Outcomes of women treated with progestin and metformin for atypical endometrial hyperplasia and early endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: Progestin therapy is the recommended fertility-sparing management of atypical endometrial hyperplasia or early-stage endometrial cancer in reproductive-aged women. Our objective was to evaluate disease relapse after progestin and metformin versus progestin therapy alone in patients with endometrial hyperplasia or cancer. Our secondary outcomes were disease remission, clinical pregnancy and live birth rate. METHODS: A systematic review of the literature was conducted (MEDLINE, Web of Science, Cochrane Library, CINAHL, LILACS, clinicaltrials.gov) from inception to April 2021. Studies of reproductive-aged women with atypical endometrial hyperplasia or early endometrial cancer who received progestin and metformin or progestin alone for fertility-sparing management, were included in the review. Early endometrial cancer was defined as grade 1, stage 1 disease. Exclusion criteria included women with higher grade endometrial cancer and when conservative management was not for fertility-sparing purposes. Data are presented as odds ratios (ORs) and 95% confidence intervals (CIs) with fixed or random effects meta-analysis. Quality scoring was based on the Newcastle-Ottawa and Jadad scales. RESULTS: In total, 271 reports were identified and six studies met the inclusion criteria. These studies included 621 women; 241 (38.8%) patients received combined therapy and 380 (61.2%) received progestin therapy alone. Relapse rates were lower for progestin and metformin than for progestin therapy alone (pooled OR 0.46, 95% CI 0.24 to 0.91, p=0.03). The remission rates were not different (pooled OR 1.35, 95% CI 0.91 to 2.00, p=0.14). Women who received progestin and metformin achieved pregnancy and live birth rates similar to those who received progestin therapy only (pooled OR 1.01, 95% CI 0.44 to 2.35, p=0.98; pooled OR 0.46, 95% CI 0.21 to 1.03, p=0.06). CONCLUSION: For reproductive-aged women with atypical endometrial hyperplasia or early endometrial cancer, progestin and metformin therapy compared with progestin therapy alone is associated with lower relapse rates, and similar remission, clinical pregnancy and live birth rates. PROSPERO REGISTRATION NUMBER: CRD42020179069.disease remission.

Regional disparities in access to assisted reproductive technology: assessment of patient satisfaction when employing modern technology to close the gap.

PURPOSE: Geographic disparities for assisted reproductive technology (ART) continue to exist. Travel cost and time off work may create additional barriers for patients living remotely. Implementing telehealth can alleviate these barriers by reducing office visits. The aim of this study was to evaluate patient satisfaction with telehealth during ART. METHODS: This was a cross-sectional survey and retrospective cohort study. Patients living remotely who underwent ART utilizing telehealth between 2015 and 2018 at a single institution were selected for the telehealth group. The non-telehealth control group included randomly selected patients who underwent IVF at the same institution between 2015 and 2018. Demographic variables and treatment outcomes were obtained for both groups. A patient satisfaction questionnaire was distributed to telehealth patients. Statistical analysis using χ2 test was performed to compare ART outcomes between both groups. RESULTS: Ninety-seven control and 97 telehealth patients were included. For telehealth patients, the mean number of office visits and distance traveled was 2.9 (± 0.8 SD) and 143.1 miles (± 49.2 SD) respectively. 58.8% of patients completed the survey. 44/57 participants had an oocyte retrieval and 42/44 underwent embryo transfer. For those who completed the survey, the clinical pregnancy rate was 31/44 and the live birth rate was 25/44. There was no difference in treatment outcomes between telehealth compared to controls. 73% of patients were highly satisfied with telehealth. CONCLUSIONS: Telehealth can improve access to ART in underserved areas and results in high patient satisfaction. Reproductive health providers could consider telehealth as a safe and efficacious tool to ameliorate geographic disparities.

Emergent Oocyte Cryopreservation with a Novel Ovarian Transposition Technique in a Colorectal Cancer Patient: A Combined Approach for Fertility Preservation. A Case Report.

