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Fetal intra-abdominal umbilical vein (FIUV) varix is a rare prenatal abnormality characterised by a focal intrahepatic or extrahepatic dilatation of the intra-abdominal portion of the umbilical vein. Usually, it is an isolated finding, but in some cases it can be associated to other fetal anomalies. Thrombosis is a possible complication of FIUV varix and it can lead to poor fetal or neonatal outcome. We describe four consecutive cases of FIUV varix diagnosed in our Unit and managed with low-dose aspirin (LDA) prophylaxis until the 35th week of gestation. None of the fetuses developed thrombosis of the varix and the neonatal outcomes were good in all the cases.

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OBJECTIVE: To assess maternal serum activin A, an early phase response protein in systemic infection, as an early marker of intrauterine infection in women with preterm prelabour rupture of membranes (PPROM). STUDY DESIGN: A prospective cohort study of women with singleton pregnancies complicated by PPROM at 24 to 34 weeks' gestation. Serum was collected for activin A and cytokine measurements. Activin A was measured using commercial enzyme-linked immunosorbent assay. Cytokines were measured using commercial multiplex assay. Pregnancy outcomes including infection were determined by case-record review. RESULT: Eighteen women with PPROM were studied, with seven developing intrauterine infection. Serum activin A in women with and without infection did not differ. Peripheral white cell count, interleukin (IL)-6 and IL-10 were higher (P=0.03, 0.05 and 0.009, respectively) and IL-7 lower (P=0.04) 72 h before delivery in women with infection. CONCLUSION: Activin A is not a clinically useful marker of intrauterine infection in women with PPROM.

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OBJECTIVE: From early gestation the human trophoblast secretes large amounts of inhibin A and activin A, and their measurement provides a value for predicting the outcome in women who become pregnant after assisted reproductive techniques. The aim of the study was to investigate the putative role of maternal serum inhibin A and activin A levels as markers of a viable trophoblast in women who miscarry. DESIGN: Controlled cross-sectional study. METHODS: One group consisted of 65 healthy pregnant women (controls), progressing to deliver a healthy singleton baby and another group consisted of 54 miscarriages (38 incomplete (27 non-viable, 11 anembryonic pregnancies) and 16 complete). Maternal blood samples were collected between 5 and 12 weeks of gestation. RESULTS: Serum human chorionic gonadotrophin concentrations in women with incomplete or complete miscarriages were significantly (both P<0.001) lower than in controls; activin A levels being lowest only in women with a complete miscarriage (P<0.001). On the other hand, inhibin A levels were significantly lower in incomplete or complete miscarriage than in controls (both P<0.0001). CONCLUSIONS: Maternal serum inhibin A, but not activin A, determination reflects the lack of a viable trophoblast in complete miscarriage.

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The goal of the current study was to examine the role of the ubiquitin-proteasome system (UPS), a pathway of intracellular degradation, in the regulation of fetal fibronectin (FFN) expression in human placenta. Primary cultures of cytotrophoblasts (CTs) and placental mesenchymal cells (PMCs) were isolated from human term placentas and were maintained in serum-free medium (SFM) in the presence of inhibitors of proteasome-mediated degradation (e.g., MG132) as well as inhibitors of other proteases. Levels of secreted FFN and interleukin (IL)-8 in culture media were quantitated by enzyme-linked immunosorbent assay (ELISA), and cell viability was assessed by trypan blue exclusion. Intracellular levels of FFN and ubiquinated proteins were measured by Western blotting, and levels of fibronectin mRNA were determined following Northern blotting. We found that proteasome inhibitors (MG132, MG262, and PSI) potently suppressed levels of secreted FFN in cultures of CTs, but they not did affect levels of IL-8. Lysosomal, calpain, and serine protease inhibitors as well as the anti-inflammatory compound sulfasalazine did not markedly affect levels of secreted FFN in CT cultures. Proteasome inhibitors did not compromise cell viability during the initial 16-18 hours of treatment and did not affect intracellular levels of FFN protein or fibronectin mRNA. The efficacy of suppression of FFN in CT culture media by proteasome inhibitors reflected their effects on intracellular accumulation of ubiquinated proteins. By contrast, the presence of proteasome inhibitors did not alter levels of secreted FFN in cultures of PMCs. We conclude that inhibitors of proteasome-mediated degradation potently and specifically suppressed extracellular expression of FFN in CTs through a cell type-specific pathway that did not involve alterations in FFN synthesis. This suggests that accumulation of ubiquinated proteins in the presence of proteasome inhibitors blocks FFN secretion or promotes the extracellular degradation of FFN. This experimental paradigm will be useful for dissecting the role of the UPS in regulating CT function.

