Religious minority identity associates with stress and psychological health among Muslim and Hindu women in Bangladesh and London.

OBJECTIVES: This study examined the association of minority religious identification (Hindu or Muslim) with self-reported stress and psychological symptoms among sedentee and immigrant Bangladeshi women. METHODS: Women, aged 35-59 (n = 531) were drawn from Sylhet, Bangladesh and London, England. Muslim immigrants in London and Hindu sedentees in Sylhet represented minority religious identities. Muslim sedentees in Sylhet and Londoners of European descent represented majority religious identities. In bivariate analyses, minority religious identity was examined in relation to self-reported measures of stress, nervous tension, and depressed mood. Logistic regression was applied to examine the relationship between these variables while adjusting for marital status, parity, daily walking, and perceived financial comfort. RESULTS: In bivariate analyses, religious minorities reported more stress than religious majorities in all group comparisons (p < .05), and minority Muslims reported more nervous tension and depressed mood than majority Muslims (p < .05). In logistic regression models, minority Muslims had greater odds of high stress than majority Muslims (OR 2.00, 95% CI 1.18-3.39). Minority Muslims had greater odds of stress (OR 3.05, 95% CI 1.51-6.17) and nervous tension (OR 3.37, 95% CI 1.66-6.87) than majority Londoners. Financial comfort reduced odds of stress and symptoms in all models. CONCLUSIONS: Socioeconomic situation, immigration history, and minority ethnicity appear to influence the relationship between religious identity and psychosomatic symptoms in Bangladeshi women. Attention to personal and socioeconomic context is important for research examining the association between religion and mental health.

Hot flash report and measurement among Bangladeshi migrants, their London neighbors, and their community of origin.

OBJECTIVES: To examine hot flashes in relation to climate and activity patterns, and to compare subjective and objective hot flashes among Bangladeshi immigrants to London, their white London neighbors, and women still living in their community of origin, Sylhet, Bangladesh ("sedentees"). METHODS: Ninety-five women, aged 40-55, wore the Biolog ambulatory hot flash monitor. Objective measurements and subjective hot flash reports were examined in relation to demographic, reproductive, anthropometric, and lifestyle variables; temperature and humidity at 12:00 and 18:00; and time spent on housework and cooking. Concordance of objective and subjective hot flashes was assessed by Kappa statistics and by sensitivity of hot flash classification. RESULTS: During the study period, Bangladeshi sedentees reported more subjective hot flashes (p < .05), but there was no difference in number of objective hot flashes. White Londoners were more likely to describe hot flashes on their face and neck compared to Bangladeshis (p < .05). Sedentees were more likely to describe hot flashes on their feet (p < .05). Postmenopausal status, increasing parity, and high levels of housework were significant determinants of subjective hot flashes, while ambient temperature and humidity were not. Measures of subjective/objective concordance were low but similar across groups (10-20%). The proportion of objective hot flashes that were also self-reported was lowest among immigrants. DISCUSSION: Hot flashes were not associated with warmer temperatures, but were associated with housework and with site-specific patterns of cooking. The number of objective hot flash measures did not differ, but differences in subjective experience suggest the influence of culture.

Evaluation of the impact of maternal smoking on ultrasound and endocrinological markers of first trimester placentation.

OBJECTIVES: To study the effect of maternal smoking on 2D ultrasound measurements and maternal serum (MS) levels of endocrinologic markers of placentation. STUDY DESIGN: Prospective population-based cohort study of 32 smokers and 96 non-smoking controls with a normal pregnancy outcome. MAIN OUTCOME MEASURES: Placental thickness and 2D-volume and MS levels of pregnancy-associated plasma protein A (PAPP-A) and free-beta human chorionic gonadotrophin (fßhCG) at 11-13(+6)weeks of gestation and mid-trimester MS α-fetoprotein (AFP), unconjugated estriol (uE3) and inhibin A levels. RESULTS: The MS levels of fßhCG and PAPP-A were significantly (P < 0.01 and P < 0.001, respectively) lower in the serum and the level of inhibin A significantly (P < 0.001) higher in the smokers than in controls. There was no significant difference for the MSAFP, MSuE3 placental thickness, basal plate surface and volume between the groups. CONCLUSION: The placental morphological alterations secondary to maternal smoking are mainly at the level of the villous trophoblast and are not associated with changes in the placental size or utero-placental interface during the first trimester of pregnancy.

2D-Ultrasound and endocrinologic evaluation of placentation in early pregnancy and its relationship to fetal birthweight in normal pregnancies and pre-eclampsia.

OBJECTIVES: To study the relationships between 2D ultrasound measurements of placentation and maternal serum (MS) levels of PAPP-A, inhibin A and fßhCG in early pregnancy and subsequent fetal growth in pregnancies with a normal and abnormal outcome. STUDY DESIGN: Prospective population-based cohort study of 301 pregnancies with a normal outcome, 18 with a pregnancy complicated by pre-term delivery (PTD) and 14 with subsequent pre-eclampsia (PE). MAIN OUTCOME MEASURES: Basal placental surface area, placental thickness, ellipsivity and volume; MS PAPP-A and fßhCG at 11-13 + 6 weeks, MS inhibin A at 15-22 weeks and birthweight centile at delivery. RESULTS: In the normal group, the basal surface area showed a significantly (P < 0.001) positive correlation with placental thickness and placental ellipsivity. With the exception of placental ellipsivity, all other placental ultrasound parameters were significantly related with birthweight centile. Inhibin A showed a significant (P < 0.005) correlation with birthweight centiles. The basal plate surface area and MS PAPP-A were significantly (P < 0.01 and P < 0.001, respectively) lower and MS inhibin A significantly (P < 0.01) higher in PE than in controls. No changes were found in pregnancies complicated by PTD. CONCLUSION: The basal plate surface area at 11-14 weeks reflects indirectly normal and abnormal placentation and development of the definitive placenta. Combined with MS PAPP-A and/or inhibin A levels this parameter could be useful in identifying from the end of the first trimester, pregnancies subsequently complicated with PE.

Investigation of systemic inflammatory response in first trimester pregnancy failure.

BACKGROUND: The contribution of local and systemic inflammation to the pathophysiology of sporadic first trimester miscarriages remains unclear. The objective of this study was to investigate the inflammatory response in the circulation of women presenting with first trimester miscarriage. METHODS: Levels of tumour necrosis factor alpha (TNFα), TNF receptors 1 and 2, interferon gamma (IFNγ), interleukin (IL)-6 and IL-10 were assayed using cytometric bead arrays in plasma samples from 29 euploid and 21 aneuploid missed miscarriages, 35 normal pregnant controls and 31 non-pregnant women (NPW). Whole blood flow cytometry was carried out with samples from 17 euploid and 16 aneuploid miscarriages, 18 pregnant controls and 13 NPW. RESULTS: The plasma of women with euploid miscarriage contained significantly higher circulating levels of TNFα (P < 0.005), IFNγ (P < 0.005), IL-6 (P < 0.005) and IL-10 (P < 0.01) than that of pregnant controls, irrespective of gestational age. Significantly (P < 0.05) higher TNF-R1 levels at 6-9 weeks, and significantly higher TNFα/IL-6 (P < 0.001) and significantly lower TNFα/IL-10 (P < 0.001) and IFNγ/IL-10 (P < 0.001) ratios at 10-14 weeks, were also found in euploid miscarriage cases compared with pregnant controls. TNFα/IL-10 ratio in plasma was significantly (P < 0.05) lower in miscarriages with an abnormal karyotype than those with normal karyotype. Normal pregnant women had a significantly higher plasma level of IFNγ (P < 0.01) and IFNγ/IL-10 ratio (P < 0.005), a significantly (P < 0.005) lower TNF-R1 level, and a significant (P < 0.05) increase in stimulated TNFα in monocytes, compared with NPW. CONCLUSIONS: Our data confirm that there is an inflammatory reaction in normal pregnancy compared with the non-pregnant state, which may be disrupted during miscarriage.

The effect of coelomic fluid on the production of cytokines by the first trimester human placenta.

