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

Abstract

STUDY QUESTIONWhat is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids?SUMMARY ANSWERUPA 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 ALREADYAdministration 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, DURATIONObservational 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, METHODSStudy 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 CHANCEUPA 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 DATAN/A.LIMITATIONS REASONS FOR CAUTIONA 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 FINDINGSP 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...

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

“…However, in a murine model of myoma xenografts, PR expression was found to be unchanged after mifepristone treatment [31], probably thanks to the conferred protection against proteasomal degradation [37]. UPA treatment even increased PR expression in 2 models of breast cancer xenografts [38, 39], as well as in the Fallopian tubes [40] and normal endometrium [41-43]. Our results suggest that UPA does not downregulate PR expression in uterine myomas but instead may prevent the turnover required for their appropriate activity, thereby explaining the antagonist action of UPA.…”

Uterine fibroid management: Today and tomorrow

“…). Despite a number of recent hypotheses, it is not known exactly how SPRMs alleviate menstrual bleeding …”

“…4). Despite a number of recent hypotheses, 24 it is not known exactly how SPRMs alleviate menstrual bleeding. 25 Ulipristal acetate (UPA) has been studied in four large randomized controlled trials (RCTs).…”

The use of selective progestin receptor modulators (SPRMs) and more specifically ulipristal acetate in the practice of gynaecology

“…Abnormal stromal vessels are commonly observed . Apart from PEAC, Whitaker et al . noted a striking change in expression patterns of progesterone and androgen receptors compared with either proliferative or secretory phase samples of historical controls.…”

“…Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared to those in the proliferative phase. The authors proposed that these data should motivate the development of the SPRM as a long‐term medical therapy for heavy menstrual bleeding . Finally, PEAC changes may also occur anecdotally in ectopic endometrium …”