Eleanor Z. Wallace

STUDIES ON THE MECHANISM OF THE PLASMA 17-HYDROXYCORTICOSTEROID ELEVATION INDUCED IN MAN BY ESTROGENS*

The administration of estrogens to man produces sustained elevation above normal levels of plasma 17-hydroxycorticosteroids (17-OHCS) (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.

Further observations on adrenal cortical function during pregnancy.

Abstract 1. 1. Free plasma hydrocortisone levels are increased in the third trimester of pregnancy. 2. 2. There is an apparent exaggeration of free plasma 17-OH-corticosteroid response to ACTH in the third trimester which disappears by the end of the first week post partum. The excessive response may be partly accounted for by a delay in the clearance of hydrocortisone from plasma in late pregnancy. 3. 3. Free urinary corticoid values are increased in late pregnancy, but the response to ACTH of total urinary corticoids (free plus glucuronides) is no greater than normal. 4. 4. The hypothesis is advanced that there may be in late pregnancy a resistance to the effects of hydrocortisone upon various tissues (e.g., the anterior pituitary), perhaps because some physical factor, as yet unknown, renders a portion of the circulating corticosteroid biologically inert.

Cortisol Binding in Uremic Plasma

We measured cortisol binding to albumin in uremic plasma during a study to see if increased morning plasma free cortisol values, reported previously in chronic renal failure patients, could be explain

A variant of adrenomyeloneuropathy with hypothalamic-pituitary dysfunction and neurologic remission after glucocorticoid replacement therapy

Adrenomyeloneuropathy is a syndrome comprising spastic paraparesis, polyneuropathy, primary adrenocortical insufficiency and variable hypogonadism. We describe a 32 year old man who presented with contractures, peripheral neuropathy, primary adrenocortical insufficiency adn secondary hypogonadism. Abnormal responses of growth hormone, gonadotropins, prolactin and thyrotropin to provocative stimuli were found, without radiographic evidence of a pituitary or hypothalamic lesion. Almost complete recovery from the neurologic abnormalities occurred with glucocorticoid replacement therapy. The clinical features of this patient support a diagnosis of adrenomyeloneuropathy. The hypothalamic-pituitary dysfunction extends the clinical features of this patient support a diagnosis of adrenomyeloneuropathy. The hypothalamic-pituitary dysfunction extends the clinical spectrum of this disease. Remission of the paraparesis coincident with glucocorticoid replacement has not been reported previously.

The effect of intravenously administered hydrocortisone on the urinary 17-ketosteroids in patients with adrenal virilism.

The dramatic decrease in urinary 17-ketosteroids (17-KS) which occurs as a result of the prolonged intramuscular administration of cortisone in patients with congenital adrenal hyperplasia was first shown by Wilkins and his collaborators (1951), and has been amply confirmed (Bartter, Albright, et al., 1951; Jailer, 1951). Hydrocortisone has been shown to be equally effective (Jailer, Louchart, and Cahill, 1952). When these steroids are given intramuscularly, four to five days may elapse before the 17-KS fall to values which are considered approximately normal for the age and sex of the patient. The oral route of administration of the steroids, on the other hand, is not as effective in suppressing the adrenal cortical secretion; consequently, approximately twice the dosage of steroid must be given to achieve a comparable fall in the urinary 17-KS. The mechanism by which cortisone or hydrocortisone exert its effects is presumably by ACTH inhibition and secondary adrenocortical atrophy accompanied by decreased hormonal secretion. That this mechanism is responsible for the fall in urinary 17-KS can be best illustrated by the experiments of Bartter, Albright, and their associates (1951), who have shown that if ACTH and cortisone are given simultaneously, the usual fall in the urinary 17-KS obtained with cortisone alone does not occur. The inhibition of ACTH secretion by these steroids not only occurs in congenital adrenal hyperplasia, but may be found in normal individuals as well, since prolonged administration of cortisone may result in adrenal atrophy and even evidence of adrenal insufficiency (Salassa et al., 1953; Perera and Ragan, 1950). On the other hand, Jailer, Gold, and Cahill (1952); Gardner and Migeon (1951); Jailer, Gold, and Wallace (1954); and others have shown that, when the adrenal virilism is caused by an adrenal tumor, no significant fall in the urinary 17-KS occurs as a result of the cortisone administration. These observations have led to the hypothesis that adrenal neoplasia differs from hyperplasia in that the former is independent of ACTH control and can maintain the steroid output, even when endogenous ACTH secretion is inhibited. Since the “cortisone test” as described above may require almost 10 consecutive days of urine collection, it was hoped that, with the availability of a soluble hydrocortisone preparation suitable for intravenous administration, the test could be shortened to a 24or 48-hour period. Consequently, the following procedure has been adopted: urines were collected in -&-hour periods for 8 to 24 hours before and 16 to 24 hours after the intravenous administration of 50 to 100 mg. of hydrocortisone in glucose and water; the 17-KS were deter-