Growing evidence that endometriosis is a systemic disease.

The pathophysiology of endometriosis remains unclear. Retrograde menstruation could be a phenomenon that initiates the process, but it may not explain the entire pathophysiology of endometriosis. Current evidence suggests that endometriosis is a type of chronic inflammatory disease. Many conditions that affect the vascular endothelium, including atherosclerosis, cardiovascular disease and pre-eclampsia, have been shown to be associated with endometriosis. Evidence to date suggests a complex interaction in endometriosis between angiogenesis, hormones and immunological changes stemming from chronic inflammation, with the inflammatory cells releasing cytokines and chemokines including tumour necrosis factor-α (TNF-α). Indeed, TNF-α is considered to be one of the possible markers of endometriosis in the blood, endometrium or menstrual blood. We emphasize the importance of pursuing research for novel and safer anti-inflammatory and immunomodulatory drugs that can be used by patients with endometriosis on a long-term basis.

FIGO statement: Fertility preservation.

Fertility preservation is a growing field in reproductive medicine that may raise ethical questions. Preservation of fertility must be discussed with the patient if gonadotoxic treatment is required, whether in the case of benign or malignant pathology, or in the management of transgender identity. As a result, surgery or chemotherapy that has fewer adverse impacts on fertility should be proposed if this does not alter the prognosis of the disease. If the risk of infertility persists, then fertility cryopreservation should be proposed for children and adults of reproductive age. Sperm, oocytes, and gonadal tissue can be cryopreserved for many years. FIGO wishes to emphasize the importance of fertility preservation in the medical and surgical management of patients, and the importance of a specialized, multidisciplinary approach.

A randomized double-blind controlled proof-of-concept study of alanyl-glutamine for reduction of post-myomectomy adhesions.

STUDY OBJECTIVE: To test the hypothesis that intraperitoneal instillation of a single bolus dose of l-alanyl-l-glutamine (AG) will reduce the incidence, extent and/or severity of adhesions following myomectomy and establish preliminary safety and tolerability of AG in humans. DESIGN: Phase 1,2 Randomized, double-blind, placebo-controlled study (DBRCT). SETTING: Tertiary care gynecology surgical centre. PATIENTS: Thirty-eight women who underwent myomectomies by laparoscopy (N = 38; AG-19 vs Placebo-19) or laparotomy (N = 10; AG-5 vs Placebo-5) with a scheduled second-look laparoscopy (SLL) 6-8 weeks later. Thirty-two patients in the laparoscopy arm completed SLL. INTERVENTIONS: Bolus dose of AG or normal saline solution control (0.9% NaCl) administered intraperitoneally immediately prior to suture closure of the laparoscopic ports. The average dose was 170 mL of AG or control based on a dosing scheme of 1 g/kg bodyweight. MEASUREMENTS: Digital recordings obtained for all procedures. The primary endpoint was reduction in the incidence, severity and extent of post-operative adhesions analyzed by intention-to-treat (ITT) approach. Three independent, blinded reviewers evaluated all operative video recordings to assess presence of adhesions. Post-hoc analysis assessed presence or absence of adhesions in the peritoneal cavity. Secondary endpoints assessed safety and tolerability of AG. MAIN RESULTS: Administration of AG reduced the incidence, severity and/or extent of post-operative adhesions (p = 0.046). The presence of adhesions in the AG group was lower than in the Control group (p = 0.041). Adhesion improvement was achieved in 15 of 15 (100%) in the AG group versus 5 of 17 (29.6%) in the placebo group. No serious adverse events were reported. No differences in safety parameters were observed. CONCLUSIONS: Intraperitoneal l-alanyl-l-glutamine reduced adhesion formation in all patients following laparoscopic myomectomy. Complete absence of adhesions was achieved at all abdominal sites in 93% of patients. Results confirm AG's known effects on cellular mechanisms of adhesiogenesis and lay the foundation for new adhesion prophylaxis research and treatment.

