Meeting the demand for fertility services: the present and future of reproductive endocrinology and infertility in the United States.

The field of reproductive endocrinology and infertility (REI) is at a crossroads; there is a mismatch between demand for reproductive endocrinology, infertility and assisted reproductive technology (ART) services, and availability of care. This document's focus is to provide data justifying the critical need for increased provision of fertility services in the United States now and into the future, offer approaches to rectify the developing physician shortage problem, and suggest a framework for the discussion on how to meet that increase in demand. The Society of REI recommend the following: 1. Our field should aggressively explore and implement courses of action to increase the number of qualified, highly trained REI physicians trained annually. We recommend efforts to increase the number of REI fellowships and the size complement of existing fellowships be prioritized where possible. These courses of action include: a. Increase the number of REI fellowship training programs. b. Increase the number of fellows trained at current REI fellowship programs. c. The pros and cons of a 2-year focused clinical fellowship track for fellows interested primarily in ART practice were extensively explored. We do not recommend shortening the REI fellowship to 2 years at this time, because efforts should be focused on increasing the number of fellowship training slots (1a and b). 2. It is recommended that the field aggressively implements courses of action to increase the number of and appropriate usage of non-REI providers to increase clinical efficiency under appropriate board-certified REI physician supervision. 3. Automating processes through technologic improvements can free providers at all levels to practice at the top of their license.

Comparison of Female Ovarian Reserve Before vs After COVID-19 Vaccination.

This cohort study examines the association of COVID-19 vaccination with levels of anti-Mullerian hormone and antral follicle count in women seeking fertility treatment.

In vitro fertilization outcomes in VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies and limb anomalies): report of 2 cases.

Objective: To report 2 cases of women with vertebral defects, anal atresia, cardiac defects, tracheaesophageal fistula, renal anomalies, and/or limb anomalies (VACTERL association) and the outcomes of their in vitro fertilization (IVF) cycles. Design: A case report. We obtained informed consent from both the patients for this case report. Setting: Outpatient clinic at an academic hospital. Patients: Patient 1 was a 23-year-old woman with scoliosis, tethered spinal cord, tracheaesophageal fistula, duodenal atresia, and a common cloaca at birth. Patient 2 was a 36-year-old woman with dextrocardia, congenital heart disease, scoliosis, and an imperforate anus at birth. Interventions: Both the patients underwent IVF. Main Outcome Measures: Oocyte yield, oocyte quality, and number of embryos. Results: Patient 1 underwent 1 IVF cycle, with 16 oocytes retrieved, of which 6 were mature. However, during intracytoplasmic sperm injection, the oocytes were noted to be extremely fragile and degenerated immediately after sperm injection. No oocyte was fertilized. Patient 2 underwent 3 IVF cycles, and 2 oocyte retrievals, with a total of 7 oocytes under cryopreservation. Conclusions: Both the patients' cases presented challenges due to aberrations in pelvic anatomy and poor IVF outcomes. There is a paucity of data regarding fertility outcomes and, specifically, oocyte quality in patients with vertebral defects, anal atresia, cardiac defects, tracheaesophageal fistula, renal anomalies, and/or limb anomalies association. Their care requires a multidisciplinary assessment, an individualized approach, and continued investigation of their IVF and fertility outcomes.

Development of a dynamic machine learning algorithm to predict clinical pregnancy and live birth rate with embryo morphokinetics.

