Sexual and Reproductive Health

3. MALE HYPOGONADISM

3.1. Definition, epidemiology and classification of male hypogonadism

3.1.1. Definition

Male hypogonadism is a clinical syndrome which comprises of symptoms with or without signs and biochemical evidence of testosterone deficiency. Hypogonadism is associated with decreased testicular function and production of androgens and/or impaired sperm production [3]. This may be caused by impaired testicular function (hypergonadotropic hypogonadism or primary hypogonadism) or as a result of inadequate stimulation of the testes by the hypothalamic-pituitary axis (hypogonadotropic hypogonadism or secondary hypogonadism) (Table 1) or uncommonly by reduced ability of testosterone to stimulate the androgen receptor at the cellular level. Hypogonadism can adversely affect multiple organ functions and quality of life (QoL) [3,4]. This chapter specifically addresses the management of adult male hypogonadism also called late-onset hypogonadism (LOH). Some insights related to congenital or pre-pubertal hypogonadism are also provided.

3.1.2. Epidemiology

The prevalence of LOH increases with age, with the major causes being obesity, other comorbidities (e.g., diabetes) and overall poor health [5]. The incidence of hypogonadism has been reported to be between 12.3 and 11.7 cases per 1,000 people per year [6,7]. Aging accounts for a low percentage of hypogonadism, as there is only a small gradual decline in testosterone, up to the age of 80 years, in healthy ageing men [5]. In men aged 40-79 years, the incidence of symptomatic hypogonadism varies between 2.1 and 5.7% [6,8,9].

There is a high prevalence of LOH within specific populations, including patients with obesity, type 2 diabetes (T2DM), metabolic syndrome (MetS), cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), renal disease and cancer [9]. In particular low testosterone levels are relatively common in men with T2DM [10,11] and in those with metabolic derangements.

Klinefelter syndrome, a trisomy associated with a 47, XXY karyotype, is the most prevalent genetic cause of primary hypogonadism, with a global prevalence of 1/500-1,000 live male births [12-15]. However, < 50% of individuals with Klinefelter syndrome are diagnosed during their lifetime [16].

3.1.3. Classification

Male hypogonadism can be classified according to the aetiology into primary hypogonadism or secondary hypogonadism (Table 1) [3,17]. A compensated or subclinical form of hypogonadism, characterised by normal testosterone serum levels and elevated luteinising hormone (LH) production, has also been reported [18]; the clinical significance of this condition is unclear [18-21].

The classification of hypogonadism has also been divided into two broad categories: ‘Classical/Organic’ and ‘Functional, often but not correctly identified as LOH [58]. The clinical effects of testosterone deficiency are however common to all patients independent of the cause of the hypogonadism; although, they may vary in severity or as a result of age of onset (see below). Classical hypogonadism includes: congenital or acquired diseases causing structural and/or irreversible impairment of the pituitary and/or testes. Functional hypogonadism is diagnosed on the absence of any recognised organic alterations in the HPG axis and it is mainly a consequence of comorbidities, affecting the Hypothalamic-Pituitary-Testicular (HPT) axis and should be treated first by resolving or improving any underlying conditions (e.g., anorexia in younger male subjects). Late onset hypogonadism, conversely represents even a broader clinical entity including adulthood onset forms which can have either organic or functional origin and can be primary or secondary [22] (see below). 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. By definition LOH must comprise both persistent specific symptoms and biochemical evidence of testosterone deficiency [3,23].

Finally, hypogonadism can also result from several conditions leading to reduced sensitivity/insensitivity to testosterone and its metabolites [3].

The current guidelines maintain a classification of Primary and Secondary Hypogonadism, with special reference to LOH.

The classification, based on the aetiology of hypogonadism, allows clinicians to adequately select appropriate treatment. In patients with secondary hypogonadism, both fertility and testosterone normalisation can be theoretically achieved with adequate treatment, whereas in primary hypogonadism only testosterone therapy can be considered [3,17] (Table 1). However, it should also be recognised that symptoms and signs of hypogonadism can be similarly independent of the site of origin of the disease. Conversely, the age of onset of hypogonadism can influence the clinical phenotype [24]. Accordingly, early onset, such as that occurring during foetal life, the clinical phenotype can span from an almost complete female phenotype (e.g., complete androgen insensitivity or enzymatic defects blocking androgen synthesis) to various defects in virilisation. In the case of a pre- or peri-pubertal appearance of hypogonadism due to a milder central (isolated hypogonadotropic hypogonadism [IHH]) or a peripheral defect (such as in Klinefelter syndrome), there may be delayed puberty with an overall eunuchoid phenotype. Finally, when hypogonadism arises post-puberty, particularly with advancing age, symptoms may manifest subtly and frequently overlap with the natural ageing process, leading to confusion [24].

Table 1: Classification of male hypogonadism

* Conditions acting at central and peripheral levels resulting in either primary and secondary hypogonadism.
¹ Different autosomal translocations can cause rare cases of hypogonadism and infertility.

A brief discussion on the physiology of testosterone production can be found in Appendix 1, online supplementary evidence.

3.2. Comorbidities associated with male hypogonadism

3.2.1. Obesity

Low testosterone levels are common in men with obesity. Male hypogonadism is associated with a greater percentage of fat mass and a lower lean mass compared to men with adequate testosterone levels [25,26]. Low levels of testosterone are strongly linked to heightened visceral adiposity. Additionally, they result in lipid accumulation in the liver and muscle, correlating with atherosclerosis [25,26].

3.2.2. Metabolic Syndrome/Type 2 Diabetes

Hypogonadism is frequently associated with MetS or its related components, including central obesity, hyperglycaemia, insulin resistance and dyslipidaemia and arterial hypertension [27].

Several randomised controlled trials (RCTs) have demonstrated that testosterone therapy may improve insulin resistance and hyperglycaemia and lower total and low-density protein

(LDL) cholesterol [28-33]. Testosterone therapy in hypogonadal T2DM improved glycaemic control in some RCTs and registry trials; however, there is no conclusive evidence [29,34,35]. A 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 two years reduced the proportion of patients with T2DM regardless of a lifestyle programme [33]. Similarly, a registry study reported that testosterone therapy was associated in time with remission of T2DM [34]. High-density lipoprotein (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 untreated men [36,37], 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 ED is only found in men with T2DM and clearly reduced testosterone levels
(< 8 nmol/L or 2.31 ng/mL) [38]. From a pathophysiological perspective, 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, although data on erectile function were limited [29,38]. Similar results were derived from a meta-analysis of published trials [39]. Accordingly, a large two-year RCT of testosterone undecanoate vs. placebo showed that testosterone therapy significantly improved sexual function and ED in men with impaired glucose tolerance or newly-diagnosed T2DM low testosterone (< 14 nmol/L) [33].