Association between Endometriosis and Risk of Preeclampsia in Women Who Conceived Spontaneously: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the association between endometriosis and the risk of preeclampsia and other maternal outcomes in spontaneously conceived women. DATA SOURCES: PubMed, MEDLINE, Embase, Scopus, Cochrane Library, Web of Science, and Google Scholar were systemically searched for studies published from inception to November 2021 (CRD42020198741). Observational studies published in English or French that investigated the risk of preeclampsia in women with endometriosis who conceived spontaneously were included. METHODS OF STUDY SELECTION: A total of 610 articles were reviewed once duplicates were removed. Inclusion criteria included spontaneous conception and surgical and/or imaging ascertainment of an endometriosis diagnosis. Exclusion criteria included conception using assisted reproductive technologies, multiple pregnancies, chronic hypertension, and unclear diagnoses of endometriosis. TABULATION, INTEGRATION, AND RESULTS: Data of selected studies were extracted, and analysis was performed on Review Manager, version 5.4. Quality assessment of included studies for potential risk of bias was evaluated using the Newcastle-Ottawa Scale for cohort studies. Three cohort studies of spontaneous pregnancies were included. Endometriosis was associated with an increased risk of preeclampsia (risk ratio [RR] = 1.47, 95% CI 1.13 -1.89, p = .003; I2 = 0%; n = 3 studies). A sensitivity analysis excluding a study with adenomyosis cases yielded similar risk (RR = 1.44; 95% CI, 1.11-1.87; p = .006; I2 = 0%; n = 2 studies). Having endometriosis did not significantly increase risk of cesarean delivery (RR = 1.38; 95% CI, 0.99-1.92; p = .06; I2 = 80%; n = 2 studies) or postpartum hemorrhage (RR = 1.16; 95% CI, 0.46-2.91; p = .76; I2 = 50%; n = 2 studies). CONCLUSION: We detected an increased risk of preeclampsia in women with endometriosis who conceived spontaneously. Endometriosis did not seem to increase the risk of cesarean delivery and postpartum hemorrhage, but the number of studies was limited, and the heterogeneity was high.

Combined effects of age and endometriosis on ovarian reserve in women with infertility.

OBJECTIVE: To evaluate the combined effects of age and endometriosis on ovarian reserve in women with infertility. METHODS: We conducted a cross-sectional study using an institutional database. Women with sonographic, laparoscopic, or histologic evidence of endometriosis were defined as the study group and the remaining women served as a control group. We evaluated demographic and clinical characteristics of the groups as a whole and stratified the patients into those aged 35 years or older and those younger than 35 years at the time of ovarian reserve testing. RESULTS: Of a total of 656 women included in the final analysis, 71 women had a diagnosis of endometriosis. When compared with women without endometriosis, the median anti-Müllerian hormone (AMH) and antral follicular count (AFC) values were significantly lower in the group of women with endometriosis-median 2.1 ng/ml (interquartile range [IQR] 1.1-3.9) versus 1.2 ng/ml (IQR 0.6-2.4; P < 0.001) for AMH and 14 follicles (IQR 8-23) versus 7 follicles (IQR 5-14; P < 0.001) for AFC. When stratified into two age groups the association between a lower AFC and endometriosis remained significant for both age groups whereas the association between a lower AMH and endometriosis was significant only for the group of women aged 35 years oor older. CONCLUSION: Our study highlights a detrimental effect by endometriosis and an age enhancement effect of endometriosis on ovarian reserve.

Immunomodulation for unexplained recurrent implantation failure: where are we now?

In brief: Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies. Abstract: Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.

Evaluation of Hysteroscopic Endometrectomy: A Reappraisal.

Endometrial ablation can be performed using a variety of techniques, including resectoscopic or non-resectoscopic approaches. In this study, we compared 2 resectoscopic endometrial ablation techniques. The first technique was rollerball coagulation followed by endometrectomy (type A; n = 103), and the second was the reverse (type B; n = 107). Besides excessive bleeding in 4 cases, the procedures were uneventful in both groups of patients. We did not encounter uterine perforation or cervical laceration. Satisfaction rates were 97% and 99% with an overall hysterectomy rate of 2.9%. These results compared favorably with those in the literature. The results of our study show that hysteroscopic endometrectomy is effective with few associated complications.

Menopausal Hormone Therapy Formulation and Breast Cancer Risk.

OBJECTIVE: To evaluate whether the increased risk of breast cancer is dependent on the formulation of menopausal hormone therapy (HT) used. METHODS: We performed a population-based case-control study of women aged 50 years or older using data from the U.K. Clinical Practice Research Datalink. Women with incident cases of breast cancer were age-matched (1:10) with a control group of women with comparable follow-up time with no history of breast cancer. Exposures were classified as ever or never for the following menopausal HT formulations: bioidentical estrogens, animal-derived estrogens, micronized progesterone, and synthetic progestin. Logistic regression analyses were performed to estimate the adjusted effect of menopausal HT formulation on breast cancer risk. RESULTS: Between 1995 and 2014, 43,183 cases of breast cancer were identified and matched to 431,830 women in a control group. In adjusted analyses, compared with women who never used menopausal HT, its use was associated with an increased risk of breast cancer (odds ratio [OR] 1.12, 95% CI 1.09-1.15). Compared with never users, estrogens were not associated with breast cancer (bioidentical estrogens: OR 1.04, 95% CI 1.00-1.09; animal-derived estrogens: OR 1.01, 95% CI 0.96-1.06; both: OR 0.96, 95% CI 0.89-1.03). Progestogens appeared to be differentially associated with breast cancer (micronized progesterone: OR 0.99, 95% CI 0.55-1.79; synthetic progestin: OR 1.28, 95% CI 1.22-1.35; both OR 1.31, 0.30-5.73). CONCLUSION: Although menopausal HT use appears to be associated with an overall increased risk of breast cancer, this risk appears predominantly mediated through formulations containing synthetic progestins. When prescribing menopausal HT, micronized progesterone may be the safer progestogen to be used.

