Which Androgen Replacement Therapy for Women?1

Although the postmenopausal ovary remains an important source of testosterone (T) production, there is nevertheless a decline in total circulating androgen levels with age. A role for androgen replacement in addition to estrogens in some postmenopausal, particularly ovariectomized, women is increasingly gaining acceptance. We have compared the pharmacokinetics of two existing testosterone preparations, oral testosterone undecanoate (TU) and sc testosterone implants, with a new matrix transdermal delivery system for T. In study 1, three different doses of TU (40 mg, two 20-mg doses 6 h apart and two 10-mg doses 6 h apart, orally) were investigated in 10 postmenopausal women. Median peak levels of 18 nmol/L (range, 5.8-64.0 nmol/L; 40 mg), 12.3 nmol/L (range, 5.7-29.2 nmol/L; 20 mg), and 9.7 nmol/L (range, 7.8-28.7 nmol/L; 10 mg) were observed, but T levels varied considerably within and between subjects regardless of the dose used. In study 2, 30 women receiving s.c. estradiol therapy were randomized to receive either a 100-mg T implant or placebo. In the T-treated group, levels peaked at 8.9 +/- 1.7 nmol/L 1 month after insertion and then declined gradually to 2.9 +/- 0.4 nmol/L at 6 months. In study 3, a novel matrix transdermal delivery system for T was investigated in 6 females. Estimated daily delivery rates of 840 (TD 1), 1100 (TD2), and 3000 microg (TD3) T/24 h were investigated. T rose rapidly after a single application of TD 1 and TD2 and were relatively constant for the next 18 h, at which time peaks of 2.3 +/- 1.0 and 4.1 +/- 1.6 nmol/L, respectively, at 24 h were seen. T concentrations fell to baseline levels within 6 h after patch removal. When TD2 was applied for 7 days, a T level of 4.3 +/- 0.7 nmol was seen 24 h after application, falling gradually to 2.8 +/- 0.7 nmol/L by day 7. During twice weekly application of TD2, stable T concentrations were maintained, and all peak levels were similar (peak level, 4.2 +/- 0.3 nmol/L 24 h post-TD application) as were predose troughs (3.2 +/- 0.3 nmol). Twice weekly application of TD3 produced a similar pattern of T, and the mean peak and trough levels were 7.5 +/- 0.9 and 4.0 +/- 0.4 nmol/L, respectively. In conclusion, TU produced inappropriate high T levels at all doses, with wide variations between subjects, confirming that TU is unpredictably absorbed and unlikely to be satisfactory for use in women. Subcutaneous testosterone implants produce unphysiological T levels for at least 1-2 months. The transdermal matrix delivery system maintained relatively stable T levels within narrow ranges with little within- and between-subject variation. We conclude that such transdermal systems may be of value for androgen therapy in postmenopausal women because they provide a highly controllable way of delivering T noninvasively and reliably, and achieve mean physiological levels not possible with existing methods.