Compounded Percutaneous Testosterone Gel
Background: Current methods of testosterone replacement therapy are limited to fixed-dosage patches and depot injections. Neither of these methods provides ideal therapy because of the inflexibility of dosing and other nuisance problems associated with the patches and nonphysiologic hormone levels when depot injections are used. Testosterone gels offer the potential for convenience and ease of administration, as well as flexible dosing regimens, by means of a simple topical application.
Methods: Ten hypogonadal men were selected from the author's general practice, ranging in age from 44 to 77 years. Four of these men had newly diagnosed and 6 had preexisting hypogonadism. Patients were withdrawn from their previous hormone therapy (where applicable), and baseline laboratory studies were obtained for total testosterone, free testosterone, dihydrotestosterone, estradiol, luteinizing hormone, follicle-stimulating hormone, complete blood counts, lipid panels, and chemistry panels. The patients then started taking increasing dosages of the testosterone gel until physiologic levels of testosterone were realized or until the study period (6 weeks) was concluded. There was no blinding, and each patient served as his own control. Testosterone and free testosterone levels were monitored weekly, and estradiol and dihydrotestosterone less frequently. At the conclusion of the study, all the baseline laboratory tests were repeated. A questionnaire evaluating the psychosexual well-being of the patients was administered before and after the treatment period.
Results: The average total testosterone level rose from 136 ng/dL to 442.9 ng/dL (P < .001). Average free testosterone levels rose from 34.2 pg/mL to 120.3 pg/mL (P < .001). Average dihydrotestosterone levels rose from 20.5 to 199.2 ng/dL (P = .006). Average estradiol levels rose only slightly from 34.1 pg/mL to 40.0 pg/mL P = .191). Average total androgens (testosterone plus dihydrotestosterone) rose in all patients to therapeutic levels, from 149.3 ng/dL to 642.1 ng/dL (P = .001). The ratio of total androgen to estradiol rose from 5.1 to 17.1 (P < .002). Luteinizing hormone was suppressed in the 6 patients for whom meaningful data were available, and decreased on average from 5.66 to 1.10 mIU/mL (P = .005) Lipid effects were measured, and a 15% drop in all cholesterol fractions was noted (P < .005). Evaluation of the questionnaire showed considerable improvements in sexual function and overall well-being in all but 1 patient. No adverse effects or nuisance problems were detected during the duration of the study.
Conclusion: Topically applied testosterone gels are an effective and convenient means of hormone replacement in hypogonadal men.

Hormone replacement therapy for testosterone-deficient men can pose several challenges for the clinician. Specifically, the treating physician must deal with limited methods for delivery of testosterone, which can lead to inadequate levels of circulating sex steroid hormones. Furthermore, many patients are not satisfied with the existing methods of replacement, resulting in poor compliance. Proper replacement of androgens in hypogonadal men can avert the recognized sequelae of this condition, namely, sexual dysfunction, loss of virilization, excessive bone loss, depression, decreased cognition, and increased risk for cardiovascular disease. At the current time the best available method for delivering testosterone is administration of bimonthly injections of depot testosterone or application of impregnated plastic patches. Oral formulations of 17-alkylated androgens are not considered to be a safe or desirable means of replacement because of first-pass hepatic effects and the rare condition of peliosis hepatis.

Although the depot injection method (using the enanthate or cypionate esters of testosterone) is inexpensive and serves as the reference standard of therapy, it can be both inconvenient and painful to receive. It also requires frequent visits to the physician's office or taught self-administration. There are disadvantages in that nonphysiologic levels of testosterone result from the peak and trough values inherent in the standard 2-week dosing interval of this depot preparation. Estradiol levels can be much higher than desired because of increased aromatization of the testosterone molecule. Nankin found that estradiol levels rose to 300% of baseline during the peak levels after intramuscular testosterone enanthate injections.

Plastic patches have the advantage of mimicking the physiologic production of testosterone but have several drawbacks. There are frequent problems with skin irritation and adhesion. The Androderm patch is reported in its package insert to cause pruritus in 37% of users, a blister-like rash in 12% of users, and simple erythema or vesicles in another 7% of users. A British study with 50 hypogonadal men found that only 22% of their patients would continue with patches and that 84% experienced adverse reactions, almost all related to skin irritation. Jordan found that 12% of a study group of 60 men had true contact dermatitis from the patch, and that 32% had moderate to severe skin irritation. The newer Testoderm TTS (nonscrotal patch) package insert reports less pruritus (12%), and only 3% severe erythema, but adhesion problems were reported in 42% of men who used the patch for 14 days. The Testoderm scrotal patches require shaving the scrotum and cannot be used on a patient with an underdeveloped scrotum. Lack of adhesion is also frequently reported. The patches also offer limited opportunity for discretion and little dosing flexibility.

The above-mentioned problems become more relevant when one considers that the number of men with diagnosed and undiagnosed hypogonadism in the average primary care practice can be substantial. Although no reported studies have estimated or measured the incidence of this population in a primary care setting, many other studies have looked at various subpopulations. For example, Tenover found that 20% of healthy men aged 60 to 80 years were hypogonadal, and others found that up to 30% of men in long-term care facilities have low testosterone levels. Low testosterone levels have been found in up to 16% of men who complain of erectile dysfunction and in 62% of men who are current or former heavy drinkers of alcohol. Thirty percent of men with osteoporotic fractures have been found to have hypogonadism Diabetes is also strongly associated with low testosterone levels and, in fact, many chronic illnesses in men will cause a permanent or temporary drop in the testosterone levels.

Topically applied gels containing various concentrations of hormone have been available through compounding pharmacists for some time. These products are handmade ointments that are prepared by specially-trained pharmacists for specific patient applications as directed by a physician's prescription. The Professional Compounding Centers of America (9901 S Wilcrest, Houston, TX 77099, 1-800-331-2498) suggested several formulations. The idea of using these gels was intriguing, but I could not find documentation of their effectiveness in the English literature. The information from the compounding pharmacists was incomplete, and there is a need to define the proper way to use these products and to prove that they are viable alternatives for replacement therapy.