No impact of developmental conditions on serum estradiol levels among Bangladeshi women in the UK and Bangladesh.

INTRODUCTION: While many aspects of female ovarian function respond to environmental stressors, estradiol (E2) appears less sensitive to stressors than progesterone, except under extreme ecological conditions. However, earlier studies relied on saliva samples, considered less sensitive than blood. Here, we investigated E2 variation among 177 Bangladeshi and UK white women, aged 35-59, using single serum samples. Bangladeshi women either grew up in Sylhet, Bangladesh (exposed to poor sanitation, limited health care, and higher pathogen loads but not poor energy availability), or in the UK. METHODS: We collected samples on days 4-6 of the menstrual cycle in menstruating women and on any day for post-menopausal women. Participants included: (i) Bangladeshi sedentees (n = 36), (ii) Bangladeshis who migrated to the UK as adults (n = 52), (iii) Bangladeshis who migrated as children (n = 40), and (iv) UK white women matched for neighborhood residence to the migrants (n = 49). Serum was obtained by venipuncture and analyzed using electrochemiluminescence. We collected anthropometrics and supplementary sociodemographic and reproductive data through questionnaires. We analyzed the data using multivariate regression. RESULTS: E2 levels did not differ between migrant groups after controlling for age, BMI, physical activity, psychosocial stress, parity, and time since last birth (parous women). Paralleling results from salivary E2, serum E2 did not differ among women who experienced varying developmental conditions. CONCLUSION: Our results reinforce the hypothesis that E2 levels are stable under challenging environmental conditions. Interpopulation variation may only arise under chronic conditions of extreme nutritional scarcity, energy expenditure, and/or high disease burdens.

Life course effects on age at menopause among Bangladeshi sedentees and migrants to the UK.

OBJECTIVES: To assess how different variables experienced across the life course, but particularly during early life, might affect age at menopause among 174 Bangladeshi migrants to London by comparing them to 157 nonmigrant sedentees and 154 women of European descent in London. METHODS: Participants were aged 35-59 years, with no exogenous hormone use in the past three months, not pregnant or lactating, with no history of hysterectomy or oophorectomy. Face-to-face interviews and anthropometric measures were carried out. In addition to mean recalled age at natural menopause, median age was computed by probit analysis. Ages at menopause were examined by bivariate and Cox regression analyses in relation to demographic, reproductive, and lifestyle variables, and in relation to potential exposure to cyclones in early childhood. RESULTS: Ages at menopause were significantly earlier among Bangladeshi sedentees and immigrants compared to Londoners of European origin. Ages at menopause were earlier among sedentees compared to immigrants. Urban birthplace, more infectious diseases during childhood, and lower levels of education increased the risk of an earlier menopause. CONCLUSIONS: Changes in environmental conditions during adulthood appeared to modify age at menopause among Bangladeshi immigrants in London compared to women living in Bangladesh; however, Bangladeshi immigrants still experienced an earlier age at menopause compared with their London neighbors of European descent.

Frequency of Phytoestrogen Consumption and Symptoms at Midlife among Bangladeshis in Bangladesh and London.

There is a longstanding interest in the relationship between diet and hot flash symptoms during midlife, especially in whether phytoestrogens ease menopausal symptoms. The purpose of this study was to examine hot flashes, night sweats, trouble sleeping, and vaginal dryness in relation to the intake of foods rich in phytoestrogens among Bangladeshi women aged 35 to 59 years who were living either in Sylhet, Bangladesh (n = 157) or as migrants in London (n = 174). Consumption ranges for phytoestrogens were constructed from food frequencies. We hypothesized that diets rich in isoflavones, lignans, and coumestrol would be associated with lower symptom frequencies. However, adjusted logistic regression results showed that with each incremental increase in general phytoestrogen consumption (scale of 0 to 10), the likelihood of hot flashes increased by 1.4%. Each incremental increase in lignan consumption raised the likelihood of hot flashes by 1.6%. In contrast, the odds of vaginal dryness decreased by 2%, with each incremental increase in phytoestrogen and lignan consumption, and by 4%, with each incremental increase in isoflavone consumption. Night sweats and trouble sleeping were not associated with phytoestrogen intake in logistic regressions. Our findings add to the conflicting data on relationships between phytoestrogens and symptoms associated with menopause.

