Orhan Bukulmez

The effect of endometriosis on implantation : results from the Yale University in vitro fertilization and embryo transfer program

OBJECTIVE To investigate the effect of endometriosis on implantation. DESIGN Case-control study from Yale University IVF-ET program. PATIENTS Two hundred eighty-four consecutive IVF cycles were analyzed retrospectively. Patients with endometriosis only (n = 35; 89 cycles) were compared with an age-matched control group with tubal infertility (n = 70; 147 cycles) and also to a group with unexplained infertility (n = 15; 48 cycles). Data from the endometriosis group was analyzed further in subgroups of minimal-mild (43 cycles) and moderate-severe (46 cycles). RESULTS No difference was found in the number and the quality of oocytes retrieved and fertilization rates between the endometriosis, the tubal infertility, and the unexplained infertility groups. The quality and the number of embryos transferred in each group were comparable. A trend toward reduced pregnancy rate per transfer (14.8%) in the endometriosis versus tubal or unexplained infertility groups (25.7% and 23.3%, respectively) was observed. Implantation rate (gestational sac per transferred embryo) was significantly lower in the endometriosis versus the tubal infertility group (3.9% versus 8.1%; unexplained infertility group, 7.2%). Analysis of first cycles only across all groups revealed that the implantation rate also was significantly lower in the endometriosis versus the tubal infertility group (3.1% versus 9%; unexplained infertility group, 6.7%). Within the endometriosis group, although the pregnancy rate per cycle and per transfer were similar in subgroups, patients with minimal-mild endometriosis had the lowest implantation rate. CONCLUSION We conclude that, in patients with endometriosis, implantation rate is low. Abnormal implantation, which may be secondary to endometrial dysfunction or embryotoxic environment, is a factor in endometriosis-associated subfertility.

Diastolic dysfunction and increased serum homocysteine concentrations may contribute to increased cardiovascular risk in patients with polycystic ovary syndrome

OBJECTIVE To assess cardiac flow parameters in patients with polycystic ovary syndrome (PCOS). DESIGN A prospective case-control study. SETTING University-based hospital. PATIENT(S) Thirty consecutive patients with PCOS were enrolled. Thirty women with regular menstrual cycles served as the controls. INTERVENTION(S) Systolic and diastolic function parameters were assessed by standard two-dimensional and M-mode echocardiography. Insulin sensitivity was evaluated by a standard 75-g oral glucose tolerance test and area-under-curve insulin analysis. Serum hormones, lipid profile, homocysteine, vitamin B(12), folate, fibrinogen, uric acid, and plasminogen activator inhibitor-I concentrations were measured. MAIN OUTCOME MEASURE(S) Systolic and diastolic function parameters, insulin sensitivity and serum homocysteine levels. RESULT(S) The mean serum homocysteine and uric acid concentrations were significantly higher in the PCOS group. Patients with PCOS had significant hyperinsulinemia. All systolic function parameters were comparable between the two groups. However, patients with PCOS had significantly lower peak mitral flow velocity in early diastole and significantly lower ratio between the early and late peak mitral flow velocities and also had significantly longer isovolumic relaxation time, reflecting a trend for nonrestrictive-type diastolic dysfunction. The area-under-curve insulin correlated positively with peak mitral flow velocity in late diastole (r = 0.375). The mean cholesterol/high-density lipoprotein ratio correlated negatively with mean mitral flow velocity in early diastole (E) peak (r = -0.474). The mean fasting insulin level correlated negatively with mean E/A ratio (r = -0.387). CONCLUSION(S) Diastolic dysfunction and increased serum homocysteine concentrations may contribute to increased cardiovascular disease risk in patients with PCOS.

Mature cystic teratomas of the ovary: case series from one institution over 34 years

OBJECTIVE To evaluate bilaterality, complications and malignant changes of mature cystic teratomas of the ovary. STUDY DESIGN Retrospective study of 501 patients operated at Hacettepe University Hospital between the years of 1964 and 1998. RESULTS The median age was 35 years (range 13-76). One hundred and six cases (21.1%) were asymptomatic. The mean tumor diameter was 7.0+/-4.5 cm. The decision for cystectomy or oophorectomy was related with the patient age, gravidity and parity. The bilaterality rate when both ovaries were evaluated histopathologically was 13.2% (44/331). Total complication rate was 10.7%, torsion being the most frequent (4.9%). The rate of malignant transformation was 1.4%. CONCLUSION Ovarian mature cystic teratomas are common tumors especially during the reproductive period with low rates of covert bilaterality, complications and malignant transformation. The treatment should be directed on the basis of age, fertility desire or presence of another pelvic pathology rather than the size or bilaterality.

Assessment of ovarian reserve.

Purpose of review Various methods have been proposed and are currently used in the assessment of ovarian reserve in order to predict the outcome in assisted reproduction. This review focuses on the current information regarding the ovarian reserve markers and tests, an active area of research. Recent findings Female age alone is a rough parameter for assessing ovarian reserve. The basal follicle stimulating hormone level is not adequately sensitive to predict poor outcome and the same is true for other basal parameters, including basal estradiol, the follicle stimulating hormone/luteinizing hormone ratio, and inhibin-B levels. The clomiphene citrate challenge test has a low sensitivity but this sensitivity is greater than that of basal follicle stimulating hormone. The value of other hormonal dynamic tests remains to be determined. Among the ultrasound markers the total antral follicle count seems to be promising. Ovarian biopsy in this assessment is controversial. History of poor response to ovarian stimulation is a strong indicator for declining ovarian function. Summary There is currently no clinically useful predictive test sufficiently accurate and distinct in time from controlled ovarian stimulation to assess ovarian reserve accurately. Further research is warranted to validate the ovarian reserve tests in the general population and in populations with different causes of infertility.

The Expression and Ovarian Steroid Regulation of Endometrial Micro-RNAs

Toloubeydokhti T, Pan Q, Luo X, Bukulmez O, Chegini N. The expression and ovarian steroid regulation of endometrial micro-RNAs. Reprod Sci. 2008;15:993-1001. Following an investigation by the University of Florida providing evidence of the senior (last) author’s use of falsified or fabricated data in Figures 1, 2 and 3, the above-mentioned article has been retracted. None of the other authors, Tannaz Toloubeydokhti, Qun Pan, Xiaoping Luo, and Orhan Bukulmez, were the subject of the investigation MicroRNAs (miRNAs) which regulate gene expression stability displayed an aberrant expression profile in ectopic endometrium (ECE) as compared to eutopic (EUE) and normal endometrium (NE). We assessed the expression of miR-17-5p, miR-23a, miR-23b and miR-542-3p, their predicted target genes, steroidogenic acute regulatory protein, aromatase and cyclooxygenase-2, and influence of ovarian steroids on their expression in endometrial stromal (ESC) and glandular epithelial cells (GEC). The results indicated a lower expression of miR-23b and miR-542-3p and higher level of miR-17-5p in paired ECE and EUE as compared with NE. These levels were elevated and inversely correlated with the level of expression of their respective target genes in ECE. The expression of these miRNAs and genes was differentially regulated by 17β- estradiol, medroxyprogesterone acetate, ICI-182780 and RU-486, or their respective combinations in ESC and GEC. We concluded that altered expression of specific miRNAs in ECE, affecting the stability of their target genes expression, has direct implications in pathogenesis of endometriosis.

Intracytoplasmic sperm injection versus in vitro fertilization for patients with a tubal factor as their sole cause of infertility: a prospective, randomized trial

OBJECTIVE To compare the efficacy of intracytoplasmic sperm injection and IVF in women with a tuboperitoneal factor as their sole cause of infertility. DESIGN Prospective, randomized study. SETTING Hacettepe University Assisted Reproduction Unit, Ankara, Turkey. PATIENT(S) Seventy-six consecutively seen patients with tuboperitoneal factor infertility were randomized on an alternate basis to undergo either intracytoplasmic sperm injection (38 patients and cycles) or IVF (38 patients and cycles). INTERVENTION(S) Intracytoplasmic sperm injection and IVF. MAIN OUTCOME MEASURE(S) Fertilization, implantation, and clinical pregnancy rates. RESULT(S) A comparable number of oocytes and embryos were obtained with intracytoplasmic sperm injection and IVF. The two-pronuclei fertilization rates per metaphase II oocyte or mature cumulus-oocyte complex were similar in the two groups. The numbers of total and grade I embryos transferred also were similar. Comparisons of intracytoplasmic sperm injection and IVF did not reveal any statistically significant differences in individual implantation rates (38.75% +/- 24.46% and 34.58% +/- 16.97%, respectively) clinical pregnancy rates per cycle (21.05% and 21.05%, respectively), or take-home infant rates (18.42% and 15.79%, respectively). The type of procedure performed was not a significant predictor of clinical pregnancy. CONCLUSION(S) When a decision is made to proceed with an assisted reproductive technique in patients with a tubal factor as their sole cause of infertility, IVF should be the initial treatment of choice.

