Pharmacokinetic Delivery of Androgen Replacement in Women
Choosing both a convenient and efficient mode of androgen administration in women remains a challenge. In men, several administration modes for androgen delivery are available and pharmacokinetics have been studied. Oral testosterone preparations (methyltestosterone and testosterone undecanoate) show a broad variability with regard to intestinal absorption resulting in fluctuating levels of circulating testosterone and usually have very short half-lives due to intensive first-pass metabolism in the liver. Subcutaneous testosterone implants need to be administered every 4–6 months, but they frequently induce supraphysiological androgen levels over weeks and months and may be complicated by implant extrusion and insertion site infections. TTP are applied daily or twice a week and are more convenient to use but still have some unfavorable properties, often resulting in slightly supraphysiological levels of active androgens at higher doses. Of note, transdermal delivery bypasses first-pass metabolism and can provide consistent levels of hormone over time. The use of patches can be limited by skin irritation and/or lack of adherence. These problems are minimized by the use of testosterone gel, which has shown to provide higher and more stable testosterone bioavailability.
However, in women androgen replacement needs to achieve significantly lower circulating testosterone concentrations, as it targets the female reference range that is tenfold lower than the male reference range. Previous studies have shown unfavorable pharmacokinetic properties following administration of oral testosterone and subcutaneous testosterone depots, frequently resulting in supraphysiological androgen levels, and their use is currently not recommended. TTP have the most favorable pharmacokinetic profile of the available androgen preparations but can still result in supraphysiological active androgen levels in treated women. Studies on androgen delivery by testosterone gel in women are still scarce, but a first study showed a dose-dependent increase of bioavailable testosterone in treated women.
Alternatively, oral DHEA is a sex steroid precursor with favorable pharmacokinetic properties. It has consistently been shown that oral DHEA is readily converted to DHEAS and downstream steroids, with preferential increase in androgenic activity in both sexes and predominant increases in circulating androgens in women and increased circulating estrogens in men.[6,105] In women with severe androgen deficiency due to adrenal insufficiency, oral administration of 50-mg DHEA has been shown to yield restoration of normal levels of DHEAS, androstenedione and testosterone. The potential advantage of DHEA over testosterone is its availability for further downstream conversion in peripheral target tissues, which often requires a precursor rather than an end product of sex steroid synthesis, dependent on local expression of steroidogenic enzymes. There is limited evidence to support the use of topical vaginal DHEA administration for androgen replacement in postmenopausal women. DHEA is mainly metabolized to estrogens in vaginal epithelium and thus with regard to known efficacy and safety the administration of vaginal estrogen preparations is the preferred option here.
Expert Rev Endocrinol Metab. 2012;7(5):515-529. © 2012 Expert Reviews Ltd.