Male hypogonadism (HG) is a medical condition characterized by a failure of the testis to produce and release adequate concentrations of its products, i.e., sperms and sex steroids. It can be congenital or acquired. The latter form is far more common than the former and it is usually apparent during adulthood [1]. Adult-onset HG is mainly related to aging itself and to the presence of comorbid conditions, increasingly more prevalent in ageing men, which-might impair the regular functioning of the testis and of its controllers, such as the pituitary (follicular stimulating hormone [FSH] and luteinizing hormone [LH]) and hypothalamus (gonadotropin-releasing hormone [GnRH]) [234]. Among these potentially impairing conditions, there are metabolic disturbances which are very common in the general population, such as obesity, metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) [1456]. The mechanisms by which an altered metabolism could impair the hypothalamic-pituitary-gonadal axis is still unclear, but the possibility that a low-grade hypothalamic inflammation can cause a disruption in GnRH formation or action is growing [7]. Adult-onset HG- or more commonly defined late-onset hypogonadism (LOH) is a condition characterized by a constellation of unspecific symptoms and signs, often superimposable to those of the aging process per se. Among those, sexual dysfunctions appear as the mostly specific symptoms characterizing the androgen deficiency. In fact, there is considerable evidence that testosterone (T) plays a crucial role in regulating male sexual function [891011]. The European Male Aging Study (EMAS), a population based survey performed on more than 3,400 men recruited from 8 European centres, has clearly shown that sexual symptoms—i.e., decreased frequency of sexual thoughts, decreased morning erections, and erectile dysfunction (ED)—are the most sensitive and specific symptoms in identifying patients with low T [12]. Similar results have been more recently reported by the T Trials [13], a randomized controlled trial performed in 788 community-dwelling men recruited from 12 sites in the United States, and by Rastrelli et al [14] in a large sample of men seeking medical care for sexual dysfunction. It has been proposed that when the presence of sexual symptoms is associated with a biochemical deficiency of circulating T a diagnosis of symptomatic LOH can be made. In the European adult population, 2% of the sample satisfy these criteria, whereas 17% demonstrated an isolated T deficiency (total T <11 nmol/L) [12].

As in all endocrine disorders, the goal of treatment of HG is to restore the deficient glandular function. If fertility is the issue and the testis is under-stimulated because of a gonadotropin deficiency, FSH and LH administration is recommended. In all the other cases, testosterone therapy (TTh) is the most convenient choice [15]. Quite surprisingly, in the United States, after a 2015 Food and Drug Administration (FDA) position statement (http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm), TTh is approved only for congenital HG or for acquired forms due to an “organic” damage to the brain centres or to the testis. Hence, either comorbidity-associated or age-related HG are not recognized as true pathological conditions needing a pharmacological intervention. The recently published Guidelines of the Australian Endocrine Society [16] fully endorsed the FDA's position, suggesting that removing the underlying metabolic conditions, such as losing weight, must be the optimal therapeutic strategy for treating obesity-associated HG, and that TTh is not justified in such conditions. Hence, the concept that a distinction between a true HG (classicor organic HG) and a false, age-related, HG (the so-called low T syndrome or andropause or pseudohypogonadism) is raising [16]. It is interesting to note that among more than 4,000 subjects seeking medical care at an endocrine unit for sexual dysfunction, we found a large proportion of HG subjects (i.e., 20%, defined as total T below 10.4 nmoles/L [17]). Of this, only 15% of all causes of HG fulfil the criteria of “classic HG”, whereas the large majority presents comorbidities, including obesity, MetS and T2DM [17]. According to the FDA's position and the Australian recommendations, all these symptomatic HG subjects should be left untreated, with a pharisaic advice of conducting a healthier lifestyle. Scepticism and even reluctance to start an androgen supplementation is essentially based on two kinds of considerations regarding TTh: 1) lack of efficacy in non-organic HG and 2) side effects. In this review we will analyse evidence underlying these believes.

There is no controversy about the fact that losing weight is an effective strategy to overcome T deficiency in obese subjects. In a previous meta-analysis we demonstrated that either lifestyle changes or bariatric surgery are effective in raising gonadotropin and T secretion [118]. Besides male HG, T2DM is another obesity-associated medical condition with a growing prevalence in the general population worldwide [19]. Also for T2DM, weight reduction and change in lifestyle are the frontline therapy, but it is inconceivable to negate effectiveness of pharmacological antidiabetic intervention just because the diabetic patient is also obese [19]. In fact, metformin administration is strongly suggested in newly diagnosed T2DM, regardless of any lifestyle intervention [19]. Why, along with lifestyle changes, is pharmacological treatment with metformin advised in T2DM and TTh is not in HG? Maybe because T2DM is a more “organic” condition than HG? It is interesting to note that the well-defined organic conditions leading to diabetes represent less than 1% of all cases of diabetes [19]. All the other cases are multi-factorial conditions that may or may not have a genetic background, still largely unidentified. This does not mean that diabetes exists in all cases or that it should not be promptly treated. Similarities between T2DM and male HG are schematized in Table 1.

