Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood

Haddad, Lisa; Swaims-Kohlmeier, Alison; Mehta, C. Christina; Haaland, Richard E.; Brown, Nakita L.; Sheth, Anandi N.; Chien, Hsin; Titanji, Kehmia; Achilles, Sharon L.; Lupo, Davis; Hart, Clyde E.; Ofotokun, Igho

doi:10.1371/journal.pone.0230473

Cited by 11 publications

(15 citation statements)

References 68 publications

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“…Another progestin‐only implant, the etonogestrel implant, however, has previously been linked to higher levels of CD4+ T cells expressing the HIV co‐receptor CCR5, as well as the soluble lymphocyte activation marker (sCD40L) after 3 months of contraceptive initiation 58 . Interestingly, scD40L, among other immune mediators, was associated with an increase in HIV risk in the CAPRISA 002 trial 18 .…”

Section: Discussionmentioning

confidence: 99%

“…57 Another progestin-only implant, the etonogestrel implant, however, has previously been linked to higher levels of CD4+ T cells expressing the HIV co-receptor CCR5, as well as the soluble lymphocyte activation marker (sCD40L) after 3 months of contraceptive initiation. 58 Interestingly, scD40L, among other immune mediators, was associated with an increase in HIV risk in the CAPRISA 002 trial. 18 While this demonstrates that implants have been linked to changes in the genital immune environment, ultimately, we do not understand the mechanisms behind this possible relationship and our findings remain surprising.…”

Section: High Baseline Inflammationmentioning

confidence: 98%

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Genital inflammatory status and the innate immune response to contraceptive initiation

Radzey

Harryparsad

Meyer

et al. 2022

American J Rep Immunol

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Problem Data on the effects of contraceptives on female genital tract (FGT) immune mediators are inconsistent, possibly in part due to pre‐existing conditions that influence immune mediator changes in response to contraceptive initiation. Methods This study included 161 South African women randomised to injectable depot medroxyprogesterone acetate (DMPA‐IM), copper intrauterine device (IUD), or levonorgestrel (LNG) implant in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial. We measured thirteen cytokines and antimicrobial peptides previously associated with HIV acquisition in vaginal swabs using Luminex and ELISA, before, and at 1 and 3 months after contraceptive initiation. Women were grouped according to an overall baseline inflammatory profile. We evaluated modification of the relationships between contraceptives and immune mediators by baseline inflammation, demographic, and clinical factors. Results Overall, LNG implant and copper IUD initiation were associated with increases in inflammatory cytokines, while no changes were observed following DMPA‐IM initiation. However, when stratifying by baseline inflammatory profile, women with low baseline inflammation in all groups experienced significant increases in inflammatory cytokines, while those with a high baseline inflammatory profile experienced no change or decreases in inflammatory cytokines. Conclusion We conclude that pre‐contraceptive initiation immune profile modifies the effect of contraceptives on the FGT innate immune response.

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Section: Discussionmentioning

confidence: 99%

Section: High Baseline Inflammationmentioning

confidence: 98%

Genital inflammatory status and the innate immune response to contraceptive initiation

Radzey

Harryparsad

Meyer

et al. 2022

American J Rep Immunol

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“…It is assumed that P 4 protects against HIV-1 infection by reducing the expression of CCR5, the main co-receptor for HIV entry into human cells. The synthetic progestins etonogestrel and MPA increase the rate of virus penetration, although this may be due to the thinning of the endometrium [ 125 ].…”

