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      Risks and Benefits of Late Onset Hypogonadism Treatment: An Expert Opinion

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          Abstract

          Late-onset hypogonadism (LOH) is a syndromic condition that has a well-recognized association with sexual and reproductive failure. LOH is frequently associated with chronic conditions including cardiovascular diseases (CVD), obesity, osteoporosis, HIV infection, renal failure, and obstructive pulmonary diseases. Despite this evidence, in patients with these conditions, LOH is still only rarely investigated and testosterone replacement therapy (TRT) rarely considered. In this paper, we critically reviewed the available evidence on LOH treatment focusing on possible risks and benefits. Medical therapy of LOH should be individualized depending on the etiology of the disease and the patient's expectations. The fear of prostate cancer and the risk of erythrocytosis probably represent the main limitations of TRT in aging men. However, TRT in healthy older men in near physiological doses does not appear to incur serious adverse events, although regular monitoring of prostate-specific antigen and hematocrit levels is required. Available evidence also suggests that TRT might ameliorate central obesity and glycometabolic control in patients with metabolic syndrome and type 2 diabetes. In addition, TRT has been associated with an increase in bone mineral density in men with osteoporosis, with an improvement in lean body mass in subjects with human immunodeficiency virus infection or chronic obstructive pulmonary disease, as well as with peripheral oxygenation in patients with chronic kidney diseases. Despite this evidence, however, it should be recognized that the results of these trials were heterogeneous and limited by small sample sizes. Hence, further research is required regarding the long-term benefits and adverse effects of TRT in LOH.

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          Most cited references85

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          Identification of late-onset hypogonadism in middle-aged and elderly men.

          The association between aging-related testosterone deficiency and late-onset hypogonadism in men remains a controversial concept. We sought evidence-based criteria for identifying late-onset hypogonadism in the general population on the basis of an association between symptoms and a low testosterone level. We surveyed a random population sample of 3369 men between the ages of 40 and 79 years at eight European centers. Using questionnaires, we collected data with regard to the subjects' general, sexual, physical, and psychological health. Levels of total testosterone were measured in morning blood samples by mass spectrometry, and free testosterone levels were calculated with the use of Vermeulen's formula. Data were randomly split into separate training and validation sets for confirmatory analyses. In the training set, symptoms of poor morning erection, low sexual desire, erectile dysfunction, inability to perform vigorous activity, depression, and fatigue were significantly related to the testosterone level. Increased probabilities of the three sexual symptoms and limited physical vigor were discernible with decreased testosterone levels (ranges, 8.0 to 13.0 nmol per liter [2.3 to 3.7 ng per milliliter] for total testosterone and 160 to 280 pmol per liter [46 to 81 pg per milliliter] for free testosterone). However, only the three sexual symptoms had a syndromic association with decreased testosterone levels. An inverse relationship between an increasing number of sexual symptoms and a decreasing testosterone level was observed. These relationships were independently confirmed in the validation set, in which the strengths of the association between symptoms and low testosterone levels determined the minimum criteria necessary to identify late-onset hypogonadism. Late-onset hypogonadism can be defined by the presence of at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter (3.2 ng per milliliter) and a free testosterone level of less than 220 pmol per liter (64 pg per milliliter). 2010 Massachusetts Medical Society
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            Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis.

            Low testosterone levels have been associated with outcomes that reduce survival in men. Our objective was to perform a systematic review and meta-analysis of published studies to evaluate the association between endogenous testosterone and mortality. Data sources included MEDLINE (1966 to December 2010), EMBASE (1988 to December 2010), and reference lists. Eligible studies were published English-language observational studies of men that reported the association between endogenous testosterone and all-cause or cardiovascular disease (CVD) mortality. A two-stage process was used for study selection. 1) Working independently and in duplicate, reviewers screened a subset (10%) of abstracts. Results indicated 96% agreement, and thereafter, abstract screening was conducted in singlicate. 2) All full-text publications were reviewed independently and in duplicate for eligibility. Reviewers working independently and in duplicate determined methodological quality of studies and extracted descriptive, quality, and outcome data. Of 820 studies identified, 21 were included in the systematic review, and 12 were eligible for meta-analysis [n = 11 studies of all-cause mortality (16,184 subjects); n = 7 studies of CVD mortality (11,831 subjects)]. Subject mean age and testosterone level were 61 yr and 487 ng/dl, respectively, and mean follow-up time was 9.7 yr. Between-study heterogeneity was observed among studies of all-cause (P < .001) and CVD mortality (P = 0.06), limiting the ability to provide valid summary estimates. Heterogeneity in all-cause mortality (higher relative risks) was observed in studies that included older subjects (P = 0.020), reported lower testosterone levels (P = 0.018), followed subjects for a shorter time period (P = 0.010), and sampled blood throughout the day (P = 0.030). Low endogenous testosterone levels are associated with increased risk of all-cause and CVD death in community-based studies of men, but considerable between-study heterogeneity, which was related to study and subject characteristics, suggests that effects are driven by differences between cohorts (e.g. in underlying health status).
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              Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.

              The risks of testosterone therapy in men remain poorly understood. The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men. We searched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies. Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility. Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data. The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl; 95% confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes. The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.
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                Author and article information

                Journal
                World J Mens Health
                World J Mens Health
                WJMH
                The World Journal of Men's Health
                Korean Society for Sexual Medicine and Andrology
                2287-4208
                2287-4690
                August 2013
                31 August 2013
                : 31
                : 2
                : 103-125
                Affiliations
                [1 ]Endocrinology Unit, Medical Department, Azienda Usl, Maggiore-Bellaria Hospital, Bologna, Italy.
                [2 ]Sexual Medicine and Andrology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy.
                Author notes
                Correspondence to: Mario Maggi. Sexual Medicine, Andrology Unit1, Department of Experimental, Clinical and Biom edical Sciences, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy. Tel: +39-55-4271415, Fax: +39-55-4271413, m.maggi@ 123456dfc.unifi.it
                Article
                10.5534/wjmh.2013.31.2.103
                3770846
                24044106
                6684b3b1-686e-42f4-bcb2-61e04f135cda
                Copyright © 2013 Korean Society for Sexual Medicine and Andrology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 May 2013
                : 02 June 2013
                : 10 June 2013
                Categories
                Review Article

                testosterone,hypogonadism,prostate,diabetes mellitus,erectile dysfunction

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