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The catechol estrogens, the 2- or 4-hydroxylated metabolites of estrone and estradiol, have pharmacologic properties of both estrogens and catecholamines and are formed from estrogens in peripheral tissues and in the brain. This has led to speculation that they may mediate some of the feedback effects of estrogens upon gonadotropins and prolactin (PRL). Studies testing these hypotheses are still few and have not been conclusive. There have been reports that the catechol estrogen 2-hydroxyestrone (2-OHE1) might act as a partial estrogen antagonist, stimulating gonadotropin secretion; and that it might have dopamine-like effects, suppressing the secretion of PRL. In studies testing the chronic and acute effects of catechol estrogens on LH, FSH, and PRL in men and women, we found that they behaved as estrogens, suppressing gonadotropins when given in doses high enough to compensate for their rapid clearance and degradation. We found no evidence that they suppress PRL secretion. The weight of available evidence suggests that these effects are mediated by estrogen receptor interactions; and that the formation of catechol estrogens is not an obligatory step in the feedback effects of estrogens, although it may have a modulatory role. Plasma levels of catechol estrogens are too low for them to exert circulating neuroendocrine effects.

Plasma levels of 2-hydroxyestrone (2-OHE1) and 2-hydroxyestradiol (2-OHE2) were determined by a new radioimmunoassay which employed a short Sephadex LH-20 column chromatography for the purification of samples and the antiserum to 2-hydroxyestrone-17-(O-carboxymethyl)oxime-BSA conjugate for assay. The plasma value was below the detection limit for the assay (approximately 15 pg/ml) in men and non-pregnant women, but rose 20-200 pg/ml during pregnancy in 2-OHE1 and around 15 pg/ml in the 3rd trimester of pregnancy in 2-OHE2. There was no significant difference of plasma 2-OHE1 level between normal pregnancy and toxemic pregnancy with hypertension, in the 3rd trimester. The plasma level was very low in all of three subjects with the placental dysfunction in toxemic pregnancy. The plasma metabolic clearance rate (MRCp) of 2-OHE1 and 2-OHE2 were determined in normal adults by two methods; infusion of unlabeled 2-OHE1 and 2-OHE2 to equilibrium with radioimmunoassay of their plasma levels, and infusion of [3H]-2-OHE1 and [3H]-2-OHE2 to equilibrium with measurement of chromatographically purified their tritium. The MCRs by the former and latter methods was 40-70 X 10(3) and 15-50 X 10(3) in 2-OHE1, and 18-29 X 10(3) and 12-14 X 10(3) l/day in 2-OHE2, respectively. The major plasma metabolite comigrated with 2-methoxy compounds to each catecholestrogen. The t1/2 of disappearance rate by the method of infusion of unlabeled compounds was approx. 45 s in 2-OHE1 and 90 s in 2-OHE2. When [3H]-2-OHE1 and [3H]-2-OHE2 were incubated with blood samples of adults, 2-methoxy compounds also rapidly formed. From these results it is concluded that the extremely high MCRp of 2-OHE1 and 2-OHE2 make it unlikely these compounds circulate peripherally except in pregnancy in levels sufficient to produce the physiological effects on estrogen receptors or catecholamines.

Primary cortisol resistance in man is a familial disease. It is characterized by increased plasma cortisol concentrations, high urinary free cortisol excretion, a normal circadian pattern of cortisol secretion, resistance to adrenal suppression by dexamethasone and absence of clinical stigmata of Cushing's syndrome. In its severe form, hypertension and hypokalemic alkalosis are present, owing to increased secretion of the sodium-retaining corticoids, corticosterone and deoxycorticosterone. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the disease is revealed only by detailed examination of several parameters of cortisol metabolism. In the whole-cell assay (peripheral mononuclear leukocytes or fibroblasts) the glucocorticoid receptor shows a low affinity for dexamethasone. The receptor may be unsaturable as suggested by decreased receptor concentrations in broken-cell systems. Thus, generalized target-tissue resistance to cortisol, including the pituitary gland and the hypothalamus, is accompanied by a decreased negative feedback of the cortisol-ACTH feedback system resulting in increased ACTH secretion. This causes higher plasma cortisol to compensate for the end-organ resistance and also increases the production of adrenal mineralocorticoids, as by-products. Thus hypertension and hypokalemic alkalosis depends on the degree of the resistance. Cortisol resistance in many New World primate species is characterized by greatly increased plasma cortisol concentrations, decreased cortisol binding globulin capacity and affinity, high levels of plasma and urinary free cortisol, marked resistance of ACTH suppression by dexamethasone, and no physiologic evidence of glucocorticoid hormone excess. Target tissues have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone. The New World primates, unlike man, have compensated for this cortisol resistance with intra-adrenal adaptations over the 50 million years of their evolutionary development. These primates also have abnormalities of other steroid hormone-receptor systems such as progesterone, estrogen, androgen and mineralocorticoid. In contrast, the human syndrome appears to be a recent mutation with pathophysiologic consequences.

The metabolic fate of the isomeric catecholestrogens 4-hydroxyestradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2) was studied to elucidate possible differences in their metabolism as an explanation for their different bioactivities. Healthy young men (n = 3 each) were infused (90 min) with 4-OHE2 (60 micrograms/h) or 2-OHE2 (100 micrograms/h). The main metabolites were determined in plasma and urine before, during and after infusion. Unconjugated and conjugated steroids, the latter after hot acid hydrolysis, were subjected to chromatography on LH-20 columns and measured by specific RIAs. During the infusion 4-OHE2 reached significant plasma concentrations whereas 2-OHE2 was so rapidly metabolised that its plasma levels remained virtually undetectable in spite of a higher infusion rate. The metabolism of 4-OHE2 was dominated by direct conjugation, that of 2-OHE2 by methyl ether formation. These findings were corroborated by the urinary excretion rates: during the infusion and the first hours afterwards, 4-OHE2 was mainly excreted as 4-OHE2 and 4-hydroxyestrone, while 2-OHE2 was predominantly excreted as 2-hydroxyestradiol 2-methyl ether and 2-hydroxyestrone 2-methyl ether.