Postoperative Discharge Opioid Consumption, Leftover, and Disposal after Obstetric and Gynecologic Procedures: A Systematic Review.

OBJECTIVE: To perform a systematic review on consumption, leftover, and disposal of prescribed opioids after surgery in obstetrics and gynecology (The International Prospective Register of Systematic Reviews ID 249856). DATA SOURCES: Electronic database searches on PubMed, Embase, Cochrane Library, and MEDLINE and other search methods including all studies published between the years 2000 and 2021 were used. METHODS OF STUDY SELECTION: We included all randomized trials, cohorts, case-control studies, and clinical trials. The search was limited to studies related to obstetrics and gynecology. Studies that pertained to opioid consumption, leftover, and disposal patterns were selected. We excluded review articles, meeting abstracts, case series and case reports, and abstracts without access to full texts. The search was limited to trials in humans and published in English language. Study population included women who were prescribed opioids after obstetric and/or gynecologic procedures. Information on opioid consumption, leftover, and disposal patterns were extracted and compared among different procedures. Potential risk of bias was evaluated using the Newcastle-Ottawa Scale for cohort studies and the National Heart, Lung, and Blood Institute Study Quality Assessment Tool of Controlled Interventional Studies for clinical trial. TABULATION, INTEGRATION, AND RESULTS: Of 2343 articles, 10 were used in the analysis: 9 cohorts and 1 randomized clinical trial. We found that among patients who underwent obstetric and gynecologic procedures, a considerable number of opioids are unused. The total number of consumed opioids after discharge in patients who underwent cesarean delivery was 21.8 oral morphine equivalent (OME); vaginal hysterectomy, 55.7 OME; abdominal hysterectomy, 105.8 OME; and laparoscopic hysterectomy, 89.0 OME. The number of opioids leftover in the vaginal, abdominal, and laparoscopic hysterectomy groups was 67.6 OME, 115.5 OME, and 95.3 OME, respectively. On average, 77.5% of leftover opioids were not disposed/kept, whereas only 20% discarded their medication through a disposal program. Five studies were deemed to have fair quality, and the rest were rated as good quality. CONCLUSION: Compared with those after cesarean delivery, patients undergoing gynecologic procedures consumed a large number of opioids, especially after abdominal hysterectomies. Abdominal hysterectomy was also associated with a high number of opioids leftover. Most patients did not use the entire prescribed opioids and were either keeping their unused opioids or unsure about what to do with them. We recommend perioperative opioid-specific counseling and education on opioid consumption, potential hazards of unused medication, and proper disposal for patients. Strategies to reduce opioids prescription by physicians should be considered.

MYO10 promotes transzonal projection-dependent germ line-somatic contact during mammalian folliculogenesis†.

Granulosa cells of growing ovarian follicles elaborate filopodia-like structures termed transzonal projections (TZPs) that supply the enclosed oocyte with factors essential for its development. Little is known, however, of the mechanisms underlying the generation of TZPs. We show in mouse and human that filopodia, defined by an actin backbone, emerge from granulosa cells in early stage primary follicles and that actin-rich TZPs become detectable as soon as a space corresponding to the zona pellucida appears. mRNA encoding Myosin10 (MYO10), a motor protein that accumulates at the base and tips of filopodia and has been implicated in their initiation and elongation, is present in granulosa cells and oocytes of growing follicles. MYO10 protein accumulates in foci located mainly between the oocyte and innermost layer of granulosa cells, where it colocalizes with actin. In both mouse and human, the number of MYO10 foci increases as oocytes grow, corresponding to the increase in the number of actin-TZPs. RNAi-mediated depletion of MYO10 in cultured mouse granulosa cell-oocyte complexes is associated with a 52% reduction in the number of MYO10 foci and a 28% reduction in the number of actin-TZPs. Moreover, incubation of cumulus-oocyte complexes in the presence of epidermal growth factor, which triggers a 93% reduction in the number of actin-TZPs, is associated with a 55% reduction in the number of MYO10 foci. These results suggest that granulosa cells possess an ability to elaborate filopodia, which when directed toward the oocyte become actin-TZPs, and that MYO10 increases the efficiency of formation or maintenance of actin-TZPs.

