Sublingual administration of testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men.

In search of a more physiological testosterone (T) replacement therapy for hypogonadal states, we evaluated an inclusion complex of T with 2-hydroxypropyl-beta-cyclodextrin (HPBCD). HPBCD enhances T solubility and absorption, but HPBCD is not absorbed. Five hypogonadal men (mean age, 32.4 +/- 2.3 yr) with serum T levels below the normal range were treated in two separate experimental phases with either a 2.5- or 5.0-mg tablet of sublingual (SL) T-HPBCD three times daily for 7 days. Acute pharmacodynamic changes were monitored at baseline and 10, 20, and 40 min and 1, 1.5, 2, 3, 4, and 8 h after administration of the first dose. At the 5-mg dose, a maximal concentration (Cmax) of T (85.4 +/- 11.0 nmol/L) was achieved in 20 min (63 +/- 24-fold increase), followed by a rapid decline to below the normal range (less than 12 nmol/L) at 2 h, with an estimated half-life of decline of 1.87 +/- 0.19 h. The dihydrotestosterone (DHT) Cmax (4.1 +/- 0.5 nmol/L) occurred at 32 +/- 5 min (8.9 +/- 1.3-fold increase) and declined to below the normal range (less than 1.2 nmol/L) after 3 h. The integrated 8 h value for the ratio of T/DHT was 10.0 +/- 1.1, which fell within the normal range. The increment in androstenedione paralleled that in T, and the Cmax (6.8 +/- 0.9 nmol/L) was reached in 24 +/- 4 min (2.3 +/- 0.6-fold increase). Compared to baseline, the Cmax was significantly greater for T (P less than 0.005), DHT (P less than 0.0005), and androstenedione (P less than 0.005). Both estradiol (E2) and estrone (E1) remained in the normal range (less than 200 pmol/L), although the Cmax for E1 was significantly greater than baseline (P less than 0.05). Serum LH levels were suppressed (19.0 +/- 2.6%) at 2 h (P less than 0.05), without a significant change in FSH. During 7 days of treatment, there was no cumulative increase in basal T, DHT, and E2 levels or further decline in LH or FSH levels. There was no change in sex hormone-binding globulin levels. Similar results were observed with the 2.5-mg dose, suggesting that the capacity of SL absorption may be limited to a certain dose of T-HPBCD. The fluctuations in T after SL administration of T-HPBCD resemble endogenous episodic secretion. We conclude that T, complexed with HPBCD, is rapidly absorbed by the SL route and quickly metabolized without sustained elevations of DHT or E2.