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OBJECTIVE: To explore whether abnormalities in growth hormone binding protein (GHBP) may underlie the growth restriction associated with fetal aneuploidy. DESIGN: A retrospective casecontrol study. SETTING: Monash Medical Centre. Clayton, Victoria, Australia. POPULATION: Twenty-one trisomy 18, and 30 trisomy 21 pregnancies, and 170 chromosomally normal pregnancies at 15-18 weeks of gestation representing three to five controls per case matched for source, gestation and duration of storage. METHODS: GHBP was measured using a ligand immunofunctional assay RESULTS: In the chromosomally normal pregnancies GHBP levels decreased slightly but significantly across the narrow gestational window studied. Compared with controls, levels of GHBP, expressed as median (95% CI) multiples of the median (MoM). in the trisomy 21 pregnancies were similar, 1.0 (0.92-1.39) MoM and 1.27 (1.04-1.50) MoM, respectively; P = 0.061 (Mann-Whitney U test) but were significantly reduced in the trisomy 18 pregnancies, 0.68 (0.5 1-0.84) MoM: P = 0.0014 (Mann-Whitney U test). CONCLUSIONS: These data suggest that decreased levels of maternal growth hormone binding protein, and by implication growth hormone receptor complement, may underlie the early severe growth restriction that is characteristic of trisomy 18.

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OBJECTIVE: To assess the usefulness of placental and fetal Doppler velocimetry in the surveillance of gestational diabetes mellitus (GDM). STUDY DESIGN: We studied 89 patients with GDM. All fetuses underwent umbilical, fetal descending thoracic aorta and fetal middle cerebral artery pulsatility index (PI) assessment. Doppler results were not used for management. We correlated PI with route of delivery and with the following perinatal complications: small size for gestational age, cesarean section (CS) for acute fetal distress (AFD), respiratory distress syndrome, hyperbilirubinemia, hypocalcemia, hypoglycemia, macrosomia and stay in a neonatal intensive care unit. RESULTS: Seventy-seven patients (87%) had normal Doppler measurements, while 12 (13%) showed one or more abnormal measurements. The greatest incidence of CS for AFD (42% vs. 16%, P < .001), as well as neonatal hyperbilirubinemia (25% vs. 10%, P < .001) and hypoglycemia (25% vs. 5%, P < .001) was reported among the women with abnormal Doppler measurements. CONCLUSION: Fetal placental hemodynamics are normal in most cases of GDM. In a small percentage of cases we observed abnormal fetal placental PI associated with a higher incidence of perinatal complications. Hence, the finding of abnormal PI must induce the physician to carry out more intensive obstetric care of women with GDM.

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OBJECTIVE: In a group of diabetic pregnant women, the umbilical artery pulsatility index (PI) was compared with both pregnancy complications and perinatal outcomes. METHOD: We evaluated 67 women with pregnancies complicated by insulin-dependent diabetes mellitus (IDDM), without hypertension. For the study we took the last umbilical PI value before delivery into consideration. Doppler results were not used for patient management. Umbilical artery PI was correlated with the route of delivery and the following perinatal complications: intrauterine growth retardation; cesarean sections for acute fetal distress; respiratory distress syndrome (RDS); neonatal hyperbilirubinemia; hypocalcemia; hypoglycemia; macrosomia, and neonatal intensive care unit (NICU). RESULTS: Among the 67 diabetic patients enrolled in this study, 44 (66%) had umbilical PIs ranging from the 5th to the 95th percentile (PI mean +/- SD = 1.2 +/- 0.3), while 23 (34%) had PIs above the 95th percentile (PI mean +/- SD = 1.6 +/- 0.3). Among the group with pathologic umbilical PIs, analysis of the data revealed a significantly higher incidence of both cesarean sections for acute fetal distress and perinatal complications: RDS; hyperbilirubinemia; hypoglycemia, and the need for NICU, respectively. CONCLUSION: In 34% of the diabetic pregnant women without hypertension, we found increased vascular resistances. Among these patients the incidence of perinatal complications was higher, and both closer maternal metabolic control and stricter care of fetal conditions are needed.