Relationship of Estradiol and Progesterone with Partnership and Parity Among Bangladeshi and British Women of European Origin.

Recent studies in social endocrinology have explored the effects of social relationships on female reproductive steroid hormones-estradiol and progesterone-investigating whether they are suppressed in partnered and parous women. Results have been mixed for these hormones although evidence is more consistent that partnered women and women with young children have lower levels of testosterone. These studies were sequential to earlier research on men, based on Wingfield's Challenge Hypothesis, which showed that men in committed relationships, or with young children, have lower levels of testosterone than unpartnered men or men with older or no children. The study described here explored associations between estradiol and progesterone with partnership and parity among women from two different ethnicities: South Asian and white British. We hypothesized that both steroid hormones would be lower among partnered and/or parous women with children ≤3 years old, regardless of ethnicity. In this study we analyzed data from 320 Bangladeshi and British women of European origin aged 18 to 50 who participated in two previous studies of reproductive ecology and health. Levels of estradiol and progesterone were assayed using saliva and/or serum samples and the body mass index calculated from anthropometric data. Questionnaires provided other covariates. Multiple linear regressions were used to analyze the data. The hypotheses were not supported. We argue here that, unlike links between testosterone and male social relationships, theoretical foundations for such relationships with female reproductive steroid hormones are lacking, especially given the primary role of these steroids in regulating female reproductive function. Further longitudinal studies are needed to explore the bases of independent relationships between social factors and female reproductive steroid hormones.

Inflammatory cytokines in maternal circulation and placenta of chromosomally abnormal first trimester miscarriages.

The impact of abnormal placental karyotype on the inflammatory response within the villous tissue and peripheral circulation of women with miscarriage was evaluated. Villous (n = 38) and venous blood samples (n = 26) were obtained from women with missed miscarriage. Tissue chromosome analysis indicated 23 abnormal and 15 normal karyotypes. Concentration of tumour necrosis factor alpha (TNFα), TNF-R1 and TNF-R2, and interleukin (IL)-10 were measured using flowcytometric bead array in fresh villous homogenate, cultured villous extracts, culture medium, maternal whole blood, and plasma. Plasma TNFα/IL-10 ratios were significantly (P < 0.05) lower in miscarriages with abnormal karyotype. In the abnormal karyotype group, there were significantly higher levels of TNFα (P < 0.01), IL-10 (P < 0.01), TNF-R1 (P < 0.001), and TNF-R2 (P < 0.001) in the villous extracts and culture-conditioned medium compared to normal karyotype group. In miscarriage with abnormal karyotype, there is an exacerbated placental inflammatory response, in contrast to miscarriage of normal karyotype where maternal systemic response is increased.

Hepcidin and iron species distribution inside the first-trimester human gestational sac.

We have investigated factors affecting iron distribution in the first-trimester gestational sac, by the measurement of transferrin, non-transferrin-bound iron (NTBI) and pro-hepcidin (Hep) in maternal serum, coelomic fluid (CF) and amniotic fluid (AF) and by immunostaining for Hep in villous and secondary yolk sac biopsies. These samples were obtained from 15 first-trimester pregnancies at 8-11 weeks gestation. Transferrin concentrations were significantly lower in fetal (0.56 mg/ml) than maternal serum (1.71 mg/ml), with very low concentrations in CF and AF (0.09 mg/ml). In contrast, transferrin saturations were significantly higher in fetal (77%) than maternal serum (33%). NTBI was present in fetal serum, CF and AF, presumably as a consequence of low transferrin concentrations in these compartments. Pro-Hep was present at lower levels in fetal (140.0 ± 11.1) than maternal serum (206.2 ± 9.2) and at low concentrations in CF (19.4 ± 3.1) and AF (21.8 ± 5.2). Immunostaining with Hep antibody was found in the syncytiotrophoblast of first-trimester placenta as well as in mesothelial and endodermal layers of the secondary yolk sac at 10 weeks. The presence of Hep in syncytiotrophoblast cells of first-trimester placenta as well as in mesothelial and endodermal layers of the secondary yolk sac suggest a key regulatory role for this protein in iron transfer to the first-trimester fetus. The low transferrin concentrations and the presence of NTBI in CF and AF suggest that transferrin-independent iron transfer is important in early gestation.