BACKGROUND: Fertility preservation has become a standard of care in reproductive-age oncology patients. However, research has demonstrated that the knowledge of the provider and referral practice patterns remain suboptimal. Fertility preservation should be discussed with oncology patients of reproductive age, with the full knowledge of the individual. A combined medical and surgical approach may further ensure their reproductive successes in the future. CASE: A 38-year-old, nulliparous woman with colorectal cancer desired fertility preservation prior to cancer therapy. She underwent a laparoscopic ovarian transposition using a novel percutaneous suturing technique after emergent ovarian stimulation, followed by oocyte retrieval and cryopreservation. One year after chemotherapy and pelvic radiation the patient resumed regular menstrual cycles. CONCLUSION: A combined approach using emergent oocyte cryopreservation and a novel laparoscopic ovarian transposition is an optimal fertility preservation strategy in women with colorectal cancer. Fertility preservation success is dependent upon a multidisciplinary approach of well-informed medical teams consisting of an oncologist, a surgeon, a radiation oncologist, and a reproductive specialist.

Changes in adenomyosis following elagolix vs leuprolide treatment in a patient with pelvic pain and infertility: A case report.

Adenomyosis is a uterine form of endometriosis that poses unique challenges in the management of infertility. Severe pelvic pain and menorrhagia associated with these conditions are commonly managed with intramuscular injections of a gonadotropin-releasing hormone agonist (leuprolide acetate). Since receiving approval by the US Food and Drug Administration in 2018, a novel oral gonadotropin-releasing hormone antagonist, elagolix, has also been increasingly used to manage endometriosis-associated pain. However, the efficacy of elagolix in the treatment of adenomyosis and infertility remains uncertain. In this clinical case of an infertile patient with endometriosis and diminished ovarian reserve, treatment with elagolix effectively controlled her severe endometriosis-related pelvic pain but, surprisingly, failed to prevent concurrent progression of adenomyosis. Subsequently, elagolix was changed to treatment with leuprolide acetate, which led to improvement of adenomyosis in preparation for an embryo transfer during an in vitro fertilization cycle. Women's health providers should be aware that elagolix may not as effectively suppress adenomyosis as leuprolide acetate, particularly in infertility patients undergoing treatment with assisted reproductive technologies.

Adolescent With Concomitant Transverse and Longitudinal Vaginal Septa.

A vaginal septum is a type of Mullerian anomaly that can be longitudinal or transverse, separating the vagina into two canals. Vaginal septa occur due to lack of fusion and recanalization of Mullerian structures, and often present with voiding dysfunction with potential impact on fertility and sexual function. We describe a rare case of concomitant transverse and longitudinal vaginal septa and discuss its presentation. Additionally, we present a unique surgical management of these anomalies. The patient had an uncomplicated postoperative course and had no continence issues on long term follow up.

Initial presentation of granulomatosis with polyangiitis as urethral mass mimicking urethral cancer: A case report.

Granulomatosis with polyangiitis (GPA) is a type of vasculitis in which granulomas deposit in small and medium-size vessels causing inflammation. It frequently affects the respiratory tract, both upper and lower tracts. Glomerulonephritis commonly occurs as well, and other systems can be affected such as the integumentary system and peripheral nervous system. Rarely, urogenital signs and symptoms are present. This report describes a case of a 19-year-old woman who presented with lower urinary tract symptoms and a urethral mass and was subsequently diagnosed with GPA. She responded well to treatment with corticosteroids, rituximab, and avacopan. This case highlights the importance of considering alternative diagnoses when a young woman presents with refractory urinary symptoms. It also highlights fertility issues relative to treatment of GPA that are of interest to the practicing obstetrician/gynecologist.

Perplexing findings during laparoscopic evaluation for tubal factor infertility resulting from a gastric leak after bariatric surgery: A case report.

Tubal factor is the primary type of female infertility, accounting for 25-35% of cases. Common causes include inflammation due to pelvic inflammatory disease, septic abortion, tubal surgery, and surgical adhesions. Bariatric surgery is becoming increasingly popular as rates of obesity rise, with over 256,000 surgeries performed in 2019. Half of these procedures were performed on women of reproductive age. This is the first reported case of a patient with tubal factor infertility as a result of a gastric leak from a remote sleeve gastrectomy that led to extensive abdominal and pelvic adhesions.

