Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. A multi-disciplinary panel from BSSM reviewed the available literature on TD and provide evidence-based statements for clinical practice. Evidence was derived from Medline, EMBASE and Cochrane searches on hypogonadism, testosterone therapy (T Therapy) and cardiovascular safety from May 2017 to September 2022. This revealed 1,714 articles, including 52 clinical trials and 32 placebo-controlled randomised controlled trials. A total of twenty-five statements are provided, relating to five key areas: screening, diagnosis, initiating T Therapy, benefits and risks of T Therapy, and follow-up. Seven statements are supported by level 1 evidence, eight by level 2, five by level 3, and five by level 4. Recent studies have demonstrated that low levels of testosterone in men are associated with increased risk of incident type 2 diabetes mellitus, worse outcomes in chronic kidney disease and COVID 19 infection with increased all-cause mortality, along with significant quality of life implications. These guidelines should help practitioners to effectively diagnose and manage primary and age-related TD.
Testosterone is the principal androgen in men. The term ‘testosterone deficiency (TD)’ is used throughout, in preference to hypogonadism, which refers to underactivity of both endocrine and reproductive function of the testes. TD is a well-established and significant medical condition [1,2]. Testosterone is essential for the development and maintenance of secondary male characteristics [3]. When testosterone levels fall, patients may experience physical, psychological and metabolic effects, which can compromise their cardiovascular, metabolic and general health, well-being, sexuality and fertility [4,5].
These statements have been developed for UK practice and aim to address the widespread media and scientific concerns over the appropriate treatment of men with TD with testosterone therapy (T Therapy).
NB: Somehing I was less aware of:
Finasteride and dutasteride are often prescribed to treat lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) and male pattern hair loss in men with androgenic alopecia for prolonged periods of time [29]. It is postulated that men treated with these drugs are in a state of androgen deficiency and are at high risk of developing erectile dysfunction (ED), NAFLD, IR, T2DM, dry eye disease, potential kidney dysfunction, among other metabolic and psychiatric dysfunctions. Reviews suggest that greater attention is taken to assess patients at risk before prescribing long term. A similar syndrome of prolonged sexual dysfunction is seen with isotretinoin treatment for acne [30].
For these reasons, we believe that the clinical community should recognize these new potential health risks associated with these drugs and the need for assessment of sexual dysfunction, measurement of testosterone levels and testosterone and PDE5 inhibitor therapy for enduring symptoms associated with low testosterone levels, and LUTS/BPH.
TD has well established symptoms [1]. The Fourth International Consultation for Sexual Medicine (ICSM) [6] made the following recommendations for the clinical diagnosis of TD, based on the signs and symptoms:
- Sexual dysfunction, especially low sexual desire, reduced morning and night-time erections, and ED are prominent, commonly presenting symptoms, particularly suggestive of TD when associated with each other (LoE 1, Grade A) [6]. As the link between morning erections and cardiovascular disease (CVD) is well established, it is important that the question is asked to patients not currently involved in physical relationships [1].
- Less-specific symptoms such as fatigue, sleep disturbance, loss of physical strength, reduced energy and motivation, and depressed mood are often present (LoE 1, Grade B) [6].
- Visceral obesity, and reductions in muscle mass and bone mineral density (BMD), are commonly observed (LoE 1, Grade A) [6]
- Hot flushes, and changes in cognition and memory, can be associated with TD (LoE 3, Grade C) [6].
- On physical examination, features suggestive of TD include reduced body hair, decreased testicular size and gynaecomastia, but these are not always present (LoE 1, Grade B) [6]. Fine wrinkling of the skin, especially around the mouth, may also be apparent.
TD is often associated with an increased waist circumference, obesity, metabolic syndrome and impaired health status [1]. In a primary care population of men aged 45 years and older, the reported odds ratios for TD with comorbid conditions were obesity 2.38, T2DM 2.09, hypertension 1.84, dyslipidaemia 1.47, chronic obstructive pulmonary disease (COPD) 1.40 and LUTS/BPH 1.20 [31,32,33].
Significant TD is associated with an increased risk of chronic anaemia and osteoporosis. See Table 1 for a list of the conditions associated with an increased prevalence of TD.
Many signs and symptoms of TD are multifactorial in origin and associated with various lifestyle and psychological factors, as well as with normal ageing, so they may be found in men with normal testosterone levels [4,34].
Although it is commonly stated that testosterone levels decline with age [34,35] over 80% of men maintain normal testosterone levels into old age [9]. The age-related rise in SHBG does cause a fall in FT and bioavailable testosterone, but the increased rates of TD seen in older men are primarily related to an increased prevalence of obesity, T2DM and chronic illness [36].
The signs and symptoms of TD vary depending on age of onset, duration and severity [1,4]. While the prevalence of TD increases with advancing age, it can occur in adult men of any age (LoE 1, Grade B) [6].The more signs/symptoms a man has, the greater the probability that he has genuine TD [36,37].
The prevalence of hypogonadal symptoms increases when TT levels fall below 12.1 nmo/L (Level 2b, Grade A) [26,36,37]. However, they are also seen at levels higher than this. A cross-sectional cohort study investigating complaints structures in 434 hypogonadal men aged 50–86 years, reported loss of erections with a TT of around 8 nmol/L, diabetes and depression at 10 nmol/L, obesity at 12 nmol/L and reduced vigour at 15 nmol/L. They found no evidence for a uniform structure of testosterone concentrations and complaints though, instead concluding that in aging men, psychosomatic complaints and metabolic risk relate to testosterone in a symptom-specific manner [37].
