Monitoring testosterone levels in testosterone-treated men

Abstract

Dose adjustment with transdermal testosterone preparations should recognize the variability of serum total testosterone levels between applications and over the course of 24 h. Dose adjustments are also made difficult by between-laboratory assay variability. Low SHBG with obesity and diabetes lowers the total testosterone level, and free or bioavailable testosterone may prove to be a better choice for monitoring the progress and dosing of testosterone-treated men with adult onset hypogonadism.

Keywords: :

• Free testosterone
• Hypogonadism
• SHBG
• Total testosterone
• Transdermal testosterone

Transdermal testosterone preparations were developed nearly 30 years ago because intramuscular injections of testosterone can be painful. Furthermore, the commonly used T-enanthate and T-cypionate preparations produce peak levels at 1–3 days which gradually decline to trough levels at 2–3 weeks that may be as low as 25% of the peak value, and these fluctuations are sometimes accompanied by mood swings. Moreover, high peak levels are associated with an increased risk for polycythemia1 and perhaps cardiovascular disease2.

Transdermal drug delivery is an expanding technology with over 3700 Medline citations, which is particularly applicable to low molecular weight lipid-soluble substances such as steroid hormones to which the skin is highly permeable. Proprietary chemical penetration enhancers, or absorption promoters or accelerants, and the physicochemical properties of the steroid determine the rate at which the molecule diffuses across the skin with the aim of achieving a relatively constant therapeutic drug concentration.

In this issue of Current Medical Research and Opinion, Muram and Ni3 present results from a multicenter clinical trial sponsored by Eli Lilly and Company in which men with hypogonadism were treated with 2% testosterone solution (Axiron ) applied to both axilla, once daily in the morning. The authors show that the 2–4 h post-treatment blood level may substantially exceed the average concentration (C_avg) of serum testosterone over 24 h which may result in erroneous dose adjustment by the physician. From the published graphs, it appears that the 8–12 h point may better approximate the C_avg. Thus, for this preparation, it may be wiser to apply the drug in the evening, and measure the drug level in the morning, although users must be cautious to avoid testosterone transfer to others4. A similar observation was made recently for a second transdermal product, Androgel III 1%5. Moreover, the authors of that publication highlighted the substantial day-to-day variability that may occur in the testosterone levels produced by a transdermal product. Thus the testosterone dose should not be modified until an abnormal value is confirmed.

An equally important issue is the assay method used to measure testosterone. For many steroid hormones, including testosterone, there is substantial variability among laboratory methods. Thus a single laboratory should be used for ongoing monitoring. The therapeutic target range during treatment is often a total testosterone level of 500 ng/dL to 800 ng/dL. For the diagnosis of hypogonadism, the US Endocrine Society guidelines suggest measuring the level of free or bioavailable testosterone, using an accurate and reliable assay, for those men in whom total testosterone concentrations are near the lower limit of the normal range and in whom alterations of sex hormone-binding globulin (SHBG) are suspected6. In the original report7 of the study population re-examined by Muram and Ni3, 80% of the men had diabetes or adult-onset hypogonadism, and their mean BMI was 29.5 ± 3.9 kg/m². The study populations in most other industry-sponsored trials have been similar. In those men who have obesity and diabetes, SHBG levels are often low such that the total testosterone level during treatment may be proportionately lower than the free or bioavailable testosterone level, causing their total testosterone level to be below the therapeutic target, which could result in a (unnecessary?) dose increase. Previous studies using transdermal testosterone preparations reveal the potential impact of dose-dependent side effects8. Therefore, standardized free or bioavailable testosterone levels may prove to be as useful in monitoring the progress and dosing of testosterone-treated men as they are in clarifying the diagnosis of adult-onset male hypogonadism.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

S.J.W. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

Notes

* Axiron is a registered trade name of Ely Lilly and Co., Indianapolis, Indiana, USA

† Androgel is a registered trade name of AbbVie, Inc, North Chicago, Illinois, USA