Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives.

INTRODUCTION: Diabetes mellitus, the prevalence of which has increased dramatically worldwide, may put patients at a higher risk of cancer. The aim of our study is the clarification of the possible mechanisms linking diabetes mellitus and gynecological cancer and their epidemiological relationship. MATERIALS AND METHODS: This is a narrative review of the current literature, following a search on MEDLINE and the Cochrane Library, from their inception until January 2012. Articles investigating gynecologic cancer (endometrial, ovarian, and breast) incidence in diabetic patients were extracted. RESULTS: The strong evidence for a positive association between diabetes mellitus and the risk for cancer indicates that energy intake in excess to energy expenditure, or the sequelae thereof, is involved in gynecological carcinogenesis. This risk may be further heightened by glucose which can directly promote the production of tumor cells by functioning as a source of energy. Insulin resistance accompanied by secondary hyperinsulinemia is hypothezised to have a mitogenic effect. Steroid hormones are in addition potent regulators of the balance between cellular differentiation, proliferation, and apoptosis. Inflammatory pathways may also be implicated, as a correlation seems to exist between diabetes mellitus and breast or endometrial carcinoma pathogenesis, although an analogous correlation with ovarian carcinoma is still under investigation. Antidiabetic agents have been correlated with elevated cancer risk, while metformin seems to lower the risk. CONCLUSION: Diabetes mellitus is associated with an elevation in gynecologic cancer risk. Moreover, there are many studies exploring the prognosis of patients with diabetes and gynecological cancer, the outcome and the overall survival in well-regulated patients.

Response to hormonal treatment of young females with primary or very premature ovarian failure.

The aim of this study was to evaluate the impact of hormone treatment (HT) on several endocrinologic, metabolic and bone parameters in young women with primary or very premature ovarian failure. The study included 40 phenotypically females of 14-20 years old with primary or secondary amenorrhoea and female external genitalia. Study subjects were categorised in three groups: Group A included 12 subjects with Turner syndrome, Group B included 19 subjects with Swyer syndrome and Group C included 9 subjects with very premature ovarian failure. HT was administered for 24 months and included conjugated oestrogens and medroxyprogesterone acetate. In all groups, HT provided a beneficial hormonal profile and resulted in safe and adequate serum oestrogens levels. In Group A, no adverse effects on metabolic or coagulation parameters were noted; significant increases in high-density lipoprotein cholesterol (HDL) levels and bone density were observed. Similar positive effects of HT were observed in Group B. Finally, in Group C, no adverse effects of HT were noted, but the favourable increase in HDL was absent; bone density kept significantly increasing until the 12-month evaluation. In conclusion, the administration of HT is remarkably beneficial for young women with primary or very premature ovarian failure.

Altered Resistin Concentrations in Mid-trimester Amniotic Fluid of Fetuses With Trisomies 18 and 13: A Window onto the Pathophysiology of Trisomies 18 and 13.

BACKGROUND/AIM: The study aimed to examine whether resistin is present in second trimester amniotic fluid from pregnancies with trisomy 18 and 13 and evaluate its concentration in comparison with euploid pregnancies. PATIENTS AND METHODS: The study included 37 women who underwent amniocentesis. Eleven fetuses had trisomy 18, 3 had trisomy 13, while 23 had a normal karyotype. RESULTS: Resistin was detected in all cases. The mean level of resistin in trisomy 18 was statistically significantly lower compared to euploid controls. Resistin levels in all abnormal cases were below its median concentration in euploid controls. ROC analysis showed very good prognostic value for both trisomies. CONCLUSION: Resistin is a constituent of mid-trimester amniotic fluid of pregnancies with trisomies 13 and 18, exhibiting lower levels than those in euploid fetuses. The reduced levels of resistin in amniotic fluid may be associated with early changes in metabolic pathways and immunoinflammatory responses.

Serum adiponectin during pregnancy and postpartum in women with gestational diabetes and normal controls.

AIMS: To investigate changes in serum adiponectin during pregnancy and postpartum and assess its relationship with insulin resistance as measured by homeostasis model assessment (HOMA-IR). METHODS: Twenty-two normal pregnant women were compared with 22 women diagnosed with gestational diabetes mellitus (GDM). Serum adiponectin levels were measured at the time of the glucose challenge test as well as in the immediate postpartum period and the correlation of adiponectin to HOMA-IR was performed. RESULTS: Adiponectin was significantly lower in women with GDM than in controls during pregnancy (5381 vs. 8449 ng/dl, p = 0.004), as well as postpartum (3278 vs. 6958 ng/ml, p = 0.002). A significant reduction in adiponectin (3278 vs. 5381 ng/ml, p = 0.002) was observed postpartum in GDM women but not in controls. Using a lower cut-off value of 5253 ng/ml, maternal adiponectin could exclude GDM with a sensitivity of 86.4% and a specificity of 59.1% (area under the curve = 0.752, standard error = 0.77, 95% confidence interval 0.601-0.903, p = 0.004). Adiponectin levels during pregnancy were negatively correlated with HOMA-IR (r = -0.375, p = 0.012). CONCLUSION: GDM is associated with decreased serum adiponectin levels both in pregnancy as well as postpartum. Adiponectin is negatively correlated to HOMA-IR. A reduction in maternal adiponectin after delivery indicates a significant placental contribution to adiponectin production.

Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women.

OBJECTIVE: To assess the association between endogenous sex hormones and risk factors for atherosclerosis in healthy postmenopausal women. DESIGN: Cross-sectional study in a university menopause clinic. METHODS: Serum sex hormones and lipid-lipoprotein profile, arterial pressure, homocysteine and insulin resistance, measured by the homeostasis model assessment of insulin resistance (HOMA-IR), were assessed in 598 healthy postmenopausal women not on hormone therapy. RESULTS: Compared with women in the lowest testosterone quartile (Q), women in the highest testosterone quartile had higher total cholesterol (Q1: 225.2 +/- 41.3 vs Q4: 246.2 +/- 38.4 mg/dl, P < 0.01), low-density lipoprotein (LDL)-cholesterol (Q1: 146.9 +/- 37.2 vs Q4: 171.8 +/- 35.3 mg/dl, P < 0.001), atherogenic index of plasma (AIP) (Q1: -0.224 +/- 0.238 vs Q4: -0.087 +/- 0.254, P < 0.01), apolipoprotein B (ApoB) (Q1: 100.7 +/- 23.1 vs Q4: 113.9 +/- 23.8 mg/dl, P < 0.001) and higher high-density lipoprotein (HDL)-cholesterol (Q1: 60.7 +/- 14.5 vs Q4: 52.9 +/- 13.0 mg/dl, P < 0.01). Accordingly, women in the highest free androgen index (FAI) quartile had higher AIP (Q1: -0.232 +/- 0.254 vs Q4: -0.078 +/- 0.243, P < 0.001) and ApoB (Q1: 102.4 +/- 25.5 vs Q4: 114.2 +/- 25.8 mg/dl, P < 0.01) and lower HDL-cholesterol (Q1: 62.0 +/- 15.7 vs Q4: 51.9 +/- 11.6 mg/dl, P < 0.001) and apolipoprotein A (Q1: 159.6 +/- 25.6 vs Q4: 147.9 +/- 24.1 mg/dl, P < 0.01) compared with women in the lowest FAI quartile. These differences remained significant after adjustment for age, body mass index (BMI), insulin resistance and social habits. The free estrogen index (FEI) exhibited similar associations to the FAI. HOMA-IR showed an independent positive association with total testosterone (Q1: 2.00 +/- 1.36 vs Q4: 2.66 +/- 1.60, P < 0.01), FAI (Q1: 1.70 +/- 1.12 vs Q4: 3.04 +/- 1.66, P < 0.001) and FEI (Q1: 1.70 +/- 0.91 vs Q4: 3.08 +/- 1.77, P < 0.001). CONCLUSIONS: Increased androgenicity in healthy postmenopausal women is associated with an unfavorable cardiovascular risk profile. High endogenous estradiol is related to a pro-atherogenic lipid profile, an association which may, in part, be mediated by insulin resistance.

