Safety of treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate

Jacques Donnez, Olivier Donnez, Marie-Madeleine Dolmans

Abstract


Introduction: During the last decade, there has been increased emphasis on the role of progesterone in the promotion of fibroid growth, as well as heightened interest in modulating progesterone pathways by use of selective progesterone receptor modulators. Among them, ulipristal acetate (UPA) has proved its efficacy in the management of symptomatic myomas by controlling bleeding and inducing amenorrhea, and reducing the size of myomas in the majority of cases.

Areas covered: In this review, we summarize published scientific studies exploring evidence of the safety of selective progesterone receptor modulators and particularly UPA, a drug approved for the management of symptomatic uterine fibroids. We focus essentially on endometrial changes induced by UPA, and also evaluate other safety outcomes.

Expert opinion: Data from published reports of randomized controlled trials over 5 years have demonstrated that UPA does indeed induce endometrial changes (known as progesterone receptor modulator-associated endometrial changes), but they have been shown to be both benign and reversible.

Novel algorithms published very recently provide an extensive overview that may be considered as the latest expert opinion. Thus, in infertile women of reproductive age, two courses of 3 months of UPA are recommended in case of type 2 myomas or multiple myomas distorting the uterine cavity. Subsequent therapy is determined depending on the response and restoration of the uterine cavity. If there is no desire for pregnancy, long-term (four courses) intermittent therapy may be initiated. In case of a good response, treatment is stopped and restarted only if symptoms recur. In premenopausal women wishing to preserve their uterus, four courses of 3 months is the proposed strategy.

Contraindications to prescribing UPA include pregnancy, breastfeeding, genital bleeding of unknown etiology of origin other than uterine fibroids, and presence of uterine, cervical, ovarian, or breast cancer.


Keywords


uterine fibroids; selective progesterone receptors modulators; ulipristal acetate; safety; progesterone receptor modulator-associated endometrial changes

References


Kim, J.J., Sefton, E.C. “The role of progesterone signaling in the pathogenesis of uterine leiomyoma.” Mol Cell Endocrinol 358.2 (2012): 223–31.

Donnez, J., Dolmans, M.M. “Uterine fibroid management: from the present to the future.” Hum Reprod Update 22.6 (2016): 665–86.

Biglia, N., Carinelli, S., Maiorana, A., et al. “Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids.” Drug Des Devel Ther 20.8 (2014): 285–92.

Chabbert-Buffet, N., Meduri, G., Bouchard, P., et al. “Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications.” Hum Reprod Update 11 (2005): 293–307.

Nieman, L.K., Blocker, W., Nansel, T., et al. “Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study.” Fertil Steril 95.2 (2011): 767–72.

Donnez, J., Tatarchuk, T.F., Bouchard, P., et al., PEARL I study group. “Ulipristal acetate versus placebo for fibroid treatment before surgery.” N Engl J Med 2.366 (2012): 409–20.

Donnez, J., Tomaszewski, J., Vázquez, F., et al., PEARL II study group. “Ulipristal acetate versus leuprolide acetate for uterine fibroids.” N Engl J Med 2.366 (2012): 421–32.

Donnez, J., Vázquez, F., Tomaszewski, J., et al. “Long-term treatment of uterine fibroids with ulipristal acetate.” Fertil Steril 101 (2014): 1565–73.

Donnez, J., Hudecek, R., Donnez, O., et al. “Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids.” Fertil Steril 103.5 (2015): 519–27.

Donnez, J., Donnez, O., Matule, D., et al. “Long-term medical management of uterine fibroids with ulipristal acetate.” Fertil Steril 105 (2016): 165–73.

Donnez, J., Arriagada, P., Donnez, O., et al. “Current management of myomas: the place of medical therapy with the advent of selective progesterone receptor modulators.” Curr Opin Obstet Gynecol 27 (2015): 422–31.

