Update on testosterone deficiency and therapeutic options for testosterone replacement therapy

[madman]

Fig. 1 | Hypothalamic–pituitary–gonadal axis regulation.

Abstract

Testosterone deficiency, or male hypogonadism, is a clinical syndrome characterized by the presence of clinical features with persistently low serum testosterone levels. Testosterone deficiency is an important health concern owing to its wide-ranging effects on sexual function, metabolic health, bone integrity, mood and overall quality of life. Testosterone deficiency can be classified as primary (testicular), secondary (hypothalamic–pituitary) or functional hypogonadism — the latter is commonly associated with ageing, obesity and chronic systemic disease. Diagnosis requires both clinical symptoms and biochemical confirmation of low testosterone levels, typically assessed using morning serum testosterone measurements. In instances of borderline values or discordance between symptoms and total testosterone levels, free testosterone and sex hormone-binding globulin measurements can provide additional diagnostic clarity. Evidence demonstrates that testosterone replacement therapy can provide clinically meaningful benefits in appropriately selected men with confirmed testosterone deficiency. Improvements have been reported in sexual function, mood, anaemia, body composition, bone mineral density and metabolic parameters, and contemporary data do not support an increased risk of prostate cancer or major adverse cardiovascular events when therapy is appropriately monitored. Multiple therapeutic formulations are available, including transdermal, oral, intramuscular, subdermal and intranasal preparations, each with distinct pharmacokinetic profiles and practical considerations. Individualized treatment selection, careful patient counselling and ongoing monitoring are essential to optimize clinical outcomes and minimize potential risks in men undergoing testosterone therapy.








Conclusions

TTh is primarily aimed at relieving the symptoms of testosterone deficiency in men. Available evidence suggests that, in appropriately selected patients, TTh might confer improvements in sexual function, mood, BMD, body composition, anaemia and overall QoL, with potentially favourable effects on metabolic parameters.

TTh is available in multiple formulations that differ in route of administration, pharmacokinetics, treatment burden and adverse effect profiles. Transdermal and intramuscular preparations are most commonly used, reflecting a balance between efficacy, tolerability, patient preference and desire to preserve fertility. Consequently, treatment selection should be individualized through shared decision making, taking into account patient priorities, comorbidities and access to treatment.

 

[madman]

Table 1 | Clinical features of testosterone deficiency2,3

 

[madman]

Fig. 2 | The hypogonadal–obesity–adipocytokine hypothesis. Increased adipose tissue mass is associated with insulin resistance, altered leptin signalling and increased production of pro-inflammatory cytokines. Increased adipose aromatase activity enhances the conversion of testosterone to oestradiol, whereas inflammatory and metabolic signals suppress hypothalamic kisspeptin signalling, pituitary gonadotrophin secretion and testicular testosterone production. Reduced testosterone can, in turn, promote adipose tissue accumulation and reduce muscle mass, establishing a bidirectional cycle between obesity and functional testosterone deficiency. Arrows indicate stimulation, bars indicate inhibition and dashed arrows indicate reinforcing relationships. FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; HPG, hypothalamic–pituitary–gonadal; LH, luteinizing hormone; TNF, tumour necrosis factor.

 

[madman]

Fig. 3 | Clinical decision-making tool to identify appropriate candidates for testosterone therapy. Men presenting with symptoms suggestive of testosterone deficiency should first undergo clinical assessment to determine whether their symptoms are compatible with the condition. When symptoms are compatible, morning fasting total testosterone should be measured on at least two occasions. A concentration of <9.2 nmol/l supports a diagnosis of testosterone deficiency, whereas concentrations of 9.2–12 nmol/l represent a diagnostic grey zone in which free testosterone and potentially reversible causes should be assessed. Testosterone deficiency is unlikely when total testosterone is >12 nmol/l. Before treatment, fertility intentions and cardiovascular risk should be assessed, and the decision to initiate testosterone therapy should be made through shared decision making.

 

[madman]

Box 1 | Key components in the evaluation and diagnosis of testosterone deficiency and hypogonadism

 

[madman]

Box 2 | Testosterone therapy effects on multiple health parameters.

 

[madman]

Table 2 | Therapeutic options for testosterone deficiency