A NEWLY-APPROVED SELECTIVE PROGESTERONE RECEPTOR MODULATOR

Update

12/30/2010: ELLA: A NEWLY-APPROVED SELECTIVE PROGESTERONE RECEPTOR MODULATOR

Stephen R. Hammes Division of Endocrinology & Metabolism, Department of Medicine, University of Rochester School of Medicine & Dentistry Laurence L. Brunton Professor of Pharmacology and Medicine, Department of Pharmacology, University of California San Diego School of Medicine Related To: Chapter 57. Estrogens and Progestins View in chapter The FDA has recently approved ulipristal for post-coital contraception. Ulipristal could be considered “Plan C”, similar in overall effect to the current “Plan B”, mifepristone. Ulipristal can inhibit follicular rupture when administered prior to ovulation (Brache et al, 2010) and is effective post-coitally in preventing pregnancy (Fine et al, 2010; Glasier et al, 2010). The clinical studies with ulipristal have raised some questions about the drug’s equivalence to existing medications (Page and Verhaeghe, 2010) and prompted an interesting discussion of the ethics of including a placebo-control in a study of efficacy of a drug such as this one (Glasier and Gainer, 2010). As may be expected, ulipristal has also provoked an adverse reaction in the United States by opponents of the termination of pregnancy. Ulipristal is included in the recently published 12th edition ofGoodman & Gilman's The Pharmacological Basis of Therapeutics. (Chapter 40, Estrogens and Progestins) Chemistry. Ulipristal (PubChem CID: 130904) is another derivative of 19-norprogesterone (PubChem CID: 95585) that functions as a selective progesterone receptor modulator (SPRM) with both agonistic and antagonistic effects on the progesterone receptor. Ulipristal has the same dimethyl-aminophenol group at the 11b position as seen in mifepristone (PubChem CID: 55245) with an additional acetoxy group at position 17. Unlike mifepristone, ulipristal appears to be a relatively weak glucocorticoid antagonist. Pharmacological Actions. Ulipristal is known to have anti-proliferative effects in the uterus at high doses; however, its most relevant actions to date are its ability to inhibit ovulation. While still not clear, ulipristal’s anti-ovulatory actions likely occur due to progesterone regulation at many levels, including inhibition of LH release through the hypothalamus and pituitary, as well as inhibition of LH-induced follicular rupture within the ovary. Dosing. A 30 mg dose of ulipristral can inhibit ovulation when taken up to five days after intercourse. In fact, ulipristal can block ovarian rupture at or even just after the time of the LH surge, confirming that at least part of its effects are directly in the ovary. Ulipristal may also block endometrial implantation of the fertilized egg, although whether this contributes to its ability to function as an emergency contraceptive (see below) is not clear. Therapeutic Uses. Ulipristal acetate, which is sold as ella and ellaOne, has recently been licensed in Europe and the United States as an emergency contraceptive. Studies comparing ulipristal to levonorgestrel (progesterone-only emergency contraception, or POEC) have found that ulipristal is at least as effective when taken up to 72 hours after unprotected sexual intercourse. Most importantly, while levonorgestrel does not work well beyond 72 hours after unprotected intercourse, ulipristal remains effective up to 120 hours (5 days) after intercourse, making ulipristal a more versatile emergency contraceptive. The most severe side effect in clinical trials using ulipristal has been a self-limited headache and some abdominal pain. The drug should not be taken by women who are breastfeeding or who are pregnant and wish to remain so. REFERENCES Brache V, Cochon L, Jesam C, et al. Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture. Hum Reprod 2010;25:2256-63. [PMID: 20634186] Fine P, Mathé H, Ginde S, et al. Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception. Obstet Gynecol 2010;115:257-63. [PMID: 20093897] Glasier A, Gainer E. Correspondence: Ulipristal acetate for emergency contraception? Authors’ reply. Lancet 2010;375:1608. [PMID: 20452518] Glasier AF, Cameron ST, Fine PM, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet 2010;375: 555-562. [PMID: 20116841] Page GH, Verhaeghe V. Correspondence: Ulipristal acetate for emergency contraception? Lancet 2010;375:1608. [PMID: 20452519]

Hammes Stephen R, Brunton Laurence L, "ella: a Newly-Approved Selective Progesterone Receptor Modulator" (Update). Laurence L. Brunton, John S. Lazo, Keith L. Parker: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11e: http://www.accesspharmacy.com.ezp.imu.edu.my/updatesContent.aspx?aid=1001699.