Placental,maternal serum and amniotic fluid molecular weight forms of inhibin A and pro-alphaC

Previous studies have identified the presence of unidentified small molecular weight (mol wt) forms of inhibin and the pro-alphaC region of the inhibin alpha subunit in serum from women during late pregnancy. The aim of this study was to investigate if these gestational-related changes in mol wt forms arose from changing placental production. Pooled placental extracts, derived from normal healthy singleton pregnancies in the 1st, 2nd and 3rd trimesters of pregnancy, were fractionated by a combined immunoaffinity chromatography, preparative PAGE and electroelution procedure. Inhibin A, inhibin B and the pro-alphaC region of the inhibin alpha subunit were determined in the eluted fractions by specific ELISAs, with the profiles of immunoactivity characterized in terms of molecular size and percentage recovery. Inhibin B was undetectable in all samples. Mol wt peaks of 36k, 75K and 97K for inhibin A and 29k, 55K and 97K for pro-alphaC were detected in placental extracts across all three trimesters. The relative abundancy of small mol wt inhibin A forms (<30K) present in the placenta increased significantly in the third trimester placenta, increasing from 0.3 per cent in the first trimesters to 6 per cent in the third trimester (P=0.01, chi-squared test). The relative abundances of various mol wt forms of pro-alphaC was similar at all three gestations (P=0.67). In serum, small mol wt inhibin A and pro-alphaC forms accounted for 23.4 per cent and 37.4 per cent of inhibins, respectively, in the third trimester.These data suggest that the presence of small mol wt forms of both inhibin A and pro-alphaC in maternal serum is only partially attributed to placental production and/or secretion. We conclude that inhibin A and pro-alphaC inhibins in maternal serum are processed in late pregnancy by more than one mechanism to form low mol wt circulating forms of, as yet, undetermined structure.     

Serum inhibin A, inhibin B, and pro-alphaC levels are altered after surgically or pharmacologically induced menopause

OBJECTIVE: To evaluate the course of changes in serum inhibin A, inhibin B, and pro-alphaC levels in women with surgically or pharmacologically induced menopause. DESIGN: Longitudinal study. SETTING: Academic Health Center of Siena, Siena, Italy. PATIENT(S): Four groups of women were studied: [1] surgical menopause including bilateral oophorectomy (n = 15), [2] amenorrhea induced by GnRH-analogue for treatment of endometriosis (n = 13), [3] amenorrhea induced by antineoplastic chemotherapy before (n = 15) and after chemotherapy (n = 13), and [4] control physiological menopause (n = 67). INTERVENTION(S): Collection of blood specimens. MAIN OUTCOME MEASURE(S): Serum inhibin A, inhibin B, and pro-alphaC concentrations were measured by using specific two-site ELISAs. RESULT(S): Following oophorectomy, serum inhibin A, inhibin B, and pro-alphaC levels were decreased on the first postoperative day; on the fifth postoperative day they were still significantly reduced. Women with amenorrhea induced by GnRH-analogue treatment exhibited serum inhibin A and pro-alphaC levels that were significantly higher than those observed in physiological menopause. Patients undergoing antineoplastic chemotherapy had higher serum inhibin A levels than those in physiological menopause, whereas inhibin B and pro-alphaC levels did not differ. During the course of chemotherapy, median serum inhibin A concentrations were similar to those of patients evaluated after the suspension of treatment. In postmenopause, inhibin A, and inhibin B levels were low, whereas levels of pro-alphaC were still detectable. CONCLUSION(S): Circulating levels of inhibin A, inhibin B, and pro-alphaC are reduced after oophorectomy. Women with amenorrhea induced by GnRH-analogue treatment or by antineoplastic chemotherapy still produce inhibin A and pro-alphaC. This probably reflects a residual ovarian function and hormone synthesis. Therefore, the ovary may be a source of pro-alphaC after menopause; significant amounts of pro-alphaC are present in circulation after natural menopause, but not after oophorectomy.     

