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Maternal serum activin A levels in 20 cases of fetal Down syndrome (W) and 100 unaffected, control pregnancies (X). Values are shown as multiples of the median (MoM). The horizontal line at 1.0 MoM represents the median of the activin A values in unaffected samples.
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Previous data have shown that inhibin A (alpha/betaA) is increased about twofold in maternal serum samples from Down syndrome pregnancy. Our objectives were to determine whether activin A (betaA/betaA) was similarly increased in maternal serum from pregnancies affected with fetal Down syndrome, and to investigate whether increased expression of eac...
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Context 1
... ng/ml, range ¼ 0.4-3.0 ng/ml) pregnancies. Total activin A levels were not significantly correlated with gestational age in the time period studied (r ¼ 0.10, P ¼ 0.35), and therefore a single median value was determined for the unaffected pregnancies. The MoM (multiples of the median) values in the Down syndrome cases and controls are shown in Fig. 1. The median total activin A value in the Down syndrome cases was 0.82 ...
Citations
... This demonstrates that the method used is able to identify relevant DS screening biomarkers. In addition, the list contains several other proteins which have been examined for their potential as DS screening biomarkers by several research groups, such as the inhibin chains INHA and INHBA[273][274][275][276] , the (protein-identical) placental lactogen genes CSH1 and CSH2 160 , ...
Down syndrome (DS) is the most common chromosomal abnormality, with an incidence of approximately 1 per 500 to 800 live births. The first-trimester combined test is mostly used for the prenatal prediction of carrying a child with DS. The test is composed of the maternal serum parameters pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin (f?-hCG), and an ultrasound measurement of the foetal nuchal translucency (NT), combined with maternal age. The detection rate (DR) of DS screening in the Netherlands is currently 70-75%, which is rather low as compared to other countries. The aim of this research was to investigate ways to improve the performance of the current DS screening programme. The extra chromosome in DS not only leads to anomalies of the foetus, but also of the placenta. The inability of placental cells to develop properly is associated with a decrease of trophoblastic products. If this differential expression is traceable in maternal blood these products could have potential as new screening markers. Several markers have been investigated and found to be potentially useful as predictors of DS. One of those markers is placental protein 13 (PP13) which was found to be decreased in DS pregnancies. Moreover, serum concentrations of a disintegrin and metalloprotease 12 (ADAM12) and placental growth factor (PlGF) are decreased, while total hCG (thCG) is increased in first-trimester DS pregnancies. However, the addition of these markers to the current first-trimester combined test only slightly increases the DR. Therefore, a dedicated search for more markers was set up. An extensive review of the literature was carried out to study normal placental development and function during early pregnancy. Furthermore, a bioinformatics approach was developed using data from the literature on genes and protein expression. This way, a list of potential DS screening markers was generated. The list included three biomarkers that are already used for DS screening and several others, among which PP13 and PlGF. A more experimental approach was carried out by analyzing 90 different proteins from a pre-existing immunoassay. By comparing the protein concentrations in a small cohort of DS and control sera, seven potential screening markers were identified. To confirm the predictive value of these seven markers a subsequent validation study was carried out. Epidermal growth factor (EGF) and EN-RAGE were confirmed to be potential screening markers for DS and improved the DR of the current first-trimester combined test with approximately 6%. In addition, Cancer Antigen 19-9 (CA19-9), was found to be strongly predictive for DS and even further increased the DR. It turned out that the predictive power of serum markers differs within the first trimester. Therefore, it would be useful to draw two separate blood samples and analyze several markers to increase the DR of first-trimester screening to almost 90%. If such a screening test is to be developed, simultaneous assessment of markers is crucial and demands innovation of the test, i.e. by using Antibody microarrays.
