: Clinical Research Directions” [5]. Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass [6], [7], [8], [9], [10], and [11]. Key questions of the effects of testosterone on patient-reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed.

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2. Process for development of recommendations

Recent guidelines for the testosterone treatment of younger hypogonadal men are available from professional societies [12], [13], and [14]. Recommendations for the diagnosis, treatment, and monitoring of late-onset hypogonadism (LOH) was published by the International Society for the Study of Aging Male (ISSAM) in 2002 [15]. In 2005, a writing committee formed by the International Society of Andrology (ISA), ISSAM, and the European Association of Urology (EAU) prepared a set of recommendations specifically on the “Investigation, Treatment and Monitoring of Late-Onset Hypogonadism.” In order to reach a large audience, these recommendations were published in the International Journal of Andrology, the Journal of Andrology, Aging Male, and European Urology [16], [17], [18], and [19]. In view of the growing interest from practitioners on the treatment of older men with testosterone, the ISA, ISSAM, EAU, European Academy of Andrology (EAA), and American Society of Andrology (ASA) convened meetings of the writing group with expert representatives from each of the societies. The writing group membership from 2005 was expanded to include additional urologists. Members of the writing group met in Berlin, Germany, in 2007; in Toronto, Canada, in 2007; and in Tampa, Florida, in 2008 to revise these recommendations. There was no corporate funding or support for the development of these recommendations. The revised recommendations are supported by a selection of appropriate references and categorized by the level of evidence and grade of recommendation according to the US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research (1992) (see Table 1). To ensure broad outreach to multidisciplinary audiences, these recommendations are published in several journals simultaneously.

Table 1 Levels of evidence and grades for revised recommendations.

Level Type of evidence
1a Evidence obtained from meta-analysis of randomized trials
1b Evidence obtained from at least one randomized trial
2a Evidence obtained from one well-designed controlled study without randomization
2b Evidence obtained from at least one other type of well-designed quasiexperimental study
3 Evidence obtained from well-designed nonexperimental studies, such as comparative studies, correlation studies, and case reports
4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities
Grade Nature of recommendations
A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial
B Based on well-conducted clinical studies but without randomized clinical trials
C Made despite the absence of directly applicable clinical studies of good quality
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3. Recommendation 1: Definition

LOH (also referred to as age-associated testosterone deficiency syndrome [TDS]) is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels (below the young healthy adult male reference range) [16], [17], [18], [19], and [20]. This condition may result in significant detriment to quality of life and adversely affect the function of multiple organ systems.

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4. Recommendation 2: Clinical diagnosis and questionnaires

  • (1)At present, the diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency (level 3, grade A) [12], [16], [17], [18], and [19]. The symptom most associated with hypogonadism is low libido (level 3, grade A) [21], and [22]. Other manifestations of hypogonadism include erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, decreased vitality, and depressed mood. None of these symptoms are specific to the low androgen state but may raise suspicion of testosterone deficiency. One or more of these symptoms must be corroborated with a low serum testosterone level (level 3, grade A) [1], [23], [24], and [25].

  • (2)Questionnaires such as Aging Male Symptom Score (AMS) [26], and [27] and Androgen Deficiency in Aging Men (ADAM) [28] are not recommended for the diagnosis of hypogonadism because of low specificity (level 3, grade B) [24], [29], and [30].

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5. Recommendation 3: Laboratory diagnosis

  • (1)In patients at risk or who are suspected of hypogonadism, a thorough physical and biochemical work-up is necessary (level 4, grade A). Transient decreases of serum testosterone levels such as those due to acute illnesses should be excluded by careful clinical evaluations and repeated hormone measurement. Hypogonadism (primary or secondary) can occur at all ages, including in elderly men. Risk factors for hypogonadism in older men may include chronic illnesses (including diabetes mellitus, chronic obstructive lung disease, and inflammatory arthritic, renal, and HIV-related diseases), obesity, metabolic syndrome, and hemachromatosis [12]. Such chronic diseases should be investigated and treated (level 4, grade A).

  • (2)A serum sample for total testosterone determination should be obtained between 07.00 and 11.00 h (level 2a, grade A) [31]. The most widely accepted parameters to establish the presence of hypogonadism is the measurement of serum total testosterone. There are no generally accepted lower limits of normal. There is, however, general agreement that total testosterone level above 12 nmol/l (350 ng/dl) does not require substitution. Similarly, based on the data of younger men, there is consensus that patients with serum total testosterone levels below 8 nmol/l (230 ng/dl) will usually benefit from testosterone treatment. If the serum total testosterone level is between 8 and 12 nmol/l, repeating the measurement of total testosterone with sex hormone binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful (see 3.5 and 3.7 below) (level 2b, grade A).

