Testosterone and Mortality

 

Vakkat Muraleedharan, T. Hugh Jones

Abstract and Introduction

Abstract

Epidemiological studies have found that men with low or low normal endogenous testosterone are at an increased risk of mortality than those with higher levels. Cardiovascular disease accounts for the greater proportion of deaths in those with low testosterone. Cancer and respiratory deaths in some of the studies are also significantly more prevalent. Disease-specific studies have identified that there are higher mortality rates in men with cardiovascular, respiratory and renal diseases, type 2 diabetes and cancer with low testosterone. Obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease and inflammatory disorders are all associated with an increased prevalence of testosterone deficiency. Two major questions that arise from these findings are  is testosterone deficiency directly involved in the pathogenesis of these conditions and/or a contributory factor impairing the body's natural defences or is it merely a biomarker of ill health and the severity of underlying disease process? Does testosterone replacement therapy retard disease progression and ultimately enhance the clinical prognosis and survival? This review will discuss the current state of knowledge and discuss whether or not there are any answers to either of these questions. There is convincing evidence that low testosterone is a biomarker for disease severity and mortality. Testosterone deficiency is associated with adverse effects on certain cardiovascular risk factors that when combined could potentially promote atherosclerosis. The issue of whether or not testosterone replacement therapy improves outcomes is controversial. Two retrospective studies in men with diagnosed hypogonadism with or without type 2 diabetes have reported significantly improved survival.

Introduction

The prevalence of hypogonadism in male populations is not known with certainty, in part due to a lack of consensus on the threshold that should be used to define testosterone insufficiency. Hypogonadism is defined as a clinical syndrome which comprises both symptoms and biochemical evidence of testosterone deficiency.Clinical guidelines have provided some direction for cut-off levels of testosterone, but these also differ. Differences in the measurement of testosterone between assays and laboratories also lead to problems interpreting these thresholds. The European Male Aging Study (EMAS), involving 3369 men, defined late-onset hypogonadism as the presence of at least 3 sexual symptoms (loss of morning erections, low sexual desire and erectile dysfunction), total testosterone (TT) <320 ng/dl (11 nmol/l) and free testosterone (fT) <64 pg/ml (220 pmol/l). Using this definition, the overall prevalence of hypogonadism in the EMAS study population was 2·1% and increased with age from 0·1% for men 40 to 49 years of age to 5·1% for those 70–79 years. However, men already receiving testosterone replacement therapy (TRT) were excluded so this figure may represent an underestimate of the overall prevalence of hypogonadism. The Boston Area Community Health (BACH) study reported a prevalence of symptomatic hypogonadism of 4·2% in men aged 39–50 years and 8·4% between 50 and 79 years.

Testosterone deficiency is associated with reduced insulin sensitivity, central obesity, dyslipidaemia, hypertension, osteoporosis, muscle weakness and frailty, cognitive impairment, lethargy and fatigue and sexual dysfunction. Low testosterone is also an independent risk factor for the future development of obesity, the metabolic syndrome and type 2 diabetes. Each of these conditions has a high prevalence in Klinefelter's syndrome.Acute and/or chronic illness (including cardiovascular disease) can lead to suppression of the hypothalamic–pituitary–testicular axis. This raises the question as to whether testosterone deficiency is merely a biomarker for ill health or is bidirectional having an adverse effect on the underlying disease progression.