... This demonstrates that the method used is able to identify relevant DS screening biomarkers. In addition, the list contains several other proteins which have been examined for their potential as DS screening biomarkers by several research groups, such as the inhibin chains INHA and INHBA [24]–[27], the (protein-identical) placental lactogen genes CSH1 and CSH2 [28], placental growth hormone (GH2) [29]–[31], placental growth factor (PGF) [32], IGFBP1 [30], or PP13 (LGALS13) [33]. For five of these proteins (INHA, CSH1, CSH2, GH2, PGF), significant differences in concentration exist between DS and euploid pregnancies, and therefore these can be used as a biomarker in DS screening. ...
To facilitate the experimental search for novel maternal serum biomarkers in prenatal Down Syndrome screening, we aimed to create a set of candidate biomarkers using a data mining approach.
Because current screening markers are derived from either fetal liver or placental trophoblasts, we reasoned that new biomarkers can primarily be found to be derived from these two tissues. By applying a three-stage filtering strategy on publicly available data from different sources, we identified 49 potential blood-detectable protein biomarkers. Our set contains three biomarkers that are currently widely used in either first- or second-trimester screening (AFP, PAPP-A and fbeta-hCG), as well as ten other proteins that are or have been examined as prenatal serum markers. This supports the effectiveness of our strategy and indicates the set contains other markers potentially applicable for screening.
We anticipate the set will help support further experimental studies for the identification of new Down Syndrome screening markers in maternal blood.
... *P , 0.05, **P , 0.001, ***P , 0.001 versus healthy controls and threatened abortion with ongoing pregnancy. (Lambert-Messerlian et al., 1998), suggesting that increased a subunit expression is one of the mechanisms leading to increased levels of inhibin A in serum. Indeed, during the second trimester of gestation, inhibin A levels were significantly elevated in maternal serum of women carrying a Down's syndrome pregnancy (Van Lith et al., 1992;Spencer et al., 1993;Cuckle et al., 1994), even in the presence of unchanged inhibin B (Wallace et al., 1998a,b) and activin A levels , at least between 16 and 19 weeks of gestation. ...
A great deal of new information has arisen in the recent years concerning inhibin physiology and clinical relevance in reproductive medicine. It is now recognized that the two inhibin isoforms, named inhibin A and inhibin B, are produced by the gonads in the course of gamete maturation and in women have a different pattern of secretion throughout the menstrual cycle. Since inhibins are also produced by placenta and fetal membranes, it has been suggested that there is an involvement in physiological adaptation of pregnancy. Evidence from several sources has underlined the clinical usefulness of the measurement of inhibin-related proteins in the diagnosis and follow-up of different fertility disturbances and early pregnancy viability. In the male, inhibin B is produced in the testis, principally by the Sertoli cells. Inhibin B expression and secretion are positively correlated with Sertoli cell function, sperm number, and spermatogenic status and are negatively correlated with FSH. This review covers the most recent advances on the role of inhibins in human reproductive function. Considerable progress in the understanding of inhibin physiology has resulted from selective measurement of the two inhibin molecular forms, named inhibin A and B. Newly recognized alterations of inhibin levels in gynaecological diseases as well as in normal and pathological pregnancy are discussed, with particular emphasis on the potential clinical usefulness of assessing inhibin levels in serum and other biological fluids.
... Similarly, while an early report suggested that immunoreactive inhibin levels fell more rapidly than hCG following treatment of gestational trophoblastic disease (Yohkaichiya et al., 1989), offering the potential for inhibin to replace hCG in this setting, it became apparent subsequently that some cases of persistent or recurrent tumour detected by rising hCG may be missed by inhibin (Badonnel et al., 1994). Activin A has also been assessed as a marker of trophoblastic disease and similarly found wanting (Lambert-Messerlian et al., 1998). ...