The fetus that is small for gestational age.

The symmetric small for gestational age (SGA) fetus presents a complex management problem for the obstetrician, but the growth restriction affects morbidity and mortality at all stages of life. The differential diagnosis in symmetric growth aberration includes the constitutionally small fetus, the fetus with pathology, and the cases with incorrect dating of pregnancy. The ultrasonographic examination focuses in the detection of anomalies, signs of intrauterine infection, and serial assessment of fetal growth. Accuracy of fetal biometry may be improved by using individualized fetal growth curves. From the available surveillance tools, the uterine artery Doppler has a value in predicting poor perinatal outcome. Magnetic resonance imaging is also useful in the evaluation of anomalies. Cesarean section is not justified for all symmetric SGA fetuses that may carry a guarded prognosis.

Bisphosphonates.

Bisphosphonates belong to a class of compounds similar to pyrophosphate. In these compounds the oxygen atom of the pyrophosphate is replaced by a carbon atom resulting in a P-C-P bond. They exert a potent inhibitory effect on osteoclasts and are therefore potent antiresorptive agents. They reduce bone turnover, increase bone mineral density, and decrease fracture risk both at the lumbar spine and the hip. Bisphosphonates have a high affinity for bone surfaces, where they accumulate, mainly at sites of bone remodeling. Due to their selectivity in action, they are usually not associated with systemic side effects. Their main unwanted effect is upper gastrointestinal irritation. Alendronate and risedronate are the two most widely used compounds in the treatment of postmenopausal osteoporosis. They are administered orally either daily or once weekly. Ibandronate is a highly potent newer third-generation bisphosphonate administered once monthly with similar efficacy with respect to bone mineral density and fracture risk. Zoledronate, another potent third-generation bisphosphonate, currently approved for the treatment of malignancy-associated hypercalcemia, is currently undergoing phase III trials for the treatment of postmenopausal osteoporosis as an intravenous (i.v.) infusion once annually.

The effect of raloxifene and tibolone on the uterine blood flow and endometrial thickness: a transvaginal Doppler study.

OBJECTIVES: To evaluate and compare the effect of different than classical hormone therapy medications, such as raloxifene and tibolone, on the uterine arteries and endometrium of postmenopausal women using transvaginal ultrasonography. METHODS: The prospective study included 62 healthy, postmenopausal women recruited from the Menopausal Clinic of the 2nd Department of Obstetrics and Gynecology of the University of Athens. Subjects were randomly allocated to receive raloxifene HCl in a daily dose of 60 mg orally (Group A-31 women) or tibolone in a daily dose of 2.5 mg orally (Group B-31 women). The study period was 6 months and all subjects were assessed using transvaginal ultrasonography before treatment initiation as well as after 3 and 6 months for evaluation of the endometrial thickness and the pulsatility (PI) and resistance (RI) indices at the level of the uterine arteries. RESULTS: No significant differences in RI, PI and endometrial thickness were observed in the raloxifene group during the 6-month treatment. In the tibolone group, PI and RI values decreased linearly from baseline to the end of the study, whereas the endometrial thickness was significantly increased during the first 3 months remaining unaltered thereafter. Comparisons between the two study groups revealed significant percent change of values in the pre-treatment to month-3 period and no difference with regard to pre-treatment, month-3 and month-6 absolute values. CONCLUSION: Raloxifene and tibolone exert dissimilar effects on uterine blood supply parameters and endometrial thickness.

The effect of low dose hormone therapy on mammographic breast density.

OBJECTIVES: To evaluate the effect of two standard and one low dose continuous hormone therapy regimens on mammography. METHODS: One hundred and thirty-two non-hysterectomized postmenopausal women were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=38), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, n=44) or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA, n=50). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month mammograms. RESULTS: Five (13.2%) women in the CEE/MPA group showed an increase in breast density. Fourteen (31.8%) women on E2/NETA and 6 (12.2%) on low E2/NETA treatment revealed an increase in breast density. No woman exhibited an involution of fibroglandular tissue. CONCLUSIONS: Different hormone therapy regimens have a variable impact on breast density probably depending on the steroid used. Low dose hormone therapy associates with significantly lesser increase in breast density.