Serum activin A and inhibin A elevated in pre-eclampsia: no relation to insulin sensitivity

OBJECTIVE: To assess the possible role of serum levels of activin A, inhibin A and pro-alpha inhibin (pro-alphaC) in insulin sensitivity in pre-eclampsia. DESIGN: A prospective study. SETTING: Helsinki University Central Hospital. PARTICIPANTS: Twenty-two nulliparous women with proteinuric pre-eclampsia and 16 healthy nulliparous controls in the third trimester of pregnancy. METHODS: Serum samples were collected before and after intravenous injection of glucose (0.3 g/kg) and insulin (0.03 IU/kg) (the minimal model for testing insulin sensitivity), and were assayed for activin A, inhibin A and pro-alphaC. MAIN OUTCOME MEASURES: Comparison of the levels of activin A, inhibin A and pro-alphaC between pre-eclamptic and healthy pregnant women, and the association of these proteins with insulin sensitivity. RESULTS: In pre-eclampsia elevated levels of activin A (139%, P = 0.0001), inhibin A (39%, P = 0.003), and pro-alphaC (92%, P = 0.0008) were observed. The amount of proteinuria (0.3-10.5 g/day) correlated positively with serum concentrations of activin A (P = 0.01) and inhibin A (P = 0.02). These glycoproteins were not associated with insulin sensitivity either in women with pre-eclampsia or controls. A 2.9-fold rise in blood glucose and a 52.5-fold rise in insulin during testing using the minimal model were not accompanied by any significant changes in activin A, inhibin A, and pro-alphaC. CONCLUSION: Activin A, inhibin A, and pro-alphaC are elevated in pre-eclampsia but do not appear to relate to the insulin sensitivity in pre-eclamptic or normal pregnancies.     

Serum inhibin A, inhibin B, pro-alphaC, and activin A levels in women with idiopathic premature ovarian failure

Serum inhibin A, inhibin B, pro-alphaC, and activin A levels in 30 women with idiopathic premature ovarian failure (POF), 30 postmenopausal women, and 30 age-matched fertile women were determined. Women with POF showed low levels of inhibin A and inhibin B, but not of activin A, whereas the levels of pro-alphaC were significantly higher than in postmenopausal women. Thus, the circulating level of pro-alphaC could be a marker for assessing residual ovarian function in women with POF.     

Midtrimester maternal serum inhibin A levels after multifetal pregnancy reduction

OBJECTIVE: To investigate the relationship between the maternal serum inhibin A concentrations and the number of fetuses. Further, the maternal serum inhibin A levels for twin pregnancies and multiple pregnancies reduced to twins in the second trimester were compared. METHODS: Three groups of women with pregnancies following in vitro fertilization and embryo transfer were recruited for this study. Groups 1, 2 and 3 included 20 singleton pregnancies, 37 twin pregnancies, and 35 multifetal pregnancies, respectively. In group 3, multifetal reduction was performed during 10-12 weeks of gestation. Blood samples were obtained longitudinally at 10th, 12th, 15th and 18th week of gestation. RESULTS: There was a significant association between the number of fetuses and maternal plasma inhibin A prior to multifetal reduction. The inhibin A levels were not significantly different between twin and multifetal reduced twin pregnancies at 15th and 18th weeks of gestation. CONCLUSION: In multifetal reduction to twin pregnancies, the maternal serum levels of inhibin A decrease to the level of twin pregnancies during the second trimester. Therefore, inhibin A may be effectively used as a marker for Down syndrome screening in cases of twin pregnancy following multifetal reduction.     

Serum inhibin A levels in pregnant women with systemic lupus erythematosus or antiphospholipid syndrome