OBJECTIVE: To investigate the modulatory effects of coelomic fluid (CF) on the production of tumour necrosis factor-alpha (TNFα) and its receptors, TNF-R1 and TNF-R2, interferon gamma (IFNγ) and interleukin (IL)-10 by placental villous explants cultured under physiological oxygen (O(2)) concentration. STUDY DESIGN: In vitro culture of placental villous explants at atmospheric and physiological (6%) O(2) levels at varying concentrations of CF. MAIN OUTCOME MEASURES: Concentration of TNFα, TNF-R1, TNF-R2, IFNγ and IL-10 in culture medium and villous explant homogenates, measured using flowcytometric bead arrays. RESULTS: The median level and interquartile range of cytokines and receptors present in CF were: TNFα 0.9 pg/ml (0.85, 0.95); IFNγ 5.38 pg/ml (4.96, 6.18); IL-10 1.59 pg/ml (1.45, 1.76); TNF-R1 6043.65 pg/ml (5961.39, 6187.35) and TNF-R2 3563.52 pg/ml (3390.26, 3635.19). The PO(2) of CF was 48.74 mmHg (SEM 1.59), equivalent to 6% O(2). Increasing doses of CF significantly (p < 0.05) increased the levels of TNFα, TNF-R1 and TNF-R2 in the culture medium at both O(2) concentrations. TNF-R1 levels measured in placental homogenate increased up to 2-fold at both O(2) concentrations, but were significantly lower (1.96 fold; p = 0.03) at 6% O(2) compared to 20% O(2). CONCLUSIONS: The exocoelomic cavity in humans contains high levels of both soluble TNF-R1 and TNF-R2. The addition of CF to placental tissue explants in culture modulates the placental secretion of TNFα-receptors and TNFα at both physiological and atmospheric O(2) tension resulting in a concentration much higher than that found in the CF. This may contribute to the maternal inflammatory response previously reported in normal early pregnancy.

The normal menstrual cycle in women.

The menstrual cycle in women is characterised by high variability in cycle length (26-35 days), 5-day menses, a fertile phase from 5 days before to the day of ovulation, and low fertility which is dependent on cycle length and age. All women show an FSH rise at the luteal-follicular transition, stimulating a cohort of follicular growth and inhibin B secretion in the early follicular phase. The ovulatory dominant follicle (DF) is selected in the mid-follicular phase, and as this DF grows it increasingly secretes oestradiol and inhibin A for a week before ovulation. Gonadotrophin responsiveness, IGF binding protein expression and degradation, and vascularisation have been identified to be crucial for DF selection and progression. Two-thirds of women show two follicle waves and 1/3 show 3 follicle waves per cycle. Three-wave women have longer cycles, and a later oestradiol rise and LH surge. The corpus luteum secretes progesterone, oestradiol and inhibin A in response to LH pulses, and reaches its peak in terms of size, secretions, and vascularization 6-7 days after ovulation. Luteal regression is passive and independent of the uterus, but can be prevented by hCG, the luteotrophic signal from the trophoblast, from 8 days after conception. Reductions in systemic steroid and protein hormone concentrations may be responsible for the FSH rise characteristic of premenopausal women. The functional layer of the endometrium shows steroid hormone-dependent proliferation, differentiation, and shedding in the absence of the trophoblast. Menstruation is initiated by progesterone responsive decidual cells, and executed by PGE and PGF2α, vasoconstriction and matrix metalloprotease secretion by leukocytes. Ovarian function and also hormone fluctuations during the menstrual cycle are similar to oestrous cycles of cows and mares, justifying research into comparative aspects of menstrual and oestrous cycles in monovulatory species.

Effect of antihypertensive therapy with alpha-methyldopa on uterine artery Doppler in pregnancies with hypertensive disorders.

OBJECTIVES: Antihypertensive drugs lower blood pressure by direct vascular effects or central vasodilatory mechanisms. Their effect on uterine artery Doppler resistance indices in hypertensive disorders of pregnancy is uncertain. This study aimed to evaluate the impact of antihypertensive therapy with alpha-methyldopa on maternal uterine artery Doppler pulsatility index (PI) and resistance index (RI) in women presenting with hypertensive disorders of pregnancy. METHODS: This was a cross-sectional study of 51 women with pre-eclampsia, 29 with gestational hypertension and 80 matched normotensive controls. Uterine artery PI and RI were measured at recruitment (between 24 and 40 weeks' gestation) and, in the hypertensive groups, 24-48 h after starting alpha-methyldopa. Differences between mild and severe, and between early- and late-onset pre-eclampsia were compared using the Mann-Whitney test. The Wilcoxon rank sum test was used to compare measurements before and after treatment. RESULTS: Prior to treatment, uterine artery PI and RI were significantly higher in women with pre-eclampsia compared with those with gestational hypertension and controls (P < 0.0001). The median uterine artery PI multiple of the median (MoM) was significantly higher (P < 0.0001) in early-onset than in late-onset pre-eclampsia (1.83 (range, 0.88-3.65) vs. 1.19 (range, 0.91-1.72)) and in severe compared with mild disease (2.26 (range, 2.02-3.65) vs. 1.29 (range, 0.88-2.9)). Uterine artery PI- and RI-MoMs in both pre-eclampsia and gestational hypertension, before and after 34 weeks' gestation, were not affected by alpha-methyldopa treatment. CONCLUSIONS: Antihypertensive therapy using alpha-methyldopa in women presenting with hypertensive disorders of pregnancy has no significant effect on uterine artery resistance to blood flow, suggesting that it does not impair uteroplacental circulation in these cases.