A 5-year study on the effect of hormone therapy, tibolone and raloxifene on vaginal bleeding and endometrial thickness.

OBJECTIVES: To study the effect of standard and low-dose estrogen-progestin therapy (EPT), tibolone and raloxifene on the incidence of vaginal spotting/bleeding and endometrial thickness over a 5-year period. METHODS: Seven hundred eighty-six postmenopausal women were studied in an open prospective design. Vaginal spotting/bleeding and endometrial thickness as assessed by transvaginal ultrasonography was compared between six categories of women over a 5-year period: three categories in women on continuous combined estrogen-progestin therapy, one category under tibolone, one category under raloxifene and one under no treatment. More specifically, women received tibolone 2.5 mg (N = 204), raloxifene HCl 60 mg (N = 137), conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 5mg (N = 122), 17beta-estradiol 2mg/norethisterone acetate 1mg (N = 58), 17beta-estradiol 1mg/norethisterone acetate 0.5mg (N = 76) or no therapy (controls, N = 189). Women with suspected endometrial pathology were referred for hysteroscopy. RESULTS: Bleeding/spotting incidence was highest among standard dose EPT users (conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 5mg: 40.1%, 17beta-estradiol 2mg/norethisterone acetate 1mg: 44.8%, p < 0.001 compared to controls). Low-dose EPT associated with lower incidence of spotting/bleeding (34.1%). The incidence under tibolone and raloxifene was 22.5% and 2.9%, respectively, while 3.2% of women not receiving therapy reported vaginal spotting/bleeding. Mean endometrial thickness was not significantly affected in any of the groups studied. The drop-out rate due to spotting/bleeding was higher in the two higher dose EPT regimens. After logistic regression analysis, age at baseline was the only significant predictor of subsequent spotting/bleeding (b = -0.25, S.E. = 0.09, p = 0.006), while menopausal age and pre-treatment serum FSH had marginal significance. CONCLUSIONS: EPT, tibolone and raloxifene do not appear to associate with significant changes in endometrial thickness in the majority of cases. The low-dose EPT regimen associated with a decreased incidence of unscheduled spotting/bleeding compared to the standard dose regimens. Tibolone expressed a favorable endometrial profile, as seen in its effect on unscheduled spotting/bleeding and mean endometrial thickness. Raloxifene associated with the lowest incidence in S/B and the lowest drop-out rate.s.

The effect of hormone therapy and raloxifene on serum matrix metalloproteinase-2 and -9 in postmenopausal women.

OBJECTIVE: The aim of the study was to investigate the effect of continuous-combined hormone therapy and raloxifene on the total and active forms of serum matrix metalloproteinase (MMP) -2 and -9. DESIGN: The study was double-blinded, with a placebo run-in period of 28 to 50 days. Twenty-eight women received either 17beta-estradiol 2 mg + norethisterone acetate 1 mg (E2/NETA) or raloxifene HCL 60 mg for a period of 6 months. Total and active forms of MMP-2 and -9 were estimated at baseline and at month 6. RESULTS: Total MMP-2 increased significantly in both E2/NETA and raloxifene groups (raloxifene baseline: 278.1 +/- 18.1 ng/mL; 6 months: 303.1 +/- 29.9 ng/mL, P = 0.008) (E2/NETA baseline: 281.9 +/- 27.5 ng/mL; 6 months: 298.8 +/- 12.7 ng/mL, P = 0.025). Similarly, both treatments increased the active MMP-2 fraction, although only the raloxifene-associated increase acquired significance (raloxifene baseline: 24.9 +/- 8.6 ng/mL; 6 months: 31.6 +/- 15.3 ng/mL, P = 0.045) (E2/NETA baseline: 21.7 +/- 5.7 ng/mL; 6 months: 27.4 +/- 5.8 ng/mL, P = 0.128). Total as well as active fractions of MMP-9 were not significantly affected by either treatment. CONCLUSIONS: Both E2/NETA and raloxifene increased the total and active MMP-2 serum levels. MMP-9 was not significantly affected by either regimen. Larger, long-term clinical trials are needed to elucidate the effect of HT and raloxifene on MMPs and the possible clinical implications for cardiovascular health.

