Endometriosis: where are we and where are we going?

Endometriosis currently affects ~5.5 million reproductive-aged women in the U.S. with symptoms such as painful periods (dysmenorrhea), chronic pelvic pain, pain with intercourse (dyspareunia), and infertility. It is defined as the presence of endometrial tissue outside the uterine cavity and is found predominately attached to sites within the peritoneal cavity. Diagnosis for endometriosis is solely made through surgery as no consistent biomarkers for disease diagnosis exist. There is no cure for endometriosis and treatments only target symptoms and not the underlying mechanism(s) of disease. The nature of individual predisposing factors or inherent defects in the endometrium, immune system, and/or peritoneal cavity of women with endometriosis remains unclear. The literature over the last 5 years (2010-2015) has advanced our critical knowledge related to hormones, hormone receptors, immune dysregulation, hormonal treatments, and the transformation of endometriosis to ovarian cancer. In this review, we cover the aforementioned topics with the goal of providing the reader an overview and related references for further study to highlight the progress made in endometriosis research, while concluding with critical areas of endometriosis research that are urgently needed.

Genetic associations with diminished ovarian reserve: a systematic review of the literature.

PURPOSE: Diminished ovarian reserve (DOR) affects 10 % of women seeking fertility treatment. Although it is much more prevalent than premature ovarian failure, less is known about its etiology. The purpose of this article is to review the possible genetic causes of, and associations with, pathologic DOR. METHODS: A systematic review was conducted using PubMed from 1966 through November 2013. RESULTS: Twenty-one articles identified genes associated with DOR: one gene mutation (FMR1), three polymorphisms (GDF9, FSHR, and ESR1), and seven genes differentially expressed between women with DOR and controls (AMH, LHCGR, IGF1, IGF2, IGF1R, IGF2R and GREM1). Six candidate genes were discovered in mice, including Foxl2, Gdf9, Bmp15, Aire, Wnt4, and Gpr3. Two case reports of chromosomal translocations were also identified. CONCLUSIONS: While the etiology of pathologic DOR is likely multifactorial, it is possible that many cases attributed to an idiopathic cause may have a genetic component. Larger studies are needed to expose the impact gene mutations, polymorphisms, and epigenetics have on pathologic DOR.

Elevated serum chemokines are independently associated with both endometriosis and uranium exposure.

Endometriosis is a complex disease impacted by the hormonal and immune systems. Cytokines and chemokines are serum biomarkers that maybe useful to develop a noninvasive disease diagnosis. Individuals in the Fernald Community Cohort were exposed to uranium, a heavy metal with radioactive properties and estrogenic potential; therefore, serum samples from women in this cohort with or without uranium and with or without endometriosis were compared for alterations in chemokine, cytokine, and matrix metalloproteinase (MMP) levels. Control women were matched to endometriosis cases by uranium exposure, age, and body mass index. MMP levels were not altered. Five chemokines and one cytokine significantly increased in endometriosis cases versus controls irrespective of uranium exposure. Uranium exposure alone was associated with an increase in inflammatory chemokines. The majority of the elevated chemokines in endometriosis cases play important roles in attracting T helper-2 cells, which may be vital to understanding the immune response in endometriosis.

Use of a Mouse Model of Experimentally Induced Endometriosis to Evaluate and Compare the Effects of Bisphenol A and Bisphenol AF Exposure.

BACKGROUND: Endometriosis is a gynecological disease affecting 1 in 10 women of reproductive age. Endometriosis incidence has risen; however, whether this rise is due to disease awareness or environmental contamination is not known. OBJECTIVE: The objective of this study was to determine if bisphenol A (BPA) or bisphenol AF (BPAF) potentiate the development of endometriosis and if hormonal status alters how toxicant exposure affects disease. METHODS: A mouse model of endometriosis, where minced uterine tissue is injected into the peritoneal cavity of a host mouse, was used to examine the effects of BPA and BPAF on endometriosis lesion development in ovariectomized and hormonally intact mice. BPA and BPAF were delivered through diet to include no-observed-adverse-effect-level (NOAEL) and the low-observed-adverse-effect-level (LOAEL) exposure levels. After six weeks (at necropsy), lesions, ovaries, and blood were collected to examine characteristics, gene expression, and hormonal regulation. RESULTS: BPA and BPAF treatments affected endometriosis in a manner specific to dose and hormonal status of the host mouse. Estrogen and endometriosis-mediated differences in lesion target gene expression also depended on hormonal status. In intact mice, ovarian steroidogenic pathways were disrupted, progesterone levels were lowered, and atretic oocyte numbers were higher with toxicant exposure. BPAF, more so than BPA, resulted in more endometriosis lesion growth, but both toxicants disrupted normal ovarian signaling. CONCLUSION: These findings further our understanding of the effects and hormonal impacts of BPA and BPAF on endometriosis perturbation in ovariectomized and hormonally intact mice. BPAF appeared to be similar if not more estrogenic than BPA and may be affecting an environmental contribution of the increased incidence of endometriosis. https://doi.org/10.1289/EHP3802.