  • (3)Measurements of serum LH will assist in differentiating between primary and secondary hypogonadism and serum prolactin is indicated when the serum testosterone is lower than 5.2 nmol/l (150 ng/dl) [32], [33], [34], and [35] or when secondary hypogonadism is suspected [12], [36], and [37] (level 3, grade B).

  • (4)Since there are known variations among assay methods, it is imperative that the practitioners utilize reliable laboratories and are acquainted with the reference ranges for testosterone from their local laboratory [38], [39], [40], and [41] (level 2b, grade A).

  • (5)Current immunometric methods for measurement of testosterone can distinguish between hypogonadism and normal adult men; however, methods based on mass spectrometry are more accurate and precise [39], [40], and [41] (level 2b, grade A) and are increasingly recognized as the method of choice for serum testosterone measurement.

  • (6)Measurement of free or bioavailable testosterone should be considered when the serum total testosterone concentration is not diagnostic of hypogonadism, particularly in obese men. There are no generally accepted lower limits of normal for free testosterone for the diagnosis of hypogonadism; however, a free testosterone level below 225 pmol/l (65 pg/ml) can provide supportive evidence for testosterone treatment [37], [38], and [42] (level 3, grade C). Threshold values for bioavailable testosterone depend on the method used and are not generally available [38].

  • (7)Equilibrium dialysis is the gold standard for free testosterone measurement. Free testosterone assays based on analog displacement immunoassays are widely available but do not give an accurate measurement of free testosterone; thus, they should not be used [43], and [44]. Alternately, measuring serum SHBG levels together with a reliable serum total testosterone level provides the data necessary for calculating free testosterone levels (level 2b, grade A). Calculated free testosterone correlates well with free testosterone by equilibrium dialysis [38], and [42]. Efforts to create standardization of testosterone assays, agreement on standards for testosterone measurement, and accurate reference ranges for testosterone by LC-MS/MS are being developed. International reference standards, characterization of methodology, and population-based reference ranges for free testosterone by equilibrium dialysis are needed. Consensus on the equilibrium constants for testosterone binding to SHBG and albumin will allow improved calculation of free testosterone [38].

  • (8)Salivary testosterone has also been shown to be a reliable substitute for free testosterone measurements but cannot be recommended for general use at this time, since the methodology has not been standardized and adult male ranges are not available in most hospital or reference laboratories [45] (level 3, grade B).

  • (9)Alterations in other endocrine systems occur in association with aging (ie, estradiol, GH, and DHEA), but the significance of these changes is not well understood. Determinations of estradiol, thyroid hormones, cortisol, DHEA, DHEA-S, melatonin, GH and IGF-I are not indicated unless other endocrine disorders are suspected based on the clinical signs and symptoms of the patient [12] (level 2, grade A).

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6. Recommendation 4: Assessment of treatment outcome and decisions on continued therapy

Improvement in signs and symptoms of testosterone deficiency should be sought.

Failure to benefit from clinical manifestations within a reasonable time interval (3–6 mo is adequate for libido and sexual function, muscle function, and improved body fat; improvement in bone mineral density requires a longer interval to show improvement) should result in discontinuation of treatment. Further investigation for other causes of symptoms is then mandatory (level 1b, grade A).

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7. Recommendation 5: Body composition

In men with hypogonadal values of testosterone, testosterone administration improves body composition (decrease of fat mass, increase of lean body mass [5], [7], [9], [10], and [46] (level 1b, grade A). Secondary benefits of these changes of body composition in strength, muscle function, and metabolic and cardiovascular dysfunction are suggested by available data but require confirmation by large-scale studies.

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8. Recommendation 6: Bone density and fracture rate

Osteopenia, osteoporosis, and fracture prevalence rates are greater in hypogonadal younger and older men [47]. Bone density in hypogonadal men of all ages increases under testosterone substitution [8], [11], and [48] (level 1b, grade A). Fracture data are not yet available; thus, the long-term benefit of testosterone requires further investigation. Assessment of bone density at 2-yr intervals is advisable in hypogonadal men, and serum testosterone measurements should be obtained in all men with osteopenia [49], and [50].

