Hormonal Contraceptive Use, Cervical Ectopy, and the Acquisition of Cervical Infections

Morrison, Charles; Bright, Patricia; Wong, Emelita L.; Kwok, Cynthia; Yacobson, Irina; Gaydos, Charlotte A.; Tucker, H.; Blumenthal, Paul D.

doi:10.1097/01.olq.0000137904.56037.70

Cited by 100 publications

(75 citation statements)

References 26 publications

(32 reference statements)

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“…It is also noteworthy that there are data to indicate that progestin-based contraceptives increase the susceptibility of a woman to develop gonococcal disease (13,32,36). I have now similarly shown that Pg, in a dose-dependent manner, augments the ability of gonococci to invade and to survive within pex cells.…”

Section: Discussionmentioning

confidence: 54%

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Edwards

2010

Infect Immun

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Neisseria gonorrhoeae is an obligate human pathogen that causes gonorrhea. We have shown previously that complement receptor 3 and Akt kinase play important roles in mediating cervical infection. At present, there are limited data to indicate how hormonally induced changes to the mucosal epithelia of the female genital tract mediate the course of gonococcal disease. Hence, I have expanded upon previous work to investigate the interaction of gonococci with primary human cervical epithelial (pex) cells under the variable estrogen and progesterone concentrations likely to be encountered in vivo throughout the female menstrual cycle. My data indicated that the ability of gonococci to survive and to replicate within pex cells was increased under progesterone-predominant conditions. Using bacterial survival, immunological, and kinase assays, I show that progesterone functioned in an additive manner with gonococcal phospholipase D to augment Akt kinase activity. This, in turn, resulted in a parallel increase in nitric oxide synthase expression. Nitric oxide production by pex cells was dependent upon Akt activity and was increased under progesterone-predominant conditions. Whereas both inducible and endothelial nitric oxide synthase contributed to nitric oxide production, only inducible nitric oxide synthase activity promoted gonococcal survival within pex cells. Collectively, these data provide the first clues as to how steroid hormones potentially modulate the course of gonococcal disease in women. In addition, these data demonstrate that host-derived nitric oxide likely is not protective against gonococci, in vivo; rather, nitric oxide may be required to sustain cervical bacterial disease.Neisseria gonorrhoeae is an exclusive human pathogen that causes the sexually transmitted disease, gonorrhea. The gonococcus is highly human adapted and thus has developed variable mechanisms of pathogenesis that are, in part, dependent upon the site of infection (reviewed in reference 6). We have shown previously that complement receptor type 3 (CR3) serves as the key receptor by which gonococci initiate cervical infection in vivo, as well as ex vivo in primary human cervical epithelial (pex) cells (8). Gonococci exposed to pex cells release a group of proteins, including a phospholipase D (NgPLD), that facilitate cervical adherence and invasion (9).Invasion of certain epithelial cells by gonococci triggers (host) Akt activity (7, 31). Akt is a serine-threonine kinase implicated in diverse cellular functions, and several bacterial and viral pathogens have developed mechanisms by which to subvert Akt signaling to promote disease (7,22,26,28,53,56). In contrast to vulvular epidermal carcinoma (A-431) cells, in which gonococcus-induced Akt activity requires phosphatidylinositol 3-kinase (PI3K) (31), Akt activation in pex cells occurs independently of PI3K and results from the direct interaction of NgPLD with cervical Akt (7).Despite the many advances made in our understanding of gonococcal pathogenesis, the factors governing the diver...

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Section: Discussionmentioning

confidence: 54%

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Edwards

2010

Infect Immun

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“…16 DMPA usage has also been associated with increased acquisition of cervical chlamydial and gonococcal infections. 21 These STIs have also been linked to increased HIV-1 acquisition. Consistent with the clinical data, MPA increases susceptibility to vaginal simian-human immunodeficiency virus (SHIV) transmission and suppresses the antiviral cellular immune response in SHIV-infected rhesus macaques.…”

Section: Introductionmentioning

confidence: 99%

Differential Glucocorticoid Receptor‐Mediated Effects on Immunomodulatory Gene Expression by Progestin Contraceptives: Implications for HIV‐1 Pathogenesis

Hapgood

Ray

Govender

et al. 2014

American J Rep Immunol

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Whether hormonal contraceptives increase HIV‐1 acquisition, transmission and disease progression are critical questions. Clinical research has been hampered by a lack of understanding that different progestins used in contraception exhibit differential off‐target effects via steroid receptors other than the progesterone receptor. Of particular, relevance is the relative effects of medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET‐EN), widely used as injectable contraceptives in sub‐Saharan Africa. While most high‐quality clinical studies find no increased risk for HIV‐1 acquisition with oral contraception or injectable NET‐EN, most do find an increase with MPA, particularly in young women. Furthermore, mounting evidence from animal, ex vivo and biochemical studies are consistent with MPA acting to increase HIV‐1 acquisition and pathogenesis, via mechanisms involving glucocorticoid‐like effects on gene expression, in particular genes involved in immune function. We report that MPA, unlike NET and progesterone, represses inflammatory genes in human PBMCs in a dose‐dependent manner, via the glucocorticoid receptor (GR), at concentrations within the physiologically relevant range. These and published results collectively suggest that the differential GR activity of MPA versus NET may be a mechanism whereby MPA, unlike NET or progesterone, differentially modulates HIV‐1 acquisition and pathogenesis in target cells where the GR is the predominant steroid receptor expressed.

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“…Clinical and epidemiological evidence suggests that the use of MPA as a contraceptive may increase the risk of acquiring genital tract infections such as herpes simplex virus type (HSV)-2 (17), Chlamydia (18), gonorrhea (19), and HIV-1 (6, 20 -22). The lower female genital tract is the primary site of exposure to the majority of these sexually transmitted pathogens (23)(24)(25)(26).…”

mentioning

confidence: 99%

Medroxyprogesterone Acetate Differentially Regulates Interleukin (IL)-12 and IL-10 in a Human Ectocervical Epithelial Cell Line in a Glucocorticoid Receptor (GR)-dependent Manner

Toit

Hapgood

Africander

2014

Journal of Biological Chemistry

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Background:Little is known about the mechanism of action of MPA in the female genital tract. Results: GR mediates MPA-induced up-regulation of IL-12 and down-regulation of IL-10 mRNA and protein levels. Conclusion: MPA favors a pro-inflammatory milieu in ectocervical epithelial cells. Significance: MPA used in hormonal therapy may modulate inflammation in the ectocervical environment via this genomic mechanism.

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Hormonal Contraceptive Use, Cervical Ectopy, and the Acquisition of Cervical Infections

Abstract: DMPA use, but not OC use, appeared to be significantly associated with increased acquisition of cervical chlamydial and gonococcal infections.

Cited by 100 publications

References 26 publications

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Differential Glucocorticoid Receptor‐Mediated Effects on Immunomodulatory Gene Expression by Progestin Contraceptives: Implications for HIV‐1 Pathogenesis

Medroxyprogesterone Acetate Differentially Regulates Interleukin (IL)-12 and IL-10 in a Human Ectocervical Epithelial Cell Line in a Glucocorticoid Receptor (GR)-dependent Manner

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