Testosterone therapy has been associated with a reduced percentage of body fat and increase in lean body mass [40]. Data from a registry study have suggested that testosterone therapy with long-acting intramuscular testosterone undecanoate over eleven years was associated with a substantial but gradual loss of weight, along with a reduction in waist circumference [41]

3.2.3. Sars-CoV-2 / COVID-19

Data seem to suggest that low circulating testosterone levels are more frequently associated with worse clinical outcomes in men with COVID-19 [42-49]. Accordingly, a cohort study, analysing two large academic health systems databases, including 723 men with a history of COVID-19 reported that hypogonadal men had a higher risk of being hospitalised [50]. In addition, a meta-analysis suggested that reduced testosterone levels detected at hospital admission for COVID-19 are associated with a four- five-fold increased risk of being admitted to the Intensive Care Unit (ICU) or dying, after adjustment for potential confounders [51].

Although no information on the role of testosterone therapy in the acute phase of the disease is available currently, data also showed that the hypogonadal patients under testosterone therapy had a reduced risk to be hospitalised after SARS-CoV-2 infection [50]. However, whether or not low testosterone can directly contribute to worse COVID-19 outcomes is still under investigation. The possibility that low testosterone in the acute phase of COVID-19 infection represents an adaptive response mechanism to dampen non-essential activities non conducive to recovery (physical and sexual activities) by turning off testosterone-dependent functions, cannot be excluded [52,53]. Accordingly, a meta-analysis showed that secondary or mixed hypogonadism is more frequently observed in the acute phase of the infection [51].

Studies evaluating patients in the recovery phase of COVID-19 have documented either restored [54,55] or persistently low testosterone levels in the majority of cases [56]. A longitudinal evaluation study showed that during the recovery phase a further improvement of testosterone levels can be observed up to twelve months after COVID-19. Male subjects who have recovered from COVID-19 should be accurately followed-up to exclude any long-term andrological consequences including impairment in sperm and testosterone production [51].

Table 2: Main factors associated with an increase or reduction of SHBG circulating levels

3.3. Late-onset hypogonadism

Testosterone production declines with ageing. The European Male Aging Study (EMAS) reported a 0.4% per annum (log hormone-age) decrease in total testosterone and a 1.3% per annum decline in free testosterone (fT) [5]. Late onset hypogonadism is the term frequently used to describe this phenomenon and the detection of hypogonadism in adulthood. Evidence indicates that several associated diseases and chronic comorbidities can interfere with the HPG axis leading to the development of primary hypogonadism or, more frequently, secondary hypogonadism in adulthood, thus significantly influencing the physiological age-dependent decline of testosterone. Combining the data from three different waves of the Massachusetts Male Aging Study (MMAS), demonstrated that associated comorbidity and obesity significantly decreased, whereas smoking tended to increase total, free and bio-available testosterone concentrations [57]. Data derived from the EMAS confirmed these findings [5,19]. Based upon these data and other evidence, as previously reported the concept of functional and organic hypogonadism has been more recently introduced (see above) [58]. Considering that suppression of HPG axis activity is functional, and potentially reversible by empiric measures, such as weight loss, the need for testosterone therapy has been questioned [58].

3.3.1. Clinical Diagnosis and Evaluation

The mainstay of LOH diagnosis includes signs and symptoms consistent with hypogonadism, coupled with biochemical evidence of low morning serum total testosterone levels on two or more occasions, measured with a reliable assay and in fasting conditions.

3.3.2. History taking

Specific symptoms associated with hypogonadism, including LOH, are shown in Table 3. These symptoms are non-specific and need to be recorded and taken in context with the clinical and biochemical state. Several self-reported questionnaires or structural interviews have been developed for screening of hypogonadism. Although these case-history tools have demonstrated clinical utility in supporting the biochemical diagnosis of hypogonadism, or in the assessment of testosterone therapy outcomes, their specificity remains poor and they should not be used for a systematic screening of hypogonadal men [59]. Headache and/or visual disturbance may indicate a pituitary-related disorder. History of surgical intervention for cryptorchidism or hypospadias must be taken into account as possible signs of congenital defects. Chronic and systemic comorbidities must be comprehensively investigated in every patient. Use of drugs that potentially interfere with the HPG axis should be excluded (Table 1). Acute diseases are associated with development of functional hypogonadism and determination of serum total testosterone levels should be avoided in these conditions; however, the role of testosterone in the case of acute illness remains to be clarified [42,46,51,60]. Fertility issues should be always discussed.

Table 3: Specific symptoms associated with LOH

3.3.3. Physical examination

Since obesity is frequently associated with hypogonadism (mostly functional), the determination of body mass index (BMI) and the measurement of waist circumference are strongly recommended in all individuals. Testicular and penile size, as well as the presence of sexual secondary characteristics can provide useful information regarding overall androgen status. In addition, upper segment/lower segment ratio (n.v. > 0.92) and arm-span to height ratio (n.v. < 1.0) can be useful to identify a eunuchoid body shape, especially in subjects with pre-pubertal hypogonadism or delayed puberty. Finally, digital rectal examination (DRE) should be performed in all subjects to exclude prostate abnormalities before testosterone therapy (any type) or to support suspicion of hypogonadism (in case of reduced volume) [61].

3.3.4. Laboratory Diagnostics

Testosterone levels are produced in a circadian variation, which may persist in ageing men [62,63]. Testosterone levels are also potentially influenced by food intake [64]; therefore, serum total testosterone should be measured in fasting conditions in the morning (between 07.00 and 11.00 hours). A confirmatory measurement should always be undertaken in the case of a primary pathological value, and before starting any testosterone therapy.

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) represents the most accurate method for sex steroid evaluation; however, standardised automated platform immuno-assays for total testosterone assessment demonstrate a good correlation with LC-MS/MS [65]. Available immuno-assays are not able to provide an accurate estimation of fT; therefore, direct fT evaluation with these methods is not recommended and should be avoided [66]. Equilibrium dialysis is the most accurate method for total testosterone measurement and FT calculation [67]. Alternatively, fT can be derived from specific mathematical calculations using total testosterone as derived by common immunoassays and taking into account serum sex hormone binding globulin (SHBG) and albumin levels [68] (http://www.issam.ch/freetesto.htm).

Data from meta-analyses have shown that testosterone therapy is ineffective when baseline levels are > 12 nmol/L (3.5 ng/mL). Positive outcomes are documented when testosterone levels are < 12 nmol/L, being higher in symptomatic patients with more severe forms of hypogonadism (< 8 nmol/L). Hence, 12 nmol/L should be considered as a possible threshold for starting testosterone therapy in the presence of hypogonadal symptoms [40,69].

In clinical conditions that may interfere with SHBG levels, evaluation of fT should be considered to better estimate actual androgen levels (Figure 1). Unfortunately, despite its potential clinical value [70], no validated thresholds for fT are available from clinical studies and this represents an area of uncertainty; however, data from the EMAS indicated that fT levels < 220 pmol/L (6.4 ng/dL) increased the likelihood to correct identify hypogonadism as compared with total testosterone level alone, particularly when total testosterone levels are between 8.0 and 11 nmol per litre [8,71,72].

