Endometrial microbiota composition is associated with reproductive outcome in infertile patients.

BACKGROUND: Previous evidence indicates associations between the female reproductive tract microbiome composition and reproductive outcome in infertile patients undergoing assisted reproduction. We aimed to determine whether the endometrial microbiota composition is associated with reproductive outcomes of live birth, biochemical pregnancy, clinical miscarriage or no pregnancy. METHODS: Here, we present a multicentre prospective observational study using 16S rRNA gene sequencing to analyse endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection undergoing assisted reproductive treatments. RESULTS: A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. CONCLUSIONS: Our findings indicate that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome, offering an opportunity to further improve diagnosis and treatment strategies. Video Abstract.

Multicentric, prospective observational data show sperm capacitation predicts male fertility, and cohort comparison reveals a high prevalence of impaired capacitation in men questioning their fertility.

RESEARCH QUESTIONS: Can a previously defined relationship between sperm capacitation and the probability of a man generating pregnancy within three cycles, prospectively predict male fertility in diverse clinical settings? A second study asked, what is the prevalence of impaired sperm fertilizing ability in men questioning their fertility (MQF), and does this relate to traditional semen analysis metrics? DESIGN: In the multicentric, prospective observational study, data (n = 128; six clinics) were analysed to test a published relationship between the percentage of fertilization-competent, capacitated spermatozoa (Cap-Score) and probability of generating pregnancy (PGP) within three cycles of intrauterine insemination. Logistic regression of total pregnancy outcomes (n = 252) assessed fit. In the cohort comparison, Cap-Scores of MQF (n = 2155; 22 clinics) were compared with those of 76 fertile men. RESULTS: New outcomes (n = 128) were rank-ordered by Cap-Score and divided into quintiles (25-26 per group); chi-squared testing revealed no difference between predicted and observed pregnancies (P = 0.809). Total outcomes (n = 252; 128 new + 124 previous) were pooled and the model recalculated, yielding an improved fit (P < 0.001). Applying the Akaike information criterion found that the optimal model used Cap-Score alone. Cap-Scores were performed on 2155 men (with semen analysis data available for 1948). To compare fertilizing ability, men were binned by PGP (≤19%, 20-29%, 30-39%, 40-49%, 50-59%, ≥60%). Distributions of PGP and the corresponding Cap-Scores were significantly lower in MQF versus fertile men (P < 0.001). Notably, 64% of MQF with normal volume, concentration and motility (757/1183) had PGP of 39% or less (Cap-Scores ≤31), versus 25% of fertile men. CONCLUSIONS: Sperm capacitation prospectively predicted male fertility. Impaired capacitation affects many MQF with normal semen analysis results, informing diagnosis versus idiopathic infertility.

The impact of supervised weight loss and intentional weight regain on sex hormone binding globulin and testosterone in premenopausal women.

What is the impact of intentional weight loss and regain on serum androgens in women? We conducted an ancillary analysis of prospectively collected samples from a randomized controlled trial. The trial involved supervised 10% weight loss (8.5 kg on average) with diet and exercise over 4-6 months followed by supervised intentional regain of 50% of the lost weight (4.6 kg on average) over 4-6 months. Participants were randomized prior to the partial weight regain component to either continuation or cessation of endurance exercise. Analytic sample included 30 obese premenopausal women (mean age of 40 ± 5.9 years, mean baseline body mass index (BMI) of 32.9 ± 4.2 kg/m(2)) with metabolic syndrome. We evaluated sex hormone binding globulin (SHBG), total testosterone (T), free androgen index (FAI), and high molecular weight adiponectin (HMWAdp). Insulin, homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI), and visceral adipose tissue (VAT) measured in the original trial were reanalyzed for the current analytic sample. Insulin, HOMA, and QUICKI improved with weight loss and were maintained despite weight regain. Log-transformed SHBG significantly increased from baseline to weight loss, and then significantly decreased with weight regain. LogFAI and logVAT decreased similarly and increased with weight loss followed by weight regain. No changes were found in logT and LogHMWAdp. There was no significant difference in any tested parameters by exercise between the groups. SHBG showed prominent sensitivity to body mass fluctuations, as reduction with controlled intentional weight regain showed an inverse relationship to VAT and occurred despite stable HMWAdp and sustained improvements with insulin resistance. FAI showed opposite changes to SHBG, while T did not change significantly with weight. Continued exercise during weight regain did not appear to impact these findings.

Hyperosmolar glucose injection for the treatment of heterotopic ovarian pregnancy.

BACKGROUND: Heterotopic pregnancy describes the relatively rare coexistence of one or more intrauterine gestations and one or more extrauterine (ectopic) gestations. We describe a unique clinical case involving successful treatment of an ovarian heterotopic pregnancy through gestational sac aspiration and injection of hyperosmolar glucose. CASE: A 31-year-old woman presented with an ovarian ectopic pregnancy and a viable intrauterine pregnancy after ovulation induction with oral medications. The ovarian gestational sac was aspirated and then injected transvaginally with a small volume of 50% glucose in water. The ectopic pregnancy resolved, and the intrauterine pregnancy was delivered at term without complication. CONCLUSION: Gestational sac aspiration and injection of hyperosmolar glucose into an ovarian ectopic pregnancy was simple and efficacious without compromising a coexisting intrauterine pregnancy.

Polycystic ovary syndrome: current infertility management.

This review summarizes the diagnosis of polycystic ovary syndrome and management of associated infertility. The goal is to guide clinicians through basic evaluation, initial treatment, and briefly describe more complex therapies.

Antichlamydial antibodies, human fertility, and pregnancy wastage.

Genital infections with Chlamydia trachomatis (C. trachomatis) continue to be a worldwide epidemic. Immune response to chlamydia is important to both clearance of the disease and disease pathogenesis. Interindividual responses and current chlamydial control programs will have enormous effects on this disease and its control strategies. Humoral immune response to C. trachomatis occurs in humans and persistent antibody levels appear to be most directly correlated with more severe and longstanding disease and with reinfection. There is a close correlation between the presence of antichlamydial antibodies in females and tubal factor infertility; the closest associations have been found for antibodies against chlamydial heat shock proteins. The latter antibodies have also been shown to be useful among infertile patients with prior ectopic pregnancy, and their presence has been correlated with poor IVF outcomes, including early pregnancy loss. We review the existing literature on chlamydial antibody testing in infertile patients and present an algorithm for such testing in the infertile couple.

Metformin and/or clomiphene do not adversely affect liver or renal function in women with polycystic ovary syndrome.

CONTEXT: Nonalcoholic fatty liver disease is common to insulin-resistant states such as polycystic ovary syndrome (PCOS). Metformin (MET) is often used to treat PCOS but information is limited as to its effects on liver function. OBJECTIVE: We sought to determine the effects of MET on serum hepatic parameters in PCOS patients. DESIGN: This was a secondary analysis of a randomized, doubled-blind trial from 2002-2004. SETTING: This multi-center clinical trial was conducted in academic centers. PATIENTS: Six hundred twenty-six infertile women with PCOS with serum liver function parameters less than twice the upper limit of normal were included. INTERVENTIONS: Clomiphene citrate (n = 209), MET (n = 208), or combined (n = 209) were given for up to 6 months. MAIN OUTCOME MEASURE: The percent change from baseline in renal and liver function between- and within-treatment arms was assessed. RESULTS: Renal function improved in all treatment arms with significant decreases in serum blood urea nitrogen levels (range, -14.7 to -21.3%) as well as creatinine (-4.2 to -6.9%). There were similar decreases in liver transaminase levels in the clomiphene citrate and combined arms (-10% in bilirubin, -9 to -11% in transaminases) without significant changes in the MET arm. When categorizing baseline bilirubin, aspartate aminotransferase, and alanine aminotransferase into tertiles, there were significant within-treatment arm differences between the tertiles with the highest tertile having the largest decrease from baseline regardless of treatment arm. CONCLUSION: Women with PCOS can safely use metformin and clomiphene even in the setting of mildly abnormal liver function parameters, and both result in improved renal function.

Age does not influence the effect of embryo fragmentation on successful blastocyst development.

We evaluated the rate of blastocyst development in day 3 embryos with appropriate cellular division and investigated whether maternal age modified the effect of embryo fragmentation on blastulation. Our data showed a significant negative correlation between the degree of embryo fragmentation and rate of blastocyst development, but age did not exert an effect on the degree of fragmentation in embryos with appropriate cleaving status, nor did it modify the significant effect embryo fragmentation had on blastocyst formation.

Endometrial thickness predicts endometrial hyperplasia in patients with polycystic ovary syndrome.

Body mass index is predictive of sonographic endometrial stripe thickness, which in turn is predictive of endometrial hyperplasia in patients with polycystic ovary syndrome. For every 1-mm increase in endometrial stripe, the odds ratio of hyperplasia increased by 1.48 (95% confidence interval, 1.04-2.10).

Effect of delayed versus immediate embryo transfer catheter removal on pregnancy outcomes during fresh cycles.

A retrospective study was performed to determine whether the timing of embryo transfer catheter removal effects pregnancy rates in fresh, day 3 IVF cycles. Two hundred eighteen patients were evaluated, and no difference was noted between delayed versus immediate catheter removal techniques.

Luteal support with intravaginal progesterone increases clinical pregnancy rates in women with polycystic ovary syndrome using letrozole for ovulation induction.

OBJECTIVE: To determine the effect of intravaginal micronized P on pregnancy rates in clomiphene citrate and letrozole ovulation induction cycles in women with polycystic ovary syndrome (PCOS). DESIGN: Retrospective chart review. SETTING: University-based assisted reproductive technology program. PATIENTS: Women with PCOS who underwent ovulation induction with either clomiphene citrate (n = 90) or letrozole (n = 31) from January 2002 to December 2008. INTERVENTION(S): Clomiphene citrate (50-250 mg x 5 days) or letrozole (5 mg x 5 days) were used for ovulation induction. After either intercourse or IUI, patients received intravaginal micronized P (200 mg twice daily) according to prescribing physician preference. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate. RESULT(S): In clomiphene cycles, clinical pregnancies were documented in 15.3% of cycles (19 of 124) in the P group, compared with 12.1% (11 of 91) of the non-P group. In letrozole cycles, clinical pregnancies were documented in 21.1% of cycles (8 of 38) in the P group, compared with none (0 of 13) in the non-P group. CONCLUSION(S): Women with PCOS who used letrozole for ovulation induction had higher clinical pregnancy rates when using intravaginal P support. Luteal supplementation with P should be strongly considered in women with PCOS, especially in those using letrozole for ovulation induction.

Metformin does not improve the reproductive or metabolic profile in women with polycystic ovary syndrome (PCOS).

To determine whether metformin, when given to women with polycystic ovary syndrome (PCOS), promotes folliculogenesis by prompting a drop in free sex steroids resulting in a compensatory follicle stimulating hormone (FSH) rise, we conducted a randomized, double-blind, placebo-controlled crossover clinical trial. Eight mid-reproductive age PCOS participants with mean obese body mass index (BMI) and normal glucose tolerance received 8 weeks of metformin, given in a step-up fashion to a maximum dose of 2000 mg daily or placebo with daily urine sampling, 4-6 weeks washout, and crossover to the remaining arm for 8 weeks. To confirm the effects of metformin on glucose and other metabolic markers, a hyperinsulinemic, euglycemic 3-dose clamp (physiologic: 30 mU/m(2) per minute, high: 400 mU/m(2) per minute) followed each treatment. Urinary FSH, luteinizing hormone (LH), or pregnanediol glucuronide (Pdg) did not differ by treatment. Glucose disposal, endogenous glucose production, BMI, ovulation rates, serum sex steroids, free fatty acids, and lipids did not significantly differ by treatment, despite good evidence for compliance with the protocol. During the clamp, high-dose insulin administration was associated with an acute drop in serum LH. We conclude that short-term, high-dose metformin exerts minimal effects on both metabolic markers and reproductive hormones in a small sample of overall morbidly obese women.

Follicle curetting at the time of oocyte retrieval increases the oocyte yield.

PURPOSE: To determine whether follicle curetting at the time of oocyte retrieval increases oocyte yield. METHODS: Retrospective review of all patients who underwent oocyte retrieval from July 1, 2003 to June 30, 2005. MAIN OUTCOME MEASURE: Number of oocytes retrieved. SECONDARY OUTCOME MEASURES: retrieval time, number of cryopreserved embryos, pregnancy rates, and incidence of ovarian hyperstimulation syndrome. RESULTS: There were no differences in patient demographics, antral follicle count, cycle stimulation characteristics, fertilization rates, embryo quantity or quality, embryo cryopreservation rates, clinical pregnancy rates, live birth rates, or ovarian hyperstimulation syndrome between the groups. Retrievals that utilized curetting took three minutes longer. Follicle curetting significantly increased the number of oocytes retrieved, 13.9 +/- 0.6 compared to 11.4 +/- 0.6 oocytes without curetting (P = 0.003). The quantity of mature oocytes was also increased with curetting (10.3 +/- 0.5 versus 8.4 +/- 0.5, P = 0.006). CONCLUSIONS: This study demonstrated that follicle curetting significantly increased oocyte yield. While it did not increase live birth rates, this increase in oocyte yield should lead to increased numbers of embryos for selection at transfer and increased embryos for cryopreservation.

Supervised short-term nutrition and exercise promotes weight loss in overweight and obese patients with polycystic ovary syndrome.

Thirty-two mid-reproductive-aged overweight and obese patients with polycystic ovary syndrome, most of whom had never exercised regularly, lost 3% to 4% of baseline weight, body mass index, and circumference of waist and hip while participating for 8.8 +/- 2.7 weeks in a medically supervised fitness program.

Case series of rosiglitazone used during the first trimester of pregnancy.

Prior to 2007, use of the insulin sensitizer metformin was widely advocated in patients with polycystic ovarian syndrome (PCOS) both to promote ovulation and decrease the incidence of PCOS-associated obstetrical complications. However, the gastrointestinal disturbances associated with metformin led many to discontinue its use. Rosiglitazone is an insulin sensitizer that, because of minimal associated gastrointestinal disturbance, was used as an alternative to metformin in PCOS patients. From 2003 to 2005, 8 women with PCOS unable to tolerate metformin used rosiglitazone for ovulation induction and during their first 12 weeks of gestation. All delivered healthy babies at term, without obstetric complications or congenital anomalies. However, given recent evidence that disputes the reproductive benefits of insulin sensitization for PCOS and that raises safety concerns of rosiglitazone, we are no longer using it for PCOS treatment.

Effects of polycystic ovarian syndrome on in vitro fertilization-embryo transfer outcomes are influenced by body mass index.

OBJECTIVE: To determine whether polycystic ovary syndrome (PCOS) adversely impacts IVF-embryo transfer outcomes in obese compared to lean patients. DESIGN: Retrospective chart review. SETTING: University-affiliated infertility program. PATIENT(S): Lean non-PCOS (n = 52), lean PCOS (n = 6), obese non-PCOS (n = 18), and obese PCOS (n = 10). INTERVENTION(S): Ninety-four fresh nondonor IVF-embryo transfer cycles analyzed. MAIN OUTCOME MEASURE(S): Cycle characteristics, clinical pregnancy (PR) and live birth rates. RESULT(S): Lean PCOS had more dominant follicles (12.2 +/- 6.0 vs. 7.7 +/- 3.6), retrieved oocytes (22.2 +/- 9.2 vs. 12.6 +/- 5.8), and frozen embryos (5 +/- 4.6 vs. 1.4 +/- 2.6) than lean non-PCOS. Lean PCOS also used fewer gonadotropin ampules (18.8 +/- 6.0 vs. 29.2 +/- 14.2), but had more retrieved oocytes (22.2 +/- 9.2 vs.14.3 +/- 4.9) than obese PCOS. Obese non-PCOS had better-grade embryos (2.1 +/- 0.8 vs. 2.7 +/- 0.8) and fewer embryos transferred (2.4 +/- 0.6 vs. 2.9 +/- 0.6) than obese PCOS, but more embryos frozen than lean non-PCOS (3.2 +/- 3.2 vs. 1.4 +/- 2.6). Implantation rates trended downward in obese patients with PCOS, but no other differences were observed. CONCLUSION(S): Patients with PCOS with a body mass index (BMI) in the lean rather than the obese range have more favorable assisted reproductive technology (ART) cycle characteristics but show no clinical outcome differences.

The nucleolar channel system of human endometrium is related to endoplasmic reticulum and R-rings.

The nucleolar channel system (NCS) is a well-established ultrastructural hallmark of the postovulation endometrium. Its transient presence has been associated with human fertility. Nevertheless, the biogenesis, composition, and function of these intranuclear membrane cisternae are unknown. Membrane systems with a striking ultrastructural resemblance to the NCS, termed R-rings, are induced in nuclei of tissue culture cells by overexpression of the central repeat domain of the nucleolar protein Nopp140. Here we provide a first molecular characterization of the NCS and compare the biogenesis of these two enigmatic organelles. Like the R-rings, the NCS consists of endoplasmic reticulum harboring the marker glucose-6-phosphatase. R-ring formation initiates at the nuclear envelope, apparently by a calcium-mediated Nopp140-membrane interaction, as supported by the calcium-binding ability of Nopp140, the inhibition of R-ring formation by calcium chelators, and the concentration of Nopp140 and complexed calcium in R-rings. Although biogenesis of the NCS may initiate similarly, the reduced presence of complexed calcium and Nopp140 suggests the involvement of additional factors.

Assessment of the proliferative status of epithelial cell types in the endometrium of young and menopausal transition women.

BACKGROUND: We determined protein and mRNA expressions of markers of normal human endometrial proliferation and hypothesized that dysregulation of the endometrial response to estradiol (E(2)) and progesterone would be observed in the older menopausal transition (MT) women compared with mid-reproductive age (MRA) controls. METHODS: Endometrial biopsies were prospectively obtained from MRA and MT non-randomized healthy volunteers during proliferative (+/- exogenous E(2)) and secretory (MRA only) menstrual cycle phases. mRNA and/or nuclear protein expressions of proliferative markers (MKI67, PCNA and MCM2), cell-cycle regulators (cyclins A1, E1 and D1 and cyclin dependent kinase Inhibitor B; CCNA1, CCNE1, CCND1 and CDKN1B) and sex-steroid receptors [estrogen receptor (ER) and progesterone receptor (PR)] were assessed in endometrial lumen, gland and stroma. RESULTS: MRA women had significantly higher proliferative than secretory expression of MKI67, PCNA, MCM2, CCNA1, CCNE1, ESR1 and PGR in lumen and gland (minimal stromal changes), whereas CDKN1B protein expression was higher during the secretory phase. E(2)-treatment of MT women led to relatively less MKI67 glandular protein expression compared with MRA women; no other age-related differences were observed. CONCLUSION: Although the MT does not appear to alter the proliferative cell phenotype of endometrial epithelium and stroma, the data suggest that prior to the MT, age is associated with a decrease in some proliferative markers and steroid receptor expression status within different endometrial cell types.

A prospective comparison of the impact of uterine artery embolization, myomectomy, and hysterectomy on ovarian function.

PURPOSE: To prospectively compare uterine artery embolization (UAE) versus myomectomy and hysterectomy with regard to ovarian function as measured by postprocedure follicle-stimulating hormone (FSH) levels and symptoms. MATERIALS AND METHODS: Fifty-five patients were prospectively enrolled in the study: 33 patients who underwent UAE, seven who underwent myomectomy, and 15 who underwent hysterectomy. Patients had serum FSH and estradiol levels measured on the third day of the menstrual cycle before their procedure and at regular follow-up visits for as long as 6 months. At these intervals, patients were also surveyed regarding menopausal symptoms. RESULTS: Although a mild transient increase in mean FSH level after UAE was noted at 3 months, there were no statistically significant differences among the three groups in mean FSH levels at 1 month, 3 months, or 6 months of follow-up. Menopausal symptoms arose in the UAE and hysterectomy groups, but there was no statistically significant difference or permanent effect in either group. CONCLUSION: There is no significant difference in impact on ovarian function after UAE, hysterectomy, or myomectomy at follow-up for a maximum of 6 months.