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Cited by 77Uterine Myomas and TreatmentsReproductive Health and ContraceptionEstrogen and related hormone effects

Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium

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Whitaker, L.H.R., Murray, A.A., Matthews, R., Shaw, G., Williams, A.R.W., Saunders, P.T.K., Critchley, H.O.D.·2017·Human Reproduction
DOI 10.1093/humrep/dew359PMC PMC5400066
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Abstract

STUDY QUESTION: What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? SUMMARY ANSWER: UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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.

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  • AR is downregulated in stromal cells in the functional layer during the secretory phase and upregulated in epithelial cells when progesterone levels decline or in response to progesterone receptor antagonists/selective modulators.

    “AR is downregulated in stromal cells in the functional layer during the secretory phase and upregulated in epithelial cells when progesterone levels decline (functional withdrawal with demise of the corpus luteum) [28] or in response to administration of progesterone receptor antagonists/selective modulators [30].”

    From Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders (2018) · cites this paper as [30]

    The Results section (page unavailable) reports reduced stromal AR staining in secretory endometrium and intense epithelial AR staining after treatment with ulipristal acetate, a selective progesterone receptor modulator. The Discussion describes epithelial AR overexpression after that treatment, but the paper does not establish epithelial AR upregulation in response to progesterone receptor antagonists generally. (LLM, conf=0.82)

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Authors
Whitaker, L. H. R., Murray, A. A., Matthews, R., Shaw, G., Williams, A. R. W., Saunders, P. T. K., & Critchley, H. O. D.
Affiliations
  • MRC Centre for Reproductive Health (GB)
  • Edinburgh Royal Infirmary (GB)
  • Centre for Inflammation Research (GB)
Corresponding author
Critchley, H.O.D.
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2017-01-26
Volume
32
Issue
3
Pages
531-543
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/dew359
PMC
PMC5400066
OpenAlex
W2581546164
Cited by
77
References
1
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 13 · 2020: 12 · 2019: 11 · 2018: 13 · 2017: 8
FWCI
14.16
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Human Reproduction (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • National Institute for Health and Care Research (12/206/52)
  • Tenovus
  • Pakistan Atomic Energy Commission
  • Medical Research Council (MR/J003611/1, G1002033, MR/N024524/1, G1100356/1, MR/N022556/1)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
ulipristal acetate, selective progesterone receptor modulators, endometrium, uterine fibroids, progesterone receptor, androgen receptor, estrogen receptor alpha, endometrial proliferation, Ki-67, decidualization, endometrial receptivity, FOXO1
MeSH terms
Forkhead Box Protein O1, Homeobox A10 Proteins, Adult, Contraceptive Agents, Female, Endometrium, Female, Humans, Leiomyoma, Middle Aged, Norpregnadienes, Receptors, Progesterone, Stromal Cells, Homeodomain Proteins, Insulin-Like Growth Factor Binding Protein 1, Interleukin-15, Cell Proliferation, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins

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