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9. Recommendation 7: Testosterone and sexual function

  • (1)The initial assessment of all men with erectile dysfunction and/or diminished libido should include determination of serum testosterone. These dysfunctions, with or without a testosterone deficiency, might be related to comorbidities (ie, diabetes mellitus, hyperprolactinemia, the metabolic syndrome, bladder outlet obstruction, peripheral vascular disease) or medications [51] (level 2a, grade A).

  • (2)Men with erectile dysfunction and/or diminished libido and documented testosterone deficiency are candidates for testosterone therapy (level 2a, grade A). An inadequate response to testosterone treatment requires reassessment of the causal mechanisms responsible for the erectile dysfunction (see 7.4 below).

  • (3)In the presence of a clinical picture of testosterone deficiency and borderline serum testosterone levels, a short (eg, 3 mo) therapeutic trial may be justified. An absence of response calls for discontinuation of testosterone administration. A satisfactory response might be placebo-generated so that continued assessment is advisable before long-term treatment is recommended [52] (level 2a, grade B).

  • (4)There is evidence suggesting therapeutic synergism with combined use of testosterone and phosphodiesterase type 5 inhibitors (PDE5-I) in hypogonadal or borderline eugonadal men [53], and [54] (level 1b, grade B). These observations are still preliminary and require additional study; however, the combination treatment should be considered in hypogonadal patients with erectile dysfunction (ED) failing to respond to either treatment alone. It is unclear whether men with hypogonadism and ED should be treated initially with PDE5-I, testosterone, or the combination of the two.

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10. Recommendation 8: Testosterone and obesity, metabolic syndrome, and type 2 diabetes

  • (1)Many of the components of the metabolic syndrome (obesity, hypertension, dyslipidemia, impaired glucose regulation, and insulin resistance) are also present in hypogonadal men. Numerous epidemiological studies have established a close relationship between obesity and low serum testosterone levels in healthy men [55]. Twenty percent to 64% of obese men have a low serum total or free testosterone level [56]. The metabolic syndrome and type 2 diabetes mellitus are associated with low plasma testosterone [25], [55], [57], [58], [59], [60], [61], and [62]. Serum testosterone should be measured in men with type 2 diabetes mellitus with symptoms suggestive of testosterone deficiency (level 2b, grade A).

  • (2)The effects of testosterone administration on glycemic control of men with diabetes mellitus are much less certain [63], [64], and [65]. It is premature to recommend testosterone treatment for the metabolic syndrome or diabetes mellitus in the absence of laboratory and other clinical evidence of hypogonadism. In men with hypogonadism and diabetes and or the metabolic syndrome, testosterone treatment for traditional hypogonadal symptoms may have other unproven benefits for their metabolic status (level 2a, grade B).

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11. Recommendation 9: Prostate cancer and benign prostatic hyperplasia

  • (1)At the present time, there is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia (BPH) [66], and [67]. There is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer (level 4, grade C). There is, however, unequivocal evidence that testosterone can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer [68], and [69] (level 2a, grade A). Currently, adequately powered and optimally designed long-term prostate disease data are not available to determine whether there is any additional risk from testosterone replacement. Hypogonadal older (>45 yr) men should be counseled on the potential risks and benefits of testosterone replacement before treatment and carefully monitored for prostate safety during treatment (level 3, grade A).

  • (2)Prior to therapy with testosterone, a man's risk of prostate cancer must be assessed using, as a minimum, digital rectal examination (DRE) and determination of serum prostate-specific antigen (PSA); however, the pretreatment assessment can be improved by incorporating other risk predictors such as age, family history, and ethnicity or race. Several tools have been developed to assist the clinician in assessing prostate cancer risk (eg, online prostate cancer risk calculator) [70], and [71]. These tools have not been validated for patients with LOH (or TDS). If the patient and physician feel that the risk is sufficiently high, further assessment may be desirable [71], and [72] (level 2a, grade B); however, pretreatment prostate ultrasound examinations or biopsies are not recommended as routine requirements.

  • (3)After initiation of testosterone treatment, patients should be monitored for prostate disease at 3–6 mo, 12 mo, and at least annually thereafter (level 3, grade C). Should the patient's prostate cancer risk be sufficiently high (suspicious finding on DRE, increased PSA, or as calculated using a combination of risk factors noted above), transrectal ultrasound-guided biopsies of the prostate are indicated [73], [74], [75], and [76] (level 2b, grade A).

  • (4)Severe lower urinary tract symptoms (LUTS) evident by a high (>21) International Prostate Symptom Score (IPSS) due to BPH represents a relative contraindication (although there are no compelling data to suggest that testosterone treatment exacerbates LUTS or promotes acute urinary retention) (level 3, grade C). After successful treatment of lower urinary tract obstruction, this contraindication is no longer applicable (level 4, grade C).

  • (5)Men successfully treated for prostate cancer and suffering from confirmed symptomatic hypogonadism are potential candidates for testosterone substitution after a prudent interval if there is no clinical or laboratory evidence of residual cancer [77], [78], [79], and [80]. As long-term outcome data are not available, clinicians must exercise good clinical judgment together with adequate knowledge of advantages and drawbacks of testosterone therapy in this situation [81], and [82] (level 2b, grade C). The risks and benefits must be clearly discussed with and understood by the patient, and the follow-up must be particularly careful.

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12. Recommendation 10: Treatment and delivery systems

  • (1)Preparations of natural testosterone should be used for substitution therapy. Currently available intramuscular, subdermal, transdermal, oral, and buccal preparations of testosterone are safe and effective (level 1b, grade A). The treating physician should have sufficient knowledge and adequate understanding of the pharmacokinetics as well as of the advantages and drawbacks of each preparation. The selection of the preparation should be a joint decision of an informed patient and physician [83].

  • (2)Since the possible development of an adverse event during treatment (especially elevated hematocrit or prostate carcinoma) [84] requires rapid discontinuation of testosterone substitution, short-acting preparations may be preferred over long-acting depot preparations in the initial treatment of patients with LOH (level 4, grade C).

  • (3)Inadequate data are available to determine the optimal serum testosterone level for efficacy and safety. For the present time, midrange to lower young-adult-male serum testosterone levels seem appropriate as the therapeutic goal [85]. Sustained supraphysiological levels should be avoided. No evidence exists for or against the need to maintain the physiological circadian rhythm of serum testosterone levels (level 3, grade B).

  • (4)Obese men are more likely to develop adverse effects [83], and [85] (level 2b, grade B).

  • (5)Preparations of 17-alpha-alkylated androgen such as 17α-methyl testosterone are obsolete because of their potential liver toxicity and should no longer be prescribed (level 2b, grade A).

  • (6)There is not enough evidence to recommend substitution of dihydrotestosterone (DHT) in aging men; other nontestosterone androgen precursor preparations such as DHEA, DHEA-S, androstenediol, or androstenedione are not recommended (level 1b, grade A).

  • (7)Human chorionic gonadotropin (hCG) stimulates testosterone production of Leydig cells, albeit at a lower rate in older men than in younger men. Since insufficient information exists about the therapeutic and adverse effects of hCG treatment in older men and its higher cost, this treatment cannot be recommended in LOH except when fertility is an issue (level 1b, grade B).

  • (8)Antiestrogens and aromatase inhibitors have been shown to increase endogenous testosterone levels (level 2b, grade B). Adequate evidence does not exist to recommend their use. Selective androgen receptor modulators (SARMs) are under development but not yet clinically available. Many of these compounds are nonaromatizable, and the risks of long-term use are unclear.

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13. Recommendation 11: Adverse effects and monitoring

  • (1)Testosterone treatment is contraindicated in men with prostate or breast cancer (level 3, grade A). Testosterone treatment is relatively contraindicated in men at high risk of developing prostate cancer. It is unclear whether localized low-grade (Gleason score <7) prostate cancer represents a relative or absolute contraindication for treatment (see Recommendation 9 for more details) (level 4, grade, C) [83], [86], and [87].

  • (2)Men with significant erythrocytosis (hematocrit >52%) (level 3, grade A), untreated obstructive sleep apnea (level 3, grade B), or untreated severe congestive heart failure (level 3, grade B) should not be started on treatment with testosterone without prior resolution of the comorbid condition [83], and [88].

  • (3)Erythrocytosis can develop during testosterone treatment, especially in older men treated by injectable testosterone preparations. Periodic hematological assessment is indicated (ie, before treatment, then at 3–4 mo and at 12 mo in the first year of treatment and annually thereafter). While it is not yet clear what critical threshold is desirable, dose adjustments and/or periodic phlebotomy may be necessary to keep hematocrit below 52–55% [12], [82], and [83] (level 3, grade A).

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14. Recommendation 12: Summary

Age is not a contraindication to initiate testosterone treatment. Individual assessment of comorbidities (as possible causes of symptoms) and potential risks versus benefits of testosterone treatment is particularly important in elderly men (level 2a, grade A).

