Bipedalism and the dawn of uterine fibroids.

The high prevalence and burden of uterine fibroids in women raises questions about the origin of these benign growths. Here, we propose that fibroids should be understood in the context of human evolution, specifically the advent of bipedal locomotion in the hominin lineage. Over the ≥7 million years since our arboreal ancestors left their trees, skeletal adaptations ensued, affecting the pelvis, limbs, hands, and feet. By 3.2 million years ago, our ancestors were fully bipedal. A key evolutionary advantage of bipedalism was the freedom to use hands to carry and prepare food and create and use tools which, in turn, led to further evolutionary changes such as brain enlargement (encephalization), including a dramatic increase in the size of the neocortex. Pelvic realignment resulted in narrowing and transformation of the birth canal from a simple cylinder to a convoluted structure with misaligned pelvic inlet, mid-pelvis, and pelvic outlet planes. Neonatal head circumference has increased, greatly complicating parturition in early and modern humans, up to and including our own species. To overcome the so-called obstetric dilemma provoked by bipedal locomotion and encephalization, various compensatory adaptations have occurred affecting human neonatal development. These include adaptations limiting neonatal size, namely altricial birth (delivery of infants at an early neurodevelopmental stage, relative to other primates) and mid-gestation skeletal growth deceleration. Another key adaptation was hyperplasia of the myometrium, specifically the neomyometrium (the outer two-thirds of the myometrium, corresponding to 90% of the uterine musculature), allowing the uterus to more forcefully push the baby through the pelvis during a lengthy parturition. We propose that this hyperplasia of smooth muscle tissue set the stage for highly prevalent uterine fibroids. These fibroids are therefore a consequence of the obstetric dilemma and, ultimately, of the evolution of bipedalism in our hominin ancestors.

Hysteroscopic Endometrial Resection in Women Treated With Tamoxifen for Breast Cancer Provides Definitive Diagnosis and Effective Long-Term Therapy.

We evaluated resectoscopic surgery for definitive diagnosis and long-term therapy in 16 symptomatic tamoxifen-treated women with breast cancer who presented with abnormal uterine bleeding and/or intrauterine anomalies. Seven pre-menopausal women had benign pre- and post-operative endometrial biopsy, and 4 had benign polyps. At a median of 7 years of follow-up (range 2-8 y), all remained amenorrheic. Of 9 post-menopausal women, pre-operative biopsy was inadequate in 4, benign endometrium was found in 4, and non-atypical endometrial hyperplasia was found in 1. Post-operatively, all had benign pathology, 8 having polyp and 1 leiomyoma. At a median follow-up of 7 years (range 2-13 y), all were amenorrheic, with no recurrence of breast cancer or uterine pathology.

Impact of the COVID-19 Pandemic on Access to Fertility Care: A Retrospective Study at a University-Affiliated Fertility Practice.

OBJECTIVE: To elucidate the impact of the COVID-19 pandemic on access to fertility services. METHODS: A retrospective quality improvement study was conducted at a university-affiliated fertility practice in southwestern Ontario. Annual procedural volumes for intrauterine and donor inseminations (IUI/DI), in vitro fertilization and intracytoplasmic sperm injections (IVF/ICSI), and frozen embryo transfers (FET) during the COVID-19-affected year were compared with mean annual volumes from the 2 preceding years. In addition, volumes for the same procedures were compared between the first quarter of 2021 and mean first quarter volumes from 2018 to 2019. Piecewise linear regressions were conducted to evaluate whether any changes in monthly procedural volume were attributable to the COVID-19 pandemic. RESULTS: In 2020, our fertility practice attained the mean annual volumes of 89.7% for IUI/DI, 69.0% for IVF/ICSI, and 60.6% for FET. In contrast, in 2021, we performed mean first quarter volumes of 130.1% for IUI/DI, 164.3% for IVF/ICSI, and 126.8% for FET. The slopes of the pre- and post-COVID-19 segments of the piecewise linear regressions were significantly different for IUI/DI (P < 0.001) and IVF/ICSI (P = 0.001), but not for FET (P = 0.133). CONCLUSION: The COVID-19 pandemic resulted in decreased annual volumes of medically assisted reproductive procedures at a university-affiliated fertility practice in southwestern Ontario. Impact on monthly procedural volume was confirmed for IUI/DI and IVF/ICSI by linear regression. Local adaptations helped compensate and exceed expected volumes in 2021. As a result, the COVID-19 pandemic resulted in a short-lived limitation in access to fertility care.