Maternal serum hormone concentrations for prediction of adverse outcome in threatened miscarriage.

Many serum markers have been investigated in attempts to predict the outcome of pregnancy in the first trimester, with varying degrees of success. The objective of this study was to investigate whether they can be related to pregnancy outcome in women presenting with first trimester threatened miscarriage. A cohort study of women attending the Early Pregnancy Unit of a London teaching hospital was studied. A total of 122 women presenting with bleeding in the first trimester and an ongoing pregnancy, and 33 women undergoing termination of pregnancy, were recruited. The main outcome measures were gestation at delivery, birth weight and the incidence of adverse pregnancy outcome. Inhibin A, activin A, human chorionic gonadotrophin (HCG), pregnancy-associated plasma protein-A and follistatin concentrations were all significantly lower in women who subsequently miscarried when compared with live births. Serum HCG concentrations were significantly higher in cases of threatened miscarriage compared with controls (P = 0.0009). Logistic regression analysis indicated that inhibin A alone provided the best predictor for first trimester miscarriage. This pilot study suggests that placental hormone concentrations could be useful in predicting adverse pregnancy outcome in women presenting with threatened miscarriage. Inhibin A was best at predicting the likelihood of subsequent miscarriage in this group.

Predictors of ovarian reserve in young women with breast cancer.

Ovarian reserve can be diminished following treatment for breast cancer. This study evaluated biochemical and biophysical parameters of ovarian reserve in these patients. Biochemical and biophysical tests of ovarian reserve were performed simultaneously in young (age 22-42 years), regularly menstruating women with breast cancer (n=22) and age-matched controls (n=24). All tests were performed before (baseline) and after transient ovarian stimulation in the early follicular phase. Patients were recruited both before and after completion of chemotherapy, with some patients being followed up prospectively. Serum samples were analysed for follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol (E(2)), inhibins A and B, and antimullerian hormone (AMH). Biophysical (ultrasound) tests included ovarian volume, antral follicle count (AFC), ovarian stromal blood flow and uterine dimensions. Significant differences were revealed (when compared with the controls) for basal FSH (11.32+/-1.48 vs 6.62+/-0.42 mIU ml(-1), P<0.001), basal AMH (0.95+/-0.34 vs 7.89+/-1.62 ng ml(-1), P<0.001) and basal inhibin B (19.24+/-4.56 vs 83.61+/-13.45 pg ml(-1), P<0.001). Following transient ovarian stimulation, there were significant differences in the increment change (Delta) for inhibin B (3.02+/-2.3 vs 96.82+/-16.38 pg ml(-1), P<0.001) and E(2) (107.8+/-23.95 vs 283.2+/-40.34 pg ml(-1), P<0.01). AFC was the only biophysical parameter that was significantly different between patients and the controls (7.80+/-0.85 vs 16.77+/-1.11, P<0.001). Basal and stimulated biochemical (serum AMH, FSH, inhibin B and E(2)) and biophysical (AFC) tests may be potential markers of ovarian reserve in young women with breast cancer.

Relationship between male reproductive hormones, sperm DNA damage and markers of oxidative stress in infertility.

This study investigated the relationship between male reproductive hormones and sperm DNA damage and markers of oxidative stress in men undergoing infertility evaluation for male factor (n = 66) and non-male factor (n = 63) infertility. Semen samples were analysed for DNA fragmentation index (DFI). Serum samples were analysed for FSH, inhibin B, anti-Müllerian hormone (AMH), testosterone and total antioxidant capacity (TAC). Serum inhibin B was significantly lower in the male factor group compared with the non-male factor group. Inhibin B showed a positive correlation with sperm concentration and motility, and serum AMH showed a positive correlation with sperm concentration and semen volume. DFI was 3-fold higher in the male factor group and showed a negative correlation with sperm motility. Blood plasma TAC was negatively related to sperm concentration. The results confirm that AMH and inhibin B are markers of Sertoli cell function. Sperm DNA damage is moderately increased in male factor infertility, and is negatively associated with sperm motility. A negative association between antioxidant activity and sperm concentration suggests that even minimal oxidative stress may influence sperm concentration. However, there was no significant relationship between hormone concentrations, sperm DNA damage and total antioxidant capacity, suggesting other mechanisms for sperm dysfunction.