Optical Genome Mapping and Single Nucleotide Polymorphism Microarray: An Integrated Approach for Investigating Products of Conception.

Conventional cytogenetic analysis of products of conception (POC) is of limited utility because of failed cultures, as well as microbial and maternal cell contamination (MCC). Optical genome mapping (OGM) is an emerging technology that has the potential to replace conventional cytogenetic methods. The use of OGM precludes the requirement for culturing (and related microbial contamination). However, a high percentage of MCC impedes a definitive diagnosis, which can be addressed by an additional pre-analytical quality control step that includes histological assessment of H&E stained slides from formalin-fixed paraffin embedded (FFPE) tissue with macro-dissection for chorionic villi to enrich fetal tissue component for single nucleotide polymorphism microarray (SNPM) analysis. To improve the diagnostic yield, an integrated workflow was devised that included MCC characterization of POC tissue, followed by OGM for MCC-negative cases or SNPM with histological assessment for MCC-positive cases. A result was obtained in 93% (29/31) of cases with a diagnostic yield of 45.1% (14/31) with the proposed workflow, compared to 9.6% (3/31) and 6.4% (2/31) with routine workflow, respectively. The integrated workflow with these technologies demonstrates the clinical utility and higher diagnostic yield in evaluating POC specimens.

Modern management of hypervascular placental polypoid mass following spontaneous abortion: a case report and literature review.

Hypervascular placental polypoid mass is a possible source of acute hemorrhage after pregnancy. We present a case report and literature review of a rare case after spontaneous miscarriage. We describe the diagnosis, imaging, and management of placental polyps, which includes the use of iliac artery occlusion catheters with concomitant hysteroscopic resection.

Severe late-onset ovarian hyperstimulation syndrome presenting with liver dysfunction after in vitro fertilization: A case report.

Ovarian hyperstimulation syndrome (OHSS) is a feared complication of controlled ovarian stimulation (COS) and can be associated with significant morbidity and mortality. Risk factors for OHSS include a history of OHSS, young age, low body mass index (BMI), polycystic ovary syndrome, elevated serum levels of anti-Müllerian hormone (AMH), large number of recruited follicles, elevated serum levels of estradiol, and higher gonadotropin doses during COS. However, OHSS may develop in patients with minimal risk factors. We present the case of a patient with minimal risk factors who developed severe late-onset OHSS in early pregnancy with liver dysfunction requiring hospitalization. After hospital discharge, her pregnancy resulted in a term live birth. We recommend that clinicians include OHSS in the differential diagnosis of elevated levels of liver enzymes in early pregnancy.

Intraovarian injection of autologous human mesenchymal stem cells increases estrogen production and reduces menopausal symptoms in women with premature ovarian failure: two case reports and a review of the literature.

