Can A Man Age Graciously In The Era of Testosterone Replacement Therapy?

In 1935, three independent research teams led by Adolf Butenandt, Karoly Gyula David, and Leopold Ruzicka (sponsored by Schering, Organon, and Ciba, respectively) were successful in the synthesis of a hormone which “when injected into castrated animals, would restore their maleness”.

This hormone was named testosterone, since it arose from the testes. It was not until 1939, that Butenandt and Ruzicka received the Nobel Prize for Chemistry, for their seminal work (pun intended) on the male hormone.

Interestingly, the word “testis” also means “witness” in Latin and the male gonads are called “testes” as they “bear witness” to a man’s virility.

Testicular function declines progressively with age, but unlike menopause where the ovaries undergo rapid functional involution, the change in testicular function is incremental and of the same magnitude as that of other bodily organs. The rate of serum testosterone decline is estimated to be 1% per year, once a man reaches his third decade of life.

Testosterone is secreted according to a circadian rhythm, with peaks in the morning and troughs during the evening hours. This is why serum testosterone levels are usually checked between 7.00am and 11.00am.

Controversies behind Testosterone Replacement Therapy (TRT )


The main deterrent to Testosterone Replacement Therapy (TRT) among primary care physicians, is its presumed detrimental effect on the prostate gland. We now know that there is little evidence to suggest that TRT may increase the risk of developing subsequent prostate cancer, and that it is safe for men, regardless of race or family history of prostate cancer1.

Regarding the effect of testosterone on benign prostatic growth, there is evidence to show that TRT can be administered to patients with pre-existing lower urinary tract symptoms (LUTS) from benign prostatic hypertrophy. Studies have even shown that TRT improves LUTS2.

Recently, TRT was also associated with increased cardiovascular risk. It was shown that the studies quoted suffered from significant limitations that weakened their evidentiary value for confirming a causal relationship between TRT and adverse cardiovascular outcomes. The limitations include short follow-up times, which preclude the assessment of TRT’s long-term benefits, unclear and questionable statistical methods, inability to compare results across studies due to differing outcomes and populations, and other limitations that involve unascertained information, nonvalidated endpoints, and the lack of compliance data.

The latest meta-analysis retrieving trials, which included 2,016 TRTtreated and 2,448 placebo-treated men for a mean duration of 34 weeks, showed that TRT is not related to any increase in cardiovascular risk even when composite or single adverse events were considered. Not only is there no causal role between TRT and cardiovascular events, a protective effect of TRT on cardiovascular risk through the improvement of metabolic profile, reduction of body fat and increase in lean muscle mass were also observed in hypogonadal men with metabolic derangements3.

Investigations Prior to TRT


The key to TRT is to offer it to men with confirmatory laboratory levels of low serum testosterone, with symptoms suggestive of testosterone deficiency (TD), and to replace the serum testosterone to physiological levels. Most common symptoms of TD include erectile dysfunction, decreased libido and decreased energy levels. Serum total testosterone levels of 8 nmol/L or less are widely accepted as low, and levels of 12 nmol/L and above are considered normal. Free testosterone levels should be measured if the total testosterone levels fall in the range between 8 to 12 nmol/L. Symptomatic males with free testosterone levels less than 250 pmol/L would benefit from TRT.

Other blood investigations that should be measured would be luteinising hormone levels and prolactin levels. If the serum prolactin is found to be elevated, the patient should be referred to the endocrinologist with a view to perform a magnetic resonance imaging (MRI) of the pituitary to rule out prolactinoma where indicated.

Prior to initiating TRT, a digital rectal examination (DRE) and serum prostate specific antigen (PSA) level must be performed. Men with abnormal DRE and/or elevated PSA should be referred to the urologist to rule out prostate cancer. Any requested fertility in the immediate future should be discussed with the patient as exogenous testosterone renders men subfertile. Other contraindications include breast cancer.

These men should be assessed for symptomatic improvement, serum testosterone, haematocrit, PSA levels on a three-month interval and DRE annually. In the event of raised PSA and/or abnormal DRE, referral to the urologist is recommended.

Methods of TRT Delivery

In Singapore, we have topical, oral and intramuscular preparations for TRT. Topical preparations require daily dosing. Intramuscular testosterone enanthate or cypionate are short-acting and administered every fortnightly, whereas testosterone undecanoate needs to be administered every three months. Oral preparations are not well absorbed and require intake with a fatty meal, and are hence less popular.

TRT allows symptomatic hypogonadal men to age graciously, as replacement to physiological levels of testosterone increases life expectancy, improves general wellbeing and controls cardiovascular risk factors.


Dr Tan Ban Wei, Ronny is a Consultant from the Department of Urology in Tan Tock Seng Hospital. He graduated with MBBS from National University of Singapore (NUS), was elected a Member of the Royal College of Surgeons (Edinburgh) and conferred a Masters of Medicine (Surgery) from NUS. He completed his Advanced Specialist Training (Urology), board-certified in 2012 and became a Fellow of the Academy of Medicine, Singapore. He received the National Healthcare Group-Health Manpower Development Programme award and undertook his clinical fellowship in andrology, sexual medicine and urology prosthetic surgery with Professor Wayne Hellstrom at Tulane University (USA). He is an executive committee member of the Society for Men’s Health Singapore and a member of the International Society for Sexual Medicine.

  • Tan Ronny B W, Silberstein John L, and Hellstrom Wayne JG. Testosterone and the Prostate. Sex Med Rev 2014;2:112–120. 
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    • Pearl JA, Berhanu D, Francois N, Masson P, Zargaroff S, Cashy J, McVary KT. Testosterone Supplementation Does Not Worsen Lower urinary Tract Symptoms. J Urol 2013;190:1828–33. 
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