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OBJECTIVE: To examine changes in maternal serum levels of activin A and follistatin during pregnancy and labour. DESIGN: In three cross sectional and three longitudinal studies venous blood was collected from women during pregnancy, spontaneous labour, labour induction and prior to elective caesarean section for the measurement of activin A and follistatin. SETTING: Monash Medical Centre, Clayton, Victoria, Australia. POPULATION: One hundred and twenty-three women participated in a cross sectional study in pregnancy, 18 women in two longitudinal pregnancy studies, 36 women in a cross sectional labour study, nine women in a longitudinal study of labour induction. Ten women undergoing elective caesarean section were also studied. METHODS: Activin A and follistatin were measured using two sensitive and specific enzyme-linked immunosorbent assays. RESULTS: In the cross sectional study of pregnancy, mean (SEM) maternal serum activin A and follistatin levels increased towards term (2.4 ng/mL (0.3) and 1.8 ng/mL (0.3) in first trimester to 18.9 ng/mL (3.8) and 5.3 ng/mL (0.9) at term, respectively), but the longitudinal study revealed that levels plateau in the last three weeks of pregnancy (16.0 ng/mL (2.6) and 6.2 ng/mL (1.4) at 37 weeks and 16.6 ng/mL (3.5) and 6.2 ng/mL (0.5) before labour for activin A and follistatin, respectively). There was no difference in levels of activin A and follistatin between women delivered by caesarean section and labouring women at term (14.9 ng/mL (2.8) vs 11.0 ng/mL (0.93) and 5.95 ng/mL (0.67) vs 5.71 ng/mL (0.63), respectively) and levels of both proteins did not alter throughout spontaneous or induced labour. CONCLUSIONS: We believe that these data argue against activin A playing an acute role in the initiation or regulation of human parturition.

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Activin A levels are elevated in maternal serum of pregnant women with hypertensive disturbances. Because follistatin is a circulating binding protein for activin A, the present study was designed to evaluate whether serum follistatin and activin A levels also change in patients with hypertensive disorders in the last gestational trimester. The study design was a controlled survey performed in the setting of an academic prenatal care unit. Healthy pregnant women (controls, n=38) were compared with patients suffering from pregnancy-induced hypertension (PIH, n=18) or pre-eclampsia (n=16). In addition, the study included a subset of patients with pre-eclampsia associated with intrauterine growth restriction (IUGR, n=5). Maternal blood samples were withdrawn at the time of diagnosis (patients) or in a random prenatal visit (controls), and serum was assayed for follistatin and activin A levels using specific enzyme immunoassays. Hormone concentrations were corrected for gestational age by conversion to multiples of median (MoM) of the healthy controls of the same gestational age. Follistatin levels were not different between controls and patients, while activin A levels were significantly increased in patients with PIH (1.8 MoM), pre-eclampsia (4.6 MoM), and pre-eclampsia+IUGR (3.2 MoM, P<0.01, ANOVA). The ratio between activin A and follistatin was significantly increased in patients with PIH (1.5 MoM) and was further increased in patients with pre-eclampsia (4.5 MoM) and in the group with pre-eclampsia+IUGR (2.6 MoM). Follistatin levels were positively correlated with gestational age in control subjects (r=0. 36, P<0.05) and in patients with PIH (r=0.46, P<0.05) or pre-eclampsia (r=0.61, P<0.01), while activin A correlated with gestational age only in the healthy control group (r=0.69, P<0.0001). The finding of apparently normal follistatin and high activin A levels in patients with PIH and pre-eclampsia suggests that unbound, biologically active, activin A is increased in women with these gestational diseases.

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Coarctation of aorta is a rare cause of hypertension in pregnancy and the case material reported in literature is limited without a univocal line of clinical conduct. A case association between isthmic coarctation of the aorta and pregnancy in a 17 year-old primigravida woman is described.

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Intrauterine growth retardation is a pathology which is found in 3-10% of all pregnancies and it is associated with around 20-25% of all fetal intrauterine deaths and with long-term neurologic sequelae. It presents an increased risk of distress during labor and delivery and a greater risk of perinatal mortality. The causes of IUGR and the cardiac and venous Doppler in normal fetuses are analyzed, and the hemodynamic cardiac modifications in IUGR fetus are discussed. The fetal cardiac function in intrauterine growth retardation shows a redistribution of the fetal cardiac output, which tends to favor the left ventricle as the mechanism to compensate for the uteroplacental insufficiency. The Doppler velocity indices are modified as the fetal condition progressively deteriorates and they represent an important tool for the management of the complicated pregnancy.

