Uterine Factor Infertility: A Clinical Review.

Uterine factor infertility (UFI) may affect up to 1 in 500 reproductive age women. The uterus is an essential component of achieving pregnancy and carrying a pregnancy to term successfully. There are many etiologies of UFI which may be categorized into either congenital or acquired causes. In this review, we discuss the different causes of UFI as well as the treatment options, which now includes uterine transplant.

Perforation During Gynecological Procedures.

This article in the Women's Health series discusses uterine perforation occurring during gynecological procedures, including prevention, identification of risk factors, recognition, management, and long-term outcomes.

Prevalence of Polycystic Ovarian Syndrome in Young and Adolescent Transmasculine Patients Presenting for Gender-Affirming Care.

STUDY OBJECTIVE: To determine the incidence of polycystic ovarian syndrome (PCOS) and hyperandrogenism among adolescent transmasculine patients presenting to a tertiary care referral center for gender-affirming care METHODS: This was a retrospective study of adolescent transmasculine patients presenting to Cleveland Clinic for gender-affirming hormone therapy. The diagnostic criteria were adolescent-specific as defined by the international evidence-based guideline for PCOS management and included oligomenorrhea and/or anovulation with clinical and/or biochemical hyperandrogenism after exclusion of other androgen excess disorders. RESULTS: The described transgender population had a prevalence of PCOS of 23.8%. The transmasculine patients who met the criteria for PCOS had both higher levels of androgens and higher body mass indexes when compared with the patients without PCOS. Additionally, the patients with PCOS had higher rates of dyslipidemia. CONCLUSION: The prevalence of PCOS among transmasculine patients may be higher compared with the general population. Transmasculine patients with PCOS should be counseled regarding the long-term health implications associated with PCOS and screened appropriately to minimize risks.

Techniques for successful vaginal anastomosis in the uterine transplantation patient.

OBJECTIVE: To demonstrate techniques for successful donor-to-recipient vaginal anastomosis in uterine transplantation including illustration of a tension-free technique. DESIGN: This video uses live-action footage from surgery, detailed animations, and illustrations to review the step-by-step technique we use for vaginal anastomosis in uterine transplantation. Institutional Review Board approval was obtained for this experimental surgery. SETTING: Academic medical center. PATIENT(S): Patients undergoing uterine transplantation. INTERVENTION(S): Preparation of recipient vagina with illustration of challenges and risk secondary to dense adhesions between bladder and neo-vagina. Use of surgical techniques. Key steps include appropriate preparation of both donor and recipient vaginal tissues and a tension-free closure with horizontal mattress stitches. MAIN OUTCOME MEASURE(S): Intraoperative techniques in the clinical research trial of uterine transplantation. RESULTS: Successful vaginal anastomosis in the uterine transplantation patient. CONCLUSION(S): This video provides a step-by-step guide to vaginal anastomosis in uterine transplantation patients. Our team has applied techniques from vaginal reconstructive surgery in an attempt to reduce the occurrence of postoperative vaginal strictures, with attention to planned donor and recipient anastomosis site tissue preparation and closure of the anastomosis using a tension-free suturing technique.

The role of pharmacotherapy in the treatment of endometriosis across the lifespan.

INTRODUCTION: Endometriosis is estimated to affect 10% of reproductive-aged women. The gold standard for treatment is surgery; however, surgery carries a significant morbidity and cost burden. There is an ongoing need for safe, effective medical therapies for endometriosis patients, both in conjunction with and independent of surgical interventions. Most conventional therapies for endometriosis work by a similar mechanism, and efficacy is variable. In recent years, there has been increased interest in the development and testing of novel pharmacotherapies for endometriosis. AREAS COVERED: This review discusses both conventional and emerging treatments for endometriosis. The authors present the application of these drugs in different presentations of endometriosis across the lifespan and discuss how emerging therapies might fit into future medical management of endometriosis. Conventional therapies include nonsteroidal anti-inflammatory drugs, combined oral contraceptives, progestins, GnRH agonists/antagonists, and aromatase inhibitors. Emerging therapies are focused on disease-specific targets such as endothelial growth factor receptors. EXPERT OPINION: The field of endometriosis therapy is moving toward modifying the immune and inflammatory milieu surrounding endometrial implants. If these drugs show efficacy in clinical trials, combining them with current medical treatment is expected to result in a profound impact on symptom and disease burden for patients who suffer from endometriosis worldwide.

A Syngeneic Murine Model of Endometriosis using Naturally Cycling Mice.