Maternal serum inhibin A levels are increased on average in pregnancies affected by Down syndrome (DS). However, some reports have found increased serum levels in women with pre-eclamptic toxaemia as well. In the current study, maternal serum inhibin A was retrospectively measured in a series of 32 serum samples from pregnant women previously diagnosed as having either systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). For comparison, normal medians were calculated from 57 unaffected control pregnancies together with a total of 854 samples tested at 13-19 weeks of gestation as part of the routine antenatal DS screening. All results were expressed in multiples of the gestation specific normal medians (MoM). A cubic regression formula was fitted, weighting for the number of women tested at each gestation. The median MoM value in the 16 cases of SLE and the 16 cases of primary APS is 0.60 (95% confidence interval 0.40-0.91) and 0.88 (95% confidence interval 0.66-1.17), respectively. For primary APS this was not statistically significant, whereas the SLE patients had a highly statistically significant reduction of serum inhibin A (p<0.002, Wilcoxon Rank sum Test, 2 tailed). Six pregnancies in the SLE group had a complicated obstetric outcome, i.e. missed abortion, placental abruption, exacerbation of the underlying disease which necessitated delivery, and severe postpartum haemorrhage. In 85% of this subgroup, serum inhibin A levels were below the normal 10th centile. The current data suggest that serum inhibin A is decreased on average in SLE patients. Those preliminary results might have various obstetric implications such as antenatal DS screening of SLE patients, identification of pregnant women at risk of developing SLE, who have presented for routine DS screening and for monitoring SLE patients throughout their pregnancy.     

Serum activin A, inhibin A, and follistatin concentrations in preeclampsia or small for gestational age pregnancies

OBJECTIVE: To determine whether maternal serum activin A, inhibin A, and follistatin concentrations in idiopathic small for gestational age (SGA) pregnancies are similar to those in normal pregnancies or elevated as in preeclampsia. METHODS: Maternal serum activin A, inhibin A, and follistatin concentrations were determined in 1) nulliparous women with idiopathic SGA (birth weight <10th percentile; n = 18), preeclampsia (systolic blood pressure > or =140 mmHg or diastolic blood pressure > or =90 mmHg plus proteinuria > or =2+ or >0.3 g/24h; n = 22), and normotensive controls, matched for gestational age at sampling (n = 22), and 2) a longitudinal series of samples collected at five intervals throughout pregnancy from nulliparous women with idiopathic SGA (n = 19), preeclampsia (n = 22), preeclampsia plus SGA (n = 15), or who had uncomplicated pregnancies (n = 20). RESULTS: Serum concentrations of activin A and inhibin A were similar in idiopathic SGA pregnancies to controls. In preeclampsia, activin A and inhibin A levels were markedly increased compared with controls or women with idiopathic SGA (P <.001), particularly in those with early-onset disease. Follistatin concentrations were only modestly (相似文献   

Second trimester levels of maternal serum inhibin A in pregnancies affected by fetal neural tube defects

Inhibin A is effective as a second trimester maternal serum marker for Down syndrome screening. In the present study, inhibin A levels were measured in second trimester maternal serum samples from 28 pregnancies affected with open neural tube defects; 12 associated with open spina bifida and 16 associated with anencephaly. Each measurement was expressed as a multiple of the median (MoM) for control singleton pregnancies (n=1464) of the same completed week of gestation. Inhibin A levels were not significantly altered in cases of open neural tube defects; the median value was 0.96 MoM in cases of open spina bifida and 1.19 MoM in cases of anencephaly. Therefore, second trimester maternal serum inhibin A levels will not have an impact on prenatal detection of open neural tube defects.     

Second-trimester maternal serum immunoreactive inhibin as a marker for fetal Down's syndrome.

We measured immunoreactive inhibin in the maternal serum of 80 pregnancies with a chromosomally normal fetus and ten Down's syndrome pregnancies in the second trimester. The inhibin level in all Down's syndrome pregnancies was above the normal median; the multiple of the normal median (MoM) was 1.9. We found a statistically significant difference between the levels of inhibin in unaffected and affected pregnancies (Kolmogorov-Smirnov test: p < 0.002). Using an arbitrarily chosen cut-off of 2.4 MoM, 40 per cent of Down's syndrome and 5 per cent of the normal pregnancies were found. We conclude that immunoreactive inhibin may be useful as a marker for fetal Down's syndrome.     

Maternal serum activin A, inhibin A, and follistatin in pregnancies with appropriately grown and small-for-gestational-age fetuses classified by umbilical artery Doppler ultrasound

OBJECTIVE: The purpose of this study was to examine the relationship of maternal serum activin A, inhibin A, and follistatin with fetal growth and placental function. STUDY DESIGN: Inhibin A, activin A, and follistatin were measured in maternal serum that was stored from normally grown (control subjects, n = 50) and small-for-gestational-age pregnancies (n = 49), prospectively classified as normal small-for-gestational-age pregnancy or fetal growth-restricted pregnancy with the use of umbilical artery Doppler ultrasound. RESULTS: Activin A and inhibin A were significantly increased in fetal growth-restricted pregnancies compared with control subjects (activin A: regression coefficient, 0.54, P <.001; inhibin A: regression coefficient, 0.47, P =.003). The activin:follistatin ratio was significantly higher in fetal growth-restricted pregnancies compared with control subjects (P <.001). There were no significant differences between analyte levels of normal small-for-gestational-age pregnancies and control subjects. CONCLUSION: Maternal serum activin A, inhibin A, and activin:follistatin ratio are raised in fetal growth-restricted pregnancies but not in normal small-for-gestational age pregnancies. This provides further evidence of the difference between subgroups within small-for-gestational-age pregnancies and emphasizes the need to stratify for this in research.     

Serum inhibin A and inhibin B--new clinical markers

During very early pregnancy, especially in the presence of complications associated with ART such as multiple gestation and OHSS, measurement of maternal levels of inhibin A offers a non-invasive test that can aid the counseling and management of patients. In the second trimester, assessment of maternal inhibin A levels has been shown to improve sensitivity of the existing serum screening tests for aneuploid pregnancies and made prove clinically useful in the early detection of pregnancies susceptible to developing pre-eclampsia. Assessment of inhibin B appears to offer useful prognostic information about ovulatory function and predictive information about response to treatment with gonadotropins.     

Elevated second-trimester maternal serum inhibin A levels in Asian pregnancies with fetal down syndrome and other chromosomal abnormalities

SUBJECTS: To evaluate second-trimester maternal serum inhibin A levels in Asian pregnancies with fetal Down syndrome and other chromosomal abnormalities. METHODS: Inhibin A level was measured from the serum samples of 25 chromosomally abnormal pregnancies, including 15 cases of Down syndrome, 4 cases of trisomy 18, 1 case of trisomy 13, and 5 cases of sex chromosome aneuploidies (4 cases of 47,XXY and 1 case of 45,X) and in a cohort of 150 controls during the second trimester of pregnancy. RESULTS: The multiple of median levels of Down syndrome (1.74) and other chromosomally abnormal pregnancies (2.03) are significantly higher than that of normal pregnancies (p = 0.002 and p = 0.024, respectively). Only 3 of 15 (20%) Down syndrome cases had inhibin A levels at or above the 95th centile of the control values. CONCLUSIONS: Inhibin A levels are raised in Asian women affected with fetal Down syndrome and sex chromosome abnormality. In spite of the poor discrepancy of inhibin A, it might be a potential marker for Down syndrome screening in Asians.     

Use of serum inhibin A and human chorionic gonadotropin measurements to predict the outcome of in vitro fertilization pregnancies

OBJECTIVE: To assess the clinical value of maternal serum inhibin A measurements in early pregnancy in the prediction of outcome of IVF pregnancies and to compare the predictive accuracy of inhibin A concentrations with serum hCG concentrations. DESIGN: Retrospective study.University-based IVF program. PATIENT(S): One hundred fifty IVF pregnancies of 150 couples were studied during a 4-year period. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The association between pregnancy outcome and age, number of collected oocytes, number of transferred embryos, and serum hCG and inhibin A concentrations in early pregnancy was studied with logistic regression. Predictive accuracy of inhibin A and hCG concentrations was calculated by receiver-operating characteristic (ROC) analysis. RESULT(S): Lower serum concentrations of inhibin A and hCG were associated with increased odds for preclinical abortion and early pregnancy loss, whereas higher inhibin A and hCG concentrations were observed in multiple ongoing pregnancies. Inhibin A measurements were superior to hCG in the prediction of preclinical abortions; no significant difference was observed between the predictive value of hCG, inhibin A, or their combination in differentiating between ongoing pregnancies and early pregnancy losses. The discriminative potential of inhibin A for prognosticating multiple ongoing pregnancies was lower than that of hCG. CONCLUSION(S): Although serum inhibin A concentrations are more accurate than hCG levels for predicting preclinical abortion after IVF, they had no advantage in forecasting ongoing or multiple ongoing pregnancies, suggesting that routine assessment of serum inhibin A concentrations during follow-up of IVF pregnancies is unjustified.     