The determination of LH must be performed along with prolactin (PRL) when pathological total testosterone levels are detected, in order to correctly define the underlying conditions and exclude possible organic causes (Figure 1). Follicle-stimulating hormone determination can further support the diagnosis of primary or secondary hypogonadism [21,73]. Due to its negative influence on libido, PRL can also be considered as first-line screening in patients with reduced sexual desire. In addition, contrast-enhanced pituitary magnetic resonance imaging (MRI) scanning, as well as other pituitary hormone evaluations, is required in the presence of specific symptoms such as visual disturbances, headache and when hyperprolactinemia is confirmed [74,75]. Limited evidence suggests also performing pituitary MRI in the case of severe hypogonadism (< 6 nmol/L, 1.75 ng/mL) with inadequate gonadotropin levels (Figure 1) [74-76].

3.3.5. Summary of evidence and recommendations for the diagnostic evaluation and screening of LOH

Figure 1: Diagnostic evaluation of Late-Onset Hypogonadism

TT = total testosterone; cFT = calculated free testosterone; PRL = prolactin; SHBG = sex hormone-binding globulin; LH = luteinising hormone; MRI = Magnetic resonance imaging.

3.4. Treatment of Classical and LOH

3.4.1. Indications and contraindications for treatment of hypogonadism

Patients with symptomatic hypogonadism (total testosterone < 12 nmol/L) without specific contraindications are suitable candidates to receive testosterone therapy (Table 4).

Absolute contraindications are untreated breast and prostate cancer (PCa). Similarly, conditions such as cardiovascular events as well as uncontrolled or poorly controlled congestive heart failure should be considered when prescribing testosterone therapy [77]. Conversely, severe lower urinary tract symptoms (LUTS) [International Prostate Symptom Score (IPSS) score > 19] represent a relative contraindication, as there is insufficient data on the long-term effects of testosterone therapy in these patients [66]. A positive family history for venous thromboembolism requires further analysis to exclude a condition of undiagnosed thrombophilia-hypofibrinolysis [78]. These patients need to be carefully counselled prior to testosterone therapy initiation. A haematocrit (HCT) > 54% should require testosterone therapy withdrawal, reduction in dose, change of formulation and venesection depending on the clinical situation to avoid any potential cardio-vascular complications. Lower baseline HTC (48-50%) should be carefully evaluated before testosterone therapy initiation, to avoid pathological increases during treatment, especially in high-risk men such as those with COPD or Obstructive Sleep Apnoea Syndrome (OSAS). Accordingly, the Framingham Heart Study showed that HCT > 48% represented a condition associated with increased risk of coronary artery disease (CAD) and mortality and was associated with cardiovascular disorders [79]. Testosterone therapy suppresses gonadotropin and endogenous testosterone secretion as well as spermatogenesis [80]; therefore, testosterone therapy is contraindicated in individuals who desire fertility [81]. Secondary hypogonadism is characterised by low or inappropriately normal gonadotropin levels; therefore, the rationale is to substitute the gonadotropin deficiency with simultaneously FSH and LH analogues, if fertility is desired [82].

Table 4: Main contraindications of testosterone therapy

3.4.2. Testosterone therapy outcomes

3.4.2.1. Sexual dysfunction

Sexual concerns are the main symptoms of hypogonadal patients [3,8,83,84]. A consistent body of evidence shows that testosterone therapy in hypogonadal men (total testosterone < 12 nmol/L) may have a beneficial effect on several aspects of sexual life; in contrast, there is no evidence of benefits in using testosterone therapy for treating sexual dysfunction in eugonadal men [69,85-87]. The beneficial effect on sexual function seems to be more related to testosterone level normalisation than the specific testosterone formulations used [87,88].

A meta-analysis of placebo-controlled RCTs showed that testosterone therapy significantly improves erectile function (as measured by IIEF-Erectile Function domain score) and that patients with more severe hypogonadism (i.e., total testosterone < 8 nmol/L) are more likely to achieve better improvement than patients with milder hypogonadism (i.e., total testosterone < 12 nmol/L) [69]. Similar results were observed for sexual desire; however, the presence of metabolic comorbidity (such as diabetes and obesity) decreased the magnitude of these improvements. In particular, testosterone therapy alone resulted in a clinically effective outcome only in patients with milder ED [69]. Similar results have also been confirmed in an update analysis [89] and in a recently published Cochrane review [1970]. In line with these data, report from the non-inferiority “Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE)” study, showed in middle-aged and older hypogonadal (total testosterone < 10.4 nmol/L) men with pre-existing or a high risk of CVD, testosterone therapy with gel for two years improved sexual activity, hypogonadal symptoms, and sexual desire, but not erectile function [90].

Other sexual function parameters, such as intercourse, orgasm and overall satisfaction, were all improved compared with placebo [69,89]. Men with a comorbidity, such as T2DM, usually show modest improvements in terms of sexual function after testosterone therapy and may potentially require concomitant phosphodiesterase type 5 inhibitors (PDE5Is) to improve effectiveness [3,87]. A meta-analysis including 913 patients derived from eight RCTs suggested that combination therapy (testosterone and PDE5Is) was superior when compared to PDE5Is alone in improving erectile function [92]. The specific beneficial effect derived from the combined use of testosterone therapy and PDE5Is is unclear [85]. Similarly, information related to the combined use of testosterone therapy with other ED drug therapies is lacking [3,87].

The Sexual Function Trial of the Testosterone Trials (TTrials) (one of the largest placebo-controlled trials on testosterone therapy) documented consistent improvements in 10 of 12 measures of sexual activities in older (≥ 65 years) hypogonadal men, particularly in frequency of intercourse, masturbation and nocturnal erections (as measured by PDQ-Q4) [93,1973]. The magnitude in improvement was shown to be proportional to the increase in serum total testosterone, fT and E2 levels, it was not possible to demonstrate a threshold level [94]. A study of 220 men with MetS with or without T2DM also found that sexual function improved in men who reported sexual problems with improvement in IIEF scores, with specific increases in libido and sexual satisfaction [29].

3.4.2.2. Vitality and physical strength

The role of testosterone in stimulating muscle growth and strength is well established. Accordingly, androgenic-anabolic steroids (AAS) have been used as performance-enhancing agents to increase physical performance in competitive sport [95]. In this regard, testosterone therapy in hypogonadal men has been shown to increase muscle mass and reduce fat mass, with limited effects on final weight [40]. Despite this evidence, the role of testosterone therapy in older men with mobility limitations remains unclear. The National Health and Nutrition Examination Survey 1999-2004 [96] was unable to detect any association between overall circulating testosterone levels and the amount of physical activity. However, among non-obese men, those in the highest physical activity tertile were significantly less likely to have low or low-normal testosterone than those in the lowest tertile. Data from TTrials indicated that testosterone therapy did not substantially increase the fraction of men whose six-minute walking distance increased > 50 m or the absolute increase in the distance walked by those enrolled in the physical function trial [93]. However, when the whole population of the TTrials was considered, a significant, although modest, positive effect on these two parameters was reported [93]. Similar data were derived from the Vitality Trial [93]. As support of the aforementioned considerations, a recent meta-analysis including 2043 subjects older than 60 years failed to show a significant improvement of muscle strength of testosterone therapy when compared to placebo [97].

3.4.2.3. Mood and cognition

Several observational studies have documented a relationship between depressive symptoms, reduced QoL and hypogonadism [98,99]. However, the specific relationship between hypogonadism and the incidence of depression is still unclear [99]. Only a few placebo-controlled RCTs have investigated the role of testosterone therapy in improving depressive symptoms. Data derived from TTrials showed that testosterone therapy improved mood, and depressive symptoms as continuous measures using several instruments [93]. However, the final effect was small in magnitude. In line with this data, the largest meta-analysis of available studies, including 1,890 hypogonadal men (baseline total testosterone < 12 nmol/L or fT < 225 pmol/L) men from 27 RCTs, documented that the positive effect of testosterone therapy was particularly evident in patients with milder symptoms [100]. The BLAST study of testosterone therapy in T2DM reported that those men with depression were less likely to respond with regards to symptoms of sexual dysfunction compared to men without depression [35].

Robust data on the effect of testosterone therapy on QoL are limited. Although recent meta-analyses suggest a significant effect of testosterone therapy over placebo, the magnitude is low and the heterogeneity high, therefore reducing the scientific value of the effect [88,101].

The role of testosterone therapy in patients with cognitive impairment is even more uncertain. The TTrials evaluated the effect of testosterone therapy in 493 individuals with age-associated memory impairment to assess possible improvement of several aspects of cognitive function. However, results failed to demonstrate any beneficial effect of testosterone therapy in improving cognitive function [93]. Similarly, a meta-analysis involving 17 studies enrolling 1,438 patients with a mean age of 70.4 years and a mean follow-up of 45.6 weeks did not find any effect of testosterone therapy on cognitive domains [102].

3.4.2.4. Body composition and metabolic profile

Late onset hypogonadism is associated with a greater percentage of fat mass and a lesser lean mass compared to testosterone-repleted men [103]. The major effect of low testosterone is to increase visceral adiposity but it also leads to deposition of lipids in the liver and muscle and is associated with atherosclerosis [25]. Some published data have suggested that testosterone therapy reduces percentage body fat and increases lean mass [104]. Testosterone therapy has also been found to decrease waist circumference, body weight and BMI, with these effects more predominant after twelve months of treatment [104-106]. Over two years, the T4DM RCT reported that men on testosterone therapy and a lifestyle programme had a greater reduction in waist circumference, total and abdominal fat mass and an increase in total and arm muscle mass and an increased strength in the non-dominant hand compared to a lifestyle programme alone [33]. There was a trend toward reduction in body weight although this approached significance but did not reach significance. The latter result is probably compounded by the increase in muscle mass as well as the decrease in fat mass. However, it should be recognised that the results of previous studies are mainly derived from registry and observational trials, which have important limitations due to the risk of selection bias for the non-random assignment of testosterone exposure. Accordingly, data derived from RCTs showed only an improvement of fat mass and lean mass of the same amount without any modifications in body weight [40]. A meta-analysis including seventeen RCTs specifically investigated the role of testosterone therapy on several metabolic parameters in patients with T2DM and/or MetS [39]. In line with what was reported in the general population, testosterone therapy was associated with an improvement in body composition either in T2DM or MetS without any effects on body weight. Similarly positive effects were also observed on fasting glycemia and insulin resistance (HOMA index) whilst more conflicting data were obtained for HbA1c and lipid profile [39].

3.4.2.5. Bone

Evidence suggests that bone mineralisation requires circulating sex steroids within the normal range [107]. The possible association between mild hypogonadism and osteopenia/osteoporosis is weak, whereas severe hypogonadism (total testosterone < 3.5 nM) is frequently associated with bone loss and osteoporosis, independent of patient age [107]. Three independent meta-analyses showed a positive effect of testosterone therapy on bone mineral density (BMD), with the highest effect at the lumber level [108-110]. Interestingly, the latter meta-analysis has provided novel evidence that the role of testosterone on BMD was even higher in patients with diabetes [110], who are at a higher risk of hypogonadism and bone fracture [39,111,112]. Similarly, data derived from TTrials and the T4DM studies confirmed that testosterone therapy increased BMD in hypogonadal ageing men [93,113]. However, available data are insufficient to determine the effect of testosterone therapy alone on the risk of fractures [107]. Recent data from the aforementioned TRAVERSE trial quite surprisingly showed an increased incidence of overall bone fractures among men who have received testosterone therapy compared to those who received placebo [1971]. However, it should be recognized that no difference in major osteoporotic fractures (i.e., hip, wrist, humerus, clinical spine and hip) were observed between groups. Moreover, this observation was derived from patient reports and therefore it deserves to be more specifically adjudicated. In conclusion, it should be recognized that the use of testosterone therapy as an adjunct to anti-resorptive treatment in hypogonadal patients at high risk of fractures has not been established. Therefore, anti-resorptive therapy must be the first-choice treatment in hypogonadal men at high risk for bone fractures. The combination of anti-resorptive treatment and testosterone therapy should be offered only in conjunction with hypogonadism-related symptoms.

3.4.2.6. Summary of evidence and recommendations for testosterone therapy outcome

3.4.3. Choice of treatment

3.4.3.1. Lifestyle factors

As reported above, functional hypogonadism is frequently associated with obesity and metabolic disorders [114]. Therefore, weight loss and lifestyle changes should be the first approach for all overweight and obese men with hypogonadism. A previous meta-analysis documented that a low-calorie diet can to revert obesity-associated secondary hypogonadism by increasing total testosterone and fT, reducing oestrogens and restoring normal gonadotropin circulating levels [115]. This was confirmed in an updated meta-analysis showing that the increase in testosterone is significantly associated with weight reduction [116]. Similar results can be obtained through physical activity, which is associated with the duration of scheduled exercise and weight loss obtained [116]. However, it should be recognised that the increase in testosterone levels observed after a low-calorie diet and physical activity is small (1-2 nmol) [115,116]. In addition, 60-86% of weight lost is regained after three years and 75-121% after five years [117]. Lifestyle changes represent an essential part of the management of obesity; however, some evidence suggests that when compared to lifestyle modifications alone, testosterone therapy-treated obese men benefit most from relief of their symptoms associated with testosterone deficiency, whereas those not treated did not benefit [82]. There is limited evidence to suggest that combination of life-style interventions and testosterone therapy in symptomatic hypogonadal men might result in better outcomes [103]. As described above, the T4DM study has demonstrated that over two-years testosterone therapy with lifestyle intervention was superior to lifestyle intervention alone in reducing waist circumference and total and abdominal fat content. There was no significant reduction in body weight when compared to lifestyle intervention alone [33]. Interestingly, recent data also showed that weight loss obtained thought the use of Glucagon-like peptide-1 analogues analogues can result in better testosterone increases as compared with diet programs alone [1972].