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15. Conclusions

The diagnosis of late-onset testosterone deficiency is based on the presence of symptoms or signs and persistently low serum testosterone levels. The benefits and risks of testosterone therapy must be clearly discussed with the patient and assessment of prostate and other risk factors considered before commencing testosterone treatment. Response to testosterone treatment should be assessed. If there is no improvement of symptoms and signs, treatment should be withdrawn and the patient investigated for other possible causes of the clinical presentations.
Author contributions: Christina Wang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wang, Nieschlag, Swerdloff, Schulman, Wu, Morales.

Acquisition of data: Wang, Nieschlag, Swerdloff, Behre, Hellstrom, Gooren, Kaufman, Legros, Lunenfeld, Morales, Schulman, Morley, Thompson, Weidner, Wu.

Analysis and interpretation of data: Wang, Nieschlag, Swerdloff, Behre, Hellstrom, Gooren, Kaufman, Legros, Lunenfeld, Morales, Schulman, Morley, Thompson, Weidner, Wu.

Drafting of the manuscript: Wang, Nieschlag, Swerdloff, Behre, Hellstrom, Gooren, Kaufman, Legros, Lunenfeld, Morales, Schulman, Morley, Thompson, Weidner, Wu.

Critical revision of the manuscript for important intellectual content: Wang, Nieschlag, Swerdloff, Behre, Hellstrom, Gooren, Kaufman, Legros, Lunenfeld, Morales, Schulman, Morley, Thompson, Weidner, Wu.

Statistical analysis: Wang, Nieschlag, Swerdloff, Behre, Hellstrom, Gooren, Kaufman, Legros, Lunenfeld, Morales, Schulman, Morley, Thompson, Weidner, Wu.

Obtaining funding: None.

Administrative, technical, or material support: Wang, Nieschlag, Swerdloff, Behre, Hellstrom, Gooren, Kaufman, Legros, Lunenfeld, Morales, Schulman, Morley, Thompson, Weidner, Wu.

Supervision: Wang, Nieschlag, Swerdloff, Behre, Hellstrom, Gooren, Kaufman, Legros, Lunenfeld, Morales, Schulman, Morley, Thompson, Weidner, Wu.

Other (specify): None.

Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: C. Wang has been a temporary consultant for Indevus and has received research support from Acrux, Indevus, M et P Pharma AG, Clarus Therapeutics, and Besins Health Care. She has received honoraria, but none from a pharmaceutical company directly. E. Nieschlag has received honoraria for lectures on testosterone. R. Swerdloff has been a consultant and grant recipient for Acrux, Ardana, Clarus, GlaxoSmithKline, Indevus, and Repros. He has been a consultant, grant recipient, and speaker for Auxillium and Solvay Pharmaceuticals. He has also been a grant recipient for Organon and a consultant for Pierre Fabre. He is not a stockholder or owner of any of these companies. H.M. Behre has received honoraria for lectures on testosterone. J.-J. Legros has received honoraria from Organon BioSciences for one lecture. A. Morales has received research support from Solvay. J.E. Morley has been a consultant for Solvay Pharmaceuticals. He also has stock ownership in Mattern Pharmaceuticals.

Funding/Support and role of the sponsor: None.

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Footnotes

a Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles BioMedical Research Institute, Torrance, California, USA

b Centre for Reproductive Medicine and Andrology, University of Muenster, Muenster, Germany

c Center for Reproductive Medicine and Andrology, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany

d Department of Urology, Tulane University, New Orleans, Louisiana, USA

e Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands

f Department of Endocrinology, Academish Ziekenhuis, Gent, Belgium

g Centre Hospitalier Universitaire, Sart-Tilman, Liège, Belgium

h Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel

i Centre for Applied Urological Research, Queen's University, Kingston, Canada

j Division of Geriatric Medicine, St. Louis University, and GRECC, St. Louis VA Medical Center, St. Louis, Missouri, USA

k Department of Urology, Erasme Hospital, University Clinics Brussels, Brussels, Belgium

l Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

m Department of Urology and Pediatric Urology, University Hospitals, Justus-Liebig-University, Giessen, Germany

n Department of Endocrinology, University of Manchester, Manchester Royal Infirmary, Manchester, United Kingdom

lowast Corresponding author. General Clinical Research Center, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509, USA.

Article information

PII: S0302-2838(08)00972-X
DOI: 10.1016/j.eururo.2008.08.033
© 2008 European Association of Urology. Published by Elsevier B.V.

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