Lower levels of inhibin A and pro-alphaC during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin

OBJECTIVE: To investigate the effect of triggering oocyte maturation with GnRH agonist on corpus luteum function by measuring luteal phase levels of inhibin A and pro-alphaC. DESIGN: Prospective randomized trial. SETTING: In vitro fertilization (IVF) program at a university hospital. PATIENT(S): Infertile women undergoing IVF-ET treatment. INTERVENTION(S): Controlled ovarian hyperstimulation with FSH and GnRH antagonist, triggering of final oocyte maturation with either hCG (n = 8) or GnRH agonist (n = 8), IVF-ET, and collection of blood samples every 2-3 days during the luteal phase. MEASUREMENTS AND MAIN RESULTS: Luteal phase serum levels of inhibin A and pro-alphaC, P, and E(2). RESULT(S): Levels of inhibin A, pro-alphaC, estrogen, and P were significantly lower from day 4 to day 14 after triggering final oocyte maturation by GnRH agonist compared with hCG. Maximal luteal serum inhibin A and pro-alphaC levels were 91.5 +/- 23.6 and 184.1 +/- 23.5 pg/mL in the GnRH agonist-treated women compared with 464.7 +/- 209.1 and 7,351.6 +/- 934.3 pg/mL in women treated with hCG. CONCLUSION(S): Triggering final oocyte maturation with GnRH agonist instead of hCG in IVF cycles dramatically decreases luteal levels of inhibins, reflecting significant inhibition of the corpus luteum function. This effect may explain, at least in part, the mechanism of ovarian hyperstimulation syndrome prevention by the use of GnRH agonist.     

High maternal serum inhibin A levels following the loss of one fetus in a twin pregnancy

Inhibin A levels are elevated in the second trimester of pregnancies affected with fetal Down syndrome, on average, two times the level in unaffected pregnancies. Inhibin A levels are also two times higher in twin than in singleton pregnancies. Prenatal serum screening using inhibin A levels as a second trimester marker began at the Women and Infants Hospital in March 1998. We describe a case of a 17-year-old woman thought to have had a complete spontaneous abortion of a twin pregnancy but later found to be continuing the pregnancy with a single fetus. Routine second trimester prenatal serum screening revealed an extremely elevated inhibin A level of 39 MoM (multiples of the median). The patient delivered an apparently healthy female infant at 41 weeks of gestation. Therefore, inhibin A may be extremely elevated in the second trimester of a twin pregnancy after the loss of one fetus and this increased inhibin A level does not have any obvious adverse maternal or fetal effects.     

First trimester serum inhibin A in normal pregnant women

Objectives To establish reference ranges for maternal serum inhibin A in normal first trimester pregnant women. Materials and methods This was a cross-sectional study. We measured maternal serum inhibin A in normal pregnant women gestation age between 6⁺⁰ and 14⁺⁶ weeks using the enzyme-linked immunosorbent assay (ELISA) method. Maternal serum inhibin A was analyzed according to gestational ages (GA). Results Serum of 300 pregnancies was analyzed and the outcome demonstrated the median of maternal serum inhibin A according to gestational age. The levels of maternal serum inhibin A during the 6⁰–6⁺⁶ week of gestations are lowest when compared with other gestational age. The levels of maternal serum inhibin A during 9⁰–9⁺⁶ week of gestations are maximal. Maternal serum inhibin A then declined until 14 weeks of gestation. Conclusion Serum inhibin A can be measured during the first trimester of pregnancy by using the recent ELISA technique. Our reference ranges might be useful for further studies, such as prediction of adverse pregnancy outcome in threatened abortion.     