Uterine kisspeptin receptor critically regulates epithelial estrogen receptor α transcriptional activity at the time of embryo implantation in a mouse model.

Embryo implantation failure is a major cause of infertility in women of reproductive age and a better understanding of uterine factors that regulate implantation is required for developing effective treatments for female infertility. This study investigated the role of the uterine kisspeptin receptor (KISS1R) in the molecular regulation of implantation in a mouse model. To conduct this study, a conditional uterine knockout (KO) of Kiss1r was created using the Pgr-Cre (progesterone receptor-CRE recombinase) driver. Reproductive profiling revealed that while KO females exhibited normal ovarian function and mated successfully to stud males, they exhibited significantly fewer implantation sites, reduced litter size and increased neonatal mortality demonstrating that uterine KISS1R is required for embryo implantation and a healthy pregnancy. Strikingly, in the uterus of Kiss1r KO mice on day 4 (D4) of pregnancy, the day of embryo implantation, KO females exhibited aberrantly elevated epithelial ERα (estrogen receptor α) transcriptional activity. This led to the temporal misexpression of several epithelial genes [Cftr (Cystic fibrosis transmembrane conductance regulator), Aqp5 (aquaporin 5), Aqp8 (aquaporin 8) and Cldn7 (claudin 7)] that mediate luminal fluid secretion and luminal opening. As a result, on D4 of pregnancy, the lumen remained open disrupting the final acquisition of endometrial receptivity and likely accounting for the reduction in implantation events. Our data clearly show that uterine KISS1R negatively regulates ERα signaling at the time of implantation, in part by inhibiting ERα overexpression and preventing detrimentally high ERα activity. To date, there are no reports on the regulation of ERα by KISS1R; therefore, this study has uncovered an important and powerful regulator of uterine ERα during early pregnancy.

Guideline No. 412: Laparoscopic Entry for Gynaecological Surgery.

OBJECTIVE: To evaluate the benefits and risks of laparoscopic surgery and provide clinical direction on entry techniques, technologies, and their associated complications in gynaecological surgery. TARGET POPULATION: All patients, including pregnant women and women with obesity, undergoing laparoscopic surgery for various gynaecological indications. OPTIONS: The laparoscopic entry techniques and technologies reviewed in formulating this guideline included the closed (Veress needle-pneumoperitoneum-trocar) technique, direct trocar insertion, open (Hasson) technique, visual entry systems, and disposable shielded and radially expanding trocars. OUTCOMES: Implementation of this guideline should optimize decision-making in the selection of entry technique for laparoscopic surgery. EVIDENCE: We searched English-language articles from September 2005 to December 2019 in PubMed/MEDLINE, Embase, Science Direct, Scopus, and Cochrane Library using the following MeSH search terms alone or in combination: laparoscopic entry, laparoscopy access, pneumoperitoneum, Veress needle, open (Hasson), direct trocar, visual entry, shielded trocars, radially expanded trocars, and laparoscopic complications. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Canadian Task Force on Preventive Health Care approach (Appendix A). INTENDED AUDIENCE: Surgeons performing laparoscopic gynaecological surgery. SUMMARY STATEMENTS: RECOMMENDATIONS.

Uterine aquaporin expression is dynamically regulated by estradiol and progesterone and ovarian stimulation disrupts embryo implantation without affecting luminal closure.

The study investigated the effect of normal and supraphysiological (resulting from gonadotropin-dependent ovarian stimulation) levels of estradiol (E2) and progesterone (P4) on mouse uterine aquaporin gene/protein (Aqp/AQP) expression on Day 1 (D1) and D4 of pregnancy. The study also examined the effect of ovarian stimulation on uterine luminal closure and uterine receptivity on D4 of pregnancy and embryo implantation on D5 and D7 of pregnancy. These analyses revealed that the expression of Aqp3, Aqp4, Aqp5 and Aqp8 is induced by E2 while the expression of Aqp1 and Aqp11 is induced by P4. Additionally, P4 inhibits E2 induction of Aqp3 and Aqp4 expression while E2 inhibits Aqp1 and Aqp11 expression. Aqp9, however, is constitutively expressed. Ovarian stimulation disrupts Aqp3, Aqp5 and Aqp8 expression on D4 and AQP1, AQP3 and AQP5 spatial expression on both D1 and D4, strikingly so in the myometrium. Interestingly, while ovarian stimulation has no overt effect on luminal closure and uterine receptivity, it reduces implantation events, likely through a disruption in myometrial activity and embryo development. The wider implication of this study is that ovarian stimulation, which results in supraphysiological levels of E2 and P4 and changes (depending on the degree of stimulation) in the E2:P4 ratio, triggers abnormal expression of uterine AQP during pregnancy, and this is associated with implantation failure. These findings lead us to recognize that abnormal expression would also occur under any pathological state (such as endometriosis) that is associated with changes in the normal E2:P4 ratio. Thus, infertility among these patients might in part be linked to abnormal uterine AQP expression.

