Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice.

The percutaneous route is an effective method for delivery of reproductive hormones. Several transdermal therapeutic systems (TTS) releasing estrogens, progestogens and androgens from patches attached to the skin are currently in clinical use. For women, transdermal systems have been developed for hormonal replacement therapy (HRT) and recently for contraception. HRT with patches releasing only estradiol (E2) should be supplemented with a progestogen to protect the endometrium. Patches simultaneously releasing both E2 and a progestogen are also available. Combined regimens are either continuous or sequential. In the latter, estrogen-only patches are applied for 14 days, followed by 14-day application of patches releasing both hormones. Transdermal HRT successfully treats menopausal symptoms and has a bone-sparing effect. Transdermal contraceptive patches deliver ethinyl E2 in combination with the progestogen norelgestromin. This system provides an effective contraceptive and acceptable bleeding pattern not different from that of oral contraceptives. The types of adverse events experienced are approximately the same as with oral contraceptives. Reactions at the application site cause about 3% women to discontinue the use of patches. Transdermal systems also have been designed to supplement testosterone in hypogonadal men. Testosterone released from patches produces positive effects on mood and sexual behavior and significantly increases bone mass. Men using testosterone patches have to be regularly monitored for an increase in prostate volume and changes in prostate-specific antigen. Reproductive steroids delivered by the skin avoid first-pass liver metabolism, typical of oral dosing; consequently, the liver tissue is affected to a lesser degree. Other advantages include rapid onset and termination of action, noninvasive self-administration and attainment of therapeutic hormone levels with low daily doses. Reduced frequency of dosing has the potential to improve patient compliance. While compliance is important for any hormone, it is particularly important for contraceptive purposes. Like oral delivery of sex steroids, percutaneous absorption is characterized by intra- and interindividual variability. New technologies under development, combining electronics and low-frequency ultrasound, have the potential to provide precise dosing as well as drug delivery "on demand."