The effect of increasing obesity on the response to and outcome of assisted reproductive technology: a national study

OBJECTIVE To evaluate the effect of increasing female obesity on response to and outcome of assisted reproductive technology (ART) treatment. DESIGN Historical cohort study. SETTING Clinic-based data. PATIENT(S) A total of 152,500 ART cycle starts from the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System for 2007-2008, limited to women with documented height and grouped by body mass index (BMI, [weight/height(2)]). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Cycle cancellation overall, cycle cancellation due to low response, treatment failure (not pregnant vs. pregnant), and pregnancy failure (fetal loss or stillbirth vs. live birth), as adjusted odds ratios and 95% confidence intervals, with cycles among normal-weight women as the reference group. RESULT(S) Cycle cancellation overall and cancellation due to low response using autologous oocytes significantly paralleled increasing BMI. The odds of treatment failure rose significantly with autologous-fresh cycles, from 1.03 for cycles among overweight women (BMI 25.0-29.9) to 1.53 for cycles among women with BMIs ≥ 50.0 kg/m(2). Likewise, the odds of pregnancy failure were most significant with increasing BMI among women with autologous-fresh cycles, increasing from 1.10 for cycles to overweight women to 2.29 for cycles to women with BMI ≥ 50.0 kg/m(2). CONCLUSION(S) These results indicate significantly higher odds of cycle cancellation. In addition, treatment and pregnancy failures with increasing obesity significantly increased starting with overweight women.

Monocyte chemotactic protein-1 expression in human preovulatory follicles and ovarian cells

There is a considerable population of macrophages (5-15% of the cells) within the human ovarian follicle at the time of ovulation. Macrophages are also present within the ovarian stroma, mostly near perifollicular capillaries. We hypothesized that macrophage migration in and around the preovulatory follicle is hormonally regulated and that regulation of macrophage migration occurs through local modulation of monocyte chemotactic protein-1 (MCP-1) that chemoattracts and activates monocytes/macrophages. In this regard, we investigated the expression and regulation of MCP-1 in human follicular fluid and in ovarian stromal and granulosa-lutein cell cultures. The concentration of MCP-1 in follicular fluid samples obtained from women prior to the administration of hCG was (n = 4) 90 +/- 27 (mean +/- S.E.) pg/ml; in samples obtained 12 h after the hCG administration it was (n = 3) 135 +/- 23 pg/mL; in follicular fluids obtained 34 h after the hCG administration it was (n = 126) 322 +/- 46 pg/mL (P = 0.007 vs. pre-hCG). The mean ratio of follicular fluid/serum MCP-1 levels was 4.18. There was a correlation between follicular fluid MCP-1 levels and follicular fluid or serum progesterone levels (r = 0.21, P = 0.02; r = 0.29, P = 0.03, respectively). MCP-1 mRNA and the protein were expressed in ovarian stromal and granulosalutein cells in culture and were increased by interleukin-1 alpha and tumor necrosis factor-alpha in a time- and concentration-dependent manner. LH/hCG induced higher levels of MCP-1 mRNA expression and protein production in both cell cultures. We propose that regulation of MCP-1 in ovarian stromal and granulosa-lutein cells by cytokines may play a role in the physiology of periovulatory events.

Perinatal outcome in adolescent pregnancies: a case-control study from a Turkish university hospital.

OBJECTIVE To determine whether adolescent pregnancy is associated with increased risk for adverse pregnancy outcome. STUDY DESIGN Retrospective case-control study which enrolled 1460 singleton adolescent pregnancies and 2980 controls, delivered at Hacettepe University Hospital between January 1990 and January 1998. RESULTS Significantly higher rate of perinatal and severe perinatal complications were noted in adolescents. The presence of historical risks, multiparity, young age and lack of prenatal care were significant predictors of these complications. Exclusion of them except for age, revealed comparable perinatal and severe perinatal complications in both groups. CONCLUSION Adolescent women who receive adequate prenatal care are at no greater risk of an adverse obstetric outcome than adult women of a similar sociodemographic background.

Urinary follicle-stimulating hormone (FSH) versus recombinant FSH in clomiphene citrate–resistant, normogonadotropic, chronic anovulation: a prospective randomized study

OBJECTIVE To compare the efficacy and safety of urinary FSH and recombinant FSH for ovulation induction in patients with clomiphene citrate-resistant, normogonadotropic, chronic anovulation. DESIGN Prospective, randomized trial. SETTING University-based infertility clinic. PATIENT(S) Fifty-one women. INTERVENTION(S) Subjects were randomized to receive either urinary FSH (35 patients, 64 cycles) or recombinant FSH (16 patients, 32 cycles). A maximum of three cycles using the low-dose step-up protocol with the same gonadotropin were undertaken. MAIN OUTCOME MEASURE(S) Cumulative ovulation and pregnancy rates after three cycles, total gonadotropin dose, duration of stimulation, and single follicle development rate. RESULT(S) Cumulative ovulation rates were 89.3% and 93.1% for the urinary FSH and recombinant FSH groups, respectively. The threshold and total doses of FSH and the duration of stimulation were similar between the two groups. Significantly more single follicle development was noted in the recombinant FSH group. The respective clinical pregnancy rates per noncanceled cycles in the urinary FSH and recombinant FSH groups were 23.2% and 27.6%. There were three sets of twins in the urinary FSH group. No case of ovarian hyperstimulation syndrome was encountered. CONCLUSION(S) Urinary FSH and recombinant FSH are both efficient and safe for inducing ovulation with the low-dose step-up protocol.