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Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone

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Abstract

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (PRM), which is used as an emergency contraceptive in women. Recent studies demonstrated the efficacy of an UPA contraceptive vaginal ring (UPA-CVR) as a blocker of ovulation. However, the endometrium of women exposed to UPA over a 6-month period display glandular changes, termed PRM-associated endometrial changes (PAECs). We, therefore, investigated whether UPA-induced PAECs are associated with altered expression of the transcription factor heart- and neural crest derivatives-expressed protein 2 (HAND2) whose downregulation is observed in endometrial epithelial hyperplasia and cancer. Our results showed that while exposure to mifepristone, a well-known PRM, leads to suppression of endometrial HAND2 expression, long-term exposure to UPA-CVR did not cause downregulation of this marker. Further studies, using human primary endometrial stromal cells, confirmed that whereas mifepristone-mediated suppression of HAND2 elevated the levels of its downstream target fibroblast growth factor 18, UPA did not significantly alter the expression of this growth factor. A rationale for the differential regulation of HAND2 by these PRMs was provided by our observation that mifepristone-bound progesterone receptors turn over at a faster rate than those bound to UPA. Collectively, these results support the selective effects of different PRMs and indicate that chronic exposure to UPA does not alter the HAND2 pathway whose dysregulation is linked to complex atypical endometrial hyperplasia and cancer. The results from this study involving a limited number of clinical samples should pave the way for a larger study to determine the safety of UPA for long-term use.

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Authors and Affiliations

  1. Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Athilakshmi Kannan PhD, Arpita Bhurke MS & Indrani C. Bagchi PhD

  2. Center for Biomedical Research, Population Council, New York, NY, USA

    Regine Sitruk-Ware MD

  3. Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden

    Parameswaran G. Lalitkumar PhD & Kristina Gemzell-Danielsson MD

  4. Department of Pathology, University of Edinburgh, Edinburgh, Scotland

    Alistair R. W. Williams MD

  5. Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Robert N. Taylor MD, PhD

  6. Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Milan K. Bagchi PhD

Authors
  1. Athilakshmi Kannan PhD
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  2. Arpita Bhurke MS
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  3. Regine Sitruk-Ware MD
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  4. Parameswaran G. Lalitkumar PhD
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  5. Kristina Gemzell-Danielsson MD
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  6. Alistair R. W. Williams MD
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  7. Robert N. Taylor MD, PhD
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  8. Milan K. Bagchi PhD
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  9. Indrani C. Bagchi PhD
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Corresponding author

Correspondence to Indrani C. Bagchi PhD.

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Kannan, A., Bhurke, A., Sitruk-Ware, R. et al. Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone. Reprod. Sci. 25, 320–328 (2018). https://doi.org/10.1177/1933719117746764

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  • DOI: https://doi.org/10.1177/1933719117746764

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