Chemokine expression is dysregulated in the endometrium of women using progestin-only contraceptives and correlates to elevated recruitment of distinct leukocyte populations.
BACKGROUND
Breakthrough bleeding (BTB) is the most common reason for discontinuation of progestin-only (p-only) contraceptives, yet the causes are unknown. Use of p-only contraceptives is associated with elevated influx of endometrial leukocytes, similar to that observed perimenstrually or within decidualized endometrium. We hypothesized that chemokine expression is altered in women using p-only contraceptives, leading to abnormal leukocyte recruitment and BTB.


METHODS
Expression of eight highly abundant endometrial chemokines was examined using immunohistochemistry and real-time PCR, in endometria from women using subdermal and intrauterine levonorgestrel and correlated to leukocyte subpopulations.


RESULTS
Macrophage-derived chemokine (MDC), hemofiltrate CC chemokine-1 (HCC-1), monocyte chemoattractant protein-3 (MCP-3), interleukin-8 (IL-8) and eotaxin were strongly produced by epithelial glands, comparable to levels in premenstrual phase endometrium. Stromal cells were negative for chemokines in atrophic/shedding endometria, but intensely positive in highly decidualized tissues for MDC, MCP-3, HCC-1 and 6Ckine. Macrophage inflammatory protein-1beta (MIP-1b) and HCC-4 were suppressed in all p-exposed endometria.


CONCLUSIONS
These data demonstrate that chemokine expression is dysregulated in p-exposed endometria, consistent with the morphological appearance of the endometrium and the leukocyte subsets present. This reinforces a potential role for chemokines in the elevated leukocyte recruitment that contributes to endometrial fragility and BTB.
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Rebecca L
RL
Jones
Naomi B
NB
Morison
Natalie J
NJ
Hannan
Hilary O D
HO
Critchley
Lois A
LA
Salamonsen
D049109:Cell Proliferation; D054413:Chemokine CCL11; D054422:Chemokine CCL22; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D018925:Chemokines / Q000096:biosynthesis* / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D003270:Contraceptive Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016912:Levonorgestrel / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D011372:Progestins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
C515456:CCL11 protein, human; C481939:CCL16 protein, human; C515482:CCL22 protein, human; C515450:CCL7 protein, human; C515300:CCR1 protein, human; D054413:Chemokine CCL11; D054422:Chemokine CCL22; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D018925:Chemokines; D019742:Chemokines, CC; D003270:Contraceptive Agents; D016207:Cytokines; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D011372:Progestins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D016912:Levonorgestrel