... While subsequent studies were less promising Cuckle, 1994;Wallace et al., 1994), it was suggested that specific inhibin isoforms may be altered in pregnancies with a Down's syndrome fetus while other inhibins may not (Wallace et al., 1994). Indeed, the development of the specific inhibin assays has confirmed this, showing that while inhibin A is significantly elevated almost two-fold in association with Down's syndrome, pro-αC is less discriminatory (Cuckle et al., 1995;Wallace et al., 1996;D'Antona et al., 1998b;Lambert-Messerlian et al., 1998). Accordingly, the addition of inhibin A to existing second trimester maternal serum marker combinations increases the detection rate by 10 -15% (Aitken et al., 1996;Cuckle et al., 1996) such that inhibin A is now widely used in preferred marker combinations (Wenstrom et al., 1997). ...
... Diagnosis of Down's syndromeWallace et al. (1995Wallace et al. ( , 1998) have demonstrated that inhibin A levels in maternal serum are elevated in women carrying a child with Down's syndrome, whereas the levels of pro-a C and inhibin B are not. The levels of these proteins in amniotic ¯uid were also elevated (Wallace et al., 1997b) and the levels of a and b A mRNAs expression were also increased in the placentae of Down's syndrome pregnancies (Lambert-Messerlian et al., 1998). These observations added to earlier data obtained using assays directed to the inhibin a-subunit (Van Lith et al., 1992;Spencer et al., 1993;Cuckle et al., 1994) which suggested that inhibin measurements could contribute additional diagnostic speci®city to the existing components of the triple test (a-fetoprotein, unconjugated estriol and b-hCG), increasing the predictive value to 77%. ...
The regulation of reproductive processes involves a complex network of communication systems between the brain, endocrine organs, the gonads and other reproductive tissues. Classically, our understanding has focused on the role of endocrine hormones, but more recently interest has also dwelt on the paracrine and autocrine regulation of these cell systems. In this review, the structure and physiology of the inhibins, activins and follistatin are discussed in terms of the evidence supporting their role as endocrine hormones, and how they might function as paracrine factors within the pituitary, gonad and associated tissues. With the advent of more specific techniques and assays for their measurement, the potential of inhibins, activins and follistatin as clinical markers of reproductive function and in the screening of various pathologies is also evaluated.
Inhibin hormone is synthesize and secreted by granulosa and theca cells of ovary having glycoprotein in nature. Inhibin is effectively important for the control of reproductive functions in mammalians. It also produced during pregnancy in females from different foetal structure whereas it is secreted from sertoli cells of testis in males. In cattle and goats FSH and inhibin A were found to be inversely correlated, highlighting the crucial role of dominant follicle-produced inhibin in bringing the FSH transitory peaks to an end. FSH and Inhibin have an inverse correlation whereas; inhibin and estradiol-17 are positively correlated in the plasma of the animals. Plasma levels of Inhibin B are now known to be a non-invasive diagnostic tool to measure the amount of spermatogenesis. Clinical applications of inhibin for induction of fertility, inhibin inhibits FSH concentration via directly acts on pituitary gonadotrophs and thus offer offers potential for increased fertility. Guo et al. (2020) reported that immunisation against inhibin, increases the frequency of ovulations that can increase either in-vivo or in-vitro fertility in dairy cows. Ma et al. (2021) performed meta-analysis and quality evaluation techniques for evaluation of fertility in cattle immunised with inhibin. Superovulation technology in cattle is more effective and labor-saving because to inhibin immunity. The ability to maximise the number of ovarian developing follicles (Superovulation response) depends on the methods employed to induce superovulation in cattle. Introduction In India livestock plays an important role in production and economy development. For continue production and maintain the biology of livings, reproduction is essential tool and complex process depends on the various factors such as environmental factors and physical status of animals that are properly timed and supported by hormones. Hormones secreted from endocrine system work other hormones of the body system to regulate reproduction cycle in domestic animals (Bhardwaj et al., 2012) [5]. Inhibin is important hormone for the control of reproductive functions in animals. It was first introduced by D. Roy McCullagh in 1932 via isolation as peptides from gonads and considered as the main regulator of reproduction (Makanji et al., 2014) [26]. Inhibin also produced during pregnancy in females from different foetal structure. The Molecular weight of inhibin is 32 kDa molecule composed of two active heterodimers subunits forms in circulation with 134 amino acid and 116 amino acids residue designated as inhibin A which is made up by α (alpha) with βA subunits and inhibin B, which is made by an α with βB subunit. By modulating FSH biosynthesis, inhibin plays a crucial role in the negative feedback regulation of pituitary gonadotropin hormones secretion. This is done by either reducing steady-state FSH m-RNA in pituitary gonadotropins or decreasing the stability of FSH m-RNA.
Pregnancy is a complex, irreversible dynamic process in which there are dramatic changes in the mother for accommodating embryo implantation and nourishing its growth [1]. During pregnancy, both the mother and the fetus are at some uncertain risk. Many complications related to gestation include preeclampsia, ectopic pregnancy, and placental abruption, leading to the mortality and morbidity of the mother and the fetus [2]. Moreover, the vast majority of birth defects or genetic disorders are largely incurable and can be a heavy burden for the family and the society. For this reason, regardless of risk, all pregnant women should undergo prenatal genetic testing to predict and reduce pregnancy-related complications and birth defects.
Even before a woman becomes pregnant, the parents-to-be wonder about the health of their future child. This natural concern is why prenatal screening for fetal disorders has attracted considerable attention over the past two decades or more. The interest is both professional and personal. The promise of foretelling the health of the developing baby puts new demands on laboratorians, clinicians, and patients alike. Laboratorians must be fully cognizant of the clinical implications of their screening service, clinicians must liaise with laboratories to provide accurate clinical information, and patients face new choices in the information that they can now receive about their pregnancy.
Background:
Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life.Non-invasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing.Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have.
Objectives:
To estimate and compare the accuracy of first trimester ultrasound markers alone, and in combination with first trimester serum tests for the detection of Down's syndrome.
Search methods:
We carried out extensive literature searches including MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), and The Database of Abstracts of Reviews of Effects (the Cochrane Library 2011, Issue 7). We checked reference lists and published review articles for additional potentially relevant studies.
Selection criteria:
Studies evaluating tests of first trimester ultrasound screening, alone or in combination with first trimester serum tests (up to 14 weeks' gestation) for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection.
Data collection and analysis:
Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses.
Main results:
We included 126 studies (152 publications) involving 1,604,040 fetuses (including 8454 Down's syndrome cases). Studies were generally good quality, although differential verification was common with invasive testing of only high-risk pregnancies. Sixty test combinations were evaluated formed from combinations of 11 different ultrasound markers (nuchal translucency (NT), nasal bone, ductus venosus Doppler, maxillary bone length, fetal heart rate, aberrant right subclavian artery, frontomaxillary facial angle, presence of mitral gap, tricuspid regurgitation, tricuspid blood flow and iliac angle 90 degrees); 12 serum tests (inhibin A, alpha-fetoprotein (AFP), free beta human chorionic gonadotrophin (ßhCG), total hCG, pregnancy-associated plasma protein A (PAPP-A), unconjugated oestriol (uE3), disintegrin and metalloprotease 12 (ADAM 12), placental growth factor (PlGF), placental growth hormone (PGH), invasive trophoblast antigen (ITA) (synonymous with hyperglycosylated hCG), growth hormone binding protein (GHBP) and placental protein 13 (PP13)); and maternal age. The most frequently evaluated serum markers in combination with ultrasound markers were PAPP-A and free ßhCG.Comparisons of the 10 most frequently evaluated test strategies showed that a combined NT, PAPP-A, free ßhCG and maternal age test strategy significantly outperformed ultrasound markers alone (with or without maternal age) except nasal bone, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). In both direct and indirect comparisons, the combined NT, PAPP-A, free ßhCG and maternal age test strategy showed superior diagnostic accuracy to an NT and maternal age test strategy (P < 0.0001). Based on the indirect comparison of all available studies for the two tests, the sensitivity (95% confidence interval) estimated at a 5% FPR for the combined NT, PAPP-A, free ßhCG and maternal age test strategy (69 studies; 1,173,853 fetuses including 6010 with Down's syndrome) was 87% (86 to 89) and for the NT and maternal age test strategy (50 studies; 530,874 fetuses including 2701 Down's syndrome pregnancies) was 71% (66 to 75). Combinations of NT with other ultrasound markers, PAPP-A and free ßhCG were evaluated in one or two studies and showed sensitivities of more than 90% and specificities of more than 95%.High-risk populations (defined before screening was done, mainly due to advanced maternal age of 35 years or more, or previous pregnancies affected with Down's syndrome) showed lower detection rates compared to routine screening populations at a 5% FPR. Women who miscarried in the over 35 group were more likely to have been offered an invasive test to verify a negative screening results, whereas those under 35 were usually not offered invasive testing for a negative screening result. Pregnancy loss in women under 35 therefore leads to under-ascertainment of screening results, potentially missing a proportion of affected pregnancies and affecting test sensitivity. Conversely, for the NT, PAPP-A, free ßhCG and maternal age test strategy, detection rates and false positive rates increased with maternal age in the five studies that provided data separately for the subset of women aged 35 years or more.