3.4.3.2. Medical preparations

Several testosterone formulations are available (Table 5). Direct comparisons among different testosterone products are still lacking. Candidates for testosterone therapy should be adequately informed about the possible risks and benefits of all available testosterone preparations. The final choice should be based on the clinical situation, testosterone formulation availability, and patient needs and expectations [22,118].

3.4.3.2.1. Oral formulations

An oral formulation has been available in oleic acid since the 1970s, and has been recently reformulated in a mixture of castor oil and propylene glycol laureate (testosterone undecanoate [TU] caps), to allow the drug to be maintained at room temperature without degradation [22,118]. The main limitation is related to poor bioavailability, which is strongly dependent on dietary fat content [22,118]. The US Food and Drug Administration (FDA) approved a new formulation of oral TU in a liquid-filled soft gel capsule, which improved oral availability [119]. Available evidence showed that TU capsule formulations can reach steady 24-hour average serum testosterone levels in more than 80% of hypogonadal men, thus resulting in a significant improvement of all sexual function domains at all time points when compared to baseline along with an excellent safety profile [119]. More recently, the FDA has approved a new oral formulation which contains as carriers Vitamin E, phytosterol esters, polyoxyl 40 hydrogenated castor oil and propylene glycol monolaurate [119]. For all new oral TU formulations a mild increase in arterial blood pressure has been reported. Hence, the FDA has required a black box warning that these drugs can induce a blood pressure increase [119].

Mesterolone is a 5α-dihydrotestosterone (DHT) derivate available for oral administration. Along with DHT, mesterolone cannot be converted to oestrogens and can only be used for a limited period and for specific indications, such as the presence of painful gynaecomastia. However, the lack of a full spectrum of testosterone bioactivity strongly limits its long-term use [22].

3.4.3.2.2. Parenteral formulations

Injectable testosterone preparations can be classified according to their half-lives (Table 5). Testosterone propionate is a short-term ester formulation requiring multiple fractionated doses (usually 50-100 mg, every two to three days), thus representing a major limitation for its use [22,118]. Cypionate and enanthate-T esters are short-term formulations, requiring administration every two to four weeks. A formulation containing mixed testosterone esters (TU, isocaproate, phenyl propionate, propionate) which has the benefit of a steady release of testosterone into the circulation, is available in some countries. The use of these older formulations is associated with wide fluctuations in plasma testosterone concentrations and is often reported as unpleasant by patients potentially resulting in adverse effects, such as polycythaemia [22,118,120]. A longer-lasting TU injectable formulation is widely available [22,118], with a good safety/benefit profile allowing the maintenance of normal stable testosterone levels at a dose of 1,000 mg initially every twelve weeks, following a six-week loading dose, but can be adjusted to a frequency of ten to fourteen weeks dependent on the trough (pre-injection level) after three to five injections to maintain levels in the therapeutic range (usually > 12 and < 18 nmol/L) [22,118,121].

3.4.3.2.3. Transdermal testosterone preparations

Among the available transdermal formulations, testosterone gels represent the most frequently used preparations. The gel is quickly absorbed by the stratum corneum, creating a reservoir within the subcutaneous tissues from where testosterone is continuously delivered for 24 hours, after a single daily application. These formulations have been shown to normalise serum testosterone levels with an excellent safety profile [22,118]. The introduction of specific devices and skin enhancers has resulted in better skin penetration of the drugs, thus reducing potential adverse effects. Local skin adverse effects are limited when compared to those with traditional testosterone patches, but they potentially allow transference of testosterone during close contact with the skin surface. The risk can be reduced by wearing clothing or by applying the gel on skin surfaces not usually touched (e.g., the inner thigh surface) [22,118]. To reduce the total amount of gel applied and residual quantities remaining on the skin, new formulations of testosterone gel have been introduced with a testosterone concentration of 1.62-2% [22,118]. Another transdermal testosterone formulation includes a topical, alcohol-based testosterone (2%) solution, which must be applied to the underarm once daily, using a metered dose applicator [22,118]. This testosterone formulation is not available in Europe. Testosterone levels should be monitored to optimise the testosterone dose. Blood collection is best taken two to four hours after gel application to use the peak level of testosterone absorbed as a reference for adequate therapeutic levels. Levels of testosterone after application can vary and a repeat measurement may be indicated especially as sometimes, inadvertently, the skin over the venipuncture site can be contaminated by the gel, leading to falsely elevated results.

In some European countries, DHT is available as a hydroalcoholic 2.5% gel. It is rapidly absorbed, reaching a steady state in two to three days [22,118]. Similar to that reported for mesterolone, DHT is not aromatised but can be useful for treating particular conditions, such as gynaecomastia and microphallus [22,118].

3.4.3.2.4. Transmucosal formulations

A testosterone buccal system is still available in several countries. It consists of a sustained-release muco-adhesive buccal-testosterone-tablet requiring twice-daily application to the upper gums. The tablet does not dissolve completely in the mouth and must be removed after twelve hours. This formulation has been proven to restore testosterone levels within the physiological range with minimal or transient local problems, including gum oedema, blistering and gingivitis [22,118].

A gel for intranasal administration is available in some countries, including the USA and Canada. It requires administration two or three times daily using a specific metered-dose pump. The application is rapid, non-invasive, and convenient, and avoids secondary transference observed with other topical products [22,118]. Preliminary results suggest that intranasal testosterone is associated with lower suppression of Gn levels and with a lower risk of haematocrit increases [122].

3.4.3.2.5. Subdermal depots

The implantation of testosterone pellets, available in a limited number of countries, represents the longest available testosterone formulation lasting from four to seven months. The procedure is invasive and may be unattractive to patients [22,118].

3.4.3.2.6. Anti-oestrogens

Anti-oestrogens, including selective oestrogen receptor (ER) modulators (SERMs) and aromatase inhibitors (AI) have been suggested as off-label treatments to restore testosterone levels and fertility in men with functional secondary hypogonadism or idiopathic infertility. They work by preventing down-regulation of the HPG axis by oestrogens and for this reason are particularly useful in men with obesity and metabolic disorders [116,123]. In the latter case, the hypothesis is that the excess of adipose tissue leads to increased aromatase activity and oestrogens levels resulting in impairment of the HPG [114]. Due to their putative mechanism of action, they require an intact HPG axis and cannot work in primary hypogonadism or secondary hypogonadism due to organic damage of the HPG axis. Both types of SERMs, which bind ERs with an agonist or antagonist effect depending upon the target tissue, and AIs, which prevent androgens from being converted into oestrogens by aromatase, have been used in clinical practice [22,118]. The evidence published so far is poor; all these products are off-label treatments and SERMs, due to their agonistic effect on venous vessels, could predispose men to the development of venous thromboembolism [22,118]. In this context patients should be warned of the potential increased risk of venous thromboembolism, although data are lacking. Long-term use of these agents can lead to reduced bone density and the development of osteoporosis, potentially increasing fracture risk.