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OBJECTIVE: In the second trimester of pregnancy, inhibin A is significantly increased in maternal serum and decreased in amniotic fluid in Down's syndrome pregnancies compared to normal. We wished to further evaluate the levels of inhibin A, inhibin B, pro-alpha C inhibin, activin A and the binding protein follistatin in amniotic fluid in Down's syndrome and control pregnancies. DESIGN: Case-matched control study. PATIENTS: 29 Down's syndrome and 290 chromosomally normal control pregnancies were identified from records and amniotic fluid, collected at second trimester amniocentesis, retrieved from routine storage for analysis. MEASUREMENTS: Inhibin A, inhibin B, pro-alpha C inhibin, total activin A and follistatin were measured using sensitive and specific enzyme linked immunosorbent assays. RESULTS: The median (10th-90th percentiles) amniotic fluid inhibin A level in the control pregnancies increased from 334 (122-553) ng/l at 14 weeks' to 695 (316-1475) ng/l at 19 weeks' gestation. The corresponding figures for inhibin B and the alpha-subunit precursor inhibin pro-alpha C were 632 (185-1354) and 2062 (1237-3381) ng/l, respectively at 14 weeks' and 2439 (748-5307) and 3115 (2021-6567) ng/l, respectively at 19 weeks' gestation. Total activin A increased from 3795 (1554-5296) at 14 weeks' to 5086 (3059-8224) at 18 weeks' gestation. Expressed as multiples of the median (MoM) the median (95% CI) amniotic fluid levels of inhibin A, inhibin B, pro-alpha C inhibin and acitivin A in the Down's syndrome samples were 0.77 (0.59-0.85), 0.94 (0.63-1.23), 0.77 (0.49-0.84) and 0.77 (0.53-0.87), respectively. Compared to controls the levels of inhibin A, pro-alpha C inhibin and activin A were significantly lower in Down's syndrome pregnancies (P < 0.01, Mann-Whitney U test). Follistatin levels in the controls declined slightly from 2106 (1421-3538) ng/l at 14 weeks' to 1600 (1281-2543) ng/l at 18 weeks' gestation. Levels in the Downs' syndrome pregnancies were similar to controls. CONCLUSIONS: The data suggest that the production, secretion or metabolism of the inhibin alpha- and beta A-subunits is altered in Down's syndrome pregnancies in the second trimester.

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Using two enzyme-linked immunosorbent assays specific for inhibin A and pro-alpha C inhibin, levels of the two proteins were assessed in maternal serum from 43 Down syndrome and 300 chromosomally normal pregnancies at 15-17 weeks' gestation. Compared to the control pregnancies, both inhibin A and pro-alpha C inhibin were significantly elevated in the Down syndrome pregnancies with median levels, expressed as multiples of the normal median, of 1.53 MoM and 1.34 MoM, respectively (P < 0.001 and P = 0.046 compared to controls). Levels of inhibin A and pro-alpha C inhibin were weakly but significantly correlated in both the control and the Down syndrome sera (r = 0.25, P < 0.0001; r = 0.4, P = 0.008, respectively). These data suggest that the mechanism(s) underlying the elevated inhibin levels observed in Down syndrome may affect the regulation of both the inhibin alpha- and beta A-subunits.

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OBJECTIVE: Flutamide is a non-steroid antiandrogen that specifically blocks the androgen receptor. We have investigated the effect of flutamide treatment on the adrenal androgen response to corticotrophin releasing factor (CRF) in eight patients with polycystic ovary syndrome (PCOS). PATIENTS: Eight women with moderate to severe hirsutism, ranging in age from 19 to 23 years were enrolled in the study. Basal hormonal pattern showed anovulatory cycles, increased concentrations of LH, androstenedione and testosterone and increased LH/ FSH ratio. A baseline ultrasound scan revealed polycystic ovaries in all patients. Each received 250 mg of Flutamide twice a day for 6 months. MEASUREMENTS: Before treatment and at the end of the sixth month, women were evaluated for hirsutism score and a CRF test was performed to evaluate ACTH, cortisol and adrenal androgen responses. RESULTS: Androstenedione (delta 4), DHEA-S, 17-hydroxy-progesterone, testosterone and free-testosterone showed significantly reduced responses after six months of flutamide therapy whereas ACTH and cortisol response were similar to those before treatment. Clinical improvement in the degree of hirsutism was observed in all patients. The Ferriman-Gallwey scores decreased from a mean of 22 +/- 2 to 8 +/- 1.5. CONCLUSION: Flutamide induces a significant reduction in adrenal androgen response to the CRF test but not in the response of ACTH and cortisol. The finding that flutamide does not alter the pituitary-adrenal axis shows that flutamide acts by reducing adrenal androgens. These results demonstrate that flutamide is not only effective in the treatment of hirsutism but also reduces adrenal androgen secretion.

