Outcomes of androgen replacement therapy in adult male hypogonadism: recommendations from the Italian society of endocrinology

In HG subjects with MetS and/or T2DM, a limited number of studies show a tendency towards improved glycaemic control after TS [1]. However, this trend is not evident in the general HG population [2‐4] and is less evident in MetS. Conversely, lipid profile, which is tested in a higher number of studies, seems to improve after TS in all HG patients [5‐8], but this is not so evident in HG subjects with MetS and/or T2DM [9‐11]. Body mass index (BMI) is not affected by TS in HG subjects with or without metabolic disorders [3, 9, 10]. A clear-cut decrease in fat body mass during TS is reported in almost all studies performed in unselected HG subjects [12] and in the fewer studies performed in HG patients with MetS and/or T2DM [9‐11, 13, 14]. Similarly, lean mass increases in all HG patients receiving TS, although the trend is less evident in patients with dysmetabolism.

We place an important value on changes to body composition and metabolic profile in men with unequivocally reduced T levels.

Although the efficacy of TS in improving body composition has been consistently replicated, the task force remarks that TS should not be administered as an alternative to appropriate lifestyle changes [15], which should be pursued prior to or, in selected cases, alongside TS.

T has a fundamental role in bone maturation: at the end of puberty to reach peak bone mass, and during adult life to maintain it [16]. HG men have significantly lower bone mineral densities (BMD) than eugonadal age-matched men [16]. The prevalence of HG in osteoporotic men, however, has not been properly assessed. Studies estimate HG in up to 20 % of men with vertebral fractures and 50 % of hip fractures [17]. Some non-placebo-controlled trials and/or trials in strictly selected non-HG men without other major comorbidities are available [18‐22]. Taken together, these studies suggest a positive effect of TS on lumbar spine but not femoral neck BMD. Only two RCTs [23, 24] have been conducted in elderly and clearly HG men (T < 12 nmol/L), for a total of 41 subjects [23, 24], treated with intramuscular T injection. These studies show a significant effect of TS on femoral BMD, as compared to placebo (+2.7 %) [23, 24], and a more pronounced effect (+10.2 %) on lumbar BMD, after 36 months [23]. Another controlled study, performed on 99 HG men with a history of fracture or T-score <–2.0 and frailty, shows a positive effect of transdermal TS on lumbar BMD [20]. One non-placebo-controlled RCT study performed on 40 HG men with sexual symptoms and MetS or T2DM shows a positive relationship between serum T and BMD increments at both the lumbar and femoral sites after 36 months of T undecanoate treatment [18].

Although there is no doubt that T is a key hormone for skeletal health, a careful diagnosis should be made to characterise HG, excluding other causes of low BMD and understanding the relative role of other comorbidities, especially in men with only a marginal reduction in T levels. No studies report effects on fracture rates after TS, nor is there any evidence for the effects of co-treatment with agents with proven anti-fracture efficacy (e.g. bisphosphonates) and/or vitamin D/calcium supplementation. Similarly, there is no clear evidence of better results with T injections than with transdermal administration. For this reason, the task force suggests adding other pharmacological agents to treat osteoporosis if the fracture risk is high. Men with a modest or borderline risk of fracture can be treated with TS alone. In general, the decision on if and when to add vitamin D, calcium and/or another specific treatment and which T formulation to use should be based on an assessment of the risks and benefits for the patient concerned.

The effects of TS on cardiovascular function, events and mortality of HG patients are poorly known [25]. Some studies show beneficial effects on surrogate markers of cardiovascular health [8, 14, 26]. The few RCTs and subsequent meta-analyses [27‐29] suggest that TS in men is not associated with a consistent CV effect. Most trials rely on too few adverse events to reach reliable conclusions. A recent meta-analysis of RCTs [30] identified 27 trials including 2,994 middle-aged or elderly men (1733 T-treated) with a baseline T level ranging between 7.0 and 20.0 nmol/L, reporting 180 CV-related events, including CV-related deaths. T treatment increased the risk of CV-related events (OR 1.54, 95 % CI 1.09–2.18), including CV-related deaths (OR 1.42; 95 % CI 0.70–2.89), independently of baseline T level [30]. However, a more recent meta-analysis [31] on a much larger population (5,508 men, 3,040 treated with T) confutes these findings, showing no effect on major cardiovascular events (MACE) and mortality, and a somewhat CV-protective effect in a subgroup of HG men with metabolic diseases (OR 0.19 95 % CI 0.04; 0.85). The major limitation is that none of these RCTs had CV function or events as the primary or secondary outcome, and all studies were underpowered to address this issue. In addition, reporting of adverse events, bias linked to trial funding [30, 32] and study duration too short to define CV safety all undermine the validity of the currently available data. A qualitative review of the trials seems to suggest that long-acting injectable T esters or transdermal preparations should be preferred to reduce the risk of excessive haematocrit increase during TS [28, 33], although a formal quantitative appraisal is still lacking [30].

The recommendation to offer TS to elderly HG men places a relatively low value on avoiding the burden of TS and its unclear cardiovascular effects.

The risks of treating elderly HG men with TS appear to be related to age, history of previous CV events and rise in haematocrit. In younger and middle-aged HG subjects [34], these risk factors seem, on the whole, to play a minor role compared to the potential benefits of TS in reducing several other cardiovascular risk factors.

Observational data show that sexual complaints, including ED, are the most common symptoms associated with HG [35, 36]. Simple correlation, however, does not imply causation. Several non-placebo-controlled trials are available [37‐40]. The few RCTs contain a sufficiently large number of treated subjects to draw reliable conclusions [37‐39]. The effects of TS on libido have recently been meta-analysed [38]. In 17 RCTs, enrolling 1,111 men, TS determined an improvement in the libido of severely HG subjects (T < 8 nmol/L), but not in those with milder forms of HG. The effects of TS on sex-related erections were assessed in 1,431 individuals, proving effective only in men with reduced T levels (<12 nmol/L) [38]. An inverse relationship between mean T levels at enrolment and the effect of TS on overall erectile function was observed. Amongst studies providing International Index of Erectile Function (IIEF) data, TS resulted in a weighted mean improvement of about 40 % (range: 22–79 %), corresponding to a weighted mean delta of 4 ± 2 points in the IIEF-5 score (range: 3–8) [39]. Clinical studies document that T not only controls libido and erectile function but is also involved in the regulation of the orgasmic component of male ejaculatory reflex, acting both centrally and peripherally [38]. Ten studies enrolling 677 patients investigated the effect of TS on orgasm, confirming the relationship between baseline mean T levels and the effect size on TS orgasmic function.

The decision as to whether or when to treat HG men to improve sexual symptoms remains problematic. ED generally has a multifactorial aetiology; vascular factors are predominant amongst the comorbidities and hamper the beneficial effects of TS. In young HG subjects, TS is often sufficient to improve sexual function. In older men, the low T level may be the consequence rather than the cause of ED [41]. A large number of HG ED patients could be safely treated with PDE5-I monotherapy and TS could be offered as an add-on treatment only for those with persistently low T levels, [39, 41]. The decision to start TS in older HG men depends on the patient’s individual benefit/risk ratio.

The task force places a relatively high value on the recommendation to offer TS to HG men with major depressive disorders and in those resistant to the use of common antidepressants, and a high value on TS in HIV-infected men with HG to prevent and/or combat wasting syndrome by improving lean body mass.

It should be recognised that evidence for the role of TS in depressed or HIV men is limited, considering both the number of patients enrolled and the follow-up. Further information on the long-term benefits and adverse effects of T use in these subjects is therefore required. The outcomes of TS in other disorders, including CPOD and ESRD, in frail subjects or in those treated with glucocorticoids or opioids are the same as for patients with classic androgen deficiency [47, 48].

There are no data suggesting that TS is associated with an increased risk of prostate cancer [49]. Observational data on >1,100 subjects revealed that about 64 % of HG men treated with T do not show an increase in PSA. Six RCTs found that TS increases PSA values [6, 23, 50‐53], but only in two was the increase significant [52, 53]. The majority of patients had a clinical condition of HG with markedly reduced T levels (< 8 nmol/L) or T levels between 8 and 12 nmol/L and symptoms of HG. A smaller proportion of patients showed comorbidities such as T2DM or MetS [9, 10, 54]. Only 23 % of 250 patients had an increase in prostate volume (assessed by digital rectal examination or prostate ultrasound scan) [6, 23, 55], whilst in the remaining it was within the normal range.

The task force places high value on the recommendation that TS, when appropriately given to HG men, has no carcinogenic effect on an otherwise unaffected prostate gland.

The effects of TS on the prostate gland are not such as to advise limiting its use, given its potential benefits on various cardiovascular, metabolic and sexual outcomes. TS may therefore be considered safe for the prostate gland in all patients without clinically evident PCa, as long as accurate screening is performed beforehand and adequate follow-up is performed.

TS induces a dose-dependent increase in haematocrit within 1 month [27, 28]. This effect is higher with short-acting than with long-acting, injectable T esters or transdermal preparations [33]. The increase is caused by both erythropoietin and the direct effect of T on bone marrow [56]. Fernandez-Balselles et al. [28] showed that T-treated men had a 3.15-times higher risk of developing erythrocytosis compared to placebo-treated controls, especially with intramuscular T formulations. However, this rarely results in thrombosis, as demonstrated by meta-analyses considering all cardiovascular events [1, 27, 28]. Nevertheless, frequent monitoring is necessary to avoid critically elevated levels, with 54 % considered the cut-off for suspension [48]. Polycythaemia reverts to baseline after T withdrawal. RCTs rarely report increased haematocrit as an adverse event of TS (Table 1). Some studies report a significant haematocrit increase with intramuscular TS [10, 57‐59]. However, only a small number of HG patients were considered and haematocrit was not the primary endpoint.

TS down-regulates the hypothalamus–pituitary axis, depressing LH and FSH and further decreasing endogenous T synthesis, thereby inhibiting sperm production [48]. Androgens have been actively studied for potential use in male hormonal contraception. The negative effect of T on fertility is transient and fully reversible, with a predictable course [60].

Few studies have considered the effects of TS on obstructive sleep apnoea syndrome (OSAS) in patients with HG. One randomised, placebo-controlled study showed that intramuscular T undecanoate acutely worsened sleep hypoxaemia in patients with obesity and OSAS. An open-label study on five HG men reported worsened OSAS with intramuscular T enanthate [61]. However, Snyder et al. [62] did not find any change in respiratory distress index in 108 HG men treated with transdermal T for 36 months.

Few randomised, placebo-controlled trials indicate which adverse events resulted in patients dropping out of the study. In men treated with transdermal T erythema, pruritus and nasopharyngitis occurred in about 45 % of patients in both the study and control groups [10]. Transdermal approaches might increase the risk of transfer of T to others during close skin contact, although this was found unlikely in a randomised controlled study [63].