3.4.3.2.7. Gonadotropins

Gonadotropin therapy should be considered the standard in men with secondary hypogonadism who desire paternity (Table 5) [22,118]. Recombinant hCG (rhCG) and LH (rLH) formulations offer comparable effects to urinary-derived preparations [118]. According to a meta-analysis of the available evidence, hCG should be administered with FSH since combined therapy results in better outcomes. Similar to recombinant hCG, recombinant FSH (rFSH) offers comparable effects to urinary-derived preparations [121].

Table 5: Available preparations for hypogonadism treatment

NA = not applicable.
* Testosterone ester mixture - propionate (30mg), phenylpropionate (60mg), isocaproate (60mg), decanoate (100mg)

3.4.3.2.8. Summary of evidence and recommendations for choice of treatment for LOH

3.5. Safety and follow-up in hypogonadism management

3.5.1. Hypogonadism and fertility issues

Pharmacological management of hypogonadism aims to increase testosterone levels to normal levels which resolve or improve symptoms of hypogonadism. The first choice is to administer exogenous testosterone. However, while exogenous testosterone has a beneficial effect on the clinical symptoms of hypogonadism, it temporarily inhibits gonadotropin secretion by the pituitary gland, resulting in impaired spermatogenesis and sperm cell maturation [124]. Therefore, testosterone therapy is contraindicated in hypogonadal men seeking fertility treatment [81]. When secondary hypogonadism is present, gonadotropin therapy may maintain normal testosterone levels and restore sperm production [3].

3.5.2. Male breast cancer

Studies have documented that breast cancer growth is significantly influenced by testosterone and/or by its conversion to oestradiol (E₂) through different mechanisms and pathways [125]. Accordingly, the use of SERMs still represents an important therapeutic option in the management of this cancer [125]. No information is available on the role of testosterone therapy in patients successfully treated for male breast cancer; therefore, treated and active male breast cancer should be recognised as absolute contraindications for testosterone therapy.

3.5.3. Lower urinary tract symptoms/benign prostatic hyperplasia (BPH)

A trial of 60 patients undergoing testosterone therapy for six months showed no significant differences on post-void residual urine and prostate volume, while storage symptoms as measured by IPSS significantly improved, despite an increase in prostate-specific antigen (PSA) level [126]. A larger pre-treatment prostate volume was a predictive factor of improvement in LUTS. Similarly, a placebo-controlled RCT including 120 hypogonadal (total testosterone < 12 nmol/L) men with MetS and listed for BPH surgery, showed that testosterone therapy did not result in a difference in LUTS severity compared to placebo. Conversely, an improvement in ultrasound markers of inflammation in the expression of several pro-inflammatory genes was found in the treatment active arm [127]. A long-term study of 428 men undergoing testosterone therapy for eight years demonstrated significant improvements in IPSS, no changes in max flow rate (Q_max) and residual urine volume, but also a significant increase in prostate volume [128]. Similar data from the Registry of Hypogonadism in Men (RHYME), including 999 patients with a follow-up of three years, did not demonstrate any significant difference in PSA levels or total IPSS in men undergoing testosterone therapy, compared to untreated patients [129]. Similar results were reported in an Italian registry (SIAMO-NOI), collecting data from 432 hypogonadal men from fifteen centres [130]. Meta-analyses have not found significant changes in LUTS between patients treated with testosterone or placebo [131-137]. According to the most recent literature, there are no grounds to discourage testosterone therapy in hypogonadal patients with BPH/LUTS and there is evidence of limited benefit from androgen administration. The only concern is related to patients with severe LUTS (IPSS > 19), as they are usually excluded from RCTs; therefore, limiting the long-term safety data of testosterone therapy in this specific setting [61].

3.5.4. Prostate cancer (PCa)

A considerable number of observational studies have failed to demonstrate any association between circulating higher testosterone levels and PCa [138]. In contrast, studies investigating the relationship between low levels of testosterone and risk of PCa have found that men with very low levels of fT have a reduced risk of developing low-to-intermediate-grade PCa, but have a non-significantly increased chance of developing high-grade PCa [138]. This peculiar pattern was also reported in trials such as the Health Professionals Follow-up Study, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE), with varying magnitudes of significance [139].

A meta-analysis, including 27 placebo-controlled, RCTs, found no evidence of increased PSA levels following testosterone therapy for one-year. When considering eleven studies reporting on the occurrence of PCa, the meta-analysis found no evidence of increased risk of PCa. However, a one year follow-up may be considered too short to draw firm conclusions on the risks of developing PCa. Furthermore, the analysis was restricted to studies with > 1-year follow-up, but no significant changes in PSA levels nor increased risk of PCa were found [132]. After five-year of median follow-up in three independent registry studies with > 1,000 patients undergoing testosterone therapy, PCa occurrence always remained below the reported incidence rate in the general population [140]. Similar results were reported by a large observational study including 10,311 men treated with testosterone therapy and 28,029 controls with a median follow-up of 5.3 years [141]. The same study, also showed that the risk of PCa was decreased for men in the highest tertile of testosterone therapy cumulative dose exposure as compared with controls [141].

Recently, the TRAVERSE study, a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial involving 5246 men aged 45 to 80 years, who had pre-existing or a high risk of CVD and who have been treated because of low testosterone levels (i.e., total T < 10.4 nmol/L) associated with reported symptoms of hypogonadism, did not show any difference in terms of PCa incidence or high-grade PCa rate between arms (testosterone therapy vs. placebo) at a mean follow-up, was 33.0± (SD) 12.1 months. Conversely, the same trial showed a significantly greater increase from baseline of total PSA in the treatment group as compared with the placebo arm [77].

With regards to PCa survivors, safety in terms of the risk of recurrence and progression has not yet been established. Limited data are available in the literature, with most case series not providing sufficient data to draw definitive conclusions (e.g., insufficient follow-up, small samples, lack of control arms, heterogeneity in study population and treatment regimen, etc.) [142]. A meta-analysis derived from thirteen studies including 608 patients, of whom 109 had a history of high-risk PCa, with follow-up of 1-189.3 months [143], suggested that testosterone therapy did not increase the risk of biochemical recurrence, but the available evidence is poor, limiting data interpretation [143]. Similar considerations can be derived from another, larger meta-analysis of 21 studies [144]. However, it is important to recognise both meta-analyses demonstrated high heterogeneity among the different studies and included a limited number of subjects. An RCT assessing the safety/benefit ratio of testosterone therapy in hypogonadal men successfully treated with prostatectomy for non-aggressive prostate PCa is currently ongoing [145].

