Testosterone is the principal androgen hormone in males, playing a critical role in male reproductive development, including the formation of tissues like the testicles and prostate. It promotes secondary sexual characteristics, such as muscle mass, bone density, and body hair growth. Additionally, it influences behaviour by enhancing aggression, libido, dominance, and various cognitive and social factors. 

Beyond sexual development, testosterone contributes to broader health, including metabolism, cardiovascular function, mood regulation, and bone density. Low testosterone levels, also known as Hypogonadism in men, can result in diminished muscle mass, increased body fat, anxiety, reduced sexual performance, weakened bones and erectile dysfunction. Additionally, testosterone therapy is used to address hypogonadism and breast cancer, and it can also counteract natural declines in testosterone as men age. However, it’s often misused in athletic settings to enhance physical performance, a practice banned by the World Anti-Doping Agency due to its anabolic effects.

What is Low Testosterone (Hypogonadism)?

Male Hypogonadism can arise from defects that disrupt the hypothalamic-pituitary-testicular axis, either congenitally or through acquired conditions. The condition can be classified into two types: primary Hypogonadism, where the defect lies in the testes, and secondary Hypogonadism, where the issue originates in the hypothalamus or pituitary gland. Understanding this distinction is essential for accurate diagnosis and treatment.

• Primary Hypogonadism involves the testicles’ failure to produce adequate levels of testosterone, which is primarily synthesised in the Leydig cells of the testes. This condition can stem from a variety of factors, including trauma, infection (such as mumps orchitis), chemotherapy, radiation, or congenital abnormalities like Klinefelter syndrome. Symptoms typically include reduced spontaneous erections, diminished nocturnal penile tumescence, low libido, fatigue, and smaller testicular volume. Additionally, testicular failure leads to increased levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) due to a lack of negative feedback to the hypothalamus and pituitary. These elevated levels help differentiate primary Hypogonadism from secondary forms.
• Secondary Hypogonadism, or hypogonadotropic Hypogonadism, involves dysfunction of the hypothalamus or pituitary gland, leading to insufficient secretion of gonadotropins (LH and FSH), which are crucial for stimulating testosterone production in the testes. Causes include pituitary tumours, genetic disorders such as Kallmann syndrome, head trauma, or chronic illnesses that impair the hypothalamus or pituitary. In this form of hypogonadism, LH and FSH levels are low or inappropriately normal.

Hypogonadism is significantly underreported and often misdiagnosed. The condition is prevalent, particularly in older men, with studies indicating that approximately 40% of men over the age of 45 and nearly 50% of men in their 80s are affected. Testosterone levels decline naturally with age at a rate of approximately 100 ng/dL every decade. Interestingly, Hypogonadism does not show significant variance across different racial or ethnic groups.

In diabetic populations, particularly non-obese males, 29% were found to be testosterone deficient. The visceral adiposity index (VAI), derived from waist circumference, BMI, serum triglycerides, and HDL levels, has emerged as a reliable predictor of testosterone deficiency in such patients, emphasizing the link between metabolic health and Hypogonadism. 

The overall underrecognition of hypogonadism calls for greater awareness, particularly in light of its profound impact on men’s health and quality of life. The ageing population is particularly susceptible, and metabolic factors like obesity and insulin resistance further increase the risk of testosterone deficiency. Early diagnosis and appropriate treatment are essential for improving outcomes in men affected by this hormonal disorder.

Diagnosing Hypogonadism typically involves measuring serum testosterone levels in the early morning (when testosterone levels peak). The standard reference range is usually between 300-1000 ng/dL, although values may vary depending on the laboratory. A diagnosis of Hypogonadism is generally confirmed when the serum testosterone falls below 300 ng/dL on two separate occasions, mainly when symptoms are present. 

What Is The Role of Testosterone?

Testosterone plays a vital role in male physiology, particularly in erectile function. It influences both the frequency and rigidity of erections, though the degree of testosterone required to maintain erectile function remains debated. It has always been assumed that testosterone and other androgens have played a role in erectile function. This is mainly due to:

• Testosterone levels naturally decrease with age, coinciding with an increased prevalence of erectile dysfunction (ED).
• Castration (leading to severe Hypogonadism) typically results in a marked decline in sexual function due to the loss of testosterone.
• When men with severe Hypogonadism (often due to castration) are treated with exogenous androgens (testosterone replacement therapy), sexual function usually returns to normal, restoring both sexual desire and erectile function.

Hypogonadal men often experience reduced erectile frequency and firmness, with sexual function improving when treated with exogenous androgens. As men age, testosterone levels naturally decline—total and free testosterone drop significantly due to an increase in sex hormone-binding globulin (SHBG), which binds testosterone, reducing its bioavailability. However, the threshold of Hypogonadism that causes erectile dysfunction is not established. Though testosterone diminishes with age, normal adult testosterone levels aren’t necessary for erectile function. After a certain threshold, further increases in testosterone don’t correspond to improved erectile performance. This natural decline becomes particularly evident with aging. By age 75, free testosterone levels drop to approximately 50% of those seen in younger men. Despite this, defining Hypogonadism in older men remains a point of debate, as a significant portion of aged men may still maintain sufficient free testosterone, even though their total testosterone is reduced.

How Is Low-Testosterone (Hypogonadism) Treated? 

