Contraceptive Vaginal Ring Associated With Significantly Elevated Inflammatory Responses

contraception devices
Contraception techniques against a white background.
Compared with injectable contraceptive norethisterone enanthate and combined oral contraceptive pills, contraceptive vaginal ring lowered cervical frequencies of Th17 cells, which may affect HIV risk stratification.

Compared with injectable contraceptive norethisterone enanthate (NET-EN) and combined oral contraceptive pills (OCPs), contraceptive vaginal ring (NuvaRing®, Merck & Co., Inc.) lowered cervical frequencies of Th17 cells, which may affect HIV risk stratification, according to a study published in Clinical Infectious Diseases.1 At the same time, researchers noted that any increases in the risk for HIV may be offset, because use of the vaginal ring also resulted in significantly elevated inflammatory responses, and therefore enhanced Th17 activation and Th-17-related cytokines.

In a randomized crossover study, 130 adolescent girls without HIV (median age, 17 years) from sub-Saharan Africa were randomly assigned in a 1:1:1 ratio to receive NET-EN (200 mg) twice monthly, NuvaRing inserted monthly, or OCPs (Triphasil® or Nordette®; both ethinyl estradiol and levonorgestrel) for 16 weeks. After 16 weeks, participants who received NET-EN or OCPs were switched to NuvaRing, and those receiving NuvaRing were provided a choice between NET-EN or OCPs for the remaining 16 weeks. Researchers compared the influence of each contraceptive on cervical Th17 cell frequencies and activation, because these cells comprise a major CD4 T cell subset in the cervical mucosa of adolescents and have been identified as being highly susceptible to HIV.

Of the 130 adolescent girls, 45 were assigned to the NET-EN group, 45 to the NuvaRing group, and 40 to the OCPs group. Of these, 107 completed the crossover visit (82.3%; 16 weeks), and 92 completed the study (70.8%; 32 weeks). At enrollment, there were no significant differences in demographic, sexual, or clinical characteristics among the 3 groups.

Although long-acting progestin-only injectable hormonal contraceptives have been associated with increased HIV risk in several large meta-analyses,2,3 findings from this study showed otherwise. Results showed that similar to OCPs, NET-EN use for 16 weeks did not influence the frequency of Th17 cells or CCR5 expression on these cells or changes in Th17-related cytokines. In contrast, compared with matched baseline data and in the cross-sectional analysis at 16 weeks, use of NuvaRing was associated with significant increases in both the activation status of CCR5+ Th17 cells and increased concentrations of several inflammatory and Th17-related cytokines, including interleukin-1β and interleukin-21.

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After the week 16 shift to another hormonal contraceptive, researchers found that NuvaRing-associated “induction in cytokines were significantly reduced in adolescents when they subsequently switched to NET-EN, confirming that removal of the ring resolved this response.” For adolescents who initially used NET-EN and switched to NuvaRing, no significant changes in Th17-related cytokine concentrations were observed. Transition to NuvaRing from OCPs, however, resulted in significant increases in several cytokines in women who did not have elevated inflammation previously.

Findings from this study highlighted “the need to understand biomedical impact of new [hormonal contraceptives] modalities in adolescents, particularly in the setting of high risk for HIV infection,” concluded the researchers.


1. Konstantinus IN, Balle C, Jaumdally SZ, et al. Impact of hormonal contraceptives on cervical Th17 phenotype and function in adolescents: results from a randomized cross-over study comparing long-acting injectable norethisterone oenanthate (NET-EN), combined oral contraceptive pills, and combined contraceptive vaginal rings [published online November 2, 2019]. Clin Infect Dis. doi:10.1093/cid/ciz1063

2. Polis CB, Curtis KM, Hannaford PC, et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665-2683.

3. Polis CB, Phillips SJ, Curtis KM, et al. Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence. Contraception. 2014;90(4):360-390.