Bouchard, P., Chabbert-Buffet, N., Fauser, B.C. “Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety.” Fertil Steril 96 (2011): 1175–89.

Courtoy, G.E., Donnez, J., Marbaix, E., et al. “In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment.” Fertil Steril 104 (2015): 426–34.

Mutter, G.L., Bergeron, C., Deligdisch, L., et al. “The spectrum of endometrial pathology induced by progesterone receptor modulators.” Mod Pathol 21 (2008): 591–8.

Horne, F.M., Blithe, D.L. “Progesterone receptor modulators and the endometrium: changes and consequences.” Hum Reprod Update 13 (2007): 567–80.

Williams, A.R., Critchley, H.O., Osei, J., et al. “The effects of the selective progesterone receptor modulator asoprisnil on themorphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata.” Hum Reprod 22 (2007): 1696–1704.

Williams, A.R., Bergeron, C., Barlow, D.H., et al. “Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate.” Int J Gynecol Pathol 31 (2012): 556–69.

Fauser, B., Donnez, J., Bouchard, P., et al. “Safety after extended repeated use of ulipristal acetate for uterine fibroids.” Obst Gynecol Submitted (2016).

Chantraine, F., Poismans, G., Nwachuku, J., et al. “Expulsion of a uterine myoma in a patient treated with ulipristal acetate.” Clin Case Rep 3 (2015): 240–2.

Willame, A., Marci, R., Petignat, P., et al. “Myoma migration: an unexpected “effect” with ulipristal acetate treatment.” Eur Rev Med Pharmacol Sci 20 (2016): 1439–44.

Farquhar, C.M., Lethaby, A., Sowter, M., et al. “An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding.” Am J Obstet Gynecol 181 (1999): 525–29.

Anastasiadis, P.G., Skaphida, P.G., Koutlaki, N.G., et al. “Descriptive epidemiology of endometrial hyperplasia in patients with abnormal uterine bleeding.” Eur J Gynaecol Oncol 21 (2000): 131–4.

Chabbert-Buffet, N., Pintiaux-Kairis, A., Bouchard, P.; VA2914 Study Group. “Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial.” J Clin Endocrinol Metab 92 (2007): 3582–9.

Chabbert-Buffet, N., Pintiaux, A., Bouchard, P. “The immninent dawn of SPRMs in obstetrics and gynecology.” Mol Cel Endocrinol 2 (2012): 21.

Spitz, I.M. “Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century.” Contraception 82 (2010): 442–52.

Munro, M.G., Critchley, H.O., Broder, M.S., et al. “FIGO classification system (PALM- COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. FIGO working group on menstrual disorders.” Int J Gynaecol Obstet 113 (2011): 1–2.

Huang, Y., Jensen, J.T., Brache, V., et al. “A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free method of contraception.” Contraception 90 (2014): 565–74.


GOST Style Citations


1. Kim, J.J., Sefton, E.C. “The role of progesterone signaling in the pathogenesis of uterine leiomyoma.” Mol Cell Endocrinol 358.2 (2012): 223–31.

2. Donnez, J., Dolmans, M.M. “Uterine fibroid management: from the present to the future.” Hum Reprod Update 22.6 (2016): 665–86.

3. Biglia, N., Carinelli, S., Maiorana, A., et al. “Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids.” Drug Des Devel Ther 20.8 (2014): 285–92.

4. Chabbert-Buffet, N., Meduri, G., Bouchard, P., et al. “Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications.” Hum Reprod Update 11 (2005): 293–307.

5. Nieman, L.K., Blocker, W., Nansel, T., et al. “Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study.” Fertil Steril 95.2 (2011): 767–72.

6. Donnez, J., Tatarchuk, T.F., Bouchard, P., et al., PEARL I study group. “Ulipristal acetate versus placebo for fibroid treatment before surgery.” N Engl J Med 2.366 (2012): 409–20.