In conclusion, recent literature does not support an increased risk of PCa in hypogonadal men undergoing testosterone therapy. Although it is mandatory to avoid testosterone administration in men with advanced PCa, insufficient long-term prospective data on the safety of testosterone therapy in PCa survivors [144], should prompt caution in choosing to treat symptomatic hypogonadal men in this setting. In particular, patients should receive comprehensive counselling regarding the uncertain long-term effects of testosterone therapy in this context, which necessitates further investigation. Due to the lack of strong evidence-based data on safety, the possible use of testosterone therapy in symptomatic hypogonadal men previously treated for PCa should be fully discussed with patients and limited to low-risk individuals.

3.5.5. Cardiovascular Disease

Evidence suggests that hypogonadal men have an increased risk of CVD [146,147]. Whether or not LOH is a cause or a consequence of atherosclerosis has not been clearly determined. Late-onset hypogonadism is associated with CV risk factors, including central obesity, insulin resistance and hyperglycaemia, dyslipidaemia, pro-thrombotic tendency and chronic inflammatory state [147]. Atherosclerosis is a chronic inflammatory disease, that releases pro-inflammatory cytokines into the circulation, which are known to suppress testosterone release from the HPG axis. Evidence from RCTs of testosterone therapy in men with MetS and/or T2DM demonstrates some benefit in CV risk, including reduced central adiposity, insulin resistance, total cholesterol and LDL-cholesterol and suppression of circulating cytokines [28-30,35,147,148]. However, due to the equivocal nature of these studies, testosterone therapy cannot be recommended for use outside of treatment of specific symptoms.

Published data show that LOH is associated with an increase in all-cause and CVD-related mortality [7,149-152]. These studies are supported by a meta-analysis that concluded that hypogonadism is a risk factor for cardiovascular morbidity [136] and mortality [153]. Importantly, men with low testosterone when compared to eugonadal men with angiographically proven coronary disease have twice the risk of earlier death [147]. Longitudinal population studies have reported that men with testosterone in the upper quartile of the normal range have a reduced number of CV events compared to men with testosterone in the lower three quartiles [149]. Androgen deprivation therapy for PCa is linked to an increased risk of CVD and sudden death [154]. Conversely, two long-term epidemiological studies have reported reduced CV events in men with high normal serum testosterone levels [155,156]. Erectile dysfunction is independently associated with CVD and may be the first clinical presentation in men with atherosclerosis.

The knowledge that men with hypogonadism and/or ED may have underlying CVD should prompt individual assessment of their CV risk profile. Individual risk factors (e.g., lifestyle, diet, exercise, smoking, hypertension, diabetes and dyslipidaemia) should be assessed and treated in men with pre-existing CVD and in patients receiving androgen deprivation therapy. Cardiovascular risk reduction can be managed by primary care clinicians, but patients should be appropriately counselled by clinicians active in prescribing testosterone therapy [83]. If appropriate, patients should be referred to cardiologists for risk stratification and treatment of comorbidity.

No RCTs have provided a clear answer on whether testosterone therapy affects CV outcomes. The TTrial (n=790) conducted in older men [157], the TIMES2 study (n=220) [29], along with the BLAST studies involving men with Metabolic Syndrome (MetS) and Type 2 Diabetes Mellitus (T2DM), as well as the study involving pre-frail and frail elderly men - all of which lasted for one year, and the T4DM study spanning two years - did not show any increase in Major Adverse Cardiovascular Events (MACE) increase in Major Adverse Cardiovascular Events (MACE) [29,32,33,157,158]. Randomised controlled trials, between three and twelve months, in men with known heart disease treated with testosterone have not found an increase in MACE, but have reported improvement in cardiac ischaemia, angina and functional exercise capacity [159-161]. A large cohort study (n=20,4857 men) found that neither transdermal gel or intramuscular testosterone was associated with an increased risk of composite cardiovascular outcome in men with or without prevalent CVD (mean follow-up 4.3 years) [162]. The European Medicines Agency (EMA) has stated that ‘The Co-ordination Group for Mutual recognition and Decentralisation Procedures-Human (CMDh), a regulatory body representing EU Member States, has agreed by consensus that there is no consistent evidence of an increased risk of heart problems with testosterone in men. However, the product information is to be updated in line with the most current available evidence on safety, and with warnings that the lack of testosterone should be confirmed by signs and symptoms and laboratory tests before treating men with these drugs [163].

Data recently released from the TRAVERSE study confirm the findings of the EMA [77]. The latter is the first double-blind, placebo-controlled, non-inferiority RCT with primary CV safety as an end point. The results showed that testosterone therapy was noninferior to placebo with respect to the incidence of MACE. However, a mild higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism was observed in the testosterone group [77]. The latter observations, however, need to be confirmed since previous available data do not support an increased risk of venous thromboembolism [78,164] or major arrhythmias [165] after testosterone therapy. Similarly, the long-term follow-up (median of 5.1 years since last injection) of the T4DM study showed no differences in self-reported rates of new diagnosis of CVD [166].

In conclusion, current available data from interventional studies suggest that there is no increased risk up to three years of testosterone therapy [167-171]. The currently published evidence has reported that testosterone therapy in men with diagnosed hypogonadism has neutral or beneficial actions on MACE in patients with normalised testosterone levels. The findings could be considered sufficiently reliable for at least a three year course of testosterone therapy, after which no available study can exclude further or long-term CV events [172,173].

3.5.5.1. Cardiac Failure

Testosterone therapy is contraindicated in men with severe chronic cardiac failure because fluid retention may lead to exacerbation of the condition. Some studies have shown that men with moderate chronic cardiac failure may benefit from low doses of testosterone, which achieve mid-normal range testosterone levels [160,174,175]. An interesting observation is that untreated hypogonadism increased the re-admission and mortality rate in men with heart failure [176]. If a decision is made to treat hypogonadism in men with chronic cardiac failure, it is essential that the patient is followed up carefully with clinical assessment and both testosterone and haematocrit measurements on a regular basis.

3.5.6. Erythrocytosis

An elevated haematocrit level is the most common adverse effect of testosterone therapy. Stimulation of erythropoiesis is a normal biological action that enhances the delivery of oxygen to testosterone-sensitive tissues (e.g., striated, smooth and cardiac muscle). Any elevation above the normal range for haematocrit usually becomes evident between three and twelve months after testosterone therapy initiation. However, polycythaemia can also occur after any subsequent increase in testosterone dose, switching from topical to parenteral administration and, development of comorbidity, which can be linked to an increase in haematocrit (e.g., respiratory or haematological diseases).

