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Hum. Reprod. Advance Access published online on November 8, 2006
Human Reproduction, doi:10.1093/humrep/del398
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received July 7, 2006
Revised August 22, 2006
Accepted September 11, 2006

Article

Endometrial expression of epithelial neutrophil-activating peptide-78 during the menstrual cycle or in progestin-only contraceptive users with breakthrough bleeding and the influence of doxycycline therapy

N. Chegini 1 *, X. Luo 1, Q. Pan 1, A. Rhoton-Vlasak 1, and D.F. Archer 2

1 Department of Obstetrics/Gynecology, University of Florida, Gainesville, FL, USA
2 Department of Obstetrics/Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA

* To whom correspondence should be addressed.
N. Chegini, E-mail: cheginin{at}obgyn.ufl.edu


  Abstract

BACKGROUND: Endometrial breakthrough bleeding is characterized by an inflammatory reaction and increased production of proinflammatory mediators, one of which may be epithelial neutrophil-activating peptide-78 (ENA-78), a chemokine with neutrophil-activating properties. METHODS AND RESULTS: We therefore investigated the endometrial expression of ENA-78 in Norplant users as progestin-only contraceptive with various bleeding patterns (n = 35) as compared with non-users with a normal menstrual cycle (n = 55). The endometrial stromal cells (ESCs) were the major site of ENA-78 expression with the highest levels found during the secretory phase. The expression of ENA-78 was increased in Norplant users with irregular bleeding as compared with those with regular cycles and amenorrhoea. The levels of ENA-78 detected in uterine washes and sera after the use of Norplant for 3-6 months (n = 25) increased compared with baseline (P < 0.05). These levels did not significantly change in Norplant users who received doxycycline (Dox) therapy (25 mg/twice daily for 6 months) when measured midway through or at the conclusion of study when compared with the baseline (n = 25). Treatments with medroxyprogesterone acetate (MPA) and tumour necrosis factor-{alpha} (TNF-{alpha}) (25 ng/ml), but not 17{beta}-estradiol (E2) or E2 + MPA (10-8 M), representing endometrium exposed to contraceptive and inflammatory conditions, respectively, increased the levels of ENA-78 production by ESCs, and this was reduced by co-treatments with Dox (25 µg/ml) (P < 0.05). CONCLUSIONS: The endometrial production of ENA-78 is altered in progestin-only contraceptive users experiencing breakthrough bleeding and is regulated by MPA and TNF-{alpha} in ESCs. Although Dox therapy did not alter uterine ENA-78 secretion, its suppression in ESCs suggests that Dox, acting site-specifically and through an anti-inflammatory mechanism, may influence the outcome of breakthrough bleeding in contraceptive users.

Keywords: endometrium/ENA-78/doxycycline/ovarian steroids/uterine bleeding.
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