The Effect of Contraception on Genital Cytokines in Women Randomized to Copper Intrauterine Device, Depot Medroxyprogesterone Acetate, or Levonorgestrel Implant

Abstract

Background: The ECHO trial randomized women to intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel implant (LNG-implant), or copper intrauterine device (Cu-IUD). In a substudy of the ECHO trial, we tested the hypothesis that contraceptives influence genital inflammation by comparing cervicovaginal cytokine changes following contraception initiation. In addition, we compared cytokine profiles in women who acquired HIV (cases) versus those remaining HIV negative (controls).

Methods: Women (n = 251) from South Africa and Kenya were included. Twenty-seven cervicovaginal cytokines were measured by Luminex at baseline, and 1 and 6 months after contraceptive iTanko et alnitiation. In addition, cytokines were measured preseroconversion in HIV cases (n = 25) and controls (n = 100).

Results: At 6 months after contraceptive initiation, women using Cu-IUD had increased concentrations of 25/27 cytokines compared to their respective baseline concentrations. In contrast, women initiating DMPA-IM and LNG-implant did not experience changes in cervicovaginal cytokines. Preseroconversion concentrations of IL-1β, IL-6, and TNF-α, previously associated with HIV risk, correlated with increased HIV risk in a logistic regression analysis, although not significantly after correcting for multiple comparisons. Adjusting for contraceptive arm did not alter these results.

Conclusions: Although Cu-IUD use broadly increased cervicovaginal cytokine concentrations at 6 months postinsertion, these inflammatory changes were found not to be a significant driver of HIV risk.

Clinical trials registration: NCT02550067.

Keywords: Cu-IUD; DMPA-IM; LNG-implant; inflammation; reproductive tract.

Conflict of interest statement

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Published by Oxford University Press for the Infectious Diseases Society of America 2022.

Figures

Figure 1.

A–E, Effect of 1-month contraceptive use on cervicovaginal cytokines. Concentrations of each cytokine before (Pre) and 1 month after (Post) contraceptive initiation. Grey dots indicate precontraceptive cytokine concentrations. Cu-IUD (n = 60), DMPA-IM (n = 67), and LNG-implant (n = 63) users are shown in red, blue, and green, respectively. Horizontal lines indicate the median. Statistical significance was calculated using a Wilcoxon signed rank for paired samples with adjustment for multiple comparisons using the false discovery rate step-down procedure. A P value < .05 was considered significant. Abbreviations: Cu-IUD, copper intrauterine device; DMPA-IM, intramuscular injectable depot medroxyprogesterone acetate; FGF, fibroblast growth factor; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN-γ, interferon-γ; IL, interleukin; IL-1ra, IL-1 receptor agonist; IP-10, IFN-γ inducible protein-10; LNG, levonorgestrel; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; PDGF-BB, platelet-derived growth factor-BB; RANTES, regulated on activation, normal T-cell expressed and secreted; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Figure 2.

A–E, Effect of 6-months contraceptive use on cervicovaginal cytokines. Concentrations of each cytokine before and 6 months after contraceptive initiation. Grey dots indicate precontraceptive cytokine concentrations. Cu-IUD (n = 52), DMPA-IM (n = 47), and LNG-implant (n = 50) users are shown in red, blue, and green, respectively. Horizontal lines indicate the median. Median fold change and interquartile range is represented in red for the Cu-IUD arm. Statistical significance was calculated using a Wilcoxon signed rank for paired samples with adjustment for multiple comparisons using the false discovery rate step-down procedure. A P value < .05 was considered significant. Abbreviations: Cu-IUD, copper intrauterine device; DMPA-IM, intramuscular injectable depot medroxyprogesterone acetate; FGF, fibroblast growth factor; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN-γ, interferon-γ; IL, interleukin; IL-1ra, IL-1 receptor agonist; IP-10, IFN-γ inducible protein-10; LNG, levonorgestrel; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; PDGF-BB, platelet-derived growth factor-BB; RANTES, regulated on activation, normal T-cell expressed and secreted; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Figure 3.

Visualization of clustering of cytokines 6 months after contraceptive initiation. A, Unsupervised hierarchical clustering showing the variation in cytokine concentrations in individual women and clustering women according to the similarities of their cytokine expression profiles and their contraceptive method 6 months after initiation of contraceptive. Cytokine concentrations are indicated using a color scale that ranges from blue (low) through white to red (high). The dendrogram above the heat map indicates degrees of relatedness between cytokine profiles within the study participants. The dendrogram on the left of the heat map depicts relationships between the cytokine expression levels across all the study participants. P value for statistical significance was generated using PERMANOVA. B, sPLSDA of cytokines 6 months after contraceptive initiation. C, Barplots indicate the loadings of X-variate 1 from the sPLSDA analysis. The absolute value and the negative or positive sign represent the importance of the cytokine and the correlations between the variables, respectively. Red, blue, and green represent Cu-IUD (n = 52), DMPA-IM (n = 47), and LNG-implant (n = 50), respectively. Abbreviations: Cu-IUD, copper intrauterine device; DMPA-IM, intramuscular injectable depot medroxyprogesterone acetate; expl. var, explained variation; FGF, fibroblast growth factor; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN-γ, interferon-γ; IL, interleukin; IL-1ra, IL-1 receptor agonist; IP-10, IFN-γ inducible protein-10; LNG, levonorgestrel; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; PDGF-BB, platelet-derived growth factor-BB; RANTES, regulated on activation, normal T-cell expressed and secreted; sPLSDA, sparse partial least-squares discriminant analysis; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.