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      Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids

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          Abstract

          Uterine fibroids are the most common benign tumors of the female genital tract. The management of symptomatic fibroids has traditionally been surgical; however, alternative pharmacological approaches have been proposed to control symptoms. To date, gonadotropin-releasing hormone analogs are the only available drugs for the preoperative treatment of fibroids. However, the US Food and Drug Administration recently authorized ulipristal acetate (UPA), an oral selective progesterone-receptor modulator, for the same indication. UPA is a new, effective, and well-tolerated option for the preoperative treatment of moderate and severe symptoms of uterine fibroids in women of reproductive age. According to clinical data, UPA shows several advantages: it is faster than leuprolide in reducing the fibroid-associated bleeding, it significantly improves hemoglobin and hematocrit levels in anemic patients, and it grants a significant reduction in the size of fibroids, which lasts for at least 6 months after the end of the treatment. Furthermore, UPA displays a better tolerability profile when compared to leuprolide; in fact, it keeps estradiol levels at mid follicular phase range, thereby reducing the incidence of hot flushes and exerting no impact on bone turnover. On the grounds of this evidence, the administration of 5 mg/day ulipristal acetate for 3 months is suggested for different patient categories and allows for planning a treatment strategy tailored to meet an individual patient’s needs.

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          Most cited references 33

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          Ulipristal acetate versus placebo for fibroid treatment before surgery.

          The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain. We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13, after which patients could undergo surgery. At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, 92% of those receiving 10 mg of ulipristal acetate, and 19% of those receiving placebo (P<0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were -21%, -12%, and +3% (P=0.002 for the comparison of 5 mg of ulipristal acetate with placebo, and P=0.006 for the comparison of 10 mg of ulipristal acetate with placebo). Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy. Serious adverse events occurred in one patient during treatment with 10 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo. Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. (Funded by PregLem; ClinicalTrials.gov number, NCT00755755.).
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            Variation in the incidence of uterine leiomyoma among premenopausal women by age and race.

            To quantify the incidence of uterine leiomyoma confirmed by hysterectomy, ultrasound, or pelvic examination according to age and race among premenopausal women. From September 1989 through May 1993, 95,061 premenopausal nurses age 25-44 with intact uteri and no history of uterine leiomyoma were followed to determine incidence rates of uterine leiomyoma. The self-reported diagnosis was confirmed in 93% of the medical records obtained for a sample of cases. Using pooled logistic regression, we estimated relative risks (RRs) of uterine leiomyoma according to race and examined whether adjustment for other potential risk factors could explain the variation in the race-specific rates. During 327,065 woman-years, 4181 new cases of uterine leiomyoma were reported. The incidence rates increased with age, and the age-standardized rates of ultrasound- or hysterectomy-confirmed diagnoses per 1000 woman-years were 8.9 among white women and 30.6 among black women. After further adjustment for marital status, body mass index, age at first birth, years since last birth, history of infertility, age at first oral contraceptive use, and current alcohol consumption, the rates among black women were significantly greater for diagnoses confirmed by ultrasound or hysterectomy (RR 3.25; 95% confidence interval [CI] 2.71, 3.88) and by hysterectomy (RR 1.82; 95% CI 1.17, 2.82) compared with rates among white women. We observed similar RRs when the cohort was restricted to participants who reported undergoing a screening physical examination within the 2 years before baseline. A higher prevalence of known risk factors did not explain the excess rate of uterine leiomyoma among premenopausal black women.
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              Incidence, aetiology and epidemiology of uterine fibroids.

               Stanley Okolo (2008)
              Uterine fibroids are the most common benign tumour of the female genital tract. However, their true prevalence is probably under-estimated, as the incidence at histology is more than double the clinical incidence. Recent longitudinal studies have estimated that the lifetime risk of fibroids in a woman over the age of 45 years is more than 60%, with incidence higher in blacks than in whites. The cause of fibroids remains unclear and their biology poorly understood. No single candidate gene has been detected for commonly occurring uterine fibroids. However, the occurrence of rare uterine fibroid syndromes, such as multiple cutaneous and uterine leiomyomatosis, has been traced to the gene that codes for the mitochondrial enzyme, fumarate hydratase. Cytogenetic abnormalities, particularly deletions of chromosome 7, which are found in up to 50% of fibroid specimens, seem to be secondary rather than primary events, and investigations into the role of tumour suppressor genes have yielded conflicting results. The key regulators of fibroid growth are ovarian steroids, both oestrogen and progestogen, growth factors and angiogenesis, and the process of apoptosis. Black race, heredity, nulliparity, obesity, polycystic ovary syndrome, diabetes and hypertension are associated with increased risk of fibroids, and there is emerging evidence that familial predisposition to fibroids is associated with a distinct pattern of clinical and molecular features compared with fibroids in families without this prevalence.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                20 February 2014
                : 8
                : 285-292
                Affiliations
                [1 ]Department of Obstetrics and Gynaecology, Mauriziano “Umberto I” Hospital, University of Turin, Turin, Italy
                [2 ]Department of Pathology, European Institute of Oncology, Milan, Italy
                [3 ]Department of Obstetrics and Gynecology, ARNAS Civico Hospital, Palermo, Italy
                [4 ]Department of Morphology, Surgery and Experimental Medicine, Section of Obstetrics and Gynecology, Infertility Unit, University of Ferrara, Ferrara, Italy
                Author notes
                Correspondence: Roberto Marci, Department of Morphology, Surgery and Experimental Medicine, Section of Obstetrics and Gynecology, Infertility Unit, University of Ferrara, Corso Giovecca 183, 44121, Ferrara, Italy, Email roberto.marci@ 123456unife.it
                Article
                dddt-8-285
                10.2147/DDDT.S54565
                3934585
                © 2014 Biglia et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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