Concentrations of soluble Fas in maternal serum and amniotic fluid during uncomplicated pregnancies.

OBJECTIVE: To determine, during normal pregnancy, maternal serum (MS) and amniotic fluid (AF) concentrations of soluble Fas (sFas), an apoptosis-suppressing molecule that might play a role in the apoptotic process. Soluble Fas levels might explain existing immunotolerance, fetal well being, and rupture of membranes at term. METHODS: Sixty-six healthy, nonsmoking, pregnant women (mean age 32.6 +/- 4.8 years) with uncomplicated singleton pregnancies (15 in the first trimester, 30 in the second trimester, and 21 at term vaginal delivery) and 20 healthy nonpregnant women (mean age 32.5 +/- 3.8 years) were included in the study. RESULTS: MS and AF sFas concentrations were measured by a sandwich enzyme-linked immunosorbent assay, and parametric tests were used in the statistical analysis.MS and AF sFas concentrations significantly depended on gestational age (P < .0008 and P < .0002, respectively). MS concentrations were significantly lower in the first trimester than those in the second trimester (P <.003), those at term (P < .03), and those in nonpregnant controls (P < .005). AF concentrations decreased significantly at term compared with those in the second trimester (P < .0003). AF sFas concentrations in the second trimester and at term were significantly lower than respective MS concentrations (P < .00001). CONCLUSION: MS sFas concentrations decreased significantly in the first trimester of pregnancy, possibly affecting semiallograft tolerance. In the second trimester, concentrations return to control levels and remain unchanged until delivery. AF sFas concentrations decrease at term compared with the second trimester, possibly indicating increased apoptosis in preparation for rupture of membranes.

Tension-free vaginal tape (TVT) in women with low urethral closure pressure.

OBJECTIVE(S): Aim of the study was to assess the effectiveness and the complications associated with the use of tension-free vaginal tape (TVT) in women with stress urinary incontinence and low urethral closure pressure (LUCP). STUDY DESIGN: Thirty-seven patients with stress urinary incontinence and LUCP who were treated with the TVT procedure have been included in the study. Physical examination and urodynamic investigations were carried out to all women preoperatively and at 6, 12 and 26 months (average, range: 22-30 months), postoperatively. The mean age of the patients was 69 years (+/-13), while mean parity was 2.2 (range 0-3). RESULTS: TVT procedure was carried out in all patients with epidural anesthesia. Postoperative evaluation showed 27 patients (73%) to have been completely cured, four (9.25%) to have a considerable improvement, whereas six patients (16.2%) were classified as failures. Only a few complications occurred. CONCLUSION(S): Our study indicates that the TVT procedure is an effective and well-accepted minimal invasive surgery for treatment of urinary stress incontinence in women with LUCP. The cure rate of 73% could be considered satisfactory. Women with LUCP and 'fixed' urethra, are at significantly increased risk of failure of the procedure.

Aberrant expression of collapsin response mediator proteins-1, -2 and -5 in the brain of intrauterine growth restricted rats.

Intrauterine growth restriction (IUGR) has been associated with increased perinatal morbidity, higher incidence of neurodevelopmental defects and increased risk for adult metabolic syndrome manifestations. Altered protein expression profiles associated with IUGR may be informative on the pathological mechanisms of this condition and might reveal potential markers for postnatal complications. We hypothesized that nutrient manipulation of the pregnant rat might influence the expression of important neurodevelopmental proteins in the resultant IUGR offspring. Therefore, we aimed to determine in newborn rat brain tissue the expression of collapsin response mediator proteins (CRMPs)-1, -2 and -5, commonly referred to as dihydropyrimidinase-related proteins (DPYLs) - playing a role in axon guidance, invasive growth and cell migration - and compare it to the corresponding expression in control rats. Two-dimensional electrophoresis and mass spectrometry, as well as Western blot analysis were employed in brain tissue from 24 IUGR newborn rats and 24 controls. With both methods, CRMP-1, CRMP-2 and CRMP-5 were decreased in the brains of the IUGR group as compared to the control group at the time of delivery. In conclusion, IUGR rat offspring are born with a decreased expression of CRMPs, suggesting that these proteins may be implicated in fetal stress-induced programming.