BACKGROUND: Premature ovarian failure is a relatively common condition that affects 1-3% of adult women. Premature ovarian failure occurs when there is loss of ovarian function in women younger than 40 years of age. The causes are mostly iatrogenic or idiopathic. Amenorrhea and infertility are the most important clinical manifestations. So far, no therapeutic intervention has been proved effective in restoring fertility in patients with premature ovarian failure. Attempts to stimulate ovarian function through hormone manipulation typically prove unsuccessful, and patients usually resort to egg donation to achieve pregnancy. In our preclinical work, intraovarian administration of human bone marrow-derived mesenchymal stem cells was able to restore ovarian hormone production, reactivate folliculogenesis, and reverse infertility in a chemotherapy-induced ovarian failure mouse model. CASE PRESENTATION: We present two cases of Caucasian women with premature ovarian failure who resumed ovarian estrogen production and menses 7 months following autologous bone marrow-derived mesenchymal stem cell injections into the ovary. This pilot clinical study is registered with ClinicalTrials.gov (identifier NCT02696889 ). In this report, we present data from our first two cases that have completed study procedures so far. The bone marrow-derived mesenchymal stem cells were harvested from the bone marrow of the iliac crest of the patients with premature ovarian failure and nucleated cells concentrated and enriched in bone marrow-derived mesenchymal stem cells intraoperatively, and then injected into the patient's right ovary via laparoscopy. Autologous bone marrow stem cell engraftment into the ovary resulted in several improvements in the treated patients with premature ovarian failure. In measurements by transvaginal ultrasound, there were increases of approximately 50% in volume of the treated ovaries in comparison with the contralateral control ovaries that persisted to the end of the study (1 year). Serum levels of estrogen increased by approximately 150% compared with the preoperative levels. Each of the two patients had an episode of menses, and also both of them reported marked improvement of their menopausal symptoms that also persisted to the end of the study (1 year). The bone marrow-derived mesenchymal stem cell implantation procedure was very well tolerated with no reported adverse events. CONCLUSIONS: Our study reveals promising improvement of premature ovarian failure-related clinical manifestations in two patients after intraovarian autologous bone marrow-derived mesenchymal stem cells engraftment. These early observations call for additional assessment and further development of intraovarian bone marrow-derived mesenchymal stem cell injection for possible treatment of patients with premature ovarian failure.

Hypothalamic-Pituitary-Ovarian Axis Disorders Impacting Female Fertility.

The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. Group II disorders display a eugonadal state commonly associated with a wide range of endocrinopathies. Finally, group III constitutes hypergonadotropic hypogonadism secondary to depleted ovarian function. Optimal evaluation and management of these disorders is based on a careful analysis tailored to each patient. This article reviews ovulation disorders based on pathophysiologic mechanisms, evaluation principles, and currently available management options.

Premature Ovarian Insufficiency: Procreative Management and Preventive Strategies.

Premature ovarian insufficiency (POI) is the loss of normal hormonal and reproductive function of ovaries in women before age 40 as the result of premature depletion of oocytes. The incidence of POI increases with age in reproductive-aged women, and it is highest in women by the age of 40 years. Reproductive function and the ability to have children is a defining factor in quality of life for many women. There are several methods of fertility preservation available to women with POI. Procreative management and preventive strategies for women with or at risk for POI are reviewed.

Actions of steroids in mitochondria.

Investigations of indirect and direct actions of steroids on the mitochondria are relatively new areas of research. In this review we provide brief background information regarding mitochondrial structure and function and then focus upon interactions of glucocorticoid, estrogen, androgen, and progesterone receptors with mitochondria. We evaluate the current evidence for steroid receptor localization in the mitochondria based on techniques of Western blot analysis, immunocytochemistry, electron microscopy, and mass spectrometry. Steroid receptor-dependent interactions with mitochondria may include transcriptional regulation of nuclear DNA-encoded mitochondrial proteins, transcriptional regulation of mitochondrial DNA-encoded proteins, or indirect effects on mitochondria due to interactions with cytoplasmic signaling peptides and non-genomic control of cation fluxes. These interactions may play a role in mitochondrial-dependent processes of oxidative phosphorylation and apoptosis. Physiological examples of these interactions are discussed.

Primary ovarian pregnancy after donor embryo transfer: early diagnosis and laparoscopic treatment.

Primary ovarian pregnancy is a rare type of ectopic pregnancy, particularly following in vitro fertilization. Although there have been a few reported cases of primary ovarian pregnancy following in vitro fertilization embryo transfer, we believe this is the first report involving donor embryo transfer. A high index of clinical suspicion, abnormal human chorionic gonadotropin levels, and early ultrasound evaluation may aid timely diagnosis and appropriate management. This report provides a reminder to practitioners to advise patients undergoing embryo transfer of the primary ovarian pregnancy risk. Information is provided herein regarding the diagnosis and management of primary ovarian pregnancy in women treated with in vitro fertilization. We review the criteria for early diagnosis and treatment options.

Androgen excess: Investigations and management.

Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response.