Uterine vein and maternal urinary levels of activin A and inhibin A in pre-eclampsia patients.

OBJECTIVES: The aims of this study were to investigate if (i) urinary concentrations of activin A and inhibin A are altered in pre-eclampsia (PE) and (ii) to study the relationship between uterine vein and peripheral vein concentrations of these hormones in PE patients. DESIGN AND METHOD: In a retrospective study, maternal peripheral vein and uterine vein serum and maternal urine samples collected at the time of delivery were analysed. There were three groups of patients; (i) group 1: term normal pregnancies (n = 19) (ii) group 2: patients who developed PE < or = 37 weeks (n = 17) and (iii) group 3: patients who developed PE 37-40 weeks (n = 8). Serum and urinary activin A, follistatin, inhibin A and pro alpha C and urinary creatinine levels were measured using enzyme immunoassays in the laboratory. RESULTS: Normal pregnant urine samples had very low levels of activin A and inhibin A. Both groups 2 and 3 PE patients had significantly higher levels of inhibin A (P < 0.001) and activin A (P < 0.001) compared to the controls. Pro-alpha C was not altered and follistatin was below the detection limit of the assay in the urine. Maternal peripheral serum activin A and inhibin A were significantly higher in groups 2 (P < 0.001) and 3 (P < 0.05) patients compared to the controls. Pro-alpha C-containing inhibins were higher in group 2 patients (P < 0.05) compared to the controls in the peripheral circulation. Uterine vein serum activin A and inhibin A levels were also significantly higher in groups 2 (P < 0.001) and 3 (P < 0.05) patients compared to the controls. There was a highly significant positive correlation between peripheral and uterine vein serum concentrations of activin A, follistatin, inhibin A and pro alpha C, suggesting the same source for these proteins in PE. CONCLUSION: Urinary activin A and inhibin A are raised in groups 2 and 3 PE patients. The magnitude of rise (> 25-fold) suggests these proteins may rise in patients before the onset of the clinical symptoms of PE. Uterine vein levels of these proteins are also raised in PE.

Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted reproductive technology?

OBJECTIVE: The objective of this study was to evaluate the relationship between anti-mullerian hormone (AMH), inhibin B and antral follicle count (AFC) with ovarian response. DESIGN: Retrospective study. SETTING: Fertility unit. SAMPLE: AFC was recorded, and a serum sample obtained on day 3 from all patients undergoing in vitro fertilisation (IVF). Patients were given 300 IU/L recombinant follicle stimulating hormone (FSH; Gonal F). The following day blood samples were collected. METHODS Serum samples were assayed for FSH, AMH and inhibin B using commercial immunoassay kits and oestradiol using an in house assay. MAIN OUTCOME MEASURES: Response to gonadotrophin stimulation and the number of eggs collected. RESULTS: AFC was negatively correlated to age (r=-0.426, P < 0.001). Delta inhibin B (levels of inhibin B on day 4 minus day 3) had the best association to the number of eggs collected (r= 0.533, P < 0.001) followed by basal AMH (r= 0.51, P < 0.001) and AFC (r= 0.505, P < 0.001). The number of eggs fertilised was significantly associated with basal AMH (r= 0.592, P < 0.001) and inhibin B (r= 0.548, P < 0.001). AMH with a cutoff of 0.2 ng/mL had the best sensitivity (87%) and specificity (64%) in predicting poor response. A cumulative score using basal FSH, basal AMH, delta E2 (levels of oestradiol on day 4 minus day 3), delta inhibin B, AFC and age gives the best predictive statistics to identify poor responders with 87% sensitivity and 80% specificity and a positive likelihood ratio of 4.36. CONCLUSION: Delta inhibin B had the best positive association with the number of eggs collected and basal AMH is the single best predictor of poor response. AFC has a significant association with the number of eggs collected and is predictive of clinical pregnancy. It is evident that a single parameter is of limited value in predicting ovarian response. However, we have demonstrated a cumulative score using all the above markers could be useful in predicting poor response.

