Maternal serum concentration of anti-Müllerian hormone is a better predictor than basal follicle stimulating hormone of successful blastocysts development during IVF treatment.

BACKGROUND: The conditions of diminished ovarian reserve and primary ovarian insufficiency, characterized by poor fertility outcomes, currently comprise a major challenge in reproductive medicine, particularly in vitro fertilization. Currently in the IVF industry, blastocyst developmental success rate per treatment is routinely overlooked when a live birth results from treatment. Limited data are available on this significant and actionable variable of blastocyst development optimization, which contributes to improvement of treatment success Women with elevated basal FSH concentration are reported to still achieve reasonable pregnancy rates, although only a few studies report correlations with blastocysts development. Diagnostic values of AMH/basal FSH concentrations can be useful for determining the optimal stimulation protocol as well as identification of individuals who will not benefit from IVF due to poor prognosis. The objective of this study is to identify actionable clinical and culture characteristics of IVF treatment that influence blastocyst developmental rate, with the goal of acquiring optimal success. METHODS AND FINDINGS: A retrospective observational study was performed, based on 106 women undergoing IVF, regardless of prognosis, over a six-month period from January 1, 2015 to June 31, 2015. Rate of high-quality blastocyst production, which can be used for embryo transfer or vitrification, per normally fertilized oocyte, was evaluated. Treatment was determined successful when outcome was ≥ 40% high-quality blastocysts. The data were initially evaluated with the Evtree algorithm, a statistical computational analysis which is inspired by natural Darwinian evolution incorporating concepts such as mutation and natural selection (see Supplementary Material). The analysis processes all variables simultaneously against the outcome, aiming to maximize discrimination of each variable to then create a "branch" of the tree which can be used as a decision in treatment. The final model results in only those variables which are significant to outcomes. Generalized linear model (GLM) employing logistic regression and survival analysis with R software was used and the final fitting of the model was determined through the use of random forest and evolutionary tree algorithms. Individuals presenting with an [AMH] of >3.15 ng/ml and a good prognosis had a lower success per treatment (n = 11, 0% success) when total gonadotropin doses were greater than 3325 IU. Individuals that presented with an [AMH] of <1.78 ng/ml and a poor prognosis exhibited a greater success per treatment (n = 11, 80% success). AMH emerged as a superior indicator of blastocyst development compared to basal FSH. The accuracy of the prediction model, our statistical analysis using decision tree, evtree methodology is 86.5% in correctly predicting outcome based on the significant variables. The likelihood that the outcome with be incorrect of the model, or the error rate is 13.5%. CONCLUSIONS: [AMH] is a superior indicator of ovarian stimulation response and an actionable variable for stimulation dose management for optimizing blastocyst development in culture. Women whose [AMH] is ≥3.2 mg/ml, having a good prognosis, and developing >12 mature follicles result in <40% blastocysts when gonadotropin doses exceed 3325 IU per treatment. IVF treatments for poor responders that present with infertility due to diminished ovarian reserve, if managed appropriately, can produce more usable blastocyst per IVF treatment, thus increasing rate of blastocyst developmental success and ultimately increasing live birth rates. Future studies are needed to investigate the intra-follicular and the intra-cellular mechanisms that lead to the inverse relationship of blastocysts development and total gonadotropin doses in good responders in contrast to poor responders.

Low-dose human chorionic gonadotropin alone can complete follicle maturity: successful application to modified natural cycle in vitro fertilization.

OBJECTIVE: To investigate the feasibility of utilizing low-dose hCG alone to complete follicle maturity in a natural cycle, without the need for antecedent exogenous FSH stimulation. DESIGN: Case series. SETTING: Academic fertility program. PATIENT(S): Normally ovulatory women with infertility thought to be predominantly due to male factor. INTERVENTION(S): Modified natural IVF cycles were conducted as follows: natural ovulatory cycles were monitored with serial ultrasound examinations and serum E2 determinations. When the lead follicle reached preovulatory status according to cycle day, ultrasound, and E2 levels, 0.25 mg of the GnRH antagonist ganirelix acetate was administered along with 200 IU of hCG. These medications were repeated daily for 2 to 3 days with further serial monitoring. A trigger dose of 10,000 IU of hCG was followed by follicle aspiration, IVF, and ET in a standard manner. MAIN OUTCOME MEASURE(S): Follicle maturity, live births, documentation of the feasibility of this new approach. RESULT(S): In all cases, E2 levels rose and the dominant follicle continued to increase in size in response to low-dose hCG after GnRH antagonist administration. Follicle aspiration yielded one or more mature oocytes. In vitro fertilization and ET resulted in live births. CONCLUSION(S): Low-dose hCG can be used to complete follicle maturity in a natural cycle without the need for antecedent exogenous FSH stimulation. This finding may have strong clinical utility in modified natural cycle IVF.

