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Exploring Morphologic and Molecular Aspects of Endometrial Cancer Under Progesterone Treatment in the Context of Fertility Preservation
  1. Mignon D.J.M. van Gent, MD*,
  2. Alina R. Nicolae-Cristea, MD,
  3. Cor D. de Kroon, MD, PhD*,
  4. Elisabeth M. Osse, BASc,
  5. Marjolein J. Kagie, MD, PhD,
  6. J. Baptist M.Z. Trimbos, MD, PhD*,
  7. Hans Marten Hazelbag, MD, PhD§,
  8. Vincent T.H.B.M. Smit, MD, PhD and
  9. Tjalling Bosse, MD, PhD
  1. *Departments of Gynaecology and
  2. Departments of Pathology, Leiden University Medical Center, Leiden; and Departments of
  3. Departments of Gynaecology and
  4. §Departments of Pathology, Medical Center Haaglanden, The Hague, The Netherlands.
  1. Address correspondence and reprint requests to Mignon D.J.M. van Gent, MD, Department of Gynaecology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail:


Objective The standard treatment of early-stage (FIGO [International Federation of Gynecology and Obstetrics] I) endometrioid endometrial cancer (EEC) is hysterectomy with bilateral salpingo-oophorectomy. An alternative approach for younger women with low-grade EEC who wish to preserve fertility may be hormonal treatment. Previous studies have suggested that progesterone may elicit its antitumor effect in EEC by interacting with the Wingless (Wnt) and/or phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Therefore, we explored whether common activating genetic alterations in Wnt and PI3K/Akt signaling correlated with nonresponsiveness to progesterone therapy for low-grade EEC. In addition, we investigated whether benign morphology under progesterone treatment is accompanied by the absence of genetic changes.

Methods We analyzed molecular alterations in the Wnt and PI3K/Akt signaling in 84 serial endometrial samples from 11 premenopausal patients with progesterone receptor–positive low-grade EEC conservatively treated with progesterone and correlated these with histological and clinical follow-up.

Results There were 6 responders and 5 nonresponders to progesterone treatment. The response rate to progesterone treatment was 55%, and the relapse rate was 83%. All responders had alterations in both the Wnt and PI3K/Akt pathway before treatment. In the nonresponder group, tumors inconsistently showed alterations in none, 1, or both pathways. Normalization of the endometrium morphology under progesterone treatment is accompanied by the absence of the genetic changes found in the specimen before treatment.

Conclusions We found that activating molecular alterations in either Wnt or PI3K/Akt signaling pathways did not predict resistance to progesterone treatment. It seems that morphological response goes along with disappearance of the established mutations. This exploratory study suggests that Wnt or PI3K/Akt status is unable to predict response to progesterone treatment in patients with EEC.

  • Endometrial cancer
  • Conservative treatment
  • Molecular alterations
  • Progesterone treatment
  • Fertility preservation

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  • Mignon D.J.M. van Gent and Alina R. Nicolae-Cristea contributed equally.

  • Mignon D.J.M. van Gent is the recipient of a noncommercial grant from the Landsteiner Institute, Medical Center Haaglanden, The Hague, The Netherlands.

  • Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (