Testosterone Replacement Therapy (TRT) is an important piece in the management of aging and overall health for men from their early adulthood to their golden years. The understanding of testosterone and testicular function has been pursued for thousand of years. The ancient Greeks, Romans, and Chinese used castration to create soldiers, harem guards, and infertile sexual partners. (1) This illustrates a long-standing interest in what we know today about testosterone, the endocrine system, and reproductive systems. This led to the consumption of animal testes and testicular extracts to promote fertility and strength. (2,3)
By the 1930s, our technology and knowledge allowed for extraction and synthesis of testosterone compounds for patient use. (4,5,6) The use of testosterone injections and implanted testosterone pellets became therapeutic options for treating patients with low energy, libido, and fertility issues. Increased demand led to more research and development of new forms of testosterone including oral dosage forms. Although the new oral versions proved to be effective, it was also determined that they were severely hepatotoxic and liver damage was not an acceptable risk. This gave oral forms of testosterone a bad name throughout the medical community. (7) This did not stop development of new analogues and some, like methyltestosterone and fluoxymesterone, continue to be used. The biggest problem was that each new oral androgenic compound that was introduced possessing positive benefits, also came with the unavoidable and unwanted effects and toxicities. It was also determined that oral testosterone products were severely degraded in the gut.
In the late 1970s, a new oral form of testosterone was developed in Europe. Testosterone Undecanoate was unique because it is absorbed via the lymphatic system instead of the portal system. This protects the medicine from degradation in the gut thereby preserving functionality and offers protection from liver toxicity by avoiding first pass metabolism. (8,9,10) There are a number of commercial Testosterone Undecanoate products on the market that are available in a wide variety of dosages to accommodate the needs of most patients. The downsides to these commercial products are cost (over $1000 / month) and the necessity for multiple doses per day to achieve appropriate therapeutic response.
The other option for oral testosterone therapy also avoids first pass metabolism by avoiding the gut altogether. Dosage forms that offer oral mucosal absorption, sublingual (under the tongue) or buccal (gumline/cheek), are available both commercially and through compounding pharmacies. The benefits of these dosage forms are rapid absorption, avoidance of degradation in the GI tract, and reduced impact on the liver due to no first pass effect. Compounded sublingual testosterone troches are also very affordable in comparison to any of the commercially available oral options. With PROS there are usually CONS and that is the case in this instance. While rapidly absorbed, these dosage forms are also rapidly metabolized necessitating multiple doses per day for effective testosterone replacement therapy. Multiple daily doses can lead to missed doses and noncompliance which negatively impact therapeutic outcomes. For many patients, this type of regimen is not preferable. Back to the PROS - although rapidly metabolized forms of testosterone are not ideal for TRT, they are highly effective for PRN (as needed) therapy. We commonly use sublingual testosterone troches for “on demand” libido or energy boost because it takes effect very quickly and leaves the system within a few hours. This can be a huge quality of life boost for older, fatigued, and over stressed men in today’s hectic world.
Testosterone replacement is an essential and important therapeutic option for many men. Low testosterone can impact overall health, cognitive function, physical characteristics, and sexual capacity. There are many patients who prefer the option of not using injections, having pellets implanted, or applying creams and gels as part of their regular routine. For these patients, oral forms of testosterone provide an effective alternative and allow for the benefits and quality of life they desire. As we develop new compounds and dosage options, the available alternatives will continue to grow, and more patients will benefit from the ability to choose the form of therapy that suits them best.
REFERENCES
(1) Dittenhofer MH. Eunuchs, women and imperial courts. In: Scheidel W, editor. Rome and China: comparative perspectives on ancient world empires. Oxford: Oxford University Press; 2009. pp. 83–127.
(2) Medvei VC. Carnforth UK and Pearl River NY Parthenon Publishing Group; 1993.
(3) The history of clinical endocrinology.
(4) Butenandt A. The chemical investigation of the sex hormone. Z Angew Chem. 1931:44:905-8.
(5) David K, Dingemanse E, Freud J, Laquer E. Crystalline male hormone from the testes (Testosterone) is more effective than androsterone derived from urine or cholesterin. Hoppe-Seyler's Z physiol Chem. 1935;233:281-2.
(6) Butenandt A, Hanisch G. Testosterone. The transformation of dehydroandrosterone into androstendiol and testosterone; a method for producing testosterone from cholesterin. Hoppe-Seyler's Z Physiol Chem. 1935;237:89-98"
(7) Nieschlag E. Is the use of methyltestosterone obsolete? Dtsch med Wschr. 1981;106:1123-5
(8) Behre HM, Nieschlag E. Testosterone preparations for clinical use in males. In: Testosterone: action, deficiency, substitution. 4th ed. Cambridge: Cambridge University Press; 2012. Pp. 309-35
(9) Coert A, Geelen J, de Visser J, van der Vies J. The pharmacology and metabolism of testosterone undecanoate (TU), a new orally active androgen. Acta Endocrinol. 1975;79:366-74
(10) Nieschlag E, Mauss J, Coert A, Kicovic P. Plasma androgen levels in men after oral administration of testosterone or testosterone undecanoate. Acta Endocrinol. 1975:79:366-74