Authors' conclusions:
Test strategies that combine ultrasound markers with serum markers, especially PAPP-A and free ßhCG, and maternal age were significantly better than those involving only ultrasound markers (with or without maternal age) except nasal bone. They detect about nine out of 10 Down's affected pregnancies for a fixed 5% FPR. Although the absence of nasal bone appeared to have a high diagnostic accuracy, only five out of 10 affected Down's pregnancies were detected at a 1% FPR.
Background:
Down's syndrome occurs when a person has three copies of chromosome 21 (or the specific area of chromosome 21 implicated in causing Down's syndrome) rather than two. It is the commonest congenital cause of mental disability. Non-invasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal) and false negative screening tests (i.e. a fetus with Down's syndrome will be missed). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have.
Objectives:
To estimate and compare the accuracy of first and second trimester serum markers with and without first trimester ultrasound markers for the detection of Down's syndrome in the antenatal period, as combinations of markers.
Search methods:
We conducted a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), the Database of Abstracts of Reviews of Effectiveness (the Cochrane Library 25 August 2011), MEDION (25 August 2011), the Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), the National Research Register (Archived 2007), and Health Services Research Projects in Progress database (25 August 2011). We did not apply a diagnostic test search filter. We did forward citation searching in ISI citation indices, Google Scholar and PubMed 'related articles'. We also searched reference lists of retrieved articles SELECTION CRITERIA: Studies evaluating tests of combining first and second trimester maternal serum markers in women up to 24 weeks of gestation for Down's syndrome, with or without first trimester ultrasound markers, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection.
Data collection and analysis:
Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses.
Main results:
Twenty-two studies (reported in 25 publications) involving 228,615 pregnancies (including 1067 with Down's syndrome) were included. Studies were generally high quality, although differential verification was common with invasive testing of only high risk pregnancies. Ten studies made direct comparisons between tests. Thirty-two different test combinations were evaluated formed from combinations of eight different tests and maternal age; first trimester nuchal translucency (NT) and the serum markers AFP, uE3, total hCG, free βhCG, Inhibin A, PAPP-A and ADAM 12. We looked at tests combining first and second trimester markers with or without ultrasound as complete tests, and we also examined stepwise and contingent strategies.Meta-analysis of the six most frequently evaluated test combinations showed that a test strategy involving maternal age and a combination of first trimester NT and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A significantly outperformed other test combinations that involved only one serum marker or NT in the first trimester, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate. However, the evidence was limited in terms of the number of studies evaluating this strategy, and we therefore cannot recommend one single screening strategy.
Authors' conclusions:
Tests involving first trimester ultrasound with first and second trimester serum markers in combination with maternal age are significantly better than those without ultrasound, or those evaluating first trimester ultrasound in combination with second trimester serum markers, without first trimester serum markers. We cannot make recommendations about a specific strategy on the basis of the small number of studies available.