The effect of home exercise on ovulation induction using clomiphene citrate in overweight underserved women with polycystic ovarian syndrome.

BACKGROUND: Age-adjusted rates of obesity are reported to be 35.8 % among US adult women and 49 % in some race/ethnicity, underserved populations. (1). Underserved populations often have less access to weight-loss intervention options and are at high risk for obesity related problems including anovulation, infertility, pregnancy-related complications and adverse long-term health outcomes. (2). The purpose of this study was to evaluate a home exercise plan using a pedometer on weight loss, ovulation induction and pregnancy rates in our overweight and obese underserved clinic population. METHODS: Twenty one overweight (BMI ≥ 25-29.9) and obese I-II (BMI ≥ 30-39.9) 18-42 years old were recruited. Participants received an exercise/nutrition questionnaire at the initiation and completion and called weekly for 4 weeks. Ten participants were randomly assigned to the home exercise program (PedGp). PedGp received a pedometer, daily step-count goal, and were called to increase goal by 50 % weekly. All participants then underwent clomiphene stair-step ovulation induction. All study participants were referred to the University Wellness Clinic for diet and exercise counseling. RESULTS: There were high percentages of women with co-morbidities in both groups including fatty liver, low vitamin D, hyperlipidemia, hypothyroidism, prediabetes and diabetes.1. Those completing the 4-week home program increased baseline steps by 21.2 % weekly. Only 3/10 women reached at least one weekly goal of 50 % increase. Although the goal was rarely met, participants who completed study had increased number of daily steps.2. Greater number in PedGp lost weight or stayed the same (5/10 vs. 2/11).3. Greater number in PedGp spontaneously ovulated (4/10 vs. 1/11) or became pregnant (4/10 vs. 3/11). (not statistically significant due to small sample size). CONCLUSION: There are high percentages of comorbidities in this population. Although the goal was rarely met, participants who completed study had increased number of daily steps. A greater number in PedGp lost weight or stayed the same. A greater number in PedGp spontaneously ovulated or became pregnant (not statistically significant due to small sample size). Importantly, 40 % of women who lost weight became pregnant. This is highly encouraging and suggests that the development of pedometer interventions may prove a cost effective option. Weight loss programs for this population hold promise and efficient hospital or community-based programs may prove beneficial.

Brca1 Mutations Enhance Mouse Reproductive Functions by Increasing Responsiveness to Male-Derived Scent.

We compared the gene expression profiles of ovarian granulosa cells harboring either mutant or wild type Brca1 to follow up on our earlier observation that absence of a functional Brca1 in these important regulators of menstrual/estrous cycle progression leads to prolongation of the pre-ovulatory phase of the estrous cycle and to increased basal levels of circulating estradiol. Here we show that ovarian granulosa cells from mice carrying a conditional Brca1 gene knockout express substantially higher levels of olfactory receptor mRNA than granulosa cells from wild type littermates. This led us to hypothesize that reproductive functions in mutant female mice might be more sensitive to male-derived scent than in wild type female mice. Indeed, it is well established that isolation from males leads to complete cessation of mouse estrous cycle activity while exposure to olfactory receptor ligands present in male urine leads to resumption of such activity. We found that Brca1-/- female mice rendered anovulatory by unisexual isolation resumed ovulatory activity more rapidly than their wild type littermates when exposed to bedding from cages where males had been housed. The prime mediator of this increased responsiveness appears to be the ovary and not olfactory neurons. This conclusion is supported by the fact that wild type mice in which endogenous ovaries had been replaced by Brca1-deficient ovarian transplants responded to male-derived scent more robustly than mutant mice in which ovaries had been replaced by wild type ovarian transplants. Our findings not only have important implications for our understanding of the influence of olfactory signals on reproductive functions, but also provide insights into mechanisms whereby genetic risk factors for breast and extra uterine Müllerian carcinomas may influence menstrual activity in human, which is itself an independent risk factor for these cancers.

Effect of prior oophorectomy on changes in bone mineral density and carotid artery intima-media thickness in postmenopausal women.

OBJECTIVE: To determine the effect of prior oophorectomy in healthy postmenopausal women on the rate of loss of bone mineral density (BMD) and rate of increase in carotid artery intima-media thickness (CIMT). DESIGN: Secondary analysis from a randomized controlled trial. SETTING: University-based research clinic. PATIENT(S): Two hundred twenty-two healthy postmenopausal women in the Greater Los Angeles area. INTERVENTION(S): Baseline and annual screening of BMD and assessment of CIMT every 6 months for a total of 3 years. MAIN OUTCOME MEASURE(S): Changes in BMD and CIMT during postmenopausal years. RESULT(S): Among women who were menopausal for more than 10 years, the rate of CIMT progression was statistically significantly less in women with intact ovaries compared with those in women with prior oophorectomy. In women 5-10 years postmenopause, there was a trend toward a slower loss of BMD in those who retained their ovaries, and in women more than 10 years postmenopause there was significantly less BMD loss in those who retained their ovaries. CONCLUSION(S): As time from menopausal transition increases, retained ovaries are associated with a slower rate of bone loss and a slower rate of thickening of the carotid artery wall compared with rates in menopausal women with oophorectomy.

Dystroglycan expression in human placenta: basement membrane localization and subunit distribution change between the first and third trimester.

OBJECTIVES: This study describes the distribution of dystroglycan (DG) in human placenta, membranes, and uterine decidua. STUDY DESIGN: Dystroglycan expression was characterized by Western blotting, immunohistochemistry, and immunofluorescence microscopy using human tissues and cultured cells. RESULTS: Both α-DG and ß-DG are expressed in the term syncytiotrophoblast, and α-DG is localized to the basement membrane. In first-trimester chorionic villi, α-DG and ß-DG are localized to the periphery of the cytotrophoblast. Expression varies in term fetal membranes. α-Dystroglycan is not detectable in choriocarcinoma cells or HTR cells, but ß-DG is present in both normal and cleaved forms. CONCLUSION: Dystroglycan is expressed at high levels in human trophoblasts, and localization of the α- and ß-subunits varies with gestational age and trophoblast differentiation. Because DG expression inversely correlates with invasiveness in many cancers, its pattern of expression in trophoblasts suggests a possible function in inhibition of placental invasion.

The arcuate uterine anomaly: a critical appraisal of its diagnostic and clinical relevance.

UNLABELLED: The diagnostic criteria and clinical relevance of the arcuate uterine anomaly have long been debated. Our review critically examines the contemporary and past literature regarding the definition, prevalence, and clinical impact of the arcuate uterine anomaly on reproductive outcomes. To bring a novel perspective to the debate, we examined studies evaluating the clinical significance of the presence of a residual septal stump following surgical resection, which has morphology comparable to that of the arcuate anomaly. The balance of the existing literature does not support an association of the arcuate anomaly to adverse reproductive outcomes. Hysteroscopic resection of arcuate anomaly does not appear to be universally indicated. Treatment decisions should be individualized at clinician discretion for symptomatic patients without otherwise identifiable etiology. TARGET AUDIENCE: General Obstetricians & gynecologists, Reproductive Endocrinology & Infertility Specialists and Radiologists. LEARNING OBJECTIVES: After completion of this article, the reader should be able to distinguish the arcuate uterine anomaly and its diagnosis, demonstrate its clinical significance, and what impact, if any, it may have on reproductive potential. Furthermore, the reader should be able to assess which patient population, if any, might benefit from surgical management of the arcuate anomaly.

von Willebrand disease and pregnancy: a practical approach for the diagnosis and treatment.

von Willebrand disease is caused by either a quantitative or qualitative defect in von Willebrand factor (VWF). Patients may have extensive mucosal bleeding (because of platelet dysfunction) and prolonged bleeding after surgery (because of factor VIII deficiency). Up to 6 different subtypes of the disease have been described, and diagnosis is based on clinical suspicion and laboratory confirmation. Accurate diagnosis is of paramount importance because therapy will vary according to the subtype. Bleeding complications during pregnancy are more frequent when levels of the von Willebrand ristocetin cofactor assay and factor VIII levels are <50 IU/dL. In such cases, therapy before any invasive procedure or delivery must be instituted. The mainstays of therapy are desmopressin and plasma concentrates that contain von Willebrand factor. Delayed postpartum hemorrhage may occur, despite adequate prophylaxis. Frequent monitoring and continued prophylaxis and/or treatment are recommended for at least 2 weeks after delivery.

Use of vaginal mesh in the face of recent FDA warnings and litigation.

Choosing to use mesh in vaginal reconstructive surgery for pelvic organ prolapse or stress urinary incontinence is perplexing in the face of recent US Food and Drug Administration (FDA) warnings. In October 2008, the FDA alerted practitioners to complications associated with transvaginal placement of surgical mesh. Litigation is another concern. A Google search of "transvaginal mesh" results in numerous hits for plaintiff attorneys seeking patients with complications related to use of mesh. In light of a recent decision by the US Supreme Court and strategies by manufactures of medical devices to escape liability, it is imperative that gynecologic surgeons using transvaginal mesh document proper informed consent in the medical records. The purpose of this commentary is not to deter gynecologic surgeons from using transvaginal mesh when appropriate, but to provide an overview of current medical-legal controversies and stress the importance of documenting informed consent.