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Tubal pregnancy is now commonly managed by laparoscopic salpingostomy or systemic methotrexate. A disadvantage of such conservative management is the need for appropriate follow-up, with serial measurement of serum concentrations of human chorionic gonadotrophin (HCG), to exclude persistent ectopic pregnancy (PEP). Concentrations of inhibin A, also a placental product, are significantly increased during pregnancy and the half-life of inhibin A is significantly shorter than that of HCG. To assess the suitability of inhibin A as a marker of PEP, we studied 16 women who had undergone surgery for a tubal pregnancy, measuring HCG and inhibin during follow-up. The mean +/- SEM time taken to achieve non-pregnant concentrations of inhibin A was significantly shorter than for HCG (4.2 +/- 0.8 days versus 21.6 +/- 4.4 days respectively; P < 0.001 Wilcoxon signed rank test). However, in all women the inhibin A concentration increased rapidly after reaching a nadir, reflecting the return of ovarian function, complicating the interpretation of results. In four women inhibin A was almost undetectable preoperatively, while the corresponding HCG concentration was high. These data suggest that inhibin A will not be a useful marker for PEP but that it may provide a more accurate preoperative assessment of trophoblast viability than HCG, thereby improving management.

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The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone (CRH). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before and 8 days after ovariectomy. A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed after ovariectomy. The ratio of deltamax androstenedione/17-OHP after CRH stimulation was substantially the same before and after ovariectomy, whereas deltamax 17-OHP/cortisol was significantly lower in ovariectomized women showing increased 21- and 11beta-hydroxylase activity. The results show that the acute estrogen deficit induces changes in the HPA axis characterized by reduced stimulated secretion of ACTH and steroids but normal stimulated cortisol production.

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Anovulation in women with polycystic ovary syndrome (PCOS) is the direct effect of high local androgen concentrations on the ovary. Antiandrogens are substances that prevent androgens from expressing their activity on target tissues. Flutamide is a nonsteroid antiandrogen that has been found effective in hirsute patients, although its mechanism of action is unclear. Eight girls, ranging in age from 16-19 yr, with moderate to severe hirsutism and menstrual irregularities were enrolled in this study. The basal hormonal pattern showed anovulatory cycles; increased concentrations of LH, androstenedione, and testosterone; and increased LH/FSH ratio. A baseline ultrasound scan revealed polycystic ovaries in all patients. All were given 250 mg flutamide twice a day for 6 months. LH, FSH, androstenedione, testosterone, estradiol, and progesterone were evaluated before treatment, every 4 days during the third month of treatment, and on day 24 of the sixth month of treatment. Hirsutism improved, androgen levels dropped, and ovulatory cycles were restored in all subjects. Ultrasonographic examination in follicular phase showed a significant reduction in ovarian volume and ovaries of normal appearance with one dominant follicle. The most important result of the present study was that flutamide restored ovulation in anovulatory PCOS patients. This finding supports the hypothesis that flutamide reduces androgen synthesis through restoration of ovulation, although a direct block of the steroidogenic enzymes of androgen biosynthesis in ovarian thecal cells cannot be excluded.

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The effects of 6 months of combined hormone therapy with transdermal estradiol (0.05 mg/day x 21 days) and different oral progestogens (10 mg/day medroxyprogesterone acetate [MPA] in the last 12 days, 10 mg/day dihydrogesterone in the last 12 days, and 50 mg/day cyproterone in the first 10 days), on menopausal symptoms and hypothalamo pituitary-ovarian function were studied in normal perimenopausal women. The study included 38 perimenopausal women, aged 43-49 years, with regular cycles of 26-32 days in length and menopausal symptoms. Endocrine status was determined by assay of basal levels of gonadotropins (LH, FSH), E2, and P every week until menstrual bleeding, before and during the first month of therapy. Plasma levels of LH and FSH were suppressed in the first month of therapy while E2 had a mean value of 45 +/- 12 pg/ml. Ultrasound examination and low levels of P indicated a complete block of ovulation and hypothalamo-pituitary-ovarian activity. All women reported the disappearance of vasomotor symptoms and nocturnal sweating. Transdermal estradiol and oral progestogens were well tolerated. This study shows that combined hormone therapy with low doses of transdermal estrogen patches and different oral progestogens reduces menopausal symptoms and also safeguards against unwanted pregnancies in the perimenopausal period.

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