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.
NA Bersinger, N Groome and S Muttukrishna
C Bearfield, E Jauniaux, N Groome, I L Sargent and S Muttukrishna
Objective: The objectives of this study were to investigate the effect of activin A and follistatin on first-trimester cytotrophoblast invasion in culture and to study the secretion of inhibin A, activin A and follistatin by these cells in vitro.
Design and methods: Cytotrophoblasts were isolated from human placental chorionic villous tissue obtained from 6–8, 8–10 and 10–12 weeks gestation. Cells were cultured for 3 days on cell-culture inserts coated with gelatine for invasion studies and in 24-well culture plates for secretion studies. The effects of activin A (10 ng/ml), follistatin (100 ng/ml), interleukin 1β (IL-1β; 10 ng/ml) and epidermal growth factor (EGF; 10 ng/ml) on cytotrophoblast invasion were investigated using a non-radioactive invasion assay. Secretion of inhibin A, activin A and follistatin in the presence of EGF, IL-1β, activin A and follistatin were measured using in-house ELISAs.
Results and conclusion: Activin A, follistatin and EGF had a significant stimulatory effect on cytotrophoblast invasion from 6–10 weeks gestation. IL-1β had a significant stimulatory effect at 8–10 weeks and a significant inhibitory effect on invasion at 10–12 weeks gestation. Follistatin also had a significant inhibitory effect on invasion at 10–12 weeks gestation. In the secretion study, activin A secretion at 8–10 weeks was significantly stimulated by IL-1β and EGF. At 10–12 weeks, follistatin and EGF had a significant inhibitory effect on activin A secretion. Follistatin secretion was significantly increased in the presence of IL-1β at 6–8 weeks gestation. Inhibin A secretion was not significantly altered by EGF, IL-1β, activin A and follistatin. These results show that activin A promotes invasion of first-trimester cytotrophoblasts until 10 weeks gestation. There is a difference in the control of secretion of these proteins dependent on the gestation, suggesting that there is a tight regulation in the function of first-trimester trophoblasts depending on the gestational age.
S Muttukrishna, A Farouk, S Sharma, L Evans, N Groome, W Ledger and M Sathanandan
OBJECTIVE: Inhibin, activin and follistatin are glycoprotein hormones produced by the gonads. Recent studies have shown that inhibin B is the predominant form of inhibin in the circulation in men. The objective of this study was to investigate circulating levels of activin A and follistatin in disorders of spermatogenesis in men and their relationship with FSH and inhibin B. DESIGN AND METHOD: Serum from five different groups of men was prospectively collected and stored at -20 degrees C. The groups were men with: (i) proven fertility (controls) (n=20), (ii) primary testicular failure (n=15), (iii) obstructive azoospermia (n=10), (iv) oligospermia (n=10) and (v) miscellaneous sperm dysfunction (n=40). WHO criteria (1992) were used for semen characterisation. Serum concentrations of 'total' activin A, follistatin, FSH and inhibin B were measured using specific two-site enzyme immunoassays. RESULTS: Activin A levels were significantly lower than in the controls in the obstructive azoospermia group and higher in the miscellaneous sperm dysfunction group. Serum follistatin levels did not significantly vary in any group compared with the controls. Circulating levels of FSH were higher than in the controls in the primary testicular failure and obstructive azoospermic group. Levels of inhibin B were lower than in the controls in all disorders of spermatogenesis studied. CONCLUSION: This study demonstrates that activin A and follistatin are in the circulation in males and activin A levels are significantly lower in obstructive azoospermia and higher in miscellaneous sperm dysfunction than in controls. The mechanism involved in altering the levels of activin A in these conditions is not clear. However, high follistatin:activin A molar ratios (>2.5) in all groups suggests that all activin A in the circulation is bound to follistatin in males.