Objective: To evaluate the feasibility of generating a center-specific embryo morphokinetic algorithm by time-lapse microscopy to predict clinical pregnancy rates. Design: A retrospective cohort analysis. Setting: Academic fertility clinic in a tertiary hospital setting. Patients: Patients who underwent in vitro fertilization with embryos that underwent EmbryoScope time-lapse microscopy and subsequent transfer between 2014 and 2018. Interventions: None. Main Outcome Measures: Clinical pregnancy. Results: A supervised, random forest learning algorithm from 367 embryos successfully predicted clinical pregnancy from a training set with overall 65% sensitivity and 74% positive predictive value, with an area under the curve of 0.7 for the test set. Similar results were achieved for live birth outcomes. For the secondary analysis, embryo growth morphokinetics were grouped into five clusters using unsupervised clustering. The clusters that had the fastest morphokinetics (time to blastocyst = 97 hours) had pregnancy rates of 54%, whereas a cluster that had the slowest morphokinetics (time to blastocyst = 122 hours) had a pregnancy rate of 71%, although the differences were not statistically significant (P=.356). Other clusters had pregnancy rates of 51%-60%. Conclusions: This study shows the feasibility of a clinic-specific, noninvasive embryo morphokinetic simple machine learning model to predict clinical pregnancy rates.

Hyperandrogenemia alters mitochondrial structure and function in the oocytes of obese mouse with polycystic ovary syndrome.

CAPSULE: Hyperandrogenemia in an obese PCOS mouse model results in altered glucose/insulin metabolism and mitochondrial structure and function in the oocytes, in part explaining adverse outcomes and inheritance patterns seen in PCOS. OBJECTIVE: To study the oocyte quality by means of mitochondrial structure and function in a well-established classic PCOS mouse model. DESIGN: Animal study using an obese PCOS mouse model compared with control. SETTING: Animal research facility in a tertiary care university hospital setting. ANIMALS: C57/B6J mice. INTERVENTION: Three week old mice had subdermal implants of DHT controlled release pellet or placebo for 90 days. MAIN OUTCOME MEASURES: The mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were subsequently isolated and were used to investigate mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance, histology and electron microscopy. RESULTS: Results showed glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of the oocytes demonstrated impaired inner mitochondrial membrane function, increased ATP production and mtDNA copy number, altered RNA transcript abundance and aberrant ovarian histology. Electron microscopy of the oocytes showed severely impaired mitochondrial ultrastructure. CONCLUSION: The obese PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial function.

The impact of COVID-19 on REI fellowship educational experience.

PURPOSE: To assess perceived deficiencies of reproductive endocrinology and infertility (REI) fellow education due to changes in care secondary to COVID-19. METHODS: This is a cross-sectional study performed in an academic setting. A survey was generated and administered to REI fellows and attendings practicing in programs across the United States. Descriptive statistics were used to quantify results regarding clinical volume, academic responsibilities, clinical safety, and fellowship education. RESULTS: The survey response rate was 23%. Eighty-four percent of respondents self-identified as fellows, and 16% identified as program directors or other REI academic instructors. Overall, the survey responses confirmed that the COVID-19 pandemic tremendously affected clinical volume, with 91% of participants reporting their clinical volume decreased by at least half. Although 67% of attendings believed that the changes related to COVID-19 have or will have significantly affected the clinical skills of fellows, 66% of fellows did not believe that their clinical training had been significantly impacted. Sixty-seven percent of fellows and 78% of attendings do not believe that changes related to COVID-19 will affect the ability of fellows to practice independently. CONCLUSION: Even though most attendings surveyed believed that the changes related to COVID-19 would affect the clinical skills of fellows, the cessation of clinical and research activities was short-lived, likely tempering the overall effect on clinical training. Overall, most respondents did not believe that the pandemic significantly affected fellow education.

In utero low-protein-diet-programmed type 2 diabetes in adult offspring is mediated by sex hormones in rats†.