The fact that symptoms of androgen deficiency in adulthood often overlap with those characteristics of the aging process (and its associated comorbidities) further complicates the debate. However, T2DM also is a condition characterized by unspecific symptoms, often overlapping with those of the aging process (Table 1). Interestingly, criteria for diagnosis of diabetes are based only on well-defined alterations of biochemical parameters, such as increased glycaemia or HbA1c, independently of symptoms [19]. This is not the case of HG. In fact, in LOH, all the Scientific Societies indicate that a reduction of circulating T is not enough for defining the disease. Specific symptoms must be present along with T deficiency. Symptoms of androgen deficiency include psychological (i.e., depression), physical (i.e., fatigue) and sexual concerns [202122]. Recently, Millar et al [23], reported a review of available literature to estimate the accuracy and operating characteristics of signs and symptoms for predicting low T in aging men. They found a weak correlation between signs, symptoms and T levels, uncertainty about what threshold T levels should be considered low for aging men and wide variation in estimated prevalence of the condition [23]. In addition, all relationships with symptoms are relatively poor in terms of sensitivity and specificity. However, as stated before, the EMAS study has clearly shown that sexual symptoms, and in particular their syndromic association, allow a better identification of the so-called LOH [1224]. Similar results were recently reported by us in a large cohort (n=4,890) of subjects consulting for ED at the University of Florence (UNIFI) [14]. However, in both the EMAS [12] and UNIFI [14] cohorts, Loess curve analysis did not indicate a clear-cut threshold where the association between sexual symptoms and hormonal deficiency is apparent, with a total T below 11 and 10.4 nmoles/L being the best indicators of sexual symptomatology, respectively. In contrast, in the EMAS study [12], the relationship between T deficiency and psychological and physical symptoms was rather poor or even absent.

Considering that sexual symptoms are the most genuine correlates of T deficiency, it is interesting to evaluate whether or not treating this deficiency is able to restore sexuality. If this is the case, we have the scientific demonstration that the so-called LOH does exist according to an “ex-juvantibus” criterion. A recent systematic qualitative review on the effect of TTh on several outcomes concluded that T did not show consistent benefit for sexual function [25]. However, the same Authors declared that sexual function was evaluated using different tools [25]. In addition, they included both eugonadal and hypogonadal subjects in the analysis [25]. Hence, their conclusions (based only on a personal perspective) are not derived from validated statistical methods. In contrast with the last report, we previously documented, using a meta-analytic method, that TTh is superior, when compared to placebo, in improving all aspects of sexual function [26]. Table 2 summarizes the main results of the meta-analysis. The outcomes observed were independent of age but indirectly related to the levels of T at enrolment. Furthermore, as expected, the effects of TTh were lower in the presence of vascular damage, such as in the case of T2DM [26]. Considering that metabolic conditions are often associated with relatively milder forms of T deficiency, it is possible that a lower apparent efficacy of TTh in T2DM is due to higher T baseline levels [27]. In addition, the mitigated effect of TTh in T2DM is also in line with the lower efficacy of all available treatment for ED in subjects with diabetes, due to the presence of the diabetes-associated chronic complications, which are not necessarily due to an androgen deficiency [21222829]. Although the presence of metabolic derangements could limit the efficacy of TTh on ED, the positive effect of TTh on body composition and insulin sensitivity [303132] might counterbalance the lower efficacy. Our meta-analysis confirmed epidemiological observation showing that sexual dysfunctions are a hallmark of HG, because TTh can significantly improve them. The vast majority of the subjects enrolled in the included RCTs are not those with “classic” HG. For example, in the T trial [33] 63% of the participants were obese and all were 65 years or older without apparent reason for HG other than age. In conclusion, there is robust evidence that all the forms of symptomatic HG should be treated irrespective to their “organic” or “non-organic” (metabolic) origin because most specific symptoms (sexual ones) are improved.

T esters have been available for almost 80 years; however, only over the past two decades has the introduction and use of newer, user-friendly preparations dramatically expanded the market [4]. Since their introduction to the market, the risk of prostate cancer (PC) was considered the most feared side effect related to the use of T preparations. In addition, quite recently,conflicting data have raised the possible relationship between TTh and increased cardiovascular (CV) risk. In the following section, these two aspects will be analyzed in detail.

A large body of evidence has documented that sexual symptoms are the most specific correlates of T deficiency. TTh is able to improve all aspects of sexual function independent of the pathogenetic origin of the disease supporting the scientific demonstration that the so-called LOH does exist according to an “ex-juvantibus” criterion. Although the presence of metabolic derangements could mitigate the efficacy of TTh on ED, the positive effect of TTh on body composition and insulin sensitivity might counterbalance the lower efficacy. CV safety concerns related to TTh are essentially based on a limited number of observational and randomized controlled trials which present important methodological flaws. When HG is properly diagnosed and TTh correctly performed no CV and prostate risk have beendocumented.