Development of a sensitive enzyme immunoassay for anti-Müllerian hormone and the evaluation of potential clinical applications in males and females.

BACKGROUND AND OBJECTIVE: Recent studies have found anti-Müllerian hormone (AMH) to be a potentially important marker for the assessment of ovarian reserve and prediction of the success of in vitro fertilization (IVF) treatment. The objectives of this study were to develop a sensitive and specific assay for AMH and to evaluate the potential application of the assay. This assay will be then available to our collaborators in the UK and overseas. DESIGN: Samples obtained as part of another prospective cross-sectional study from infertility patients and another prospective longitudinal study from pregnant women were used in this study to measure AMH using a new double-antibody enzyme-linked immunosorbent assay (ELISA). PATIENTS AND MEASUREMENTS: AMH levels were evaluated in (i) serum and seminal fluid from males (normal and male factor infertility males), (ii) serum and follicular fluid from females (normal and female with unexplained infertility) and (iii) serum, amniotic fluid (AF) and coelomic fluid (CF) from pregnant women. AMH levels in the samples were measured by a newly developed ELISA. RESULT: The assay had a detection limit of<0.078 ng/ml. High recoveries of spiked recombinant protein were observed from male and female sera and also from follicular, seminal, coelomic and amniotic fluids. The intra- and interassay coefficients of variation (CVs) were 3.6% and 4.0%, respectively. Serially diluted human samples gave dose-response curves parallel to the standard curve. Immunoreactivity was stable to sample storage at room temperature for several days and to multiple cycles of freezing and thawing. In seminal fluid, the AMH concentrations in a group of men with male factor infertility were insignificantly different from those in fertile men. By contrast, serum AMH concentrations were lower in the male factor infertility group than the normal group of patients. Women with unexplained infertility had similar concentrations of AMH in serum and follicular fluid compared to controls. Pregnant women had higher concentrations of AMH in the circulation in early pregnancy compared with nonpregnant women, suggesting a foeto-placental contribution and a possible biological role for this molecule in early pregnancy. CONCLUSION: We have developed a sensitive and specific assay for AMH. Serum AMH in men with male factor infertility is lower than in normal men. Levels of AMH in pregnancy are higher than normal menstrual cycle levels suggesting a foeto-placental contribution.

The secretion and effect of inhibin A, activin A and follistatin on first-trimester trophoblasts in vitro.

OBJECTIVE: The objectives of this study were to investigate the effect of activin A and follistatin on first-trimester cytotrophoblast invasion in culture and to study the secretion of inhibin A, activin A and follistatin by these cells in vitro. DESIGN AND METHODS: Cytotrophoblasts were isolated from human placental chorionic villous tissue obtained from 6-8, 8-10 and 10-12 weeks gestation. Cells were cultured for 3 days on cell-culture inserts coated with gelatine for invasion studies and in 24-well culture plates for secretion studies. The effects of activin A (10 ng/ml), follistatin (100 ng/ml), interleukin 1beta (IL-1beta; 10 ng/ml) and epidermal growth factor (EGF; 10 ng/ml) on cytotrophoblast invasion were investigated using a non-radioactive invasion assay. Secretion of inhibin A, activin A and follistatin in the presence of EGF, IL-1beta, activin A and follistatin were measured using in-house ELISAs. RESULTS AND CONCLUSION: Activin A, follistatin and EGF had a significant stimulatory effect on cytotrophoblast invasion from 6-10 weeks gestation. IL-1beta had a significant stimulatory effect at 8-10 weeks and a significant inhibitory effect on invasion at 10-12 weeks gestation. Follistatin also had a significant inhibitory effect on invasion at 10-12 weeks gestation. In the secretion study, activin A secretion at 8-10 weeks was significantly stimulated by IL-1beta and EGF. At 10-12 weeks, follistatin and EGF had a significant inhibitory effect on activin A secretion. Follistatin secretion was significantly increased in the presence of IL-1beta at 6-8 weeks gestation. Inhibin A secretion was not significantly altered by EGF, IL-1beta, activin A and follistatin. These results show that activin A promotes invasion of first-trimester cytotrophoblasts until 10 weeks gestation. There is a difference in the control of secretion of these proteins dependent on the gestation, suggesting that there is a tight regulation in the function of first-trimester trophoblasts depending on the gestational age.

