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

Fertility and pregnancy outcomes following uterine artery embolization (UAE) for uterine arteriovenous malformation (AVM)

A 19-year-old patient presented with intractable uterine bleeding, 11 weeks post-abortion. A pelvic ultrasound with Doppler and color imaging suggested a uterine arteriovenous malformation. Failing conservative therapies, the patient consented to uterine artery embolization (UAE). Two months later, she conceived and had an uneventful normal vaginal delivery at term. Since this is an extremely rare condition, allowing limited clinical exposure and experience, there may be an underlying reluctance by general practitioners to treat these cases with uterine artery embolization for fear of compromising future fertility and pregnancies. However, data from the 20 pregnancies embolized for uterine AVM cited in the present report and data from embolization for uterine fibroids indicate that such fears may be unfounded since pregnancy rates and outcomes may not be compromised after UAE. © 2009 Springer-Verlag

Ureteric Injury During Transvaginal Ultrasound Guided Oocyte Retrieval

Background: Transvaginal ultrasound guided oocyte retrieval during in vitro fertilization is performed routinely around the world and has reduced the occurrence of intra-abdominal injury considerably over laparoscopic procedures. Despite this, injuries do occur. Case: We report a case of a 37-year-old patient who underwent IVF and encountered a ureteric injury during oocyte retrieval, which was recognized early and treated with ureteral stents with full resolution. During a subsequent IVF cycle, stenting of the ureters allowed better visualization, resulting in an uneventful retrieval and subsequent pregnancy. Conclusion: Ureteric injury can occur during transvaginal ultrasound guided egg retrieval. Prompt recognition is vital to successful treatment. Stenting of the ureters is the most common therapeutic modality and can be used in subsequent retrievals to identify the ureters

Postablation endometrial carcinoma

Background: Many women have undergone both resectoscopic and nonresectoscopic (or global) endometrial ablation (EA) during the past 20 years. These women are now approaching their sixth and seventh decades of life, a time frame in which endometrial carcinoma (EC) is most frequently diagnosed. Database: In several reports, surgeons have expressed concern that endometrial ablation may leave a sequestered island of EC that may escape detection, possibly delaying its diagnosis or causing it to appear at an advanced stage. Others suggest that EA artifact does not hinder the evaluation and treatment planning in the presence of EC. Data bases used are from Medline and PubMed. Discussion: We introduce 6 new cases of postablation endometrial carcinoma (PAEC), 4 of which occurred after the introduction of global endometrial ablation (GEA) techniques. In addition, we examine several key questions regarding the impact of EA on the subsequent development of EC, including the manner in which PAEC presents, the efficacy of traditional diagnostic modalities, the ablation-to-cancer interval, and the stage of PAEC at the time of diagnosis. Finally, we explore the use of reoperative hysteroscopic surgery (RHS) as a diagnostic modality and address the possible role ultrasound surveillance as a screening method for women at risk of EC

Long-term clinical outcomes of repeat hysteroscopic endometrial ablation after failed hysteroscopic endometrial ablation

The study aims to describe patient characteristics, uterine cavity shape and histopathology, complications, and long-term clinical outcomes of women who failed hysteroscopic rollerball or loop endometrial ablation (HEA) and subsequently consented to repeat hysteroscopic endometrial ablation (RHEA), and is a retrospective cohort study (Canadian Task Force classification II-2). The study was conducted in the university-affiliated teaching hospital. Patients included women who failed primary hysteroscopic endometrial ablation (PHEA, n = 183) and subsequently underwent RHEA by the senior author (GAV) from 1993 through 2007 with a minimum follow-up of 5 years. RHEA was performed under general anesthesia using 26 F (~9 mm) resectoscope, monopolar loop electrode in 136 (74.3 %), 3–5 mm rollerball in 41 (22.4 %) or combination in 6 (3.3 %) women. Patient characteristics, uterine cavity, and clinical outcomes of women who failed PHEA and subsequently consented to RHEA were evaluated by retrospective chart review and patient follow-up including office visits and/or telephone interview. The corresponding median age (range) for PHEA and RHEA was 40 (26–70) and 43 (29–76) years. Indications for PHEA included abnormal uterine bleeding (AUB, 52.7 %), AUB and dysmenorrhea (25.8 %), dysmenorrhea (18.8 %), and others (2.7 %). Indications for RHEA included persistent AUB (53 %), AUB and uterine/pelvic pain (26.2 %), uterine/pelvic pain only (19.1 %), postmenopausal bleeding (1.1 %), and thickened endometrium (0.5 %). Complications of RHEA (n = 7, 3.8 %) included false passage (3), uterine perforation (2), and bleeding (2). One patient with excessive bleeding required immediate hysterectomy. At a median follow-up of 9 years (5–19), 69 % of women avoided hysterectomy. Repeat hysteroscopic endometrial ablation is a feasible, safe, and long-term effective alternative to hysterectomy for abnormal uterine bleeding from benign causes when performed by experienced surgeons