Venous Gas Embolism during Hysteroscopic Endometrial Ablation: Report of 5 Cases and Review of the Literature.

STUDY OBJECTIVE: To highlight the circumstances, presentation, and treatment of venous gas embolism (VGE) and provide guidance and propose potential changes in surgical practice and perioperative monitoring to minimize the adverse consequences and sequalae of this potentially serious complication. DESIGN: A case series. SETTING: A university-affiliated teaching hospital. PATIENTS: Five women developed VGE during hysteroscopic endometrial ablation. INTERVENTIONS: From 1990 through 2014, the principle author (G.A.V.) performed 5249 primary and 458 repeat hysteroscopic endometrial ablations under general anesthesia using a monopolar 26F (9-mm) resectoscope connected to a peristaltic pump-driven active inflow and outflow irrigation and distension system (1.5% glycine) and an 8-mm monopolar loop electrode at a 120-W continuous (cut) and/or a 3- to 5-mm rollerball interrupted (coagulation) waveform or a combination of them. MEASUREMENTS AND MAIN RESULTS: Among 5707 procedures, we encountered 5 (0.09%, 1/1140) incidents of VGE during primary ablations. All patients exhibited the same symptoms of ventilatory and hemodynamic decompensation, beginning with a reduction in end-tidal carbon dioxide and arterial oxygen desaturation. All patients recovered after immediate cessation of the surgery and resuscitation including ventilatory support with 100% O2 and intravenous fluids. CONCLUSIONS: Although entrainment of some air/gas bubbles is common during hysteroscopy, life-threatening/fatal VGE is rare (1/1140 cases). Situational awareness and strict adherence to certain principles including understanding the conditions, prerequisites, and pathophysiology of VGE; attention to surgical principles and operative technique; close communication with the anesthesiologist; and early therapeutic intervention are of paramount importance to avoid this rare but potentially serious complication.

Histopathology and Clinical Outcomes of 151 Women with Postmenopausal Bleeding Treated with Resectoscopic Surgery.

STUDY OBJECTIVE: Because postmenopausal bleeding (PMB) is associated with up to 10% of endometrial neoplasia and office endometrial sampling fails in approximately 10% and is inadequate in 30% of cases, the objective was to determine the role of hysteroscopic endometrial resection (HER) for the diagnosis and treatment of women with PMB. DESIGN: A retrospective cohort. SETTING: A university-affiliated teaching hospital. PATIENTS: One hundred fifty-one women with PMB (September 1990-December 2010). INTERVENTION: HER in the operating room. MEASUREMENTS AND MAIN RESULTS: The median (range) age and body mass index were 58 (50-87) years and 29 (21-52) kg/m2, respectively. Office endometrial biopsy failed in 30 (19.8%), was inadequate in 20 (13.2%), identified nonatypical endometrial hyperplasia (NAH) in 21 (14%), atypical hyperplasia (AH) in 4 (2.6%), and endometrial cancer (EC) in 2 (1.3%) women. HER in 151 women identified 7 new cases of AH (3 from failed/inadequate office biopsy and 4 from NAH) and 9 EC (5 from failed/inadequate office biopsy, 1 from proliferative endometrium, 2 from NAH, and 1 from AH). All 27 women with NAH were treated by HER alone. Of 8 women with AH, 6 were treated with HER and 2 with hysterectomy; no residual endometrium was found in hysterectomy specimens. Of the 11 women with EC, 2 refused hysterectomy and are well 10 and 15 years after HER. Hysterectomy was performed for 9 of 11 EC cases, 2 of 8 AH cases, and 1 for abnormal uterine bleeding. Six women had repeat HER for persistent abnormal uterine bleeding, and 10 were lost to follow-up. At a median follow-up of 11.5 years (range, 7-20 years), 132 (12 hysterectomies + 10 lost) of 151 (87.4%) women were satisfied with no further bleeding. CONCLUSION: In women with PMB, hysteroscopic endometrial resection concomitantly with resection of intrauterine pathology by experienced surgeons is feasible, safe, and effective for diagnosis in all cases and treatment of the majority of intrauterine pathology including NAH and selected cases of AH and EC.