Criteria, prevalence, and phenotypes of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly prevalent disorder effecting reproductive-aged women worldwide. This article addresses the evolution of the criteria used to diagnosis PCOS; reviews recent advances in the phenotypic approach, specifically in the context of the extended Rotterdam criteria; discusses limitations of the current criteria used to diagnosis, particularly when studying adolescents and women in the peri- and postmenopause; and describes significant strides made in understanding the epidemiology of PCOS. This review recognizes that although there is a high prevalence of PCOS, there is increased variability when using Rotterdam 2003 criteria, owing to limitations in population sampling and approaches used to define PCOS phenotypes. Last, we discuss the distribution of PCOS phenotypes, their morbidity, and the role that referral bias plays in the epidemiology of this syndrome.

Identification of Polycomb Group Protein EZH2-Mediated DNA Mismatch Repair Gene MSH2 in Human Uterine Fibroids.

Uterine fibroids (UFs) are benign smooth muscle neoplasms affecting up to 70% of reproductive age women. Treatment of symptomatic UFs places a significant economic burden on the US health-care system. Several specific genetic abnormalities have been described as etiologic factors of UFs, suggesting that a low DNA damage repair capacity may be involved in the formation of UF. In this study, we used human fibroid and adjacent myometrial tissues, as well as an in vitro cell culture model, to evaluate the expression of MutS homolog 2 (MSH2), which encodes a protein belongs to the mismatch repair system. In addition, we deciphered the mechanism by which polycomb repressive complex 2 protein, EZH2, deregulates MSH2 in UFs. The RNA expression analysis demonstrated the deregulation of MSH2 expression in UF tissues in comparison to its adjacent myometrium. Notably, protein levels of MSH2 were upregulated in 90% of fibroid tissues (9 of 10) as compared to matched adjacent myometrial tissues. Human fibroid primary cells treated with 3-deazaneplanocin A (DZNep), chemical inhibitor of EZH2, exhibited a significant increase in MSH2 expression (P < .05). Overexpression of EZH2 using an adenoviral vector approach significantly downregulated the expression of MSH2 (P < .05). Chromatin immunoprecipitation assay demonstrated that enrichment of H3K27me3 in promoter regions of MSH2 was significantly decreased in DZNep-treated fibroid cells as compared to vehicle control. These data suggest that EZH2-H3K27me3 regulatory mechanism dynamically changes the expression levels of DNA mismatch repair gene MSH2, through epigenetic mark H3K27me3. MSH2 may be considered as a marker for early detection of UFs.

Spontaneous adrenal hemorrhage during pregnancy: a review of the literature and a case report of successful conservative management.

Spontaneous adrenal hemorrhage is an acute hemorrhage of the adrenal gland that occurs in the absence of trauma or anticoagulant therapy. The incidence of this condition in pregnancy is unknown. We describe a patient with spontaneous unilateral adrenal hemorrhage that occurred during the third trimester of pregnancy. She was successfully managed conservatively with complete resolution of symptoms and had an uncomplicated perinatal outcome. We review the literature on spontaneous adrenal hemorrhage, including clinical signs and symptoms, diagnostic tests, and management of spontaneous adrenal hemorrhage, to help other practitioners to recognize and appropriately treat this rare condition.

Polycystic ovaries and ovarian hyperstimulation syndrome: a systematic review*.

OBJECTIVES: To assess and quantify the relationship between polycystic ovaries (PCOs) and ovarian hyperstimulation syndrome (OHSS). DATA SOURCES: Published studies, any language, identified through MEDLINE, EMBASE, BIOSIS, Web of Science, and bibliographies. Studies were selected if exposure (ultrasound findings of PCO before treatment) and outcome (OHSS) could be abstracted to two-by-two tables. RESULTS: Ten studies, meeting inclusion and exclusion criteria, were analyzed. When PCO were present, the combined odds ratio for OHSS was 6.8 (95% confidence interval 4.9-9.6). CONCLUSION: There is a significant and consistent relationship between PCO and OHSS. When PCO are present before treatment with assisted reproduction, deliberate policies to moderate treatment appear justified.