The Management of Uterine Leiomyomas

Objectives: The aim of this guideline is to provide clinicians with an understanding of the pathophysiology, prevalence, and clinical significance of myomata and the best evidence available on treatment modalities. Options: The areas of clinical practice considered in formulating this guideline were assessment, medical treatments, conservative treatments of myolysis, selective uterine artery occlusion, and surgical alternatives including myomectomy and hysterectomy. The risk-to-benefit ratio must be examined individually by the woman and her health care provider. Outcomes: Implementation of this guideline should optimize the decision-making process of women and their health care providers in proceeding with further investigation or therapy for uterine leiomyomas, having considered the disease process and available treatment options, and reviewed the risks and anticipated benefits. Evidence: Published literature was retrieved through searches of PubMed, CINAHL, and Cochrane Systematic Reviews in February 2013, using appropriate controlled vocabulary (uterine fibroids, myoma, leiomyoma, myomectomy, myolysis, heavy menstrual bleeding, and menorrhagia) and key words (myoma, leiomyoma, fibroid, myomectomy, uterine artery embolization, hysterectomy, heavy menstrual bleeding, menorrhagia). The reference lists of articles identified were also searched for other relevant publications. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to January 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, and national and international medical specialty societies. Benefits, Harms, and Costs: The majority of fibroids are asymptomatic and require no intervention or further investigations. For symptomatic fibroids such as those causing menstrual abnormalities (e.g. heavy, irregular, and prolonged uterine bleeding), iron defficiency anemia, or bulk symptoms (e.g., pelvic pressure/pain, obstructive symptoms), hysterectomy is a definitive solution. However, it is not the preferred solution for women who wish to preserve fertility and/or their uterus. The selected treatment should be directed towards an improvement in symptomatology and quality of life. The cost of the therapy to the health care system and to women with fibroids must be interpreted in the context of the cost of untreated disease conditions and the cost of ongoing or repeat investigative or treatment modalities. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Caadian Task Force on Preventive Health Care (Table 1)

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 \u3c 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

Corrigendum to ‘Guideline No. 412: Laparoscopic Entry for Gynaecological Surgery’ [Journal of Obstetrics and Gynaecology Canada 43 (2021) 376−389](S1701216320310343)(10.1016/j.jogc.2020.12.012)

The authors regret that the print version of this article contained the incorrect reference 51. Reference 51 should have been: Bernante P, Foletto M, Toniato A. Creation of pneumoperitoneum using a bladed optical trocar in morbidly obese patients: technique and results. Obes Surg. 2008 Aug;18(8):1043-6. doi: 10.1007/s11695-008-9497-8. The online version of the article has now been corrected The authors would like to apologize for any confusion this caused. DOI of original article: https://doi.org/10.1016/j.jogc.2021.03.00

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

Beyond the brain-Peripheral kisspeptin signaling is essential for promoting endometrial gland development and function

Uterine growth and endometrial gland formation (adenogenesis) and function, are essential for fertility and are controlled by estrogens and other regulators, whose nature and physiological relevance are yet to be elucidated. Kisspeptin, which signals via Kiss1r, is essential for fertility, primarily through its central control of the hypothalamic-pituitary-ovarian axis, but also likely through peripheral actions. Using genetically modified mice, we addressed the contributions of central and peripheral kisspeptin signaling in regulating uterine growth and adenogenesis. Global ablation of Kiss1 or Kiss1r dramatically suppressed uterine growth and almost fully prevented adenogenesis. However, while uterine growth was fully rescued by E2 treatment of Kiss1-/- mice and by genetic restoration of kisspeptin signaling in GnRH neurons in Kiss1r-/- mice, functional adenogenesis was only marginally restored. Thus, while uterine growth is largely dependent on ovarian E2-output via central kisspeptin signaling, peripheral kisspeptin signaling is indispensable for endometrial adenogenesis and function, essential aspects of reproductive competence