Pro- and antiinflammatory cytokines in threatened miscarriages.

OBJECTIVE: The purpose of this study was to evaluate circulating and intracellular levels of Th1 and Th2 cytokines in women with threatened miscarriage (TM) and subsequent outcome. STUDY DESIGN: Plasma levels of tumor necrosis factor (TNF)-receptors 1 and 2, TNFα, interferon gamma (IFNγ), and interleukins (IL) -6 and -10 were measured by flow cytometric bead assays in 80 women with TM: 53 women with normal outcome and 27 women who miscarried. Fluorescent antibody labeling was also performed on whole blood in a subgroup of 27 women of TM: 16 women with normal outcome and 11 women who miscarried. RESULTS: Monocyte expression of TNFα and circulating levels of TNFα, IFNγ, IL-10, IL-6, and TNF-R1 were significantly lower, whereas circulating levels of TNFα/IL-10, IFNγ/IL-10, and TNFα/IL-6 ratios were significantly higher, in women with TM who subsequently miscarried, compared with the women with normal outcome. CONCLUSION: An increased Th1 type of immune response, which was similar to that observed in preterm delivery, was found in TM cases that were complicated by a subsequent miscarriage.

Mismatch: a comparative study of vitamin D status in British-Bangladeshi migrants.

BACKGROUND AND OBJECTIVES: Low levels of vitamin D among dark-skinned migrants to northern latitudes and increased risks for associated pathologies illustrate an evolutionary mismatch between an environment of high ultraviolet (UV) radiation to which such migrants are adapted and the low UV environment to which they migrate. Recently, low levels of vitamin D have also been associated with higher risks for contracting COVID-19. South Asians in the UK have higher risk for low vitamin D levels. In this study, we assessed vitamin D status of British-Bangladeshi migrants compared with white British residents and Bangladeshis still living in Bangladesh ('sedentees'). METHODOLOGY: The cross-sectional study compared serum vitamin D levels among 149 women aged 35-59, comprising British-Bangladeshi migrants (n = 50), white British neighbors (n = 54) and Bangladeshi sedentees (n = 45). Analyses comprised multivariate models to assess serum levels of 25-hydroxyvitamin D (25(OH)D), and associations with anthropometric, lifestyle, health and migration factors. RESULTS: Vitamin D levels in Bangladeshi migrants were very low: mean 25(OH)D = 32.2 nmol/L ± 13.0, with 29% of migrants classified as deficient (<25 nmol/L) and 94% deficient or insufficient (≤50 nmol/L). Mean levels of vitamin D were significantly lower among British-Bangladeshis compared with Bangladeshi sedentees (50.9 nmol/L ± 13.3, P < 0.001) and were also lower than in white British women (55.3 nmol/L ± 20.9). Lower levels of vitamin D were associated with increased body mass index and low iron status. CONCLUSIONS AND IMPLICATIONS: We conclude that lower exposure to sunlight in the UK reduces vitamin D levels in Bangladeshi migrants. Recommending supplements could prevent potentially adverse health outcomes associated with vitamin D deficiency. LAY SUMMARY: Vitamin D deficiency is one example of mismatch between an evolved trait and novel environments. Here we compare vitamin D status of dark-skinned British-Bangladeshi migrants in the UK to Bangladeshis in Bangladesh and white British individuals. Migrants had lower levels of vitamin D and are at risk for associated pathologies.

Placental production and maternal serum and urine levels of inhibin A and activin A are modified by antihypertensive therapy in hypertensive disorders of pregnancy.