Inhibin, activin, follistatin, activin receptors and beta-glycan gene expression in the villous tissue of miscarriage patients.

Maternal circulating levels of inhibin A are significantly lower in patients with clinical symptoms of miscarriage. The objective of this study was to quantify relative expression of inhibin alpha, inhibin/activin betaA, betaB, betaC, follistatin, activin receptors and beta-glycan genes and content of inhibin A, activin A and follistatin protein in villous tissue of first trimester miscarriages and gestation-matched normal pregnancies. Twelve women with clinical symptoms of miscarriage were matched with 12 normal pregnancies for gestational age. Total RNA was isolated from placental samples. Complementary DNA produced by reverse transcription was used in the real-time PCR to quantify the expression of the genes. The ratio between the target and rRNA 18S was calculated to provide relative gene expression. Villous tissue homogenates were used for the determination of the content of inhibin A, activin A and follistatin protein. Maternal serum was assayed for inhibin A, activin A and follistatin. All villous samples expressed inhibin alpha, inhibin/activin betaA, betaB, betaC, follistatin, activin receptors (ACTRIA, ACTRIB, ACTRIIA, ACTRIIB) and beta-glycan genes. There was no significant difference in the relative expression of these genes between the groups. Villous content of inhibin A, activin A and follistatin were also not different between the two groups. Maternal serum levels of inhibin A were significantly lower in the miscarriage group compared to the controls. The decreased maternal levels of inhibin A in miscarriage patients could be due to a decrease in placental mass prior to embryonic demise. This finding also confirms that the trophoblast is the major source of inhibin A after the luteo-placental shift in early pregnancy.

In-vivo concentrations of inhibins, activin A and follistatin in human early pregnancy.

The aims of this study were to investigate the relationship between inhibins, activin A and follistatin in first trimester fetal fluids, maternal serum, placenta and decidua, and to investigate if these hormones are present in the circulation of the early second trimester human fetus. Amniotic and coelomic fluid, maternal serum, placental villi and decidual tissue were obtained from normal pregnancies at 8-12 weeks. Fetal blood by cardiocentesis and maternal blood were collected at 14-16 weeks gestation. Placental extracts had higher concentrations of inhibins, activin A and follistatin compared with decidual extracts. In the second trimester, inhibins and follistatin were detectable in fetal blood at 14-16 weeks gestation. Maternal serum concentrations of inhibin A (P < 0.001) and follistatin (P < 0.05) were significantly higher than fetal serum whereas inhibin B (P < 0.01) and pro-alpha C concentrations (P < 0.001) were higher in fetal serum. Inhibin B concentrations were also higher in male fetal serum samples that had higher concentrations of testosterone. The presence of all molecular forms of inhibins, activin A and follistatin in the first trimester fetal fluids, placental and decidual extracts in the first trimester confirms other reports. In the second trimester, high concentrations of inhibin B with testosterone in the fetal circulation indicate that these hormones may interact in the development of the male fetal gonads.

Endothelial cells and peripheral blood mononuclear cells are a potential source of extraplacental activin a in preeclampsia.

An excessive systemic inflammatory response, involving endothelial cells and leukocytes, underlies the maternal symptoms of preeclampsia. Activin A is raised in preeclampsia, suggesting a possible involvement in its pathophysiology. The placenta is the main source of activin A in normal pregnancy. We investigated whether peripheral blood mononuclear cells (PBMCs) and endothelium, activated by proinflammatory stimuli, were a potential source of activin A in preeclampsia. Both endotoxin and TNFalpha stimulated activin A secretion by PBMCs from nonpregnant, preeclamptic, and matched normal pregnant women (P < 0.05). Pregnancy increased the responsiveness of PBMCs to endotoxin (P < 0.05), whereas only the preeclamptic group were significantly more responsive to TNFalpha (P < 0.05). Human umbilical vein endothelial cells secreted activin A spontaneously and in response to TNFalpha (P < 0.05), but recombinant IL-1beta and IL-6 had no significant effect over the 72-h culture period. Inhibin A and follistatin were undetectable (<2 pg/ml and < 20 pg/ml, respectively) in PBMCs and human umbilical vein endothelial cell culture media. These data suggest that PBMCs and endothelium, activated by TNFalpha, could be extraplacental sources of activin A in preeclampsia. The pathological significance of increased activin A in preeclampsia is unknown, although it may have a role in the mechanisms underlying endothelium dysfunction.