Sex steroids regulate insulin sensitivity and glucose metabolism. We had characterized a lean type 2 diabetes (T2D) rat model using gestational low-protein (LP) diet programming. Our objective was to identify if endocrine dysfunction leading to decreased sex hormone levels will precede the development of T2D and if steroid replacement will prevent the onset of the disease. Pregnant rats were fed control or isocaloric LP diet from gestational day 4 until delivery. Normal diet was given to all mothers after delivery and to pups after weaning. LP offspring developed glucose intolerance and insulin resistance at 4 months. We measured sex steroid hormone profiles and expression of key genes involved in steroidogenesis in testis and ovary. Furthermore, one-month old rats were implanted with 90-day slow release T and E2 pellets for males and females, respectively. Glucose tolerance test (GTT) and euglycemic hyperinsulinemic clamp was performed at 4 months. LP-programmed T2D males had low T levels and females had low E2 levels due to dysregulated gene expression during steroidogenesis in gonads. GTT and euglycemic hyperinsulinemic clamp showed that LP males and females were glucose intolerant and insulin resistant; however, steroid supplementation prevented the onset of glucose intolerance and insulin resistance. Rats that developed T2D by LP programming have compromised gonadal steroidogenesis leading to low T and E2 in males and females, respectively. Sex steroid supplementation prevented the onset of glucose intolerance and insulin resistance indicating low sex steroid levels could cause compromised glucose metabolism ultimately leading to T2D.

Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes.

Polycystic ovary syndrome (PCOS) is the most common ovulatory defect in women. Although most PCOS patients are obese, a subset of PCOS women are lean but show similar risks for adverse fertility outcomes. A lean PCOS mouse model was created using prenatal androgen administration. This developmentally programmed mouse model was used for this study. Our objective was to investigate if mitochondrial structure and functions were compromised in oocytes obtained from lean PCOS mouse. The lean PCOS mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were isolated and were used to investigate inner mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance, histology and electron microscopy. Our results demonstrate that lean PCOS mice has similar weight to that of the controls but exhibited glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of their oocytes show impaired inner mitochondrial membrane function, elevated reactive oxygen species (ROS), increased RNA transcript abundance and aberrant ovarian histology. Electron microscopy of the oocytes showed impaired mitochondrial ultrastructure. In conclusion, the lean PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial ultrastructure and function.

Sex Dependent Dysregulation of Hepatic Glucose Production in Lean Type 2 Diabetic Rats.

We have characterized a lean type 2 diabetic rat model by gestational low protein programming. We aimed to identify if the regulation of hepatic glucose production (HGP) via gluconeogenesis and glycogenolysis is affected and if there are any sex differences. Fasting (6-7 months old) type 2 diabetic rats received 2H2O followed by a primed constant rate infusion of [6,6-2H2] glucose. Blood samples were drawn during steady states after 4 h of fasting and following a euglycemic hyperinsulinemic clamp. HGP and the fraction of glucose derived from gluconeogenesis under fasting and euglycemic states were measured from steady state glucose enrichments after the infusion of [6,6-2H2]glucose and 2H2O tracers. Glycogenolysis was determined by calculating the difference between total HGP and gluconeogenesis rates. Hepatic gene expression of enzymes involved in HGP were quantified using qPCR. HGP rates was similar during fasting in both groups and sexes. However, under simulated fed condition, HGP rate was suppressed in controls but not in type 2 diabetic rats. They also showed inefficient HGP suppression in a simulated fed state. Differential analysis showed that suppression of both gluconeogenesis and glycogenolysis under simulated fed state was affected in these low protein programmed type 2 diabetic rats. These effects were greater in females when compared to males. Further, key genes involved in these processes like G6Pase, Pepck, pyruvate carboxylase, and glycogen phosphorylase in liver were dysregulated. Our data shows impaired suppression of HGP via gluconeogenesis and glycogenolysis in type 2 diabetic rats with greater effects on females.

Preovulatory exposure to a protein-restricted diet disrupts amino acid kinetics and alters mitochondrial structure and function in the rat oocyte and is partially rescued by folic acid.

BACKGROUND: Detrimental exposures during pregnancy have been implicated in programming offspring to develop permanent changes in physiology and metabolism, increasing the risk for developing diseases in adulthood such as hypertension, diabetes, heart disease and obesity. This study investigated the effects of protein restriction on the metabolism of amino acids within the oocyte, liver, and whole organism in a rat model as well as effects on mitochondrial ultrastructure and function in the cumulus oocyte complex. METHODS: Wistar outbred female rats 8-11 weeks of age (n = 24) were assigned to three isocaloric dietary groups, including control (C), low protein (LP) and low protein supplemented with folate (LPF). Animals were superovulated and 48 h later underwent central catheterization. Isotopic tracers of 1-13C-5C2H3-methionine, 2H2-cysteine, U-13C3-cysteine and U-13C3-serine were administered by a 4 h prime-constant rate infusion. After sacrifice, oocytes were denuded of cumulus cells and liver specimens were obtained. RESULTS: Oocytes demonstrated reduced serine flux in LP vs. LPF (p < 0.05), reduced cysteine flux in LP and LPF vs. C (p < 0.05), and a trend toward reduced transsulfuration in LP vs. C and LPF. Folic acid supplementation reversed observed effects on serine flux and transsulfuration. Preovulatory protein restriction increased whole-body methionine transmethylation, methionine transsulfuration and the flux of serine in LP and LPF vs. C (p = 0.003, p = 0.002, p = 0.005). The concentration of glutathione was increased in erythrocytes and liver in LP and LPF vs. C (p = 0.003 and p = 0.0003). Oocyte mitochondrial ultrastructure in LP and LPF had increased proportions of abnormal mitochondria vs. C (p < 0.01 and p < 0.05). Cumulus cell mitochondrial ultrastructure in LP and LPF groups had increased proportions of abnormal mitochondria vs. C (p < 0.001 and p < 0.05). Preovulatory protein restriction altered oocyte expression of Drp1, Opa-1, Mfn1/2, Parl and Ndufb6 (p < 0.05) and Hk2 (p < 0.01), which are genes involved in mitochondrial fission (division) and fusion, mitochondrial apoptotic mechanisms, respiratory electron transport and glucose metabolism. CONCLUSIONS: Preovulatory protein restriction resulted in altered amino acid metabolism, abnormal cumulus oocyte complex mitochondrial ultrastructure and differential oocyte expression of genes related to mitochondrial biogenesis.

A Novel Ultrasound-Guided Technique for Hysteroscopic Adhesiolysis in High-Risk Patients.

Hysteroscopy is a common gynecologic surgical procedure. Certain diagnoses, notably intrauterine adhesions and cervical stenosis, make hysteroscopy more complicated because of an increased likelihood of complications. Three patients, 1 with cervical stenosis and 2 with Asherman syndrome, underwent ultrasound (US)-guided adhesiolysis. Access to the uterine cavity was obtained by either direct balloon-aided dilation or the US-guided Seldinger technique, followed by balloon-aided dilation to enter the endometrial cavity and disrupt intrauterine/intracervical adhesions. In this case series, we describe a novel approach of using US-guided balloon dilation to safely and effectively treat intrauterine adhesions and to decrease the risk of perforation.

Folate treatment partially reverses gestational low-protein diet-induced glucose intolerance and the magnitude of reversal is age and sex dependent.