OBJECTIVE: Levels of inhibin A and activin A are raised in pre-eclampsia (PE) but it is not known if antihypertensive therapy can affect their levels. Our aim was to investigate the effect of the antihypertensive drug alpha-methyldopa on serum, urine and placental concentrations of inhibin A and activin A in women presenting with hypertensive disorders of pregnancy. DESIGN: This was a cross-sectional study. PATIENTS: We recruited 65 women presenting with PE, 39 with gestational hypertension (GH) and 104 normotensive controls matched for maternal age, gestational age and parity. MEASUREMENTS: Using specific validated ELISAs, serum and urine levels of inhibin A and activin A, and uterine artery Doppler indices, were measured before and 24-48 h after initiating alpha-methyldopa therapy in women with PE, with GH and controls. Protein extracts were obtained from samples of placental tissue from another group of women with PE, GH and controls for the same analysis. RESULTS: In PE, but not GH, alpha-methyldopa therapy was associated with significantly (P < 0.05) lower levels of both serum and urine inhibin A and activin A. Similarly, in PE but not GH, alpha-methyldopa therapy was associated with lower placental levels of both markers (P < 0.05). There was no significant difference in pulsatility index following treatment in either PE or GH. CONCLUSIONS: Our data indicate that antihypertensive therapy with alpha-methyldopa may have an effect on the synthesis and/or release of placental proteins in pregnancies complicated by PE and that this effect may be independent of its known antihypertensive action.

A new 'total' activin B enzyme-linked immunosorbent assay (ELISA): development and validation for human samples.

BACKGROUND AND OBJECTIVE: There are currently no sensitive and specific assays for activin B that could be utilized to study human biological fluids. The aim of this project was to develop and validate a 'total' activin B ELISA for use with human biological fluids and establish concentrations of activin B in the circulation and fluids from the reproductive organs. DESIGN: The new ELISA was validated and then used to measure activin B levels in the circulation of healthy participants, IVF patients, pregnant women and in ovarian follicular fluid and seminal plasma. PATIENTS AND MEASUREMENTS: Healthy adult subjects (n = 143), subjects from an IVF clinic (n = 27) and pregnancy groups (n = 29) were sampled. RESULTS: The sensitivity of the assay was 0.019 ng/ml. Validation of the activin B ELISA showed good recovery (90.7 +/- 9.8%) and linearity in biological fluid and cell culture media and low cross-reactivity with related analytes (inhibin B = 0.077% and activin A = 0.0034%). There was a negative correlation between activin B concentration (r = -0.281, P < 0.011) and females with increasing age. Patients attending IVF clinics had significantly lower levels of activin B compared with gender-matched control subjects. Ovarian follicular fluid and seminal plasma had 50-80 fold higher levels of activin B (mean = 5.35 and 3.66 ng/ml respectively) than sera (mean = 0.071 ng/ml). CONCLUSIONS: This fully validated ELISA for activin B offers a tremendous utility for measuring this protein in a variety of normal physiological processes and in various clinical pathologies.

Development of a new antibody to the human inhibin/activin betaB subunit and its application to improved inhibin B ELISAs.

Inhibin B has emerged as a clinically useful analyte for studies of reproductive function in both men and women. The antibody to the betaB subunit (C5) used in current commercially available assays (DSL and OBI) was raised in this laboratory to a synthetic peptide from the betaB subunit. These assays require pre-treatment of samples with hydrogen peroxide to oxidise two methionines in the epitope to the sulfoxide for full immunoreactivity. It was also claimed that this antibody cross-reacted significantly with inhibin A leading to a 0.5% cross-reaction of inhibin A in the current generation of immunoassays. Both of the above immunoassays required overnight incubation with sample. The development of improved antibodies to the betaB subunit has proved difficult due to the conservation of the betaB subunit between species. We describe the development of new monoclonal antibodies to the betaB subunit, by immunisation of mice with recombinant X. laevis activin B using the RIMMS method of immunisation. The result has been the development of highly specific antibodies in a short time period. One of these antibodies 46A/F is shown to be a highly effective capture antibody in a human inhibin B ELISA, without any sample pre-treatment. The results of the validation of an improved inhibin B assay using 46A/F as the capture antibody are shown, with comparison to one of the commercially available inhibin B assays. Overall, the inhibin B assay is simplified and the performance improved by using this new antibody 46A/F. It was further shown that the cross-reaction of inhibin A in both the OBI and DSL inhibin B ELISAs is ten fold less than previously reported. This can be attributed to the poor quality of recombinant inhibin B available for use as standard in 1996. Although the present generation of inhibin B assays has proved adequate to enable the physiological function of inhibin to be determined and novel clinical applications found, the simplification of the assay made possible by the improved antibody should make possible a new generation of more rapid, sensitive, convenient and robust tools for routine use.

