Uterine leiomyomas are one of the most common and yet understudied diseases in women. These tumors, commonly known as fibroids, affect women mainly during their reproductive years and are diagnosed in up to 70% of white women and more than 80% of women of African ancestry during their lifetime. This disease has a profound impact on health care delivery and costs worldwide. Though most women with fibroids are asymptomatic, approximately 30% of them will present with severe symptoms which can include abnormal uterine bleeding, anemia, pelvic pain and pressure, back pain, urinary frequency, constipation, or infertility, and will require intervention. Furthermore, fibroids have been associated with poor obstetrical outcomes. The current options for symptomatic fibroid treatment include expectant, medical, and surgical management, and interventional radiology procedures. This article reviews the recent progress and available management strategies for uterine fibroids and highlights areas where further research is needed to find new therapeutic targets and better personalize treatments.

Steroid receptors in the stromal cells of endometrium and its disease counterpart tissue endometriosis play critical physiologic roles. We found that mRNA and protein levels of estrogen receptor 2 (ESR2) were strikingly higher, whereas levels of estrogen receptor 1 (ESR1), total progesterone receptor (PGR), and progesterone receptor B (PGR B) were significantly lower in endometriotic versus endometrial stromal cells. Because ESR2 displayed the most striking levels of differential expression between endometriotic and endometrial cells, and the mechanisms for this difference are unknown, we tested the hypothesis that alteration in DNA methylation is a mechanism responsible for severely increased ESR2 mRNA levels in endometriotic cells. We identified a CpG island occupying the promoter region (À197/þ359) of the ESR2 gene. Bisulfite sequencing of this region showed significantly higher methylation in primary endometrial cells (n ¼ 8 subjects) versus endometriotic cells (n ¼ 8 subjects). The demethylating agent 5-aza-2 0 -deoxycytidine significantly increased ESR2 mRNA levels in endometrial cells. Mechanistically, we employed serial deletion mutants of the ESR2 promoter fused to the luciferase reporter gene and transiently transfected into both endometriotic and endometrial cells. We demonstrated that the critical region (À197/þ372) that confers promoter activity also bears the CpG island, and the activity of the ESR2 promoter was strongly inactivated by in vitro methylation. Taken together, methylation of a CpG island at the ESR2 promoter region is a primary mechanism responsible for differential expression of ESR2 in endometriosis and endometrium. These findings may be applied to a number of areas ranging from diagnosis to the treatment of endometriosis.

H.O.D.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (but with no personal remuneration) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc, and Myovant Sciences GmbH. H.O.D.C. receives royalties from UpToDate for article on abnormal uterine bleeding. A.K. receives royalties from UpToDate, Wolters Kluwer for work on the topic hysterosalpingography. E.E.M. consults for Myovant Sciences. K.A.M. is coinvestigator for Bayer Essure longitudinal research study and clinical trial (all funds for this research go to the site of research [W.I.H.] e no personal compensation). K.A.M. is scientific advisor for Myovant (advises on patient questionnaires related to AUB-compensation goes to employer [C.N.E.M.G.]-no personal compensation). K.A.M. has received honoraria from ABOG, ACOG, and NIH for participating in working groups and meetings. K.A.M. is HHS Office of Population Affairs Title X Grant Reviewer (received honorarium). I.M. is employee of Igenomix R&D. C.S. is Head of the Igenomix Scientific Advisory Board. The other authors report no conflict of interest.

Our findings indicate that miRNAs are differentially expressed between human leiomyoma and matched myometrium. Given this differential expression, miRNAs may play a role in the pathogenesis of uterine leiomyoma and may serve as future therapeutic targets for the treatment of these tumors.

It has been well established that estrogen and progesterone are involved in the proliferation and maintenance of uterine leiomyoma, and the majority of medical treatments currently available for leiomyoma work by inhibiting steroid hormone production or action. A pitfall of these therapeutics is that they decrease leiomyoma size, but do not completely eradicate them, and tumors tend to regrow once treatment is stopped. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma has the potential to provide the missing link between developing therapeutics that temper leiomyoma growth and those that eradicate them.