Studies on the Mechanism of the Plasma 17-Hydroxycorticosteroid Elevation Induced in Man by Estrogens*

Abstract

The administration of estrogens to man produces sustained elevation above normal levels of plasma (1, 2). The elevated levels of plasma 17-OHCS are associated with an augmented response of plasma levels of these steroids to exogenous adrenocorticotropic hormone (ACTH) and with a marked delay in the rate of clearance of exogenous cortisol from plasma (2). The last trimester of pregnancy is associated with similar changes in levels of plasma 17-OHCS and in their response to exogenous ACTH (3-9). In the last trimester of pregnancy there is a variable increase in urinary 17-OHCS excretion, a decrease in the rate of clearance of exogenous cortisol from plasma (9-11), a decrease in the rate of clearance of exogenous tetrahydrocortisone from plasma (11) and an increase in corticosteroid-binding protein (12). The apparently normal adrenal status of pregnant women and of patients treated with estrogens for long periods of time suggests that the administration of estrogens to man elevates plasma 17-OHCS levels by altering the normal metabolism of endogenous cortisol by a mechanism similar to that seen in pregnancy. Studies have been made of urinary 17-OHCS excretion, of clearance of tetrahydrocortisone from plasma, and of plasma corticosteroid-binding protein after the administration of estrogens to man. MATERIALS AND METHODSThe patients studied were primarily adult females ranging in age from 37 to 75 years, all of whom either had been surgically castrated or were at least 3 years past a spontaneous menopause. A number of these subjects were patients with metastatic carcinoma of the * This work was supported in part by a research grant from The National Cancer Institute, Bethesda, Md. breast. One male was studied during recovery from a myocardial infarction.After appropriate control studies, the patients were treated for periods of 2 weeks to 6 months with either oral ethinyl estradiol (Estinyl), diethylstilbestrol or conjugated equine estrogens (Premarin). Only doses of these preparations which uniformly elevated plasma 17-OHCS levels above normal were used in the studies (Table I). Ethinyl estradiol 0.1 and 0.5 mg, diethylstilbestrol 15 mg, and Premarin 10 mg, daily by mouth, all caused significant increases in the levels of plasma 17-OHCS.The effect of oral ethinyl estradiol, 0.5 mg daily, on urinary excretion of free and total 17-OHCS and of 17-ketosteroids was studied. Twenty-four hour urinary excretion of steroids was determined in each patient before estrogen therapy and again after plasma 17-OHCS

Transcortin: A Corticosteroid-Binding Protein of Plasma. Iii. The Effects of Various Steroids *†

“…These observations are borne out by some of the data presented in this paper and by previous observations (1)(2)(3). In addition, recently published data (3,11,12) substantiate the hypothesis advanced by us (1,2) that the changes in cortisol metabolism seen during estrogen administration are due to changes in the plasma levels of transcortin.…”

“…In addition, recently published data (3,11,12) substantiate the hypothesis advanced by us (1,2) that the changes in cortisol metabolism seen during estrogen administration are due to changes in the plasma levels of transcortin.…”

“…In addition, we have shown that plasmiia transcortin levels are elevated during pregnancy and following administration of estrogens (1)(2)(3). A different interpretation of the findings in these two states has been given by Daughaday and AMariz (4,5).…”

Inhibition by Estrogen Administration of Adrenal-Pituitary Response to Methopyrapone*

“…%4ETHOPYRAPO (14). This elevated level of plasma corticoids depends on an increased plasma level of transcortin (4,5). These elevated plasma 17-hydroxycorticoids were presumed to be biologically inactive because estrogen-treated patients presented none of the clinical features of Cushing's syndrome, because with these high plasma levels there was no increase in the glucosuria in diabetic patients (1), and finally, because, by the demonstration of Slaunwhite, Lockie, Back, and Sandberg (15), addition of transcortin to an ini vivo system blocks cortisone effect.…”

“…The glucosuric effect of exogenous hydrocortisone was much greater when ethinyl estradiol (EE) was administered together with the steroid, while a potentiating effect was not clearly demonstrated with a number of 1,2-unsaturated steroids. Estrogen therapy has been shown to increase the plasma levels of 17-hydroxycorticoids (2,3) owing to an increase in the levels of transcortin (CBG, corticosteroid-binding globulin) (4,5), but such a change does not occur in urinary corticoids, which may show a decrease (6).…”