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Medical Options for Uterine Fibroids in the Context of Reproduction
Published in Botros R.M.B. Rizk, Yakoub Khalaf, Mostafa A. Borahay, Fibroids and Reproduction, 2020
Hoda Elkafas, Mona Al Helou, Qiwei Yang, Ayman Al-Hendy
The SPRM family includes mifepristone (the first member of this family), asoprisnil, onapristone, ulipristal acetate (UPA), lonaprisan, vilaprisan, and telapristone. These SPRMs have been investigated in clinical studies for various women's health conditions [36]. These ligands have different actions based on PR selectivity and the degree of progesterone agonist activity in vivo [37,38]. Those compounds have been evaluated in women with HMB and uterine fibroids [39], and SPRMs were capable of shrinking uterine fibroid volume by 17%–57% and reducing uterine mass by 9%–53% [25]. Unlike GnRH agonists, SPRMs lack the hypoestrogenic effect and the bone mineral density (BMD) loss. The recurrence of uterine fibroids is reduced up to 6 months, even by stopping treatment with SPRMs [40]. Cochrane review on SPRMs highlighted the improvement of the patient's quality of the life undergoing treatment with SPRMs for 3 months by reducing HMB, decrease uterine fibroid size and reduce the uterine volume compared with placebos group [41].
Medical management of endometriosis
Published in Seema Chopra, Endometriosis, 2020
Selective progesterone receptor modulators (SPRMs) are novel ligands with the potential of greater flexibility and efficacy to interact with progesterone receptors to block or modify downstream effects. They exhibit agonistic or mixed or antagonistic effects based on target tissue and presence of progesterone receptors. They induce atrophy of the endometrium by reversible suppression of blood vessels and prostaglandin production, with possible benefits on pain. Their potential benefit over other modalities in terms of maintaining hormonal milieu make them patient friendly. A number of SRPMs including, asoprisnil, mifepristone, ulipristal acetate, telapristone acetate, tanaproget, and lonaprisan have been studied on human cell lines. No drug-related serious events have been reported with their treatment.
Pharmacokinetics, toxicological and clinical aspects of ulipristal acetate: insights into the mechanisms implicated in the hepatic toxicity
Published in Drug Metabolism Reviews, 2021
Ulipristal acetate [UPA; also known as CDB-2914 (CDB: Contraceptive Development Branch of National Institute of Child Health and Human Development, NICHD); PGL4001; 11β-[4-(dimethylamino)phenyl]-17α-acetoxy-19-norpregna-4,9-diene-3,20-dione; IUPAC name (8S,11R,13S,14S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one; Ella®, Fibristal®, EllaOne®, Esmya®)] is an orally active synthetic drug that belongs to the same chemical family as the antiprogestins (or antiprogestogens) mifepristone and its major metabolite metapristone (i.e. desmethylmifepristone), onapristone, lilopristone, lonaprisan and telapristone (Figure 1). It is a selective progesterone receptor modulator (SPRM), characterized by a tissue-specific partial progesterone agonistic/antagonistic effects in the target tissues after binding to progesterone receptors (Rabe et al. 2018). UPA was originally used as an emergency contraceptive at a dose of 30 mg (Batur et al. 2016). More recently, in February 2012, a European marketing authorization was granted for 5 mg tablets (Esmya®) for the pre-operative treatment of moderate to severe symptoms of uterine myomas or fibroids in adult women of reproductive age, with the treatment duration limited to 3 months and up to 4 treatment courses (i.e. 12-week courses) (Donnez et al. 2012; Ghonim et al. 2019). Myomas or fibroids or leiomyomas are benign monoclonal hormone-sensitive tumors of uterine smooth muscle cells often resulting in metrorrhagias, pelvic pressure, and pain (Stewart 2001). In fibroid cells, UPA modulates progesterone receptor activity without suppressing E2 to postmenopausal levels, and shows proapoptotic/antiproliferative effects (Pohl, Osterloh, Gotteland 2013b; Ferrero et al. 2018).
Elagolix in the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women
Published in Expert Review of Clinical Pharmacology, 2021
Mohamed Ali, Sara A.R., Ayman Al Hendy
Selective progesterone receptor modulators (SPRMs) have been studied extensively in the last few years with initial promising effects in induction of amenorrhea and shrinking tumor size [16]. SPRMs are synthetic ligands targeting the progesterone receptor (PR) with mixed agonist and antagonist activities [92]. Their indication as emergency contraception, termination of pregnancy, premenstrual syndrome and assisted reproduction are due their tissue-selective effects [93]. Moreover, expression of PR in endometrial and fibroid cells encouraged SPRMs investigations against UF, AUB, dysmenorrhea and endometriosis [82]. SPRMs family includes Mifepristone, Asoprisnil, Onapristone, UPA, Lonaprisan, Vilaprisan, and Telapristone. Notably, enthusiasm about SPRMs was attributed to their minimal effect on serum estrogen levels therefore they are not expected to induce menopausal-like symptoms or subsequent bone loss [92–95]. Vilaprisan dosed in 1–5 mg daily for 12 week induced profound bleeding cessation in women with UFs which supported further advancement of clinical trials to evaluate vilaprisan in women with symptomatic UFs [96]. However, long-term toxicological animal studies using high doses revealed safety concerns; therefore, all current trials were paused [97]. A main known risk with the use of SPRMs is their association with a reversible morphological change in the endometrial lining known as progesterone-receptor modulator-associated endometrial changes (PAECs) after prolonged exposure [82,98]. UPA was approved and prescribed in Europe, Canada, and Australia for few years but recent studies found that UPA could cause liver failure that may require liver transplantation [17,18] and EMA called for temporary suspension of UPA (EsmyaTM) and generic medicines sales. Off note, EMA’s review is restricted only to UPA 5 mg for the treatment of UFs and does not affect its use in 30 mg as a single-dose medicine (ellaOne) for EC, as there is currently no concern about liver injury with the latter [99].