MALE HYPOGONADISM

MALE HYPOGONADISM Epidemiology and prevalence of male hypogonadism Male hypogonadism is associated with decreased testicular function, with decreased production of androgens and/or impaired sperm production [1]. This is caused by poor testicular function or as a result of inadequate stimulation of the testes by the hypothalamic-pituitary axis. Several congenital or acquired disorders causing impaired action of androgens are also described [1]. Hypogonadism may adversely affect multiple organ functions and quality of life (QoL) [2]. Late-onset hypogonadism (LOH) is a clinical condition in ageing men, which, by definition, must comprise both persistent specific symptoms and biochemical evidence of testosterone deficiency [1,3]. Late-onset hypogonadism is frequently diagnosed in the absence of an identifiable classical cause of hypogonadism, which becomes more prevalent with age, usually occurring, but not exclusively, in men aged > 40 years. Male hypogonadism has also been called Testosterone Deficiency. The EAU Guidelines 2022 Panel has agreed to use the term Male Hypogonadism, which may better reflect and explain the underlying pathophysiology. Likewise, the Panel has further agreed to continue with the term testosterone therapy. The present Guidelines specifically address the management of adult male hypogonadism also called LOH. Some insights related to congenital or pre-pubertal hypogonadism are also provided and summarised. The prevalence of hypogonadism increases with age and the major causes are central obesity, other co-morbidities (e.g., diabetes) and overall poor health [4]. In healthy ageing men, there is only a small gradual decline in testosterone; up to the age of 80 years, aging accounts for a low percentage of hypogonadism [4]. In men aged 40-79 years, the incidence of symptomatic hypogonadism varies between 2.1-5.7% [5–7]. The incidence of hypogonadism has been reported to be 12.3 and 11.7 cases per 1,000 people per year [5,8]. There is a high prevalence of hypogonadism within specific populations, including patients with type 2 diabetes (T2DM), metabolic syndrome (MetS), obesity, cardiovascular disease (CVD), chronic obstructive pulmonary disease, renal disease and cancer [7]. Low testosterone levels are common in men with T2DM [9] and a high prevalence of hypogonadism (42%) has been reported in T2DM patients [10]. Klinefelter syndrome, a trisomy associated with a 47,XXY karyotype, is the most prevalent genetic cause of primary hypogonadism (hypergonadotropic hypogonadism), with a global prevalence of 1/500-1,000 live male births [11-13]. However, < 50% of individuals with Klinefelter syndrome are diagnosed in their lifetime [14]. Body Composition and Metabolic Profile Low testosterone levels are common in men with obesity. Male hypogonadism is associated with a greater percentage of fat mass and a lesser lean mass compared to men with adequate testosterone levels [15]. There is much evidence that a low testosterone level is strongly associated with increased visceral adiposity, but it also leads to lipid deposition in the liver and muscle and is associated with atherosclerosis [15]. In vitro studies have suggested that hypogonadism impairs glucose and triglyceride uptake into subcutaneous fat depots [15]. This enhances the uptake of glucose and triglycerides into ectopic fat depots. Testosterone therapy has been associated with a reduced percentage of body fat and increase of lean body mass [16]. Data from a registry study have suggested that over a period of 11 years, testosterone therapy with long-acting intramuscular testosterone undecanoate was associated with a substantial but gradual loss of weight, along with a reduction in waist circumference [17]. Testosterone also reduces liver fat content and muscle fat storage [15]. Metabolic Syndrome/Type 2 Diabetes Metabolic Syndrome (MetS) is characterised by several specific components, including increased waist circumference, dyslipidaemia, hypertension, and impaired glucose tolerance. Hypogonadism is associated with central obesity, hyperglycaemia, insulin resistance and dyslipidaemia [low high-density lipoprotein (HDL)] cholesterol, raised total and low-density lipoprotein (LDL) cholesterol and triglycerides], hypertension and predisposition to T2DM, which are all components of MetS [18]. Several randomised controlled trials (RCTs) have shown that testosterone therapy might improve insulin resistance and hyperglycaemia and lower cholesterol and LDL-cholesterol [19–23]. Testosterone therapy in hypogonadal T2DM improved glycaemic control in some RCTs and registry trials; however, there is no conclusive evidence from RCTs and meta-analyses [20,24,25]. A recent large placebo-controlled RCT, including 1,007 patients with impaired glucose tolerance or newly-diagnosed T2DM and total testosterone < 14 nmol/L, showed that testosterone therapy for 2 years reduced the proportion of patients with T2DM regardless of a lifestyle programme [26]. Similarly, a previously published registry study reported that testosterone therapy was associated in time with remission of T2DM [24]. HDL-cholesterol may decrease, remain unchanged or increase with testosterone therapy. Testosterone therapy in men with MetS and low testosterone has been shown to reduce mortality compared to that in untreated men [27,28], although no conclusive evidence is available. Erectile dysfunction (ED) is common in men with MetS and T2DM (up to 70% of patients). The causes of ED are multi-factorial and 30% of men with ED have co-existing testosterone-deficiency hypogonadism. Some evidence has suggested that for patients with T2DM this is only found in men with clearly reduced testosterone levels (< 8 nmol/L or 2.31 ng/mL) [29]. From a pathophysiological point of view, it has been reported that this is because ED is predominantly caused by vascular and neuropathic disease, and therefore not likely in men who do not have established vascular disease. Therefore, men presenting with ED should be screened for MetS. Likewise, patients with ED and diabetes may be offered testosterone measurement. Placebo-controlled RCTs of testosterone therapy in T2DM have demonstrated improved sexual desire and satisfaction, but not erectile function [20,29]. The presence of multiple comorbidity in this group of patients may confound the response to testosterone therapy alone. In a long-term registry study in men with T2DM, parenteral testosterone undecanoate therapy led to one third of patients entering remission from diabetes during 11 years’ follow-up [30]. A large 2-year RCT of testosterone undecanoate vs. placebo showed that testosterone therapy significantly decreased progression of 999 men with low testosterone (< 14 nmol/L) from pre-diabetes to overt T2DM [26]. Physiology of testosterone production The pituitary gland regulates testicular activity through secretion of luteinising hormone (LH), which regulates testosterone production in Leydig cells and