Uterine Leiomyoma: New Perspectives on an Old Disease

James H. Segars, MD

Ayman Al-Hendy, MD, PhD

Uterine leiomyomas (fibroids) have afflicted women since antiquity, as evidenced by the calcified fibroids detected from the remains of cave women and Egyptian mummies. Though millennia have since passed, fibroids continue to adversely affect the health of millions of women today. Fibroids are present in more than 50 to 80% of women, making them the most common disease in women, more prevalent even than obesity.

This issue of Seminars in Reproductive Medicine focuses on this enigmatic disease of uterine leiomyoma. The first article in this issue analyzes the current burden of fibroid disease for the health care system and for the individual patient. The authors examine the negative impact of this disease on daily living and quality of life of affected women, particularly women of color. This article emphasizes the current unmet needs of the afflicted women.

While the root cause of fibroids remains incompletely understood, considerable advances have occurred in the past few years regarding the origin of this highly prevalent condition. The second article summarizes recent research regarding the origin of uterine fibroids. It is clear that uterine leiomyomas are monoclonal growths, and the authors provide evidence to support development from a single transformed myometrial smooth muscle stem cell and the role of epigenetic modifications in cell-signaling pathways that may increase the possibility of developing uterine fibroids later in life. The MED12 mutation is the most frequent DNA defect, detected in up to 85% of sporadic fibroid lesions. This manuscript also explores the molecular events that can lead to the emergence of these mutations, including the possible role of human tumor infiltrating cells (TICs) as compared to myometrial stem cells (MSCs). A cardinal feature of uterine leiomyoma cells is their secretion of an excessive and altered extracellular matrix (ECM), thus leading to their moniker, fibroids. The third manuscript in this issue reviews the contribution of mechanical signaling to the deposition of a stiff extracellular matrix. Additionally, possible therapeutic strategies based on the altered ECM are examined.

The next two articles in this issue review the role of inflammation in fibroid development. In the fourth article, the authors suggest that inflammation and genetic modification are likely related in a closed loop fashion to promote fibroid growth. They pose possible strategies to target the proinflammatory gene expression as a novel nonhormonal therapeutic strategy. The article by Protic et al examines the role of activin A as a novel player in mediating inflammation, immunity, wound repair, and fibrosis in fibroids. The authors found a profibrotic role of activin A in leiomyoma growth, and they review the role of activin A in myofibroblast activation and leiomyoma growth.

Prior to the development of anesthesia and surgical methods in the late 1800s, uterine bleeding caused by fibroids sometimes led to death. As a result, a hysterectomy for fibroids was among the very first surgeries performed. In the past 150 years, considerable effort has led to more conservative options for treatment, including medical and minimally invasive approaches. The article by Chwalisz and Taylor is a thorough, up-to-date, comprehensive review of medical therapy including Food and Drug Administration–approved medical options and emerging medical treatments currently in clinical development, including progesterone receptor modulators and oral gonadotropin-releasing hormone antagonists. These novel fibroid therapies hold immense promise for shifting the mainstream treatment from the surgical domain to the realm of orally administered medicines. While a hysterectomy via laparotomy was long-standing surgical approach, today minimally invasive and uterine-sparing techniques offer patients many options. There are few evidence-based reviews of minimally invasive approaches, and the next article in this issue is unique because it critically examines various options, including hysteroscopic myomectomy, laparoscopic and robotically assisted myomectomy, laparoscopic and robotically assisted hysterectomy, as well as ultrasound-guided radiofrequency ablation. The authors discuss indications, patient selection, preoperative treatment modalities, instrumentation, techniques, and pertinent intraoperative considerations for each approach. Following these two manuscripts is a forward-looking examination of new and emerging therapies for fibroids by Fritton and Borahay. These authors critically analyze both laboratory and clinical evidence for innovative therapies, also discussing novel targets for future therapies.

For patients interested in conception, uterine fibroids can impair fertility via alteration of endometrial receptivity and sexual function. Conservative management of uterine fibroids in this scenario may be especially challenging. The article by Whynott et al is a systematic, evidence-based review of clinical management in the patient with fibroid-associated infertility.

Pain, bleeding, and anemia caused by uterine fibroids debilitates the health of many women. Thus, one particularly important perspective deserving of consideration is the patient perspective of fibroid disease. This issue concludes with an up-to-date, unique overview of the existing literature on patient-centered care by Dr. Marsh from the fibroid patient perspective. The authors conclude with a discussion of possible strategies to re-envision patient care for the condition, including attention to the emotional distress caused by the disease.

Thus, the articles in this issue cover the range of challenges presented by fibroid disease, from the societal burden to the patient perspective, from current therapies to emerging novel targets, and from medical management to the latest minimally-invasive techniques. The guest editors hope that readers will enjoy the new and exciting information in this special issue devoted to this ancient, exceedingly prevalent malady of women.