Risk Benefit Analysis

Testosterone Replacement Therapy

Testosterone replacement to physiological circulating concentrations in men with hypogonadism reverses the symptoms of androgen deficiency. Thus it is able to produce improvement in libido, increase in bone mineral density and in muscle mass, and produces favourable changes in body composition with reduction in fat mass and increase in lean body mass, improvement in mood, correction of anaemia and improvement in memory performance and cognitive status. Whether testosterone therapy lessens the risk of cardio vascular disease is not established.

Prostate disease

a. Benign prostatic hyperplasia:  Trials of testosterone replacement therapy have indicated that prostate volume, as measured by ultrasound, increases significant mainly during the first 6 months of treatment to a level similar to that of men without hypogonadism. A number of studies have failed to show any deterioration in obstructive symptoms attributable to benign prostatic hyperplasia during treatment and urinary retention has not been reported at rates higher than in controls.

b. Prostate cancer: The most important theoretical danger of testosterone treatment is to increase the risk of developing prostate cancer. Whilst lowering of testosterone levels is a standard treatment for metastatic prostate cancer, there is no available evidence to suggest that replacement of low testosterone levels into the normal range, leads to any increase in the occurrence of the disease. Rhoden and Morgentaler (15) summarised the results concerning both prostate cancer and increase in prostate specific antigen (PSA) in 10 studies of testosterone replacement therapy using both intramuscular and transdermal routes.

There was no significant increase in the occurrence of prostate cancer and a variable increase in the levels of PSA which are often below normal in hypogonadal men and are restored to normal. With replacement therapy, Rhoden and Morgantaler also summarised the evidence regarding endogenous testosterone levels and prostate cancer in men and concluded that "Y" there is no compelling evidence that testosterone has a causative role in prostate cancer.

They also concluded that there was no compelling evidence "Y"that treating men who have hypogonadism with exogenous androgens increases this risk. During the monitoring of testosterone replacement therapy, regular digital rectal examination and measurement of PSA are recommended.

The Endocrine Society’s 2001 has developed guidelines for the interpretation of PSA values which should be used to indicate the need for prostate biopsy.  These include an increase of 1.5ng per ml within 2 years, or a total increase of 2ng per ml over any period.

Adverse Changes in Serum Lipids

The oral administration of alkylated testosterone derivatives is known to produce adverse changes in serum lipids particularly a reduction in serum HDL. However, physiological replacement doses of testosterone produced little if any change in serum HDL and may reduce total cholesterol.  A meta-analysis of the effects of intra-muscular testosterone (19) reported that HDL levels were reduced in 3 studies and unchanged in 15. Total cholesterol was reduced in 5 and unchanged in 12 with an increase in the other 2 and LDL levels were unchanged or reduced in 14 of 15 studies.

An extensive dose ranging study of testosterone injections in healthy eugonadal men aged 18 to 35 showed no changes in total cholesterol, LDL, VLDL, triglycerides or C reactive protein, glucose metabolism or insulin sensitivity at doses between 25 and 600mg per week.  Only the highest dose which is far beyond the physiological range was associated with a significant reduction in HDL.  Transdermal administration of testosterone has been recorded as having minimal if any effects on serum lipid concentrations.  This was borne out in the clinical trials referred to below.

Coronary Heart Disease

A major theoretical concern regarding testosterone administration is the possibility that it could increase the risk of cardio vascular disease. Such a concept is based on the higher incidence of cardio vascular events in men than in women. However, this may be much more readily explicable by protective effects of estrogen in women. There are few data to support a causal relationship between high testosterone levels and heart disease and in fact, a significant body of evidence suggests that the opposite may be true and that men with low testosterone levels may be at higher cardiovascular risk.

There are reports that testosterone replacement can improve symptoms of chronic stable angina and there are direct observations showing vasodilatation following intra-coronary injections of testosterone.  There are no reports of increasing incidence of cardio vascular disease including myocardial infarction, stroke or angina in reports of testosterone replacement therapy.

Polycythemia

A well know side effect of chronic testosterone administration, particularly using the intra muscular route, where supra-physiological levels are present for some days following each injection, is the occurrence of polycythemia, with a rise in hematocrit. It is note worthy that men with hypogonadism tend to have anaemia and reduced hematocrit concentrations and testosterone replacement leads to normalisation.

In a comparison of transdermal testosterone administration via a patch and intramuscular injections of testosterone esters, it was noted that 15% of the patch treated men and 44% of the injected men had at least one documented hematocrit value above 52%. A direct dose relationship has been observed between testosterone dose and the incidence of polycythemia.  The observation of an increase in hematocrit dictates the need for regular monitoring of this parameter during testosterone replacement.

Summary of Benefits and Risks

If attention is focused particularly on physiological testosterone replacement using transdermal patches, creams or gels, it can be concluded that benefit is substantial with restoration of normal health in the majority of symptomatic hypogonadal men.

Risks are minimal, particularly in regard to the major concerns addressed above.  Possible adverse reactions from excessive testosterone dosing are noted in the ‘adverse reactions’ section of the product information supplied with the testosterone cream under evaluation. These risks include nausea, vomiting, jaundice or swelling of the ankles. increased body hair, increased acne, signs of virilization, weight gain, persistent headaches, increased appetite, deepening of the voice, electrolyte disturbances, too frequent or persistent erections of the penis (priapism) and gynecomastia, but such adverse reactions are extremely unlikely with this form of administration.