LIFESTYLE CHANGE AND TESTOSTERONE LEVELS
Armamento-Villareal et al [38] reported that dietary interventions, with and without exercise, resulted in significant increases in testosterone level. Moran et al [39] reported on 68 men participating in a weight-loss diet. Men lost a mean of 10.3–10.8±1.2 kg over the 52-week study period and experienced significant increases in total and FT. Several studies have suggested that significant weight loss can improve testosterone levels in Male Obesity Secondary Hypogonadism (MOSH) [38]. In contrast EMAS [8] showed that a 20% reduction in BMI was required to produce a significant increase in FT level, due to the associated rise in SHBG, or meaningful increase in EF score.
Rigon [41] and colleagues evaluated bariatric surgery in 29 men with a mean baseline weight of 155.26±25.88 kg with significant improvements in TT levels from 229.53±96.45 ng/dL to 388.38±160.91 ng/dL (P<0.001).
NB: an important matter for many men but the evidence is strong to support safe use:
Concerns about T Therapy and pCa date back to 1941, when Huggins and Hodges [101] reported that marked reductions in testosterone by castration or oestrogen treatment caused metastatic cancer to regress, but administration of exogenous testosterone caused PCa to grow.
The paradox of why lowering testosterone causes PCa to regress, but raising testosterone fails to cause PCa to grow, may be explained by the saturation model, which posits a finite ability of androgens to stimulate PCa growth [102]. The AR becomes saturated in human prostate tissue at approximately 8 nmol/L in vivo [103,104] and there appears to be no further appreciable growth with increasing serum testosterone concentrations beyond a saturation point of approximately 8 to 8.7 nmol/L [105]. This explains why men with testosterone below the saturation point of approximately 8.7 nmol/L at baseline, are likely to see a rise in PSA upon treatment initiation, whereas PSA is unlikely to rise in men with testosterone above this level [105].
The REDUCE trial, which investigated dutasteride for preventing PCa and included results from 3,255 men who had prostate biopsies at 2 and 4 years, showed no association between serum testosterone or DHT and PCa risk. The risk of PCa was no greater in men with high testosterone levels than those with low testosterone levels [106].
Guidelines from the European Association of Urology (EAU) [4], the BSSM [5], the ICSM [6], the International Society of Sexual Medicine (ISSM) [7], and the Endocrine Society (ES) [22] all conclude that there is no compelling evidence that T Therapy is associated with an increased risk of PCa (LoE 2, Grade B), and the ICSM [6] states that there is no compelling evidence that T Therapy increases the risk of PCa or is associated with PCa progression [LoE 1, Grade C].
Recent research suggests that lower testosterone levels are associated with a risk of poorly differentiated cancers and greater risk of positive biopsy [106,107] and there is evidence linking low T concentrations to aggressive, high grade PCa, higher rates of positive biopsy, biochemical recurrence and disease progression in men under active surveillance [107,108].
However, estimates suggest that in order to detect a 30% difference in PCa rates between testosterone- and placebo-treated men, approximately 6,000 men aged 65–80 years with low testosterone levels would need to be randomised to testosterone- or placebo-treatment for an average of 5 years [109]. Because such an RCT would probably include relatively healthy, older men, with unequivocally low testosterone levels, but without PCa or PSA levels >4 ng/mL, it would require screening ofasignificantly greater number of older men in order to enrol the required number of eligible participants. As it seems unlikely that a study of this size will be funded, it will remain uncertain whether long-term T Therapy affects the incidence of clinically overt PCa [110].
Careful assessment of the prostate prior to starting T Therapy, and regular monitoring for prostate disease once the patient is on T Therapy, remains essential. Early rises in PSA after initiation of T therapy may unmask an occult prostate carcinoma which was undetected at baseline [110].
CONCLUSIONS
TD is a well-established and significant medical condition, encompassing somatic, sexual and psychological effects. It is also associated with increased risk of type 2 diabetes and cardiovascular and all-cause mortality. Clearly defined clinical symptoms, especially ED, loss of morning erections and reduced sexual desire should prompt swift evaluation of these, together with modification of underlying risk factors, and further investigations performed where appropriate.
In order to identify individuals who should be screened for TD, consideration should be given to routinely asking men if they have any sexual concerns, particularly those at high risk. These include men with diabetes, osteoporosis/fragility fractures, CVD, CKD, anaemia, ED, depression, COVID-19 infection and those on long-term opiate/oral glucocorticoid therapy.
T Therapy is evidence-based, effective and safe, and evidence suggests that treatment-related sustained normalisation of serum testosterone levels is associated with reduced morbidity and mortality.
However, whilst the multiple benefits of T Therapy are highly relevant to the patient, they are often underestimated by specialist physicians focused on specific outcomes related to their particular discipline. Because sexual dysfunction is often multi-faceted in nature, the treatment of men with sexual desire, arousal and ejaculation problems should be individualised and may include T Therapy, erectogenic agents and psychosexual therapy.
Until a definitive well-powered long-term study is published, treatment of TD with T Therapy should be guided by the best available evidence.