Diagnosing arthrogryposis multiplex congenita: a review.

Arthrogryposis multiplex congenita (AMC) refers either to a syndromic or to a nonsyndromic group of conditions with varied etiology and complex clinical features, including multiple congenital contractures in different body areas. Its etiology still remains unclear but generally any cause that leads to reduced fetal movement may lead to congenital contractures and in severe cases to fetal akinesia deformation sequence (FADS). It affects approximately 1 in 2-3000 live births with an approximately equal gender ratio. There are many known subgroups of AMC differing in signs, symptoms, and causes. The primary diagnosis is made when a lack of mobility and an abnormal position is noted in routine ultrasound scanning. Early diagnosis, prenatal evaluation, and further surveillance via image scanning (ultrasound and MRI) give the opportunity for family counseling concerning neonatal morbidity and mortality and labor or delivery planning. Better understanding of the ultrasound findings and the etiology of this clinical situation offers the opportunity for careful prenatal assessment.

Association of adiponectin and placental growth factor in amniotic fluid with second trimester fetal growth.

BACKGROUND: We investigated the associations between second trimester amniotic fluid (AF) levels of human adiponectin and placental growth factor (PLGF) in small for gestational age (SGA), large for gestational age (LGA) and appropriate for gestational age (AGA) fetuses. MATERIALS AND METHODS: Adiponectin and PLGF levels were determined by enzyme immunoassay in AF of 21 SGA, 13 LGA and 44 AGA fetuses between 15-22 weeks of gestation, derived from pregnant women who underwent amniocentesis. RESULTS: Adiponectin and PLGF levels were detectable in AF. Median (25th-75th percentile) adiponectin levels were 16.1 (10.9-32.3) ng/ml in SGA, 19.5 (15.1-30.9) ng/ml in AGA, and 18.2 (14.7-30.8) ng/ml in LGA fetuses. Median (25th-75th percentile) PLGF levels were 24.2 (19.9-34.9) pg/nl in SGA, 26.4 (20.9-33.8) pg/ml in AGA and 33.5 (21.8-40.4) pg/ml in LGA fetuses. The differences were not statistically significant. Nevertheless, indication of differentiation of levels existed when SGA and LGA fetuses in the extremes of distribution were considered. Specifically, very severely SGA fetuses (≤2.5th percentile) tended to have high levels of adiponectin and reduced levels of PLGF in AF. CONCLUSION: This is the first study presenting adiponectin and PLGF concentrations in early second trimester amniotic fluid in AGA, SGA and LGA fetuses. The altered concentrations of adiponectin and PLGF in very severely SGA fetuses possibly result from the growth-promoting effect of these factors through the metabolic route and the vascular integrity of the placenta, respectively.

Endocrine, paracrine, and autocrine placental mediators in labor.

Considering that preterm birth accounts for about 6-10% of all births in Western countries and of more than 65% of all perinatal deaths, elucidation of the particularly complicated mechanisms of labor is essential for determination of appropriate and effective therapeutic interventions. Labor in humans results from a complex interplay of fetal and maternal factors, which act upon the uterus to trigger pathways leading gradually to a coordinated cervical ripening and myometrial contractility. Although the exact mechanism of labor still remains uncertain, several components have been identified and described in detail. Based on the major role played by the human placenta in pregnancy and the cascade of labor processes activated via placental mediators exerting endocrine, paracrine, and autocrine actions, this review article has aimed at presenting the role of these mediators in term and preterm labor and the molecular pathways of their actions. Some of the aforementioned mediators are involved in myometrial activation and preparation and others in myometrial stimulation leading to delivery. In the early stages of pregnancy, myometrial molecules, like progesterone, nitric oxide, and relaxin, contribute to the retention of pregnancy. At late stages of gestation, fetal hypothalamus maturation signals act on the placenta causing the production of hormones, including CRH, in an endocrine manner; the signals then enhance paracrinically the production of more hormones, such as estrogens and neuropeptides, that contribute to cervical ripening and uterine contractility. These molecules act directly on the myometrium through specific receptors, while cytokines and multiple growth factors are also produced, additionally contributing to labor. In situations leading to preterm labor, as in maternal stress and fetal infection, cytokines trigger placental signaling sooner, thus leading to preterm birth.

