PMID- 31675420 OWN - NLM STAT- MEDLINE DCOM- 20210428 LR - 20240330 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 71 IP - 7 DP - 2020 Oct 23 TI - 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. PG - e76-e87 LID - 10.1093/cid/ciz1063 [doi] AB - BACKGROUND: Adolescents in sub-Saharan Africa are at risk for human immunodeficiency virus (HIV) infection and unintended pregnancies. Observational studies suggest that injectable hormonal contraceptives (HCs) increase the HIV risk, although their effects on genital inflammation, particularly HIV-susceptible T-helper 17 (Th17) cells, are unknown. In a randomized crossover 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) were randomly assigned 1:1:1 to NET-EN, CCVR, or COCPs for 16 weeks, then subsequently crossed over to another HC for 16 weeks. Estrogen, follicular stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured. Chemokine receptor 5 (CCR5), human leukocyte antigen (HLA) DR isotope, and cluster of differentiation 38 (CD38) expression by cervical cytobrush-derived CD4+ T cells was assessed by fluorescence-activated cell sorting. Th17 cells were defined as CCR6+ and 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 FSH and LH concentrations, as compared to NET-EN and COCPs, with FSH concentrations and Th17 frequencies correlating significantly. However, Th17-related cytokine concentrations (interleukin [IL]-21, IL-1beta, tumor necrosis factor-alpha, interferon-gamma) and CCR5, HLA-DR, CD38, and Th17 frequencies were significantly higher in CCVR than NET-EN and COCP. At crossover, CCVR users changing to COCPs or NET-EN did not resolve activation or cytokines, although switching from COCP to CCVRs increased cytokine concentrations. CONCLUSIONS: CCVR use altered endogenous hormone levels and associated cervical Th17 cell frequencies to a greater extent than use of NET-EN or COCPs, although Th17 cells were more activated and Th17-related cytokine concentrations were elevated. While CCVRs may impact the HIV risk by regulating Th17 numbers, increased activation and inflammation may balance any risk gains. CI - (c) The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. FAU - Konstantinus, Iyaloo N AU - Konstantinus IN AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Balle, Christina AU - Balle C AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Jaumdally, Shameem Z AU - Jaumdally SZ AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Galmieldien, Hoyam AU - Galmieldien H AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Pidwell, Tanya AU - Pidwell T AD - Desmond Tutu Human Immunodeficiency Virus Centre, University of Cape Town, Cape Town, South Africa. FAU - Masson, Lindi AU - Masson L AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Tanko, Ramla F AU - Tanko RF AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Happel, Anna-Ursula AU - Happel AU AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Sinkala, Musalula AU - Sinkala M AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. FAU - Myer, Landon AU - Myer L AD - Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. FAU - Bosinger, Steven E AU - Bosinger SE AD - Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, USA. AD - Division of Microbiology and Immunology, Yerkes National Primate Research Center, Atlanta, USA. FAU - Gill, Katherine AU - Gill K AD - Desmond Tutu Human Immunodeficiency Virus Centre, University of Cape Town, Cape Town, South Africa. FAU - Bekker, Linda-Gail AU - Bekker LG AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. AD - Desmond Tutu Human Immunodeficiency Virus Centre, University of Cape Town, Cape Town, South Africa. FAU - Jaspan, Heather B AU - Jaspan HB AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. AD - Seattle Children's Research Institute, Seattle, Washington, USA. AD - University of Washington Department of Pediatrics and Global Health, Seattle, Washington, USA. FAU - Passmore, Jo-Ann S AU - Passmore JS AD - Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. AD - National Health Laboratory Service, Cape Town, South Africa. LA - eng GR - R01 HD083040/HD/NICHD NIH HHS/United States GR - S10 OD026799/OD/NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - 0 (Contraceptives, Oral, Combined) RN - HY3S2K0J0F (norethindrone enanthate) RN - T18F433X4S (Norethindrone) SB - IM MH - Adolescent MH - Africa South of the Sahara MH - *Contraceptive Devices, Female MH - *Contraceptives, Oral, Combined MH - Cross-Over Studies MH - Female MH - Humans MH - Norethindrone/analogs & derivatives MH - Phenotype MH - Pregnancy PMC - PMC7755094 OTO - NOTNLM OT - CCVR OT - FSH OT - NET-EN OT - Th17 OT - cytokines EDAT- 2019/11/02 06:00 MHDA- 2021/04/29 06:00 PMCR- 2019/11/02 CRDT- 2019/11/02 06:00 PHST- 2019/06/11 00:00 [received] PHST- 2019/10/25 00:00 [accepted] PHST- 2019/11/02 06:00 [pubmed] PHST- 2021/04/29 06:00 [medline] PHST- 2019/11/02 06:00 [entrez] PHST- 2019/11/02 00:00 [pmc-release] AID - 5611064 [pii] AID - ciz1063 [pii] AID - 10.1093/cid/ciz1063 [doi] PST - ppublish SO - Clin Infect Dis. 2020 Oct 23;71(7):e76-e87. doi: 10.1093/cid/ciz1063.