Amniotic fluid levels of dimeric inhibins, pro-alpha C inhibin, activin A and follistatin in Down's syndrome.

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.

Clinical follow-up of high mid-trimester maternal serum intact human chorionic gonadotrophin concentrations in singleton pregnancies.

Mid-trimester biochemical screening of 38 143 pregnancies in south-east Scotland revealed 127 cases (0.34 per cent) in which the maternal serum (MS) intact human chorionic gonadotrophin (hCG) concentration was > or = 4 multiples of the median in singleton pregnancies (MOM). Three were lost to follow-up but in 72 (58 per cent) complications developed or there were associated fetal abnormalities. This percentage was greatest at very high hCG concentrations, 92 per cent with hCG > or = 10 MOM (n = 12) compared with 48 per cent with hCG concentrations of 4-4.99 MOM (n=69). 22 cases had an MS alpha-fetoprotein > or = 2 MOM in addition to an MS hCG > or = 4 MOM, and in only 3 of these was the pregnancy uneventful; 86 per cent were associated with abnormalities or pregnancy complications.

Inhibin A and pro-alpha C inhibin in Down syndrome and normal pregnancies.

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.

Systemic effects of high dose inhaled steroids: comparison of beclomethasone dipropionate and budesonide in healthy subjects.

BACKGROUND: Systemic absorption of inhaled corticosteroids may adversely influence the function of the hypothalamo-pituitary-adrenal axis, bone metabolism, and circulating leucocytes. These changes can be used to assess the safety of different types and modes of administration of these drugs. METHODS: The study was a randomised, double dummy, crossover design with nine healthy adults. It compared the effects of beclomethasone dipropionate and budesonide (given by metered dose aerosols with and without their respective large volume spacers (Volumatic and Nebuhaler) attached) on serum cortisol, 24 hour urinary free cortisol, and plasma osteocalcin concentrations, and circulating neutrophils and lymphocytes. Subjects inhaled the drug (1 mg) and matching placebo at 0900 and 2200 hours on each of six study days. Blood samples were taken hourly for six hours after the morning dose and at the end of the study period. RESULTS: All results were within the reference ranges. Both drugs caused similar reductions in serum cortisol four to six hours after inhalation. These changes were not affected by the use of a large spacer and did not persist at 24 hours. Use of spacers tended to increase the haematological effects of the steroids. Beclomethasone dipropionate inhaled through a Volumatic provoked a rise in circulating neutrophils compared with placebo although lymphocyte numbers were unaffected. Budesonide did not influence neutrophil numbers but did reduce circulating lymphocytes, numbers of which were further reduced when the Nebuhaler was used. There were no significant changes in plasma osteocalcin concentration or 24 hour urinary free cortisol excretion with budesonide, with or without a spacer. Beclomethasone dipropionate inhaled without a spacer reduced urinary cortisol and plasma osteocalcin at 24 hours; however, use of the Volumatic protected against these effects. CONCLUSIONS: Attaching a Volumatic reduces the systemic effects of 2 mg aerosol beclomethasone dipropionate on the hypothalamo-pituitary-adrenal axis and circulating osteocalcin concentrations. This study did not establish whether the Nebuhaler reduces the systemic effects of budesonide. When large spacers are used, 2 mg per day of beclomethasone dipropionate and budesonide seem to be equivalent in terms of unwanted effects.

Suppression of plasma intact parathyroid hormone levels during insulin-induced hypoglycemia in humans.

The adrenergic control of intact PTH secretion was investigated by measuring its plasma concentration during insulin-induced hypoglycemia in normal human subjects under control conditions (n = 12) and after alpha (n = 5)- or beta (n = 6)-adrenoceptor blockade. Blood samples were taken at baseline, at the time of the acute hypoglycemic reaction, and at regular intervals for 60 min thereafter. Plasma concentrations of intact PTH, catecholamines, total calcium, magnesium, albumin, phosphate, and glucose were measured in all subjects, and plasma ionized calcium was also assayed in three subjects during acute hypoglycemia without pharmacological blockade. At the time of the acute hypoglycemic reaction, the plasma concentration of intact PTH in the control subjects fell to 60.8% of baseline values and was accompanied by a small but significant increase in plasma total calcium. Intact PTH concentrations remained suppressed after the plasma calcium concentration had returned to normal. The two groups of subjects who were exposed to adrenoceptor blockade exhibited a reduced fall in plasma intact PTH and showed no significant increase in plasma total calcium. Therefore, insulin-induced acute hypoglycemia was associated with a fall in plasma intact PTH. Adrenoceptor blockade reduced, but did not abolish, the response, suggesting that other factors are involved.

The effects of lithium discontinuation and the non-effect of oral inositol upon thyroid hormones and cortisol in patients with bipolar affective disorder.

Thyroid and adrenal function was assessed in euthymic bipolar patients, stable on prophylactic lithium for at least 1 year, before and after lithium discontinuation in a randomised double-blind placebo-controlled trial. All hormonal measurements were within the reference range, but a significant increase (P less than 0.001) in plasma thyroxine (T4) levels and a decrease (P less than 0.01) in TSH levels were observed 1 month after lithium withdrawal; cortisol concentrations showed a non-significant decrease in the same period. No relationship could be demonstrated between the magnitude of the change in hormone levels and the probability of relapse of manic symptoms. In the second part of this study, inositol was added for 11 days to the diets of bipolar patients being treated with prophylactic lithium and normal controls. No modification was shown in T4 and TSH in either group before or after inositol administration. Inositol did not alleviate other side-effects such as tremor and thirst in the patient group. This result suggests that short-term dietary inositol is not equivalent to lithium withdrawal and is of no value in reducing hormonal and other adverse effects of lithium prophylaxis.

Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man.

1. 11-beta-Hydroxysteroid dehydrogenase is an enzyme complex consisting of 11 beta-dehydrogenase and 11-oxoreductase responsible for the interconversion of cortisol to cortisone in man. Inhibition of 11 beta-dehydrogenase (e.g. after liquorice ingestion) results in cortisol acting as a potent mineralocorticoid. We have evaluated the effect of the synthetic liquorice derivative, carbenoxolone, on this enzyme complex. 2. Carbenoxolone given to six volunteers in metabolic balance produced sodium retention with suppression of the renin-angiotensin-aldosterone system. Plasma potassium fell, although there was no kaliuresis. This was associated with inhibition of 11 beta-dehydrogenase (as measured by a rise in the plasma half-life of [11 alpha-3H]cortisol). Unlike liquorice, however, carbenoxolone also inhibited 11-oxoreductase (as measured by the generation of cortisol after oral cortisone acetate). 3. The mineralocorticoid activity of carbenoxolone, like liquorice, is mediated via cortisol by inhibition of 11 beta-dehydrogenase. Carbenoxolone, however, also inhibits 11-oxoreductase activity and this may relate to its effect on renal potassium excretion.