OBJECTIVES: Gestational low-protein (LP) programming causes glucose intolerance (GI) and insulin resistance (IR) in adult offspring. Folate supplementation has been shown to rescue the offspring from various programming effects. The aim of this study was to investigate whether folate supplementation during pregnancy reverses LP-induced GI and IR. METHODS: Pregnant rats were fed control (20% protein), isocaloric low-protein (LP, 6%) or LP with 5 mg/kg folate (LPF) diets from gestational day 4 to delivery. The control diet was given during lactation and to pups after weaning. Glucose tolerance test was done at 1, 2, and 3 mo of age followed by euglycemic-hyperinsulinemic clamp at 4 mo. Rats were sacrificed at 4 mo and their gonadal, renal, inguinal, brown fat, and pancreas were weighed and expressed relative to their body weight. RESULTS: LP- and LPF-fed dams showed similar weight loss during late pregnancy after decreased feed intake. Both LP and LPF pups were smaller at birth but their weights caught up like that of controls by 3 mo. In males, folate supplementation reduced LP-induced GI at 2 mo (glucose area under the curve [AUC]: 1940 mmol/L × 180 min in LP, 1629 mmol/L × 180 min in LPF, and 1653 mmol/L × 180 min in controls; P <0.05, LP versus control and P <0.01, LP versus LPF) but the effect diminished at 3 mo. In females, folate reduced GI at 1 mo (glucose AUC: 1406 mmol/L × 180 min in LP, 1264 mmol/L × 180 min in LPF, and 1281 mmol/L × 180 min in controls; P <0.05, LP versus control and LP versus LPF) but had no effect at 2 and 3 mo. Interestingly, the LPF group had higher pancreatic weights than other groups, suggesting that folate helps in pancreatic development enabling the LPF rats to produce/secrete more insulin to maintain euglycemia. Euglycemic-hyperinsulinemic clamp shows both LP and LPF are insulin resistant compared with controls by 4 mo with LPF more severe than LP in males. Interestingly, females were more insulin resistant than males. CONCLUSIONS: Folate treatment partially reverses LP-induced GI and the magnitude of reversal is age and sex dependent. Furthermore, folate treatment does not reverse IR in either sex but makes it worse in males at 4 mo. The present study demonstrated that folate treatment is not sufficient to rescue the LP programming effects.

Neonatal outcomes among twins stratified by method of conception: secondary analysis of maternal fetal medicine (MFMU) network database.

PURPOSE: To investigate whether twin pregnancies conceived by different forms of fertility treatments are associated with adverse neonatal outcomes and to examine the difference in maternal and obstetrical characteristics between patients. METHODS: Our study was a retrospective analysis of twin pregnancies conceived by fertility treatments from a prospectively collected database. Treatments were stratified into two groups: group 1 (ART) consisted of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and group 2 (non-ART) included intrauterine insemination (IUI) and ovulation induction (OI). Composite neonatal morbidity included respiratory distress syndrome, intraventricular hemorrhage, leukomalacia, chronic lung disease, and death prior to discharge. RESULTS: There were 460 neonates in our study; among them, 67% (n = 310) were in group 1, and 33% (n = 150) in group 2. Group 1 patients were more likely to be older (p = 0.004), nulliparous (p = 0.01), delivered twins with lower birth weights (2278 g ± 605 vs. 2427 ± 519, p = 0.009), and had more deliveries < 32 weeks gestation (p = 0.001). In multivariable Poisson regression model, only neonatal intensive care unit admission rate was increased for group 1 twins (aRR = 1.27, 95% CI 1.003-1.60). CONCLUSIONS: After adjusting for confounders, twins conceived via ART compared to non-ART had similar neonatal outcomes. These data can help when counseling this patient population and assist in planning larger prospective cohorts.

Cyanotic congenital heart disease following fertility treatments in the United States from 2011 to 2014.

OBJECTIVE: To examine the risk for cyanotic congenital heart diseases (CCHDs) among live births in the USA, resulting from various forms of infertility treatments. METHODS: This study is a cross-sectional analysis of live births in the USA from 2011 to 2014. Infertility treatments are categorised into two of the following groups on birth certificates: assisted reproductive technology (ART) fertility treatment (surgical egg removal; eg, in vitro fertilisation and gamete intrafallopian transfer) and non-ART fertility treatment (eg, medical treatment and intrauterine insemination). We compared the risk for CCHD in ART and non-ART fertility treatment groups with those infants whose mothers received no documented fertility treatment and were naturally conceived (NC). RESULTS: Among 14 242 267 live births from 2011 to 2014, a total of 101 494 live births were in the ART and 81 242 resulted from non-ART fertility treatments. CCHD prevalence in ART, non-ART and NC groups were 393/100 892 (0.39%), 210/80 884 (0.26%) and 10 749/14 020 749 (0.08%), respectively. As compared with naturally conceiving infants, risk for CCHD was significantly higher among infants born in ART (adjusted relative risk (aRR) 2.4, 95% CI 2.1 to 2.7) and non-ART fertility treatment groups (aRR 1.9, 95% CI 1.6 to 2.2). Absolute risk increase in CCHD due to ART and non-ART treatments were 0.03% and 0.02%, respectively. A similar pattern was observed when the analysis was restricted to twins, newborns with birth weights under 1500 g and gestational age of less than 32 weeks. CONCLUSIONS: Our findings suggest an increased risk for CCHD in infants conceived after all types of infertility treatment.