Patterns of occurrence and concordance between subjective and objective hot flashes among Muslim and Hindu women in Sylhet, Bangladesh.

This study examined the pattern of occurrence and the rate of concordance between objective hot flashes measured by sternal skin conductance and the subjective experience of "gorom vap laga" (feeling steaming hot) among Muslim and Hindu women living in Sylhet, Bangladesh. Participants were aged 40-55, not pregnant or lactating, not using hormone therapy, and with no history of hysterectomy. Thirty women wore an ambulatory hot flash monitor for 8 h on average, from mid-morning to early evening. True positive, false negative, and false positive measures of hot flashes were examined in relation to demographic, reproductive, and lifestyle variables. On body diagrams, women were most likely to indicate hot flashes on the top of their head (64%) and upper chest (68%). The greatest number of objective hot flashes occurred during the hour of 17:00, perhaps due to the heat of the day, and the clothing and activity associated with prayer. Muslim participants demonstrated more objective hot flashes per woman than Hindu participants (1.5 vs. 0.1, P < 0.05), and Muslims had more false positive measures (86%) compared with Hindu participants (0%, P = 0.06). Among all women who reported subjective hot flashes (n = 19), the proportion of true positive scores was 19%. Overall, the frequency of objective hot flashes was low compared with reports from studies in the United States. The pattern of sweating assessed by body diagrams was not associated with variation in hot flash experience.

Potential use of biomarkers for analyzing interpopulation and cross-cultural variability in reproductive aging.

OBJECTIVE: The aims of this study were (1) to document the extent of variability in physiological aspects of reproductive aging; (2) to outline those areas where more work is needed to expand our knowledge of this variability; (3) to outline available biomarkers that can be used to measure aspects of reproductive aging, such as ovarian reserve and declining hormone levels; and (4) to note potential problems with the use of these biomarkers in cross-cultural settings. DESIGN: Literature review of English and French publications using PubMed with no date restrictions. RESULTS: Substantial variability exists in both cultural and physiological aspects of reproductive aging and menopause. However, the extent of variability across populations for many areas of reproductive aging needs better documentation as well as explanation of sources of this variability. Several biomarkers exist for use in cross-cultural research, including ovarian characteristics such as ovarian volume, ovarian reserve, follicular development, and atresia, and levels of hormones such as follicle-stimulating hormone, inhibin B, and anti-mullerian hormone. CONCLUSION: We urge that further work be undertaken to evaluate and describe variability in physiological aspects of reproductive aging in cross-cultural settings. Some problems exist in the use of biomarkers to record this variability, particularly in remote settings with few logistical resources.

Hot flushes and reproductive hormone levels during the menopausal transition.

INTRODUCTION: Evidence suggests that hot flushes are associated with fluctuating levels of oestradiol (E2) during menopause, as well as changes in the levels of follicle-stimulating hormone (FSH) and inhibin B. The relationship between hot flushes and anti-Müllerian hormone (AMH) is unknown. AIM: To examine specific hormone levels and ethnic differences in relation to hot flushes. METHODS: Data were drawn from 108 women aged 40-59 years. There were three groups of participants: European women in London, UK; Bangladeshi women in Sylhet, Bangladesh; and Bangladeshi women who had migrated to London as adults. Symptom information was collected via questionnaires. Serum blood samples were collected to detect inhibin B, AMH, FSH, and E2. RESULTS: AMH and FSH were significantly associated with the experience of hot flushes in the past 2 weeks. Inhibin B and E2 were not associated with hot flushes. Body mass index (BMI), ethnicity, and education level were associated with both the occurrence and the frequency hot flushes. Menopausal status was also associated with the frequency of hot flushes. CONCLUSION: Relationships between AMH, FSH and symptoms are indicative of women's progress through the menopausal transition. The influence of BMI and education suggest that lifestyle changes may contribute to the management of symptoms. This merits further research.

