Impact of Hormonal Contraceptives on Cervical T-helper 17 Phenotype and Function in Adolescents: Results from a Randomized, Crossover Study Comparing Long-acting Injectable Norethisterone Oenanthate (NET-EN), Combined Oral Contraceptive Pills, and Combined Contraceptive Vaginal Rings

Abstract

Background Adolescents in sub-Saharan Africa are at risk for HIV infection and unintended pregnancies. Observational studies suggest that injectable hormonal contraceptives (HC) increase HIV risk, although their effects on genital inflammation, particularly HIV-susceptible Th17 cells, are unknown. In a randomized cross-over study, the effect of injectable norethisterone oenanthate (NET-EN), combined contraceptive vaginal rings (CCVR; NuvaRing®), and combined oral contraceptive pills (COCPs) on cervical Th17 cells and cytokines were compared. Methods Adolescents (n=130; 15-19 years), randomized 1:1:1 to NET-EN, CCVR, or COCPs for 16-weeks, subsequently crossed-over to another HC for 16-weeks. Estrogen (E2), follicular stimulating hormone (FSH), and luteinizing hormone (LH) were measured. CCR5, HLA-DR and CD38 expression by cervical cytobrush-derived CD4+ T cells was assessed by FACS. Th17 cells were defined as CCR6+CCR10-. Cervicovaginal Th17-related cytokines were measured by Luminex. Results CCVR use for the first 16-weeks was associated with reduced Th17 frequencies and lower FHS and LH concentrations compared to NET-EN/COCPs, with FHS concentrations and Th17 frequencies correlating significantly. However, Th17-related cytokine concentrations (IL-21, IL-1β, TNF-α, IFN-γ) and CCR5+HLA-DR+CD38+ Th17 frequencies were significantly higher in CCVR than NET-EN/COCP. At cross-over, CCVR users changing to COCPs or NET-EN did not resolve activation or cytokines, although switching from COCP to CCVRs increased cytokine concentrations. Conclusion CCVR use altered endogenous hormone levels and associated cervical Th17 cell frequencies to greater extent than NET-EN/COCPs, although Th17 cells were more activated and Th17-related cytokine concentrations were elevated. While CCVRs may impact HIV risk by regulating Th17 numbers, increased activation/inflammation may balance any risk gains.

Impact of the menstrual cycle and ethinyl estradiol/etonogestrel contraceptive vaginal ring on granulysin and other mucosal immune mediators

“…The effect of CVR use on cervicovaginal cytokines has been assessed in three previous studies, though none differentiated between follicular and luteal phase. [33][34][35] Two studies used SoftCup samples and longitudinal designs 33,34 and found similar results to ours: elevated IL-6 and IL-1β during CVR use (in addition to IFNγ and TNFα, which we did not find). The third study used cervicovaginal lavage samples and a cross-sectional design 35 and the results agreed less well with ours, in particular, their finding that IL-1β was lower in CVR users.…”

“…The effect of CVR use on cervicovaginal cytokines has been assessed in three previous studies, though none differentiated between follicular and luteal phase 33‐35 . Two studies used SoftCup samples and longitudinal designs 33,34 and found similar results to ours: elevated IL‐6 and IL‐1β during CVR use (in addition to IFN‐γ and TNF‐α, which we did not find).…”

Alteration of systemic and uterine endometrial immune populations in patients with endometriosis

“…42 HT has previously been reported to reduce frequencies of Th17 cells in the vagina during bacterial infections by reducing CD207 + Langerhans' cells, which are known to activate Th17 cells. 43 HT also promotes the expansion of iTreg cells, which play a critical role in downregulating immune responses 44 and upregulating the expression of FoxP3, PD-1, and CTLA-4 via ERα-mediated signaling. 45,46 The disadvantage of HT is that while it suppresses lesion growth it is not a viable option for women trying to achieve pregnancy, as HT interferes with ovarian and uterine endometrial function.…”

Relationship between the Oral and Vaginal Microbiota of South African Adolescents with High Prevalence of Bacterial Vaginosis

“…Participants were screened, those 18 years or older provided informed consent, while informed assent from the participant and informed consent from a parent or legal guardian were obtained for participants younger than 18 years old. Eligibility criteria are described in detail elsewhere [ 34 ] [Gill, K. et al, An Open-Label, Randomized Crossover Study to Evaluate the Acceptability and Preference for Contraceptive Options in Female Adolescents, 15–19 Years of Age, as a proxy for HIV prevention methods (UChoose), JIAS , under review]. In brief, the eligibility criteria for enrolment for the parent study included either HC naive or willingness to change method, no symptomatic sexually transmitted infections (STIs) within the prior 40 days, no known sensitivity to any of the study products and no intentions of becoming pregnant throughout the study period.…”