Interventional Uterine-Sparing Therapies for Leiomyomas: A Commentary on Myolysis.

Uterine leiomyomas (myomas, fibroids) are very common in premenopausal women and frequently are associated with abnormal uterine bleeding, bulk effects, and reproductive issues. In women who wish to retain their uterus and/or to enhance or retain fertility, interventional therapies have been introduced, including radiofrequency, laser (chromo), cryotherapy, and magnetic resonance (MR)-guided high-intensity focused ultrasound (MRgHIFU) myolysis. In formulating this commentary, all modalities of myolysis from systematic reviews, randomized controlled clinical trials, and observational studies through December 2018 were reviewed. There are only two treatment modalities available in Canada: the laparoscopic radiofrequency volumetric thermal ablation of fibroids (RFVTA) and MRgHIFU systems. In women who wish to enhance or retain their fertility, the safety and efficacy of radiofrequency and HIFU myolysis have not been clearly established, and these treatments should be offered only after extensive counselling and informed consent. Given the recent concerns regarding the incidence of undiagnosed malignant tumours, the lack of histological confirmation before or after these therapies for symptomatic fibroids mandates a thorough process of informed patient consent before any such interventions.

Uterine Tumors Resembling Ovarian Sex Cord Tumors Identified at Resectoscopic Endometrial Ablation: Report of 2 Cases.

STUDY OBJECTIVES: To report 2 cases of uterine tumors resembling ovarian sex cord tumors (UTROSCTs) and examine the clinical significance of these tumors found during hysteroscopic endometrial ablation despite benign preoperative endometrial biopsy analysis and imaging suggestive of leiomyoma. DESIGN: Case report (Canadian Task Force classification III). SETTING: Tertiary care hospital. PATIENTS: Two patients with abnormal uterine bleeding. INTERVENTIONS: Hysteroscopic endometrial ablation/resection. MEASUREMENTS AND MAIN RESULTS: Pathological analysis of intrauterine tissue/lesions obtained by curettage or resection identified 2 unexpected UTROSCTs masquerading as leiomyomas. Following hysterectomy, no residual UTROSCT was identified in the specimens, and both women are well, one at 1 year postsurgery and the other at 3 years postsurgery. CONCLUSION: Obtaining additional tissue by routine curettage before endometrial ablation and/or endomyometrial resection, in conjunction with removal of any intrauterine lesions, can identify rare unexpected endometrial lesions not sampled by endometrial biopsy, not detected with ultrasound, and masquerading as leiomyomas during endometrial ablation.

Resolution of Uterine Arteriovenous Malformation and Maintenance of Reproduction in 20 Women Treated with a GnRH Agonist Concomitantly with an Aromatase Inhibitor and Tranexamic Acid.

OBJECTIVE: This study investigated the efficacy of GnRH agonists concomitantly with transient aromatase inhibitor and tranexamic acid to treat women with uterine arteriovenous malformations (AVMs) associated with abnormal uterine bleeding (AUB) to preserve fertility and determine reproductive outcome. METHODS: This was a prospective cohort study in a tertiary centre. Doppler ultrasound demonstrated AVM in 19 women with AUB 1-28 weeks following spontaneous or therapeutic abortion and in one woman 4 years after normal pregnancy while taking an oral contraceptive. On the basis of experience from the first three cases, 17 women were treated with tranexamic acid (1 g three times daily orally for 5 days), a GnRH agonist (3.75-11.25 mg, for 1-3 months), plus an aromatase inhibitor (letrozole 2.5 mg once daily for 5days) with the initial injection of GnRH agonist. Two women required blood transfusion, and one required uterine tamponade with Foley catheter balloon in the first 48 hours to control heavy bleeding (Canadian Task Force Classification II-2). RESULTS: All 20 AVMs resolved within 1-3 months of treatment. Of 16 women who attempted pregnancy, all (100%), including two who had uterine artery embolization (one after hysteroscopic septoplasty), conceived spontaneously with 18 live births. Two women are using contraception (one taking an oral contraceptive, one using a levonorgestrel intrauterine system), and one 40-year-old is not using contraception. One woman had hysteroscopic endometrial ablation followed by vaginal hysterectomy for AUB at 1 and 2 years later. CONCLUSION: A GnRH agonist in combination with transient aromatase inhibitor and tranexamic acid is an effective management strategy to treat and maintain reproduction in women with AVMs associated with AUB.