The effects of estradiol and estriol on plasma levels of cortisol and thyroid hormone-binding globulins and on aldosterone and cortisol secretion rates in man.

The effects of estriol and estradiol on the plasma levels of cortisol- and thyroxine-binding globulin activity, and on the secretion rates of aldosterone and cortisol were studied in man. The metabolite estriol had no consistent or significant influence on plasma levels of the hormone-binding globulin activities; the hormone estradiol increased these binding capacities significantly, as expected. Cortisol secretion rate rose slightly after estriol but was unchanged after estradiol. Both compounds induced substantial increases in the aldosterone secretion rate of most treated subjects. The mechanism of this apparently paradoxical effect of estrogens is not clear; it is suggested that the "salt-retaining" action of estrogens is mediated in part by the rapid enhancement of aldosterone output which follows their administration in man. Balance experiments in four subjects suggest that both estradiol and estriol may induce a transient early natriuresis in man; but other mechanisms for estrogen stimulation of aldosterone secretion may be operative as well.

Parotid fluid cortisol and cortisone.

Parotid fluid corticosteroids, substantially comprised of cortisol and cortisone, were previously demonstrated to rise to far greater levels 4 hr after administration of ACTH than they did in the third trimester of pregnancy, although the plasma total corticosteroid concentrations were similar in these two states. It was therefore suggested that only nonproteinbound corticosteroid gains access to parotid fluid. In the present study parotid fluid cortisol and cortisone and plasma dialyzable cortisol concentrations have been measured in normal men before and 2 hr after 40 U ACTH, and, in another group, before and after 10 days of diethystilbestrol (5 mg daily). Total plasma cortisol rose from a mean of 6.3 to 17.9 mug/100 ml after ACTH and from 14.6 to 39.4 mg/100 ml after the estrogen. However parotid fluid cortisol plus cortisone rose from 0.8 to 2.6 mug/100 ml after ACTH and to only 2.2 after estrogen. This rise resembled that of the plasma dialyzable cortisol (control 0.4, ACTH 1.8, estrogen 1.2 mug/100 ml) rather than the increase in total plasma cortisol which was over twice as high after estrogen as after ACTH. Thus parotid fluid corticosteroids seem to be a good measure of nonprotein-bound corticosteroid, the cortisol available to the cell. The total amount of cortisol plus cortisone excreted is approximately constant, independent of parotid fluid flow rate. Cortisone exceeds cortisol in parotid fluid in the basal state, but after ACTH the situation is reversed.

Primary hypothyroidism and pituitary enlargement. Radiological evidence of pituitary regression.

A patient with primary hypothyroidism and pituitary gland enlargement was studies extensively before and after replacement therapy with levothyroxine sodium. She had evidence of bulging of the diaphragma sellae and increased serum prolactin levels. Thyroid replacement therapy resulted in regression of the pituitary size, as shown on pneumoencephalogram, but mildly elevated serum prolactin levels persisted.

Hyporeninemia and hypoaldosteronism in diabetes mellitus.

The changes in plasma renin activity (PRA) and plasma aldosterone concentration (PA) in response to postural stimuli were evaluated in 12 patients with stable diabetes mellitus and in five volunteers. Seven diabetic patients had hyperkalemia, and several had renal insufficiency and neurological complications. Five diabetics and had normal serum potassium concentration, a mean creatinine clearance within the normal range, and few complications. PRA and PA were measured in these patients and in the control subjects, all of whom were receiving a diet containing 10 mEq of sodium and 50 mEq of potassium while they were in a supine position, after they were tilted to a 90 degrees position, and after upright posture for two hours. The results indicate that impaired responsiveness of PRA and PA may occur in patients with complicated and those with uncomplicated diabetes and may be responsible in part for a relatively high prevalence of hyperkalemia especially in those diabetic patients with reduced renal function.

Effects of diphenylhydantoin, phenobarbital, and diazepam on the metabolism of methylprednisolone and its sodium succinate.

The metabolic clearance rates (MCR) of methylprednisolone (MP) (no. = 13) and methylprednisolone-21- Na-hemisuccinate (MPHS) (no. = 6) were studied in normal humans using tritium-labeled steroids. The cumulative appearance of the labeled steroid was examined for the whole urine and for three major urinary fractions. The MCR, half-life, and volume of distribution were, respectively, 383 +/- 72 (SD) liters/day, 165 +/- 49 minutes, and 61 +/- 12 liters for MP, and 234 +/- 37, 160 +/- 19, and 41 +/- 6 for MPHS. Diphenylhydantoin (DPH) administered to 4 subjects increased the MCR of MP from 424 +/- 71 to 977 +/- 132 (P less than 0.01), and decreased the half-life from 149 +/- 44 to 69 +/- 7 (P less than 0.001). Similar effects were found with phenobarbital (PB). Diazepam (DZP) had no effect. Major increases in urinary metabolites after DPH and PB were in the unconjugated ethyl acetate fraction, and this suggests that MP metabolism is significantly altered by hepatic microsomal hydroxylation enzyme induction by DHP and PB, but not DZP. This could occur with the formation of a 6beta-hydroxy derivative which could be readily cleared by the kidney. The urinary pattern of excretion for MPHS was similar to that of MP. The MCR of MPHS was affected to a lesser extent by DPH and PB than was the MCR of MP(P less than 0.01). Therefore, the use of hepatic microsomal hydroxylase inducers should be taken into consideration in clinical states in which MP is being used.

Effects of levodopa on the renin-aldosterone system.

Plasma renin activity and plasma aldosterone, supine and erect, and urinary aldosterone levels were measured in 18 patients on normal sodium diets and 11 patients on low sodium diets, all of whom also were on long-term levodopa therapy. Of the 230 hormone measurements, 185 were normal, 11 were high, and 34 were low. Most of the low levels were in 3 patients who had recently received fludrocortisone for orthostatic hypotension, and the renin-aldosterone systems might have been suppressed by it. In another phase of this study, 4 subjects were maintained on a constant diet for 6 wk, while the effect of gradually increasing dosages of levodopa on mineral balance and renin-aldosterone was determined. In 3 of the 4 patients there was a mild natriuretic effect of levodopa (previously demonstrated for acute levodopa therapy). There were no significant consistent changes in renin or aldosterone levels while levodopa was being administered. These studies indicate that levodopa does not usually suppress the elements of the renin-aldosterone system and that such a mechanism is unlikely to be the cause of orthostatic hypotension during the course of levodopa therapy. Since levodopa may induce natriuresis, in this situation unchanged lvels of renin and aldosterone may, however, represent an inappropriately low set of this hormonal system.

"Masked" 21-hydroxylase deficiency of the adrenal presenting with gynecomastia and bilateral testicular masses.

An infertile 27 year old man with precocious puberty is described. He presented in adulthood with unilateral and then bilateral gynecomastia, and subsequently testicular tumors developed. An early diagnosis of congenital adrenal hyperplasia would have avoided unnecessary surgery. Initial detailed metabolic evaluation led to the erroneous diagnosis of 11-hydroxylase deficiency because of the presence of an unusual steroid (21-desoxycortisol) in serum which was falsely reported as an increased 11-desoxycortisol (compound S). The observed low urinary pregnanetriol measurements would have supported this diagnosis. Subsequent specific measurements of 21-desoxycortisol established its presence in the serum and its major metabolite, tetrahydro-21-desoxycortisol, in the urine. The unique features in this case of 21-hydroxylase deficiency alert the physician to its unusual clinical presentation and the pitfalls that may be encountered when evaluating adrenal steroidogenesis.

Diabetic muscle infarction: a new perspective on pathogenesis and management.

Two patients with insulin dependent diabetes mellitus developed recurrent episodes of focal muscle pain and swelling. Clinical evaluation, magnetic resonance imaging (MRI) and muscle biopsy confirmed the diagnosis of recurrent hemorrhagic muscle infarctions. Our studies suggest that muscle infarction occurred because of hypercoagulability and associated vascular endothelial damage. Based on these findings we recommend long-term anticoagulation to prevent recurrent infarction.