There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [79,177-179]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis.

As detailed, the TRAVERSE study, which had included symptomatic hypogonadal men aged 45-80 years who had pre-existing or a high risk of CVD, showed a mild higher incidence of pulmonary embolism, a component of the adjudicated tertiary end point of venous thromboembolic events, in the testosterone therapy than in the placebo group (0.9% vs. 0.5%) [77]. However, three previous large studies have not shown any evidence that testosterone therapy is associated with an increased risk of venous thromboembolism [180,181]. Of those, one study showed that an increased risk peaked at six months after initiation of testosterone therapy, and then declined over the subsequent period [182]. In one study venous thromboembolism was reported in 42 cases and 40 of these had a diagnosis of an underlying congenital thrombophilia (including factor V Leiden deficiency, prothrombin mutations and homocysteinuria) [183]. A meta-analysis of RCTs of testosterone therapy reported that venous thromboembolism was frequently related to underlying undiagnosed thrombophilia-hypofibrinolysis disorders [78]. In an RCT of testosterone therapy in men with chronic stable angina there were no adverse effects on coagulation, by assessment of tissue plasminogen activator or plasminogen activator inhibitor-1 enzyme activity or fibrinogen levels [184]. Similary, another meta-analysis and systematic review of RCTs found that testosterone therapy was not associated with an increased risk of venous thromboembolism [164]. With testosterone therapy elevated haematocrit levels are more likely to occur if the baseline level is toward the upper limit of normal prior to initiation. Added risks for raised haematocrit on testosterone therapy include smoking or respiratory conditions at baseline. Higher haematocrit is more common with parenteral rather than topical formulations. Accordingly, a large retrospective two-arm open registry, comparing the effects of long-acting testosterone undecanoate and testosterone gels showed that the former preparation was associated with a higher risk of haematocrit levels > 50%, when compared to testosterone gels [185]. In men with pre-existing CVD extra caution is advised with a definitive diagnosis of hypogonadism before initiating testosterone therapy and monitoring of testosterone as well as haematocrit during treatment.

Elevated haematocrit in the absence of comorbidity or acute CV or venous thromboembolism can be managed by a reduction in testosterone dose, change in formulation or if the elevated haematocrit is very high by venesection (500 mL), even repeated if necessary, with usually no need to stop the testosterone therapy.

3.5.7. Obstructive Sleep Apnoea

There is no evidence that testosterone therapy can result in the onset or worsening of sleep apnoea. Combined therapy with Continuous Positive Airway Pressure (CPAP) and testosterone gel was more effective than CPAP alone in the treatment of obstructive sleep apnoea [186]. In one RCT, testosterone therapy in men with severe sleep apnoea reported a reduction in oxygen saturation index and nocturnal hypoxaemia after seven weeks of therapy compared to placebo, but this change was not evident after eighteen weeks’ treatment and there was no association with baseline testosterone levels [187].

3.5.8. Follow-up

Testosterone therapy alleviates symptoms and signs of hypogonadism in men in a specific time-dependent manner. The TTrials clearly showed that testosterone therapy improved sexual symptoms as early as three months after initiation [93]. Similar results have been derived from meta-analyses [78,85]. Hence, the first evaluation should be planned after three months of treatment. Further evaluation may be scheduled at six months or twelve months, according to patient characteristics, as well as results of biochemical testing (see below). Patients at high risk of developing elevated haematocrit should be evaluated every three months during the first year of testosterone therapy and at least every six months thereafter. Accordingly, current guidelines suggest that haematocrit should be maintained below 45% in patients with polycythaemia vera to avoid thromboembolism risk [188]. Similarly, data derived using a multi-institutional database including a large cohort of hypogonadal (total testosterone < 12 nmol/L) men who received testosterone therapy and subsequently did (n=5,887) or did not (n=4,2784) develop polycythaemia (haematocrit > 52%) showed that men who had an increased haematocrit had a higher risk of MACE or venous thromboembolism mostly during the first year of therapy [189]. The risk was even higher when a haematocrit threshold of 54% was considered whilst no risk was observed when a 50% threshold was applied [189]. Table 6 summarises the clinical and biochemical parameters that should be monitored during testosterone therapy.

TTrials were designed to maintain the serum testosterone concentration within the normal range for young men (280–873 ng/dL or 9.6-30 nmol/L) [93]. This approach resulted in a good benefit/risk ratio. A similar approach could be considered during follow-up. The correct timing for the evaluation of testosterone levels varies according to the type of preparation used (Table 5). Testosterone is involved in the regulation of erythropoiesis [120] and prostate growth [61], hence evaluation of PSA and haematocrit should be mandatory before and during testosterone therapy. However, it is important to recognise that the risk of PCa in men aged < 40 years is low. Similarly, the mortality risk for PCa in men aged > 70 years has not been considered high enough to warrant monitoring in the general population [190]. Therefore, any screening for PCa through the determination of PSA and DRE in men aged < 40 or > 70 years during testosterone therapy should be discussed with the patients.

Baseline and, at least, annual glyco-metabolic profile evaluation may be a reasonable consideration, particularly in the management of functional hypogonadism. Testosterone therapy may be beneficial for hypogonadal men with low or moderate fracture risk [107]; therefore, dual energy X-ray absorptiometry (DEXA) bone scan may also be considered at baseline and 18-24 months following testosterone therapy, particularly in patients with more severe hypogonadism [107].

Digital rectal examination may detect prostate abnormalities that can be present even in men with normal PSA values. Hence, DRE is mandatory in all men at baseline and is recommended to be performed at least annually during testosterone therapy, as long as there is no significant increase in PSA velocity.

The decision to stop testosterone therapy or to perform a prostate biopsy due to PSA increase or prostate abnormalities should be based on local PCa guidelines. There is a large consensus that any increase of haematocrit > 54% during testosterone therapy requires therapy withdrawal and phlebotomy to avoid potential adverse effects including venous-thromboembolism and CVD, especially in high-risk individuals. In patients with lower risk of relevant clinical sequelae, the situation can be alternatively managed by reducing testosterone dose and switching formulation along with venesection. A positive family history of venous-thromboembolism should be carefully investigated and the patient counselled about testosterone therapy to avoid/prevent thrombophilia-hypofibrinolysis [78]. Finally, caution should be exercised in men with pre-existing CVD or at higher risk of CVD [77].

Table 6: Clinical and biochemical parameters to be checked during testosterone therapy

¹Population with polycythaemia vera or at high risk of secondary polycythaemia (e.g., sleep apnea, morbidobesity, heavy smokers, chronic obstructive pulmonary disease); ²Prostate cancer survivors.

3.5.9. Summary of evidence and recommendations on safety and monitoring in testosterone treatment

*As for EAU risk groups for biochemical recurrence of localised or locally advanced prostate cancer(see EAU Prostate Cancer Guidelines, 2024)