There are three types of data that address the question of whether hormones affect HIV acquisition: (1) epidemiological; (2) animal studies; and (3) human studies. This presentation will focus on progestin-only methods, especially Depo-Provera.
When reviewing epidemiological data, one must consider the setting (family planning clinic versus prenatal clinic versus sex workers) and the type of study (case control versus prospective). In studies of family planning clinics, no increase in HIV risk was seen among users of oral contraceptives and Depo-Provera1,2. In prenatal clinics, there were mixed results among oral contraceptive users and no increased risk among users of Depo-Provera3–5. Among sex workers, oral contraceptive use was associated with a possible increase in risk and Depo-Provera with an increase in risk6,7. A meta-analysis of seven prospective studies evaluating the association between oral contraceptives and HIV yielded a hazard ratio (HR) of 1.32 [95% confidence interval (CI) 1.12–1.57].
Herpes appears to be more easily transmitted among mice if the epithelium is thin or under the influence of Depo-Provera, and is less easily transmitted when the epithelium is thick or under the influence of estradiol. Mice have been shown to be more susceptible to herpes during diestrus, when the vagina is atrophic, than during estrus when the vagina is thicker9. Oophorectomized mice are less susceptible if given estradiol. Depo-Provera allowed transmission whereas Depo-Estradiol blocked it10.
In 1996, Marx et al.11 published a study of 28 rhesus macaques. Eighteen received 200 mg progesterone pellets subcutaneously every 30 days for 90 days to maintain blood progesterone levels in the luteal range. They were inoculated with SIV 5 weeks after the first dose. Ten control animals received placebo on cycle day 1 or 2, and were inoculated in the follicular phase (when progesterone levels were expected to be low). Of 18 treated monkeys, 14 (78%) became infected and three rapidly progressed to AIDS. Of the 10 placebo controls, one became infected (10%) and was healthy at the study end. In addition, the plasma viral load in the first 3 months among infected treated animals was higher than in the infected placebo control, implying greater in vivo SIV replication.
In an additional experiment, three treated animals and three control animals were inoculated as before and were biopsied 3–4 days later. Two of the treated animals showed epithelial thinning and SIV infection compared with none of the controls.
A study by Hild-Petito et al.12 showed that treatment with progestins led to reversible vaginal thinning (even when Depo-Provera was present at low levels), and that medroxyprogesterone acetate in Depo-Provera was released or metabolized faster in monkeys than in women. (The transmission of SIV was not studied.) In that study, four macaques received 30 mg Depo-Provera intramuscularly and four others received Norplant II, which was removed on day 90. Biopsies were performed before treatment and 10, 30, 60, 118, and 146 days after starting treatment. No significant difference was seen between the follicular and luteal phases in terms of vaginal thickness and the number of cell layers. Depo-Provera was no longer detectable by day 70. All changes resolved by day 118 after treatment. The levonorgestrel levels in monkeys were 10-fold higher than in women on Norplant, but medroxyprogesterone levels were the same as or only two-fold higher than in women on Depo-Provera and were non-detectable by day 70, although thinning was still present.
A study by Smith et al.13 showed that progesterone did not protect oophorectomized animals against SIV, and that estrogen is associated with thicker epithelium and appears to protect oophorectomized animal against SIV. In that study, six oophorectomized rhesus macaques received a 400 mg progesterone implant, six received a 400 mg estradiol implant, and six received no implant. All animals were inoculated 60 days after treatment, and were biopsied 12 weeks after inoculation. The estrogen-treated animals were then rechallenged by the injection of SIV either intravenously or into the vaginal submucosa, bypassing the epithelium. In the untreated animals and those treated with progesterone there was epithelial thinning and most animals were infected. Among those treated with estrogen, there was thickening of the epithelium and no infection until after rechallenge, upon which all six animals were infected.
A CONRAD study showed that a single injection of Depo-Provera led to no epithelial thinning beyond that seen in the normal luteal phase and no changes in immune cells14. Sixteen women, naive to Depo-Provera, were biopsied before injection, in both the follicular and luteal phases of the normal menstrual cycle, and again 1 and 3 months after Depo-Provera injection. The average thickness and number of cell layers in the vaginal epithelium were higher in the follicular phase than the luteal phase in the untreated cycle. There was a significant downward trend over time, comparing the follicular phase and post-Depo-Provera values. There was no significant downward trend over time, comparing the luteal phase and post-Depo-Provera values. There was a significant upward trend (recovery) at 3 months. There was no change in CD1a+ dendritic cells, CD8+ and CD4+ lymphocytes, and CD68+ macrophages.
A prospective study by Miller et al.15 of 38 women before (in the luteal phase) and at 3 and 6 months after starting Depo-Provera showed changes in the mean number of cell layers and epithelial thickness that were statistically significant, but not of the magnitude seen in monkeys, and not likely to increase the risk of HIV. A decrease in hydrogen peroxide-producing lactobacillus was also seen.
A study by Bahamondes et al.16 compared 20 women who had used Depo-Provera for 2–3 years, who underwent vaginal biopsy at 90 days after the last injection, and 20 controls who had never used Depo-Provera and had been exposed to no hormones for at least 6 months, and who underwent vaginal biopsy on cycle days 20–25 (in the luteal phase). No significant differences were seen between users and controls.
(1) Monkeys handle exogenous progestins differently from women. (2) In monkeys, high progesterone levels or the administration of Depo-Provera (even low levels) leads to epithelial thinning. In women, Depo-provera causes no clinically significant thinning (compared with the luteal phase). (3) It is unclear whether the luteal phase is a time of increased risk of HIV acquisition. (4) Women at risk should continue condom use.
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