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Hum. Reprod. Advance Access originally published online on September 29, 2006
Human Reproduction 2006 21(12):3146-3156; doi:10.1093/humrep/del180
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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

Endometrial expression of the estrogen-sensitive genes MMP-26 and TIMP-4 is altered by a substitution protocol without down-regulation in IVF patients

R. Pilka1,2, I. Oborna1, V. Lichnovsky3, P. Havelka3, H. Fingerova1, P. Eriksson4, S. Hansson2 and B. Casslén2,5

1 Department of Obstetrics and Gynaecology, Palacky University, Olomouc, Czech Republic 2 Department of Obstetrics and Gynaecology, University Hospital, Lund, Sweden 3 Department of Histology and Embryology, Palacky University, Olomouc, Czech Republic and 4 Atherosclerosis Research Unit, King Gustav V Research Institute, Karolinska Hospital, Stockholm, Sweden

5 To whom correspondence should be addressed at: Biomedical centre C 14, Lund, S-221 84 Sweden. E-mail: bertil.casslen{at}gyn.lu.se

BACKGROUND: The aim of this study was to analyse the effects of an estradiol (E2)–progesterone substitution protocol on the endometrial expression of estrogen-sensitive genes during the peri-implantation period. METHODS: Peripheral blood and endometrial biopsies were obtained from 13 infertile women both in a natural cycle (NC), on days 5 and 7 after ovulation (NC5, NC7), and in an artificial (substituted) cycle (AC), on days 5 and 7 of progesterone addition (AC5, AC7). Estrogen receptor-{alpha} (ER{alpha}) and progesterone receptor (PR) were assayed by immunohistochemistry. Matrix metalloproteinase-26 (MMP-26) mRNA and tissue inhibitor of metalloproteinase-4 (TIMP-4) mRNA were semiquantitatively assessed in tissue sections using in situ hybridization (ISH) and quantified in tissue extracts using real-time PCR. RESULTS: Levels of both E2 and progesterone were higher in the peripheral blood in AC than in NC. Also on day AC5, expressions of ER{alpha}, PR and MMP-26 mRNA (focally) were increased in the epithelium and TIMP-4 mRNA in the stroma. Expression levels of these genes dropped significantly between AC5 and AC7, but not between NC5 and NC7. Abnormally high levels in AC5 samples suggest overstimulation with E2, and the rapid decrease between AC5 and AC7 suggests overstimulation with progesterone. CONCLUSIONS: In ACs, increased levels of E2 in the blood exaggerate the endometrial expression of estrogen-sensitive genes, whereas higher levels of progesterone in the blood in the secretory phase exaggerate the drop in expression of these genes. Dramatic variations in the gene expression may not be optimal for the implantation process.

Key words: estrogen/implantation/mRNA/progesterone receptor/regulation


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