Abstract
Progestin-only long-acting reversible contraceptives (LARCs) are increasingly popular among women seeking contraception; however, recent epidemiological studies suggest that systemically administered medroxyprogesterone acetate (MPA) may increase HIV acquisition. In order to determine the exact mechanisms underlying increases in transmission specific to MPA use and to test safer, alternative contraceptive progestin types and delivery methods, in vitro modeling studies must be performed. To achieve this, it is imperative that accurate hormone concentrations be utilized when modeling progestin-mediated outcomes, as the down-stream effects are dose-dependent. The local concentrations of progestins to which the lower female genital tract tissues are exposed after initiation of LARCs are unknown, but they likely differ from peripheral concentrations, dependent upon the progestin type and delivery method. Here, we measured in vivo endocervical and plasma concentrations of (1) systemically-delivered depo MPA (DMPA), (2) levonorgestrel (LNG) delivered via intrauterine system (IUS) and (3) etonogestrel (ETG) delivered via vaginal ring in women who recently initiated contraception treatment. Levels of ETG and LNG in cervical secretions were 100–200 fold higher than plasma levels. In contrast, measurable MPA levels were approximately 10-fold higher in plasma compared to cervical secretions. These results will inform the design of accurate in vitro studies on the influence of progestins on epithelial cells, tissue explants, and peripheral blood cells, to be able to better predict in vivo outcomes. Subsequent observations will aid in determining how MPA might influence HIV acquisition and may facilitate identification of optimal progestin-containing LARC alternatives for women at high risk for HIV infection.
Highlights
Long-acting reversible contraception (LARC) options, injectables and intrauterine devices, are becoming increasingly popular in developed and under-resourced countries due to their discrete nature, high efficacy, and low user-failure rates [1]
It has been hypothesized that adverse human immunodeficiency virus (HIV) transmission outcomes associated with depo MPA (DMPA) use might be secondary to non-contraceptive, immunosuppressive effects mediated by high binding affinity to the glucocorticoid receptor (GR) [13,14,15,16,17]
Other LARCs currently on the market, such as levonorgestrel (LNG), delivered via an intrauterine system (IUS), and an etonogestrel (ETG)/estradiol combination, delivered via vaginal ring, exhibit low cross-reactive GR binding affinities when compared to medroxyprogesterone acetate (MPA) and such differences may [18,19,20,21,22] explain why increased HIV acquisition has not been associated with their use in females to date
Summary
Long-acting reversible contraception (LARC) options, injectables and intrauterine devices, are becoming increasingly popular in developed and under-resourced countries due to their discrete nature, high efficacy, and low user-failure rates [1]. The mechanisms underlying increased HIV acquisition in DMPA users are not entirely known, but it is important to better understand such mechanisms to identify alternative LARCs that may be safer options for high risk women. To determine the mechanism by which MPA influences HIV transmission and to identify better contraceptive options for women at high risk for HIV acquisition, in vitro studies are required using cells and/or tissues from the female genital tract (FGT) where heterosexual transmission of HIV occurs. Other LARCs currently on the market, such as levonorgestrel (LNG), delivered via an intrauterine system (IUS), and an etonogestrel (ETG)/estradiol combination, delivered via vaginal ring, exhibit low cross-reactive GR binding affinities when compared to MPA and such differences may [18,19,20,21,22] explain why increased HIV acquisition has not been associated with their use in females to date
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