Effects of two progestin-only contraceptives, Depo-Provera and Norplant-II, on the vaginal epithelium of rhesus monkeys.

The objective of this study was to determine whether progestin-only contraceptives induce thinning of the vaginal epithelium in nonhuman primates. Eight intact rhesus monkeys (four per group) were treated with either a single intramuscular injection of 30 mg of Depo-Provera or a subcutaneous insertion of Norplant-II (2 x 75 mg rods; day 0). Norplant-II rods were removed 90 days after insertion. Vaginal biopsies were obtained during a pretreatment menstrual cycle and following treatment on days 10, 30, 60, 118, and 146. Formalin-fixed vaginal biopsies were evaluated for epithelial thickness and the degree of keratinization. The circulating levels of estradiol, progesterone, medroxyprogesterone acetate (MPA), or levonorgestrel (LNG) were monitored throughout the study by specific radioimmunoassays. Circulating levels of estradiol and progesterone confirmed the stage of the menstrual cycle in which pretreatment biopsies were obtained. Following treatment with Depo-Provera, serum levels of MPA increased to 2.3 +/- 0.6 ng/ml (x +/- SE, n = 4) within 24 hr. Serum levels of MPA were maximal on day 14 (5.5 +/- 0.9 ng/ml), dropped below 1 ng/ml by day 50, and were nondetectable by day 70. Circulating levels of LNG were elevated 24 hr after insertion of Norplant-II (5.8 +/- 3.0 ng/ml), peaked on day 2 (7.6 +/- 4.2 ng/ml), remained between 1.4 and 6.2 ng/ml from days 14 to 90, and were nondetectable by day 118, the first serum sample after removal of Norplant-II. There were no significant differences (p > 0.05) in the epithelial thickness (microm), number of epithelial cell layers, or type of epithelium present in vaginal biopsies obtained during the follicular or luteal phases of the pretreatment menstrual cycle. Conversely, a pronounced effect of progestin treatment was observed on the vaginal epithelium. There were no significant differences (p > 0.05) between the two progestin treatment groups, but a significant effect (p < 0.05) over time was observed (two-way ANOVA). Compared with pretreatment menstrual cycle controls, the vaginal epithelial thickness was decreased (p < 0.05) by day 30 or 60 following Norplant-II insertion or Depo-Provera injection, respectively. The number of epithelial cell layers was also decreased (p < 0.05) on days 30 and/or 60 in progestin-treated monkeys compared with pretreatment control cycles. Following removal of Norplant-II or metabolic excretion of MPA, the vaginal epithellium regenerated and the thickness was no longer different (p > 0.05) from the pretreatment control cycle. These data demonstrate that progestin-only contraceptives induced thinning of the vaginal epithelium in rhesus monkeys, and this effect was rapidly reversible following physical or metabolic removal of the progestin.