Section: Other Evidence Of the Anti-inflammatory And Immunomodulatory...mentioning

confidence: 99%

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

Федотчева

Shimanovsky

2022

Biomolecules

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The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P4) and progestins. The mechanisms of the anti-inflammatory and immunomodulatory P4 action are not fully clear. The anti-inflammatory effects of P4 can be defined as nonspecific, associated with the inhibition of NF-κB and COX, as well as the inhibition of prostaglandin synthesis, or as specific, associated with the regulation of T-cell activation, the regulation of the production of pro- and anti-inflammatory cytokines, and the phenomenon of immune tolerance. The specific anti-inflammatory effects of P4 and its derivatives (progestins) can also include the inhibition of proliferative signaling pathways and the antagonistic action against estrogen receptor beta-mediated signaling as a proinflammatory and mitogenic factor. The anti-inflammatory action of P4 is accomplished through the participation of progesterone receptor (PR) chaperones HSP90, as well as immunophilins FKBP51 and FKBP52, which are the validated targets of clinically approved immunosuppressive drugs. The immunomodulatory and anti-inflammatory effects of HSP90 inhibitors, tacrolimus and cyclosporine, are manifested, among other factors, due to their participation in the formation of an active ligand–receptor complex of P4 and their interaction with its constituent immunophilins. Pharmacological agents such as HSP90 inhibitors can restore the lost anti-inflammatory effect of glucocorticoids and P4 in chronic inflammatory and autoimmune diseases. By regulating the activity of FKBP51 and FKBP52, it is possible to increase or decrease hormonal signaling, as well as restore it during the development of hormone resistance. The combined action of immunophilin suppressors with steroid hormones may be a promising strategy in the treatment of chronic inflammatory and autoimmune diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages. Presumably, the hormone receptor- and immunophilin-targeted drugs may act synergistically, allowing for a lower dose of each.

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“…For Aim 1, our pilot longitudinal study among women treated with DMPA, LNG-IUD, and ENG-implant provided estimates utilized in sample size calculation. The pilot study evaluated CVL CCR5 levels at four different time points (two visits pre-contraceptive, two visits postcontraceptive) with n = 148 total visits [76]. At the precontraceptive time point, 23.0% (SD 16.1) of CVL CD4 + T-cells expressed CCR5.…”

Section: Power/sample Sizementioning

confidence: 99%

Evaluating the impact of three progestin-based hormonal contraceptive methods on immunologic changes in the female genital tract and systemically (CHIME Study): a prospective cohort study protocol

et al. 2022

Self Cite

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Background Gonadal hormones can modify immune function, which may impact susceptibility to infectious diseases, including Human Immunodeficiency Virus (HIV). There is limited knowledge about how hormonal contraceptives (HC) influence the immune response during the course of use. The CHIME study aims to evaluate the effect of long-acting progestin-based hormonal contraceptives (depot medroxyprogesterone acetate, etonogestrel implant, and levonorgestrel intrauterine device) on immunologic changes in the female genital tract (FGT) and systemic compartment. Methods CHIME is an observational cohort study where participants attend 2 visits prior to initiating the HC method of their choice, and then attend 6 visits over 12 months with biological sampling (vaginal swabs, cervicovaginal lavage, cytobrush and blood) for immunological, bacteriological, and virological analyses at each visit. Immune profiling will be evaluated by multi-color flow cytometry to determine how different T-cell subsets, in particular the CD4 T-cell subsets, change during the course of contraceptive use and whether they have different profiles in the FGT compared to the systemic compartment. The study aims are (1) to characterize the alterations in FGT and systemic immune profiles associated with three long-acting progestin-only HC and (2) to evaluate the vaginal microenvironment, determined by 16 s rRNA sequencing, as an individual-level risk factor and moderator of genital and systemic immune profile changes following exposure to three commonly used HC. Data collection started in March 2019 and is scheduled to be completed in October 2024. Discussion The CHIME study aims to contribute to the body of research designed to evaluate the comparative impact of three long-acting progestin-only HC on innate and adaptive immune functions to understand how immunologic effects alter STI and HIV susceptibility.

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Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood

Cited by 11 publications

References 68 publications

Genital inflammatory status and the innate immune response to contraceptive initiation

Genital inflammatory status and the innate immune response to contraceptive initiation

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

Evaluating the impact of three progestin-based hormonal contraceptive methods on immunologic changes in the female genital tract and systemically (CHIME Study): a prospective cohort study protocol

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