The kallikrein-kinin system in Bartter's syndrome and its response to prostaglandin synthetase inhibition.

The kallikrein-kinin system was characterized in seven patients with Bartter's syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartter's syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3+/-5.3 (S.E.M.) ng/ml per h to 3.3+/-1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4+/-4.4 ng/ml to 3.9+/-0.9 ng/ml, mean urinary kallikrein excretion from 24.8+/-3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4+/-2.0 TU/day, but increased mean urinary kinin excretion from 3.8+/-1.3 mug/day to 8.5+/-2.5 mug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartter's syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome.

The pituitary-gonadal axis in men with protein-calorie malnutrition.

The pituitary-gonadal axis was studied in 28 men with severe protein-calorie malnutrition in a Calcutta hospital. The men were selected for the severity of their malnutrition and for absence of other diseases. They had clinical findings of hypogonadism and low total and unbound plasma testosterone. During 2-5 months of refeeding there was clinical recovery and increase of plasma testosterone to normal. Plasma LH was high in malnutrition, decreased during refeeding, and remained above normal after refeeding. Some patients failed to show LH elevation in malnutrition despite low plasma tesosterone. Plasma FSH was high in malnutrition, decreased during refeeding, and was near the level of normal Indian men after refeeding. HCG 4000 IU im per day for 3 days produced subnormal increments in plasma testosterone both in malnutrition and after refeeding; corresponding decreases in FSH occurred. It is concluded that the hypogonadism of protein-calorie malnutrition is primarily on the basis of diminished Leydig cell function. Appropriate pituitary LH response is intact in some patients, but is either absent or inadequate in others. Subclinical Leydig cell insufficiency, indicated by LH elevation and subnormal response to HCG, persists after refeeding has produced recovery from malnutrition and clinical hypogonadism. FSH elevation in malnutrition may be secondary to the reduced Leydig cell function.

Subacute thyroiditis in a lateral thyroid gland: evaluation of the pituitary-thyroid axis during the acute destructive and the recovery phases.

Subacute thyroiditis in a lateral, ectopic thyroid has been previously unreported. A 4 10/12-YEAR-OLD GIRL HAD AN ENLARGING MASS IN THE LEFT UPPER ANTERIOR NECK. Initially, the serum concentration of T4 was normal, T3 was elevated, and TSH was undetectable without response to TRH. RAI uptake was 1%. The data were consistent with subacute thyroiditis. Twelve weeks later the serum concentration of T4 was low and TSH was elevated; thyroid replacement therapy was given for 20 weeks. When this was discontinued, there was an initial increase and then a decrease in the TSH values accompanied by an increase in serum concentrations of T3 and T4 to normal during eight weeks. One must consider a lateral ectopic thyroid gland in the differential diagnosis of masses in the neck. Physicians must be aware that temporary hypothyroidism occurs during the course of subacute thyroiditis.

Circulating bound and free estradiol and estrone during normal growth and development and in premature thelarche and isosexual precocity.

Serum concentrations of unconjugated estrone, estradiol, and free estradiol, were determined in normal neonates, prepubertal children, adolescents, and adults. The values were compared with those obtained in children with premature thelarche and female sexual precocity. Unconjugated E1 and E2 fell rapidly, and the percentage of FE2 more gradually during the neonatal period and remained low prepubertally. During adolescence girls had greater increases in E1 and E2 while the percentage of FE2 was higher in boys. In premature thelarche only the FE2 was significantly increased. In sexual precocity E1, E2, and FE2 were elevated. Reference standards are provided in Tables I and II for use in the diagnosis of conditions with under- or overproduction of estrogens during growth and development.

Prostaglandin synthetase inhibitors in Bartter's syndrome. Effect on immunoreactive prostaglandin E excretion.

Urinary excretion of immunoreactive prostaglandin E (iPGE) was measurably increased in five of seven patients with Bartter's syndrome. The effects of indomethacin were compared with those of either aspirin or ibuprofen in four patients. Indomethacin produced notably greater suppression of urinary iPGE, greater sodium and potassium retention, greater increases in serum potassium, and decreases in plasma renin activity and in creatinine clearance than the other inhibitors. This demonstration that there is a close correlation between the suppression of urinary iPGE excretion and the extent of correction of the clinical abnormalities in Bartter's syndrome, regardless of the chemical structure of the prostaglandin synthetase inhibitor, is further evidence for the importance of prostaglandins in the pathogenesis of this syndrome.

Prostaglandins are overproduced by the kidneys and mediate hyperreninemia in Bartter's syndrome.

In summary, the cardinal features of the syndrome of renal juxtaglomerular hyperplasia include overproduction of plasma renin activity, elevation of plasma angiotensin II concentration, elevation of aldosterone secretion and of plasma aldosterone concentration, hypokalemic alkalosis, and a resistance of arterioles to the pressor action of angiotensin II and norepinephrine. In the present studies, elevation of urinary PGE2 but not of PGF2alpha has been demonstrated. Inhibition of prostaglandin synthetase with indomethacin or ibuprofen has been shown to decrease plasma renin activity, and plasma aldosterone concentration and secretion rate, leading to a positive potassium balance and restoration of normal plasma potassium. The inhibitors decreased and glomerular filtration rate, and induced sodium retention. The results indicate that overproduction of PGE by the kidneys is a cardinal feature, but not necessary the primary one, in the pathogenesis of this syndrome.