Effect of advanced maternal age on maternal and neonatal outcomes in assisted reproductive technology pregnancies.

OBJECTIVES: To compare maternal and neonatal outcomes between women with assisted reproductive technologies pregnancy aged <40, 40-44, 45-49, and ≥50 years. STUDY: Design In a population-level analysis study, all live births by ART identified on birth certificate between 2011 and 2014 were extracted (n=101,494) using data from the Center for Disease Control and Prevention-National Center for Health Statistics (CDC-NCHS). We investigated and compared maternal and neonatal outcomes based on conditions routinely listed on birth certificates. RESULTS: Of 101,494 ART live births, 79,786 (78.6%), 16,186 (15.9%), 4637 (4.6%), and 885 (0.9%) were delivered by women aged <40, 40-44, 45-49, and ≥50 years, respectively. Comparing to women aged <40years, women aged 40-44, 45-49, and ≥50 years were at increased risk for gestational hypertension (aRR: 1.26, 1.55, and 1.61, respectively), gestational diabetes (aRR: 1.23, 1.40, and 1.31, respectively), eclampsia (aRR: 1.49, 1.51, and 2.37, respectively), unplanned hysterectomy (aRR: 2.55, 4.05, and 3.02, respectively), and ICU admission (aRR: 1.64, 2.06, and 2.04, respectively). The prevalence of preterm delivery was slightly higher in women aged 45 and older. (35%, 36.9%, and 40.2% in women aged <40 years, 45-49 years, and ≥50 years, respectively) CONCLUSIONS: Advanced age ART was significantly associated with higher rates of maternal morbidities. Except for preterm delivery, neonatal outcomes were similar between ART pregnancies in women aged ≥45 years and younger women. These data should be interpreted with caution because of potential confounding by potentially higher use of donor eggs by older women, the exact rates for which we were unable to ascertain from the available data.

Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium.

Repeated implantation failure (RIF) is an intriguing, massive failure of reproductive treatment in otherwise healthy women leading to the introduction of empirical adjuvant interventions that are costly, inefficient, and frustrating for our patients. In this article, we will try to convince the readers that RIF is neither a stigma nor a mysterious pathology but rather our failure to diagnose and properly synchronize the euploid blastocyst with the patient's personalized window of implantation.

Does an increased body mass index affect endometrial gene expression patterns in infertile patients? A functional genomics analysis.

OBJECTIVE: To analyze the transcriptomic profile of endometrial gene alterations during the window of implantation in infertile obese patients. DESIGN: Multicenter, prospective, case-control study. SETTING: Three academic medical centers for reproductive medicine. PATIENT(S): Infertile patients, stratified into body mass index (BMI) categories according to the World Health Organization guidelines, were included in the study. INTERVENTION(S): Endometrial samples were obtained from women undergoing standardized estrogen and P replacement cycles after 5 days of vaginal P supplementation. MAIN OUTCOME MEASURE(S): To identify endometrial gene expression alterations that occur during the window of implantation in infertile obese patients as compared with infertile normal-weight controls using a microarray analysis. RESULT(S): XCL1, XCL2, HMHA1, S100A1, KLRC1, COTL1, COL16A1, KRT7, and MFAP5 are significantly dysregulated during the window of implantation in the receptive endometrium of obese patients. COL16A1, COTL1, HMHA1, KRCL1, XCL1, and XCL2 were down-regulated and KRT7, MFAP5, and S100A1 were up-regulated in the endometrium of obese patients. These genes are mainly involved in chemokine, cytokine, and immune system activity and in the structural extracellular matrix and protein-binding molecular functions. CONCLUSION(S): Obesity is associated with significant endometrial transcriptomic differences as compared with non-obese subjects. Altered endometrial gene expression in obese patients may contribute to the lower implantation rates and increased miscarriage rates seen in obese infertile patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT02205866.

