ReviewMale hypogonadism associated with advanced cancer: a systematic review
Introduction
Male hypogonadism is characterised by the presence of low concentrations of circulating androgen hormones, namely testosterone.1 Subphysiological concentrations of testosterone or androgen deficiency can also be present in women, as a result of abnormal ovarian, adrenal, and peripheral tissue functions.1 However, the normal androgen concentrations in women have not been established, and diagnosis of deficiency in women is complex. The Endocrine Society guidelines suggest that no established definition of androgen deficiency in women exists on which to base clinical care. Such definition presupposes standard, valid assays and normative data that are only now being developed.2 Our review, therefore, focuses only on androgen deficiency in men or male hypogonadism associated with advanced cancer.
Male hypogonadism results from the failure of the testes to produce physiological concentrations of testosterone, and is caused by a disruption in one or more levels within the hypothalamic–pituitary–gonadal axis.3 Primary hypogonadism or primary testicular failure relates to testicular dysfunction, characterised by high amounts of gonadotropins, particularly luteinising hormone.3 Luteinising hormone is produced by the pituitary gland and acts on the Leydig cells in the testes to stimulate the production of testosterone, which controls the release of luteinising hormone via a feedback mechanism.4 Secondary hypogonadism relates to a central defect of hypothalamus or pituitary gland, which causes secondary testicular failure and is commonly diagnosed on the basis of low, or low to normal amounts of luteinising hormone.3 In male patients with cancer, primary hypogonadism can be associated with chemotherapy and higher concentrations of ghrelin or interleukin 6, whereas secondary hypogonadism is associated with higher opioid consumption and high concentrations of ghrelin.5
Male hypogonadism is normally diagnosed on the basis of low concentrations of total testosterone, free testosterone, and bioavailable testosterone, or any combination of these three values. Total testosterone is the typical measure and is defined as the sum of unbound and protein-bound testosterone in circulation.3 Protein-bound testosterone is bound to either sex-hormone-binding globulin (44%) or albumin (about 50%).6 The remaining testosterone is unbound or free testosterone, and makes up about 0·5–3·0% of that in circulation.7 Because testosterone bound to albumin is readily dissociable, it is bioavailable. Another common measure of testosterone is bioavailable testosterone, which is the sum of unbound testosterone and testosterone loosely bound to albumin.7
Symptoms such as diminished energy, poor concentration, depression, sleep disturbances, decreased physical performance (ability to accomplish tasks that require physical attributes such as muscle strength and endurance for prolonged efforts), fatigue, and weakness have been associated with male hypogonadism.8, 9, 10, 11, 12, 13 Moreover, a reduction in testosterone might lead to reduced bone mass, muscle strength, and sexual function and desire in both men and women.14, 15 Up to 50% of men with advanced cancer can present with low concentrations of testosterone before receiving chemotherapy.16, 17 Evans and colleagues18 have suggested a new operational definition and pathophysiological mechanisms for cachexia. Low concentrations of testosterone and other anabolic hormones are major contributors to cachexia-related wasting of skeletal muscle and fatigue.18
To our knowledge, no study has systematically reviewed the published work to identify potential clinical associations of androgen deficiency in advanced diseases, such as cancer, where the risk of cachexia is greater. In this qualitative systematic review we aim to assess the published work on the effect of male hypogonadism on functional and nutritional status, symptoms, and quality of life in patients with advanced cancer, and to identify gaps in the knowledge of androgen deficiency diagnosis in advanced cancer for prospective studies.
Section snippets
Search strategy
Publications specifically addressing the relation between male hypogonadism and functional status, nutritional status, body composition, symptoms, and quality of life in patients with advanced cancer were used.
One author (MP) did a review of citations from PubMed (from January, 1966), Medline (from January, 1966), and Embase (from January, 1988) up to March 1, 2009. Keywords included “hypogonadism”, “low testosterone”, “nutritional status”, “body composition”, “quality of life” “function”,
Number and type of studies included
Of 381 potentially relevant unique publications, six were eligible for inclusion in our systematic review (figure 1).5, 16, 17, 19, 20, 21 Some studies were excluded because patients with advanced cancer were not included22, 23, 24 or data on associations between male hypogonadism and clinical outcomes of interest were not reported.25, 26, 27
Population characteristics and measures of hypogonadism
The six reviewed publications included a total of 476 patients (table).5, 16, 17, 19, 20, 21 The most common cancer types assessed were lung and
Discussion
Androgen deficiency has been suggested to be an important contributing factor to cancer cachexia sequelae (eg, muscle wasting and fatigue).18 There is no definitive evidence of an association between male hypogonadism and the nutritional, functional, or quality of life characteristics in patients with advanced cancer. Factors that explain this lack of evidence include heterogeneity of taxonomy, pathophysiology of androgen deficiency in advanced cancer, variation in the normative ranges among
Conclusion
Clear epidemiological data showing whether male hypogonadism is independently associated with clinical and biological sequelae of cancer cachexia (eg, higher inflammation, fatigue, and body wasting) is not available, despite the prevalence of male hypogonadism in patients with advanced cancer16, 17 and the suggested role of androgen deficiency in the pathophysiology of cancer cachexia.18 Furthermore, whether androgen deprivation is merely a cause or a consequence of cancer cachexia is not
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