7. Donnez, J., Tomaszewski, J., Vázquez, F., et al., PEARL II study group. “Ulipristal acetate versus leuprolide acetate for uterine fibroids.” N Engl J Med 2.366 (2012): 421–32.

8. Donnez, J., Vázquez, F., Tomaszewski, J., et al. “Long-term treatment of uterine fibroids with ulipristal acetate.” Fertil Steril 101 (2014): 1565–73.

9. Donnez, J., Hudecek, R., Donnez, O., et al. “Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids.” Fertil Steril 103.5 (2015): 519–27.

10. Donnez, J., Donnez, O., Matule, D., et al. “Long-term medical management of uterine fibroids with ulipristal acetate.” Fertil Steril 105 (2016): 165–73.

11. Donnez, J., Arriagada, P., Donnez, O., et al. “Current management of myomas: the place of medical therapy with the advent of selective progesterone receptor modulators.” Curr Opin Obstet Gynecol 27 (2015): 422–31.

12. Bouchard, P., Chabbert-Buffet, N., Fauser, B.C. “Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety.” Fertil Steril 96 (2011): 1175–89.

13. Courtoy, G.E., Donnez, J., Marbaix, E., et al. “In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment.” Fertil Steril 104 (2015): 426–34.

14. Mutter, G.L., Bergeron, C., Deligdisch, L., et al. “The spectrum of endometrial pathology induced by progesterone receptor modulators.” Mod Pathol 21 (2008): 591–8.

15. Horne, F.M., Blithe, D.L. “Progesterone receptor modulators and the endometrium: changes and consequences.” Hum Reprod Update 13 (2007): 567–80.

16. Williams, A.R., Critchley, H.O., Osei, J., et al. “The effects of the selective progesterone receptor modulator asoprisnil on themorphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata.” Hum Reprod 22 (2007): 1696–1704.

17. Williams, A.R., Bergeron, C., Barlow, D.H., et al. “Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate.” Int J Gynecol Pathol 31 (2012): 556–69.

18. Fauser, B., Donnez, J., Bouchard, P., et al. “Safety after extended repeated use of ulipristal acetate for uterine fibroids.” Obst Gynecol Submitted (2016).

19. Chantraine, F., Poismans, G., Nwachuku, J., et al. “Expulsion of a uterine myoma in a patient treated with ulipristal acetate.” Clin Case Rep 3 (2015): 240–2.

20. Willame, A., Marci, R., Petignat, P., et al. “Myoma migration: an unexpected “effect” with ulipristal acetate treatment.” Eur Rev Med Pharmacol Sci 20 (2016): 1439–44.

21. Farquhar, C.M., Lethaby, A., Sowter, M., et al. “An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding.” Am J Obstet Gynecol 181 (1999): 525–29.

22. Anastasiadis, P.G., Skaphida, P.G., Koutlaki, N.G., et al. “Descriptive epidemiology of endometrial hyperplasia in patients with abnormal uterine bleeding.” Eur J Gynaecol Oncol 21 (2000): 131–4.

23. Chabbert-Buffet, N., Pintiaux-Kairis, A., Bouchard, P.; VA2914 Study Group. “Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial.” J Clin Endocrinol Metab 92 (2007): 3582–9.

24. Chabbert-Buffet, N., Pintiaux, A., Bouchard, P. “The immninent dawn of SPRMs in obstetrics and gynecology.” Mol Cel Endocrinol 2 (2012): 21.

25. Spitz, I.M. “Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century.” Contraception 82 (2010): 442–52.

26. Munro, M.G., Critchley, H.O., Broder, M.S., et al. “FIGO classification system (PALM- COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. FIGO working group on menstrual disorders.” Int J Gynaecol Obstet 113 (2011): 1–2.

27. Huang, Y., Jensen, J.T., Brache, V., et al. “A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free method of contraception.” Contraception 90 (2014): 565–74.





DOI: http://dx.doi.org/10.18370/2309-4117.2017.33.59-67

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