Novel lean type 2 diabetic rat model using gestational low-protein programming.

BACKGROUND: Type 2 diabetes (T2D) in lean individuals is not well studied and up to 26% of diabetes occurs in these individuals. Although the cause is not well understood, it has been primarily attributed to nutritional issues during early development. OBJECTIVE: Our objective was to develop a lean T2D model using gestational low-protein (LP) programming. STUDY DESIGN: Pregnant rats were fed control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery. Standard diet was given to dams after delivery and to pups after weaning. Glucose tolerance test was done at 2, 4, and 6 months of age. Magnetic resonance imaging of body fat for females was done at 4 months. Rats were sacrificed at 4 and 8 months of age and their perigonadal, perirenal, inguinal, and brown fat were weighed and expressed relative to their body weight. Euglycemic-hyperinsulinemic clamp was done around 6 months of age. RESULTS: Male and female offspring exposed to a LP diet during gestation developed glucose intolerance and insulin resistance (IR). Further, glucose intolerance progressed with increasing age and occurred earlier and was more severe in females when compared to males. Euglycemic-hyperinsulinemic clamp showed whole body IR in both sexes, with females demonstrating increased IR compared to males. LP females showed a 4.5-fold increase in IR while males showed a 2.5-fold increase when compared to their respective controls. Data from magnetic resonance imaging on female offspring showed no difference in the subcutaneous, inguinal, and visceral fat content. We were able to validate this observation by sacrificing the rats at 4 and 8 months and measuring total body fat content. This showed no differences in body fat content between control and LP offspring in either males or females. Additionally, diabetic rats had a similar body mass index to that of the controls. CONCLUSION: LP gestational programming produces a progressively worsening T2D model in rats with a lean phenotype without obesity.

Premature ovarian failure: clinical presentation and treatment.

Premature ovarian failure is a devastating diagnosis for reproductive-aged women. The diagnosis is relatively easy. However, it has serious health consequences, including psychological distress, infertility, osteoporosis, autoimmune disorders, ischemic heart disease, and increased risk for mortality. Management should be initiated immediately to prevent long-term consequences. Estrogen therapy is the mainstay of management. Postmenopausal estrogen therapy studies should not be used to determine the risks of treatment in these young women.

VCAM-1 on peritoneum and α4ß1 integrin in endometrium and their implications in endometriosis.

The objective of the study is to investigate vascular cellular adhesion molecule-1 (VCAM-1) expression on peritoneal mesothelial cells and α4ß1 integrin on eutopic endometrium as possible mechanisms in the pathogenesis of endometriosis. It is a case-control study carried out at an academic medical center. Participants are patients with (n=9) and without (n=15) endometriosis. The main outcome measures included VCAM-1 expression on peritoneal mesothelial cells and α4ß1 expression on eutopic endometrium using immunohistochemistry and flow cytometry, respectively. Patients with endometriosis were more likely to express VCAM-1 on peritoneal mesothelial cells, both in areas with and without macroscopic disease, compared with patients without endometriosis (9/9 vs. 3/15, P<0.001). No differences were found between cases and controls in regards to eutopic endometrial expression of α4ß1 integrin. The presence of VCAM-1 on peritoneal mesothelial cells is associated with endometriosis. This field effect, in addition to the similarity found with regards to the expression of α4ß1 integrin in eutopic endometrium between cases and controls, may implicate the expression of VCAM-1 in the peritoneum, and not changes in the eutopic endometrium, as a contributor to the pathogenesis of endometriosis.