For treating Hypogonadism, testosterone supplementation is only indicated in symptomatic patients with confirmed low testosterone levels. Asymptomatic patients or those with normal testosterone levels typically do not benefit from supplementation, and lifestyle interventions such as weight loss and increased physical activity should be prioritized instead. Oral testosterone, especially methyltestosterone, is generally avoided due to its potential hepatotoxicity, which includes risks like liver damage and cholestasis.

Testosterone replacement therapy (TRT) in men with confirmed Hypogonadism has shown statistically significant improvements in symptoms such as libido, anaemia, bone density, muscle mass, depression, and erectile dysfunction. While testosterone therapy may show some promise in alleviating fatigue, improving energy levels, metabolic markers (e.g., hyperlipidemia, diabetes control), cognitive function, and overall quality of life, clinical data remain inconclusive. There is also some evidence supporting its use for depressive symptoms in hypogonadal men. However, certain studies have found no benefit over placebo, indicating that more research is needed. 

How Is Testosterone Replacement Therapy (TRT) Administered?

The ideal testosterone replacement therapy should closely replicate the body’s natural daily pattern of hormone secretion while maintaining physiological levels of testosterone and its key metabolites, including dihydrotestosterone (DHT) and estradiol (E2). The treatment should also be well-tolerated, convenient to use, and cost-effective. Current administration methods include oral formulations, intramuscular injections, and transdermal options (such as patches or gels), each having distinct benefits and challenges in maintaining stable hormone levels while minimizing side effects. Some of the most common medications include:

• Clomiphene Citrate offers an effective treatment for both biochemical and clinical male Hypogonadism via a unique mechanism. As an anti-estrogen, it blocks estradiol from suppressing GnRH production in the hypothalamus, causing increased release of FSH and LH from the pituitary—this rise in FSH aids in preserving fertility and sperm production, while elevated LH boosts testosterone synthesis. Clomiphene is particularly suited for men wishing to maintain fertility. Standard dosing ranges from 25 to 50 mg daily, with testosterone levels typically monitored after 30 days.
• Human chorionic gonadotropin (hCG) promotes testosterone production by stimulating the Leydig cells in the testes, similar to clomiphene. However, unlike other testosterone therapies, hCG does not negatively impact sperm counts or spermatogenesis. Its structure mimics luteinizing hormone (LH), though it has a longer half-life of around 36 hours than LH’s 30-minute half-life. Due to this extended half-life, hCG is often preferred in men with hypogonadotropic Hypogonadism, where maintaining fertility and increasing testosterone production are treatment goals.
• Testosterone replacement therapy presents several administration options: oral, intranasal, transdermal (gel, solution, subcutaneous pellets), and intramuscular injections. Transdermal gels and intramuscular injections are the most prevalent methods in the US. An intranasal testosterone gel is accessible, delivered via a pump metered-dose applicator that dispenses 5.5 mg per activation. The recommended dose is one activation in each nostril three times daily. This approach reduces the risk of androgen transfer through contact, but many people find the frequent dosing cumbersome. There is also data indicating elevated testosterone levels in the brain, though the implications remain uncertain. Surgically implantable long-duration testosterone pellets provide a prolonged therapeutic effect, with up to six 75 mg pellets implanted every three to six months. These are placed subcutaneously in the lower abdomen, thighs, or buttocks using a trocar under local anaesthesia. However, there is limited data on the long-term maintenance of testosterone levels with this method, and the necessity for repeated procedures can make it less appealing.

Testosterone Replacement and Prostate Health

A significant risk factor linked to testosterone supplementation is its impact on the prostate. The prostate is an androgen-dependent gland, and antiandrogen agents can reduce prostate volume in patients with benign prostatic hyperplasia (BPH). As the population ages, both BPH and late-onset male Hypogonadism are expected to increase, necessitating that practitioners effectively counsel men about testosterone replacement therapy (TRT) and its effects on the prostate. In a randomized, double-blind, placebo-controlled trial involving 44 hypogonadal men, Marks et al. demonstrated that TRT over six months significantly enhances serum androgen levels but has minimal impact on prostate tissue androgen levels, biomarkers, or gene expression. Testosterone supplementation has been associated with a 12% increase in prostate size; however, lower urinary tract symptoms (LUTS) and urinary retention do not worsen in men receiving testosterone therapy. Notably, among 312 men with measurable LUTS, Hypogonadism did not predict worsening International Prostate Symptom Scores (IPSS) or maximal urinary flow rates. Some studies even report improvements in LUTS after one year of TRT. In a recent randomized controlled trial, 52 men received TRT, with 23 men receiving 250 mg of testosterone enanthate every four weeks. After one year, these men showed significant enhancements in IPSS and maximal urinary flow rates compared to baseline and control groups. Throughout the trial, no participants required additional medication or experienced urinary retention.

Although older men on testosterone therapy do experience an increase in overall prostate size, this increase is comparable to the prostatic hypertrophy observed in older men not undergoing testosterone treatment. Overall, TRT does not appear to worsen LUTS substantially and is not contraindicated in men diagnosed with BPH.

Testosterone and Male Breast Cancer

While there is no established physiological link between testosterone and the development of breast cancer, elevated testosterone levels may increase aromatization to active oestrogen derivatives. This process could potentially stimulate breast tissue receptors, raising the risk of male breast cancer. The exact role of testosterone in breast cancer development remains unclear. Current literature includes several case reports, and one retrospective review indicates an 11% incidence of breast cancer in 45 men undergoing long-term TRT over a decade. Future prospective studies with extended follow-up are necessary to clarify whether a true association exists between TRT and male breast cancer.