Endometriosis is a leading cause of pelvic pain and infertility. It is defined by the presence of endometrial tissue in extrauterine locations. The development of novel therapies and diagnostic tools for endometriosis has been limited due in part to challenges in studying the disease. Outside of primates, few mammals menstruate, and none develop spontaneous endometriosis. Rodent models are popular but require artificial induction of endometriosis, with many utilizing either immunocompromised mice or surgically induced disease. Recently, more attention has been given to models involving intraperitoneal injection. We present a murine model of endometriosis that integrates several features of existing endometriosis models into a novel, simplified system that relies on microscopic quantification in lieu of subjective grading. In this model, we perform hormonal stimulation of donor mice, intraperitoneal injection, systematic abdominal survey and tissue harvest, and histologic quantification that can be performed and verified at any time after necropsy. This model requires minimal resources and training; does not require expertise by lab technicians in murine survival surgery or in the identification of gross endometriotic lesions; can be used in immunocompromised, immunocompetent, and/or mutant mice; and reliably creates endometriotic lesions that are histologically consistent with human endometriotic disease.

Nebivolol reduces proteinuria and renal NADPH oxidase-generated reactive oxygen species in the transgenic Ren2 rat.

BACKGROUND/AIMS: Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO. METHODS: We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6-9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days. RESULTS: Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67(phox), and p47(phox)), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression. CONCLUSIONS: Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO.

Management of Endometriomas.

IMPORTANCE: Endometriomas are a unique and complex representation of the classic phenotypes of endometriosis. Associated symptoms, high recurrence rate, and multimodal approach represent ongoing challenges in the management of this chronic disease. OBJECTIVE: To review current literature regarding medical and surgical management of endometriomas. EVIDENCE ACQUISITION: An extensive literature search including PubMed and Cochrane Library was performed. Review was performed using the following key words: "endometrioma," "cystectomy," "chronic pain," "infertility," "IVF," "menopause," "recurrence." All pertinent articles were assessed. The references of those articles were then reviewed, and additional publications were evaluated. Eligibility of the studies was first assessed on titles and abstracts. Full articles were then reviewed for all selected studies, and decision for final inclusion was made at that time. CONCLUSIONS AND RELEVANCE: Cystectomy of ovarian endometriomas has been the first-line treatment for management for many years because it provides improved pain relief, reduces recurrence rates, and was thought to be favorable in in vitro fertilization. However, a growing body of evidence is demonstrating benefit, or at least no harm, in expectant management for asymptomatic patients with small, stable endometriomas. Medical management is often very effective and appropriate first line. When surgical intervention is appropriate, careful ovarian cyst excision with goal of ovarian tissue preservation and treatment of additional endometriosis by a trained surgeon can provide the patient the best long-term outcome and preservation of ovarian tissue and function.

Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat.

Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of ß-adrenergic receptor blockers in hypertension is limited because of potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory ß1-adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance. Young (age, 6-9 weeks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/(kg d) or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the homeostasis model assessment. In addition, insulin metabolic signaling, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, reactive oxygen species, and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue. The Ren2 rat demonstrated systemic insulin resistance as examined by the homeostasis model assessment, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels of reactive oxygen species in skeletal muscle tissue. Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance, and enhanced tissue RAS expression.

Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression.

Renin is the rate-limiting enzyme in renin-angiotensin system (RAS) activation. We sought to determine the impact of renin inhibition on whole-body insulin sensitivity and skeletal muscle RAS, oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2), which manifests increased tissue RAS activity, elevated serum aldosterone, hypertension, and insulin resistance. Young (aged 6-9 wk) Ren2 and age-matched Sprague Dawley control rats were treated with aliskiren [50 mg/kg . d, ip] or placebo for 21 d and administered an ip glucose tolerance test. Insulin metabolic signaling and 2-deoxyglucose uptake in soleus muscle were examined in relation to tissue renin-angiotensin-aldosterone system [angiotensin (Ang) II, mineralocorticoid receptor (MR), and Ang type I receptor (AT(1)R)] and measures of oxidative stress as well as structural changes evaluated by light and transmission electron microscopy. Ren2 rats demonstrated systemic insulin resistance with decreased skeletal muscle insulin metabolic signaling and glucose uptake. This was associated with increased Ang II, MR, AT(1)R, oxidative stress, and reduced tyrosine insulin receptor substrate-1 phosphorylation, protein kinase B/(Akt) phosphorylation and glucose transporter-4 immunostaining. The Ren2 also demonstrated perivascular fibrosis and mitochondrial remodeling. Renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport along with normalization of Ang II, AT(1)R, and MR levels, oxidative stress markers, fibrosis, and mitochondrial structural abnormalities. Our data suggest that renin inhibition improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. This is associated with reductions in skeletal muscle tissue Ang II, AT(1)R, and MR expression; oxidative stress; fibrosis; and mitochondrial abnormalities.

Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation.

Emerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine(473) phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine(136) and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects.