title: Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.
abstract: What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids?
  
  
  
  UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation.
  
  
  
  Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking.
  
  
  
  Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9-12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38-52 with fibroids were derived from institutional tissue archives.
  
  
  
  Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67.
  
  
  
  UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase.
  
  
  
  N/A.
  
  
  
  A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined.
  
  
  
  P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding.
  
  
  
  H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: L H R
authors.initials: LH
authors.lastname: Whitaker
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Murray
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: R
authors.initials: R
authors.lastname: Matthews
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: G
authors.initials: G
authors.lastname: Shaw
authors.affiliation: Division of Pathology, The University of Edinburgh, The Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK.
authors.forename: A R W
authors.initials: AR
authors.lastname: Williams
authors.affiliation: MRC Centre for Inflammation Research, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: P T K
authors.initials: PT
authors.lastname: Saunders
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: H O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D004717:Endometrium / Q000187:drug effects*; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D007889:Leiomyoma / Q000378:metabolism*; D008875:Middle Aged; D009649:Norpregnadienes / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003271:Contraceptive Agents, Female; D000071161:Forkhead Box Protein O1; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D019409:Interleukin-15; D009649:Norpregnadienes; D011980:Receptors, Progesterone; C498765:HAND2 protein, human; C032231:IGFBP1 protein, human; C069634:HOXA10 protein, human; C555622:ulipristal acetate
keywords: androgen receptor; endometrium; estrogen receptor; progesterone receptor; progesterone-regulated genes; proliferation; selective progesterone receptor modulator (SPRM)