Ethnicity or environment: effects of migration on ovarian reserve among Bangladeshi women in the United Kingdom.

OBJECTIVE: To assess whether the quality of early childhood environments among different groups of Bangladeshi women, including migrants to the United Kingdom (UK), contributes to variation in ovarian reserve and the rate of reproductive aging in later life. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 179 healthy women volunteers aged 35-59 years were divided into four groups: [1] 36 Bangladeshis living in Sylhet, Bangladesh; [2] 53 Bangladeshis who migrated to the UK as adults; [3] 40 Bangladeshis who migrated to the UK as children aged 0-16 years; and [4] a reference group of 50 women of European origin living in London. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Levels of serum antimüllerian hormone, inhibin B, FSH, and E2, and anthropometrics derived from biomarkers; reproductive, demographic, and health variables from structured questionnaires. RESULT(S): Bangladeshi migrants who moved to the UK as children and European women had a highly significantly larger, age-related ovarian reserve compared with migrant Bangladeshis who had moved to the UK as adults or Bangladeshi women still living in Bangladesh. There were no other significant covariates in the model aside from age and menopausal status. CONCLUSION(S): The study points to the importance of childhood development in considering variation in ovarian reserve across different ethnic groups. Clinical studies and research in assisted reproductive technology have emphasized the role of genes or race in determining inter-population variation in ovarian reserve. Early life developmental factors should be given due consideration when evaluating inter-group differences in response to assisted reproductive technology.

Activin and follistatin in female reproduction.

Activin and follistatin were initially identified in the follicular fluid based on their effects on pituitary FSH secretion in the mid-1980s. It is now evident that activin, follistatin and activin receptors are widely expressed in many tissues where they function as autocrine/paracrine regulators of a variety of physiological processes including reproduction. The major function of follistatin is to bind to activin with high affinity and block activin binding to its receptors. Total activin A and follistatin are also found in the maternal circulation throughout pregnancy. Activin A levels are increased in abnormal pregnancies such as pre-eclampsia, fetal growth restriction and gestational hypertension. The placenta, vascular endothelial cells and activated peripheral mononuclear cells (PBMC) may all contribute to the raised levels of activin A in pre-eclampsia with unaltered follistatin in pre-eclamptic placenta, PBMCs or vascular endothelial cells suggesting the availability of 'free' activin A that could be biologically active in these cells.

Pregnancy-associated and placental proteins in the placental tissue of normal pregnant women and patients with pre-eclampsia at term.

OBJECTIVE: Pre-eclampsia is a placental disease of unknown cause. Maternal circulating concentrations of a number of protein markers are altered (mainly increased) in pre-eclampsia in comparison with controls of matched gestational age. Inhibin A and activin A were found to be elevated even before the onset of the disease. The aim of this study was to compare the levels of inhibin A, activin A: follistatin ratio, leptin, pregnancy-associated plasma protein-A (PAPP-A), human placental lactogen (HPL), placenta growth factor (PLGF) and pregnancy-specific beta1-glycoprotein (SP1) in placental extracts of normal pregnant women and pre-eclampsia patients at term. METHODS: Placental tissue from normal pregnancies (n=14) and patients with pre-eclampsia (n=13) were collected at term (> or =37 weeks of gestation) and stored at -80 degrees C. The frozen tissue pieces were homogenised and the above-mentioned proteins were measured by specific enzyme-linked immunosorbent assays. RESULTS: Placental contents of inhibin A and PAPP-A were significantly higher (P<0.05) in pre-eclampsia placental extracts compared with the controls. Activin A:follistatin ratio was higher (23) in pre-eclampsia extracts than in the controls (15). Leptin, PLGF, SP1 and HPL levels were not altered in the term pre-eclampsia placenta. Inhibin A and PAPP-A contents were increased in the placental extracts of pre-eclampsia patients. CONCLUSION: Our data suggest that the placenta, possibly by a compensatory mechanism, is at least in part responsible for the altered serum levels observed in pre-eclampsia.

Role of inhibin in normal and high-risk pregnancy.

Inhibins are glycoprotein hormones of which there are two molecular forms, inhibin A and inhibin B. Classically, inhibin is known to have a negative feedback effect on pituitary follicle-stimulating hormone secretion. The fetoplacental unit produces inhibin throughout pregnancy. Inhibin A is the predominant molecular form of inhibin in maternal circulation from 4 weeks of gestation. Although the precise biological function of inhibin A in pregnancy is unclear, it is evident from recent studies that inhibin A could be a better marker of placental function than human chorionic gonadotropin because of its shorter half-life. The possible clinical applications for the measurement of inhibin A in early pregnancy could be in predicting miscarriage, Down's syndrome, preeclampsia, and fetal growth restriction in the first and/or second trimester before the onset of the clinical symptoms. The source of inhibins, factors controlling inhibin production, the possible functions of inhibin, and the use of inhibin measurement in normal and high-risk pregnancy are reviewed.

Women with preeclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin.

OBJECTIVE: Poor placentation in early pregnancy is thought to lead to an excessive maternal systemic inflammatory response, which causes the maternal syndrome of preeclampsia. The aims of this retrospective study were to confirm old reports of increased blood levels of pregnancy-associated plasma protein A (PAPP-A) in preeclampsia and how its levels correlate with the levels of other placental and endothelial proteins that are reported to be elevated in preeclampsia. METHODS: Nineteen women with preeclampsia symptoms were matched with 19 normal pregnant controls for gestational age, maternal age, and parity. PAPP-A, placental pregnancy-specific beta1-glycoprotein (SP1), inhibin A, activin A, and sE-selectin were measured in serum using specific ELISAs. RESULTS: Maternal serum levels of PAPP-A, inhibin A, activin A and sE-selectin were increased in women with preeclampsia (mean 157.7 vs. 76.85 mIU/mL, p=0.005; 3.08 vs. 1.51 ng/mL, p=0.002, 32.36 vs. 3.77 ng/mL, p<0.001 and 62.15 vs. 46.37 ng/mL, p=0.02 respectively), compared to controls. Serum levels of SP1 were not altered in preeclampsia. PAPP-A (r=0.636, p<0.01) had a positive correlation with sE-selectin in patients with preeclampsia. Serum inhibin A and activin A had a significant positive correlation with each other in preeclampsia. CONCLUSIONS: Raised levels of PAPP-A in preeclampsia confirm earlier reports. Activin A showed the highest increase over the controls and is thus likely to be a better serum marker for this pathology than the other markers that were tested.

In-vitro study of the effect of anti-hypertensive drugs on placental hormones and angiogenic proteins synthesis in pre-eclampsia.

INTRODUCTION: Antihypertensive drugs lower the maternal blood pressure in pre-eclampsia (PE) by direct or central vasodilatory mechanisms but little is known about the direct effects of these drugs on placental functions. OBJECTIVE: The aim of our study is to evaluate the effect of labetolol, hydralazine, α-methyldopa and pravastatin on the synthesis of placental hormonal and angiogenic proteins know to be altered in PE. DESIGN: Placental villous explants from late onset PE (n = 3) and normotensive controls (n = 6) were cultured for 3 days at 10 and 20% oxygen (O2) with variable doses anti-hypertensive drugs. The levels of activin A, inhibin A, human Chorionic Gonadotrophin (hCG), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in explant culture media on day 1, 2 and 3 using standard immunoassays. Data at day 1 and day 3 were compared. RESULTS: Spontaneous secretion of sEndoglin and sFlt-1 were higher (p < 0.05) in villous explants from PE pregnancies compared to controls. There was a significant time dependent decrease in the secretion of sFlt-1 and sEndoglin in PE cases, which was seen only for sFlt-1 in controls. In both PE cases and controls the placental protein secretions were not affected by varying doses of anti-hypertensive drugs or the different O2 concentration cultures, except for Activin, A which was significantly (p < 0.05) higher in controls at 10% O2. INTERPRETATION: Our findings suggest that the changes previously observed in maternal serum hormones and angiogenic proteins level after anti-hypertensive treatment in PE could be due to a systemic effect of the drugs on maternal blood pressure and circulation rather than a direct effect of these drugs on placental biosynthesis and/or secretion.