The role of maternal gut hormones in normal pregnancy: fasting plasma active glucagon-like peptide 1 level is a negative predictor of fetal abdomen circumference and maternal weight change.

OBJECTIVE: Maternal weight in pregnancy contributes to a glycemic environment that affects fetal growth. Gut peptides (glucagon-like peptide 1 (GLP1), glucose-dependent insulinotropic peptide (GIP), ghrelin, and peptide YY (PYY)) have been related to insulin sensitivity and secretion, weight control, and adipose tissue metabolism. This study aimed at examining the associations of gut hormones during pregnancy with maternal glucose homeostasis, maternal weight, and fetal growth. METHODS: A total of 55 pregnant nonobese, nondiabetic Caucasian women were examined during the three trimesters of pregnancy, and anthropometric measurements, evaluation of fasting maternal plasma GLP1 (active), ghrelin (active), total PYY, total GIP, and a 75-g oral glucose tolerance test were done in them. Homeostasis model assessment (HOMA-R), insulin sensitivity index (ISI), and indices of insulin secretion were calculated. Fetal growth was estimated by ultrasound. RESULTS: Fasting GLP1 increased significantly from the second to the third trimester (P<0.05). Fasting GLP1 correlated positively with high-density lipoprotein cholesterol (r=0.52, P=0.04). At the second trimester, fasting GLP1 levels correlated negatively with fetal abdomen circumference (r=-0.55, P=0.034), birth weight (r=-0.50, P=0.040), HOMA-R (r=-0.65, P=0.001), insulin secretion, and triglycerides. At the first trimester, fasting ghrelin levels correlated negatively with HOMA-R and insulin secretion, and positively with ISI. In backward multiple regression analysis, the first trimester GLP1 levels were the best negative predictors of the second trimester fetal abdomen circumference (beta=-0.96, P=0.009). In longitudinal regression model, maternal fat and HOMA-R were the positive predictors of maternal weight change during pregnancy, and fasting GLP1 levels were the negative predictors of maternal weight change during pregnancy. CONCLUSIONS: During pregnancy, maternal GLP1 might be involved in mechanisms that compensate for the pregnancy-related increase in glycemia and insulin resistance, suggesting a role of this peptide in maternal metabolism and weight and fetal growth.

Randomized controlled trial comparing superovulation with letrozole versus recombinant follicle-stimulating hormone combined with intrauterine insemination for couples with unexplained infertility who had failed clomiphene citrate stimulation and intrauterine insemination.

OBJECTIVE: To compare the efficacy of letrozole to recombinant FSH for ovarian stimulation combined with IUI in a group of patients that had failed to conceive after clomiphene citrate (CC) and IUI. DESIGN: Prospective randomized trial with human subjects. SETTING: University-based fertility center. PATIENT(S): Fifty couples with unexplained infertility that failed to conceive after three cycles of CC combined to IUI. INTERVENTION(S): Couples were randomized to undergo superovulation either with letrozole or with recombinant FSH combined to IUI. MAIN OUTCOME MEASURE(S): Clinical pregnancy per cycle of treatment and clinical pregnancy per couple. RESULT(S): Pregnancy rate (PR) per cycle was 8.9% in the letrozole group as compared with 14% in the gonadotropin IUI group. This resulted in a cumulative PR per couple of 24% versus 36% and a take home baby rate of 20% versus 28%. Endometrial thickness was significantly lower in the letrozole group (7.1 +/- 2.3 vs 8.6 +/- 1.8). CONCLUSION(S): Ovarian stimulation with letrozole is associated with acceptable PRs compared with gonadotropin with significant less cost, risks, and patient inconvenience.