To Morcellate or Not to Morcellate: A Cross-Sectional Survey Of Gynecologic Surgeons.

BACKGROUND AND OBJECTIVES: The inadvertent dissemination of uterine cancer cells with the power morcellator has received much attention in the press and a warning from the U.S. Food and Drug Administration. Many hospitals prohibit the use of the morcellator in gynecologic surgery. We conducted a survey in an attempt to assess gynecologic surgeons' beliefs regarding the intracorporeal power morcellation of fibroids in light of the risk of dissemination of malignancy in patients in whom the presence of cancer is unknown before surgery. METHODS: We conducted an Internet-based survey of 3505 members of the Society of Laparoendoscopic Surgeons (SLS) to assess demographics, current use of the intracorporeal power morcellator, and whether the recent negative press has affected gynecologic surgeons' use of the morcellator. RESULTS: Of the 3505 SLS members surveyed, 518 responded (response rate, 14.77%). Three hundred thirteen (61%) of the respondents were not using the intracorporeal power morcellator. Of those, 48% reported the reason was a hospital-wide ban, and an additional 17% reported lack of availability (not in stock). Senior attendings with >20 years of experience used the morcellator more often than junior attendings and fellows (P = .007). Furthermore, the morcellator was used significantly less among those with the belief that morcellation of occult malignancy affects survival (P = .013). Three hundred sixty-one (76%) of the participants currently perform laparotomy in fewer than a quarter of their cases; most those cases are still performed using laparoscopic and robot-assisted techniques. CONCLUSION: The recent negative press suggesting that intracorporeal power morcellation can disseminate occult malignancy and affect survival has decreased the use of the morcellator. Despite the declining use of power morcellation, most practicing gynecologic surgeons have not converted their procedures to laparotomy.

Sonohysterographic predictors of successful hysteroscopic myomectomies.

BACKGROUND AND OBJECTIVES: The purpose of this study is to assess the rate of persistent submucosal myomas and intrauterine scarring after hysteroscopic myomectomy, as well as to evaluate the preoperative and intraoperative sonohysterographic findings that will predict persistence of myomas, scarring, and the need for repeat surgery. METHODS: Charts from all hysteroscopic myomectomies performed by a single surgeon between 2003 and 2011 were reviewed for preoperative, intraoperative, and postoperative sonohysterographic findings. Predictors included myoma number, diameter and percent extension into the cavity of the largest fibroid, and percent surgically resected. These predictors were assessed with postoperative sonohysterography. Statistics included t test, logistic regression, χ(2) test, and Fisher exact test. RESULTS: Among the 79 cases with postoperative sonohysterograms, 17 (21.5%) had persistent submucosal myoma, and 9 (11.4%) had intrauterine scarring on postoperative sonohysterogram. Repeat hysteroscopic myomectomy was required in 11 (13.9%), but none required lysis of adhesions. The myoma number was not a significant predictor. A higher percentage of myoma within the cavity (63.35% vs 44.89%, P < .05) and smaller myoma size (2.22 cm vs 3.31 cm, P < .01) were significant predictors of a complete resection, a normal postoperative sonohysterogram, and avoidance of repeat surgery. On regression analysis, the percent of the myoma resected was the most significant outcome predictor (P < .001). CONCLUSION: Larger myomas with a lower percent found within the uterine cavity are less likely to be completely resected. Percent resection at the time of surgery is the most significant predictor of a normal postoperative sonohysterogram, as well as the best predictor of the need for repeat surgery.