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      Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids

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          Abstract

          Uterine fibroids (UFs, AKA leiomyoma) are the most important benign neoplastic threat to women's health, with costs up to hundreds of billions of health care dollars worldwide. Uterine fibroids caused morbidities exert a tremendous health toll, impacting the quality of life of women of all ethnicities, especially women of color. Clinical presentations include heavy vaginal bleeding, pelvic pain, bulk symptoms, subfertility, and obstetric complications. Current management strategies heavily lean toward surgical procedures; nonetheless, the choice of treatment is generally subject to patient's age and her desire to preserve future fertility. Women with UF who desire to maintain future fertility potential face a dilemma because of the limited treatment choices that are currently available to help them achieve that goal. Recently, ulipristal acetate the first of the promising family of oral selective progesterone receptor modulators has been approved for UF treatment in Europe, Canada, and several other countries and is under review for possible approval in the USA. In this review article, we discuss recent advances in the management options against UF with a bend toward oral effective long-term treatment alternatives who are particularly suited for those seeking to preserve their future fertility potential. We also explore the transformative concept of primary and secondary UF prevention using these new anti-UF agents. We envision a remarkable shift in the management of UF in future years from surgical/invasive treatment to orally administrated options; clearly, this potential shift will require additional intense clinical research.

          Summary Sentence

          We focus on oral long term anti-UF treatment options which can benefit those seek to preserve future fertility. We explore the transformative concept of primary/secondary UF prevention using these agents. We envision a futuristic shift in the UF management from invasive treatment to oral one.

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          Most cited references 151

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          MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas.

          Uterine leiomyomas, or fibroids, are benign tumors that affect millions of women worldwide and that can cause considerable morbidity. To study the genetic basis of this tumor type, we examined 18 uterine leiomyomas derived from 17 different patients by exome sequencing and identified tumor-specific mutations in the mediator complex subunit 12 (MED12) gene in 10. Through analysis of 207 additional tumors, we determined that MED12 is altered in 70% (159 of 225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. All mutations resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis.
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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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                Author and article information

                Journal
                Biol Reprod
                Biol. Reprod
                biolreprod
                Biology of Reproduction
                Oxford University Press
                0006-3363
                1529-7268
                September 2017
                28 August 2017
                28 August 2017
                : 97
                : 3
                : 337-352
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
                [2 ]Clinical Pharmacy department, Faculty of pharmacy, Ain Shams University, Cairo, Egypt
                Author notes
                [* ] Correspondence: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia (MCG), Augusta University CB-2208, 1120 15th St., Augusta, GA 30912, USA. Tel: +706-721-3833; Fax. 706-721-6211; E-mail: aalhendy@ 123456Augusta.edu
                [†]

                Grant Support: This work was supported by the National Institute of Health grant RO1 HD046228-12.

                Article
                iox094
                10.1093/biolre/iox094
                5803778
                29025038
                © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                Page count
                Pages: 16
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