Research Article:
A True Sublingual Tablet

A True Sublingual Tablet

NOT to be confused with a lozenge or troche

IFFS ‘98/AMERICAN SOCIETY FOR REPRODUCTIVE MEDICINE The pharmacokinetics of the sublingual administration of micronized estradiol, progesterone and testosterone in postmenopausal women. AA Luciano, BE Miller, LC Sequenzia, CA Benadiva, KL Slade and MJ De Souza. Center for Fertility and Reproductive Endocrinology, New Britain General Hospital, New Britain, CT

Objectives: The purpose of this study was to evaluate the pharmacokinetics and the therapeutic responses of micronized estradiol (E2), progesterone (P4), and testosterone (T) administered sublingually as a single tablet.

Design: In this double blind prospective study, postmenopausal women were randomized to the combination of either E2 0.5 mg and P4 100 mg (double therapy) or E2 0.5 mg, P4 100 mg and T 1.25 mg (triple therapy) administered as a single sublingual tablet twice a day for 6 months.

Materials and Methods: The long-term absorption was determined by measuring baseline levels of E2, P4 and T after a 12-hours fast and 12-hours after taking the last tablet at the 2-month and 6-month visits. The short-term absorption and body distribution were assessed by performing the following perturbation study. After a 12-hour fast and 12-hours after last tablet, blood samples were drawn before, at 1-hour and 2-hours after the administration of the study drug for the measurement of serum levels of E2, P4 and T.

Results: Thirty women in the double therapy and 33 women in the triple therapy participated in the study. The subjects from both groups were similar with respect to age (53 +/- 1 yrs), height (63 +/- 1 in), weight (153 +/- 6 lb), baseline FSH (67.3 +/- 4.2 mIU/L), E2 (26.3 +/- 2.4 pg/mL), P4 (0.34 +/- 0.03 ng/mL) and T (0.41 +/- 0.05ng/mL) levels. In both groups, E2 and P4 levels increased (p<0.001) from baseline in a similar manner at 2-mo (47.0 +/- 5.1 pg/mL and 1.71 +/- 0.13 ng/mL, respectively) and at 6-mo (60.3 +/- 7.4 pg/mL and 1.83 +/- 0.17 ng/mL, respectively). In the triple therapy group, T increased significantly from baseline levels of 0.43 +/- 0.04 ng/mL to 0.53 +/- 0.05 ng/mL (p<0.05) at 2-mo and to 0.61 +/- 0.09 ng/mL (p<0.03) at 6-mo. Serum T levels in the double therapy group did not change. The perturbation studies revealed immediate absorption of all hormones with peak levels at 1-hr followed by declines in serum concentration at 2-hrs after sublingual administration, as show in the following table:

Double Therapy
E2
P4
T
Triple Therapy
E2
P4
T
Baseline
51.0+/-3.7
1.65+/-0.14
0.63+/-0.09
 
54.4+/-5.3
1.83+/-0.11
0.51+/-0.07
1 hour
232.4+/-32.6*
5.73+/-0.58*
0.47+/-0.06
 
217.0+/-27.1*
5.26+/-0.70*
5.24+/-0.77*
2 hour
138.0+/-15.7*
4.3+/-0.42*
0.46+/-0.06
 
142.0+/-15.9*
4.45+/-0.68*
2.04+/-0.25*

Conclusions: The micronized preparation of E2, P4 and T is readily and consistently absorbed sublingually, restores therapeutic levels of these hormones and is well tolerated. This work was supported in part by the Thornton Fund.