Hereditary breast cancer and fertility preservation outcomes.

PURPOSE: To determine the frequency of hereditary breast cancer associated with different mutated genes and to evaluate fertility preservation (FP) outcomes among young women with hereditary breast cancer when compared to non-hereditary breast cancer. MATERIAL AND METHODS: A retrospective cohort study of women with breast cancer who underwent fertility preservation treatment at our academic fertility center between 2005 and 2019. We included all women with breast cancer aged < 40 years who had a genetic testing and underwent fertility preservation before starting gonadotoxic therapy (n = 132). Our objective was to evaluate the total number of oocytes retrieved, mature oocytes MII, embryos (where appropriate), cryopreserved oocytes, and/or embryos. RESULTS: Of 132 women with breast cancer, 40 women were found to be genetically positive (31.4%), 31 women of 40 (77.5%) had a BRCA mutation, 3 (7.5%) had ATM, 2 (5%) had CHK2, and one (2.5%) for each of the following genes: PALP2, NF, MUTYH.c.536A, and TP53. There was no significant difference between the groups in the total number of eggs retrieved and the number of MII oocytes and cryopreserved oocytes. The numbers of fertilized oocytes and cryopreserved embryos in the hereditary (n = 40) and non-hereditary (n = 92) group were (5.15 ± 6.6 vs 2.90 ± 4.2, P = 0.054) and (3.35 ± 3.7 vs 1.9 ± 2.8, P = 0.046) respectively. CONCLUSION: More than three quarters of positive mutated genes in women with breast cancer are BRCA mutations. Compared to those with non-hereditary breast cancer, women with hereditary breast cancer attained higher number of cryopreserved embryos.

Complete Erosion of Abdominal Cerclage Into the Bladder.

BACKGROUND: Abdominal cerclage is indicated for some women with cervical insufficiency. Long-term complications from cerclage are rare. CASE: Here we report the case of a patient who presented with recurrent urinary tract infection and hematuria 5 years after laparoscopic abdominal cerclage. Cystoscopy revealed bladder stones surrounding a foreign body. Another cystoscopy 3 months later showed complete erosion of the cerclage into the bladder. CONCLUSION: This case reminds us that differential diagnosis of urinary symptoms in women who have undergone cervical cerclage should include suture erosion into the bladder. Cerclage removal can be offered to women who have completed childbearing to prevent this rare complication.

Further evidence that endometriosis is related to tubal and ovarian cancers: A study of 271,444 inpatient women.

OBJECTIVE: To evaluate associations between endometriosis and tubal and ovarian cancers in a large population-based study. METHODS: The Health Care Cost and Utilization Project - National Inpatient Sample databases from 2005 to 2014 were used in this study. Data on patients with a diagnosis of tubal or ovarian cancer and endometriosis (overall and subtypes including adenomyosis and pelvic endometriosis) using International Classification of Diseases, Ninth Edition, Clinical Modification codes were extracted. Logistic regression analysis was performed to evaluate associations between tubal and ovarian cancers and endometriosis. Adjustment was made for age, race, median income level, payment plan, hospital location and obesity. RESULTS: Of 38,800,139 women aged >18 years who were hospitalized between 2005 and 2014, 271,444 women with adenomyosis and/or pelvic endometriosis, 4289 women with tubal cancer and 133,253 women with ovarian cancer were identified. The rate of tubal cancer was three-fold higher in women with endometriosis compared with women without endometriosis (0.03 % vs 0.01 %). The odds ratio (OR) adjusted for age, race, obesity, income and insurance type was 4.02 [95 % confidence interval (CI) 3.17-5.11; p < 0.01]. The rate of tubal cancer was higher in women with adenomyosis (0.04 % vs 0.01 %; adjusted OR 4.88, 95 % CI 3.66-6.50; p < 0.01) and women with pelvic endometriosis (0.02 % vs 0.01 %; adjusted OR 2.80, 95 % CI 1.84-4.27; p < 0.01) compared with women without these conditions. Similar associations were found between ovarian cancer and pelvic endometriosis and ovarian cancer and adenomyosis. CONCLUSION: Both pelvic endometriosis and adenomyosis are strongly associated with tubal and ovarian cancers.