Second-trimester maternal pregnancy-associated plasma protein a and inhibin a levels in fetal trisomies

OBJECTIVE: The aim of this study was to determine whether fetal trisomy is associated with altered levels of second-trimester maternal pregnancy-associated plasma protein A (PAPP-A) and inhibin A. METHODS: Maternal serum PAPP-A and inhibin A concentrations were measured at 15-17 weeks of gestation in 14 singleton pregnancies with fetal trisomy and in 56 matched pregnant controls. RESULTS: PAPP-A levels in the trisomy group were significantly lower than in controls. The inhibin A level with fetal trisomy 21 was slightly higher than the control group, but levels were not different between trisomies 18 and 13 and controls. CONCLUSION: Fetal trisomies 21, 18, and 13 are associated with a reduction in second-trimester maternal PAPP-A levels; trisomies 18 and 13 are not associated with increased inhibin A levels, unlike trisomy 21.     

Activin A, inhibin A, inhibin B and parturition: changes of maternal and cord serum levels according to the mode of delivery.

OBJECTIVE: To evaluate whether activin A, inhibin A, and inhibin B levels in maternal and umbilical artery serum change according to the mode of delivery. DESIGN: Maternal and cord blood specimens were collected at term after spontaneous labour and vaginal delivery, or elective caesarean section. SETTING: Universities of Pisa, Turin, Naples and Udine. POPULATION: Forty-two healthy pregnant women, at 3940 weeks of gestation, divided into two subgroups: group 1 vaginal delivery (n = 21), were delivered of 10 female and 11 male infants; group 2 elective caesarean section (n = 21), were delivered of 11 female and 10 male infants. MAIN OUTCOME MEASURES: Serum activin A, inhibin A, inhibin B concentrations in maternal and umbilical cord blood. RESULTS: At vaginal delivery, maternal serum inhibin A and inhibin B levels were lower and activin A levels higher than at elective caesarean section. Maternal levels of activin A, inhibin A and inhibin B were constantly higher than in umbilical arterial blood, independent of the mode of delivery. No significant difference was observed in umbilical arterial serum levels of the three proteins between the two modes of delivery. Umbilical arterial serum activin A and inhibin A concentrations did not show a significant difference between male and female infants in either vaginal or caesarean section, but male infants showed inhibin B levels significantly higher than female, independent of the mode of delivery. CONCLUSIONS: In the presence of active labour, the human placenta secretes larger amounts of activin A and lesser amounts of inhibin A and inhibin B into the maternal circulation. Inhibin-related proteins in the fetal circulation do not show differences according to the mode of delivery, suggesting that they have a different method of production or metabolic rate compared with maternal activin and inhibins.     

The diagnostic value of inhibin in infertility evaluation

The fertility patient is entitled to a rapid and accurate diagnosis, a realistic assessment of the prospects for achieving pregnancy, and the timely initiation of an appropriate and effective therapy. The evaluation of ovarian reserve prior to initiation of ovarian stimulation is an important aspect of the infertility work-up of a woman requiring assisted reproductive techniques (ARTs). The ability of the ovary to respond to gonadotropin stimulation by the recruitment of a cohort of follicles is central to the success of treatment such as in vitro fertilization and intracytoplasmic sperm injection. Ovarian dysfunction, often age related, is an increasingly common cause of subfertility, and hyper- and hypogonadotropic dysovulation as well as the commoner polycystic ovarian syndrome (PCOS) are frequently encountered in fertility clinic. In cases of male-factor infertility, an ability to identify an accurate serum marker of Sertoli cell function has enhanced the diagnostic process, as previous endocrine markers such as follicle-stimulating hormone and testosterone were poor correlates of spermatogenic potential. The identification, purification, and cloning of the members of the inhibin-activin superfamily and the subsequent development of sensitive and highly specific two-site enzyme-linked immunoassays for these polypeptide hormones have provided tentative answers to many of the outstanding questions concerning the regulation of the hypothalamo-pituitary-gonadal axis. Assessment of serum levels of inhibin B appears to offer useful prognostic information about ovulatory function and predictive information about response to treatment. During very early pregnancy, especially in the presence of complications associated with ART such as multiple gestation and ovarian hyperstimulation syndrome, measurement of maternal levels of inhibin A and pro-alphaC offers a noninvasive test that can aid the counseling and management of patients.