title: Steroid receptor expression in late follicular phase endometrium in GnRH antagonist IVF cycles is already altered, indicating initiation of early luteal phase transformation in the absence of secretory changes.
abstract: BACKGROUND
  Ovarian stimulation for IVF profoundly alters the early luteal phase endometrial development. It has been hypothesized that this process has already started in the late follicular phase, as the endometrium has already been exposed to high steroid concentrations since that phase. The aim of the present study was to prospectively investigate the effect of multi-follicular ovarian stimulation for IVF on the late follicular phase endometrium histology and the expression of estrogen receptor (ER) and progesterone receptor (PR).
  
  
  METHODS
  In a cross-over study, 11 infertile women with normal ovulatory function, participating in an IVF programme and treated with GnRH antagonist/recombinant FSH ovarian stimulation, were enrolled in the study. Endometrial biopsies were taken in a natural cycle on the day of the onset of the surge of the LH, and in a subsequent stimulation cycle on the day of hCG administration for final oocyte maturation. Endometrial histological dating was carried out according to Noyes' criteria. Immunohistochemistry was performed, using commercially available antibodies for ER and PR endometrial expression. The immunohistochemical signal was recorded in 1000 epithelial cells in each compartment (glands and stroma). Endometrial expression for each of the two receptors was graded on a scale of 0-3, based on the intensity of nuclear staining. Then a score range between 0 and 3000 was recorded, and expressed as a mean score per 1000 stroma or glandular cells per sample (range: 0-3).
  
  
  RESULTS
  Histological examination of biopsies both in natural and stimulated cycles showed no secretory changes. However, in stimulated cycles, PR expression was significantly up-regulated compared to natural cycles in both glands (1.67 versus 1.34, P < 0.05) and stroma (1.98 versus 1.62, P < 0.05), whereas ER was down-regulated in glands (1.15 versus 1.43, P < 0.05). In IVF cycles, the progesterone measurements, although within normal values (range 0.8-1.4 microg/l), were significantly higher than in natural cycles (0.99 vs 0.63 microg/l, respectively, P = 0.008). An ongoing pregnancy rate of 37.5% was achieved in the stimulated cycles.
  
  
  CONCLUSIONS
  Although the current study found no early secretory transformation in stimulated endometria before hCG administration, the ER and PR expression in these endometria is similar to the one described during the first days of the luteal phase in natural cycles. Supraphysiological concentrations of estradiol and subtle progesterone rises in the late follicular phase might be responsible for this modulated steroid receptor profile. This phenomenon indicates accentuated maturation of the endometrium in IVF cycles from the pre-ovulatory phase onwards.
authors.affiliation: University Hospital, Dutch-speaking Brussels Free University, AZ-VUB, Centre for Reproductive Medicine, Laarbeeklaaan 101, 1090 Jette, Brussels, Belgium. Evangelos.Papanikolaou@vub.ac.be
authors.forename: Evangelos G
authors.initials: EG
authors.lastname: Papanikolaou
authors.forename: Claire
authors.initials: C
authors.lastname: Bourgain
authors.forename: Efstratios
authors.initials: E
authors.lastname: Kolibianakis
authors.forename: Herman
authors.initials: H
authors.lastname: Tournaye
authors.forename: Paul
authors.initials: P
authors.lastname: Devroey
mesh_terms: D000328:Adult; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D004717:Endometrium / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D005640:Follicle Stimulating Hormone / Q000627:therapeutic use; D005498:Follicular Phase / Q000187:drug effects / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008183:Luteal Phase / Q000187:drug effects / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood; D010062:Ovulation Induction / Q000379:methods; D011247:Pregnancy; D011256:Pregnancy Outcome; D018873:Pregnancy Rate; D011446:Prospective Studies; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values
chemical_list: D006063:Chorionic Gonadotropin; D011987:Receptors, Steroid; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone