In male pseudohermaphrodites born with ambiguity of the external genitalia but with marked virilization at puberty, biochemical evaluation reveals a marked decrease in plasma dihydrotestosterone secondary to a decrease in steroid 5alpha-reductase activity. In utero the decrease in dihydrotestosterone results in incomplete masculinization of the external genitalia. Inheritance is autosomal recessive.

In 1948, Mason and Sprague (1) reported the isolation of hydrocortisone from the urine of a patient with Cushing's syndrome, and thus provided evidence that hydrocortisone was produced by the human adrenal cortex. Subsequently, hydrocortisone was found to be one of the principal corticoids in human adrenal gland perfusates (2) and in human peripheral blood (3). These observations strongly suggest that hydrocortisone may be the principal corticosteroid secreted by the adrenal cortex of man. Recent studies (4, 5) utilizing hydrocortisone-4-Cli have elucidated much new information regarding the metabolism and physiological disposition in man of this naturally occurring adrenal steroid.The availability of labeled hydrocortisone has made possible the direct estimation of the magnitude of the reservoir of hydrocortisone in the body, and the rate at which new, non-isotopic hydrocortisone is synthesized in the body and enters the reservoir. This report is concerned with the experimental determination of the magnitude of the miscible pool of hydrocortisone and the rate of its turnover in man. These estimations depend upon serial measurements of the specific activity of circulating hydrocortisone after the infusion of trace quantities of hydrocortisone4-0C1 and analyses of these data utilizing conventional turnover calculations (6, 7). Observations have been made in normal subjects, and subjects receiving adrenocorticotropin and A1 cortisone (prednisone). MATERIALS AND METHODSNine normal subjects (7 male and 2 female) were used for these studies. Each subject received 1 to 2.5 microcuries of hydrocortisone-4-C' dissolved in 2 to 5 ml. of 10 per cent ethanol in sterile distilled water. The steroid was administered intravenously in the fasting state in the morning over a period of approximately 3 minutes. Heparinized blood samples (40 to 60 ml. each) were collected at 30 to 40-minute intervals after injection of the isotope.Procedure for determination of sPecific activity of circulating hydrocortisone Twenty-five to 35 ml. of plasma were extracted gently for 10 minutes on a rotator (Arthur H. Thomas Co., Catalog No. 3623) in a 700-ml. Erlenmeyer flask with 5 volumes of dichloromethane (purified by passing through a column of silica gel [5]).The plasma and solvent were gently transferred to a 200-ml. ground-glass stoppered cylinder, and the plasma removed by aspiration.The dichloromethane extract was washed successively with 'A volume of 0.01 N sodium hydroxide, 'As volume of 0.1 M acetic acid, and X5 volume of water.

To determine the contribution of androgens to the formation of male-gender identity, we studied male pseudohermaphrodites who had decreased dihydrotestosterone production due to 5 alpha-reductase deficiency. These subjects were born with female-appearing external genitalia and were raised as girls. They have plasma testosterone levels in the high normal range, show an excellent response to testosterone and are unique models for evaluating the effect of testosterone, as compared with a female upbringing, in determining gender identity. Eighteen of 38 affected subjects were unambiguously raised as girls, yet during or after puberty, 17 of 18 changed to a male-gender identity and 16 of 18 to a male-gender role. Thus, exposure of the brain to normal levels of testosterone in utero, neonatally and at puberty appears to contribute substantially to the formation of male-gender identity. These subjects demonstrate that in the absence of sociocultural factors that could interrupt the natural sequence of events, the effect of testosterone predominates, over-riding the effect of rearing as girls.

The present report is concerned primarily with the physiological disposition and fate of hydrocortisone in man. Large doses of this steroid have been administered intravenously, and the rate of its disappearance from plasma has been determined in normal subjects and in patients with liver disease and various endocrinopathies. The following procedure is a modification of the recently published method of Silber and Porter (1):Principle-Hydrocortisone is extracted from plasma into dichloromethane. The dichloromethane extract is washed with aqueous alkali to remove a considerable amount of "blank" material. The dichloromethane is then shaken with a sulfuric acid-ethanol reagent, containing phenylhydrazine. The resulting colored product is measured in the acid phase spectrophotometrically at 410 mny. A correction for material in plasma reacting with sulfuric acid is made by treating an equal aliquot of dichloromethane extract of plasma with sulfuric acid-ethanol which contains no phenylhydrazine.

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Seventeen individuals from a pedigree with complete androgen insensitivity, [testicular feminization (TF)] are presented. Their hormonal evaluation was compared with those of normal males and male pseudohermaphrodites with primary 5a-reductase deficiency. The mean plasma testosterone to dihydrotestosterone ratio was 12 ± 3 in normals, 24 ± 8 in TF subjects (P < 0.001), and 41 ± 14 (P < 0.001) in 5a-reductasedeficient subjects. In 4 TF subjects the MCRs for testosterone and dihydrotestosterone were normal. The dihydrotestosterone blood production rate averaged 383 jug/day in normals, 162 jig/ day in TF subjects, and 86 /ig/day in 5a-reductase-deficient subjects. The conversion ratio of testosterone to dihydrotestosterone averaged 2.53 in normals, 1.8 in TF subjects, and 0.63 in 5a-reductase-deficient subjects. The mean plasma estradiol level was 2.8 ± 1.0 ng/100 ml in normal males, 4.8 ± 1.3 ng/100 ml (P < 0.001) in TF subjects, and 3.1 ± 1.3 ng/100 ml (P < 0.5) in 5a-reductase-deficient subjects. The fractional plasma protein binding of testosterone in TF subjects and 5a-reductase-deficient subjects was similar to that in normal males. The mean urinary etiocholanolone to androsterone ratio was 0.87 ± 0.34 in normals, 1.28 ± 0.46 (P < 0.001) in TF subjects, and 4.90 ± 2.15 (P < 0.001) in 5a-reductase-deficient subjects. The mean urinary ratio of 5/?-tetrahydrocorticosterone to 5a-tetrahydrocorticosterone was 0.53 ± 0.22 in normal males, 0.76 ± 0.21 in TF subjects (P < 0.02), and 4.59 ± 4.5 (P < 0.001) in 5a-reductase-deficient subjects. The mean urinary 5/?-tetrahydrocortisol to 5a-tetrahydrocortisol ratio was in the normal male range in the TF subjects, but was markedly elevated in the 5a-reductase-deficient subjects. The data suggest that in the TF subjects, there is a decrease in peripheral 5a-reductase activity related to C-19 androgen 5a-metabolism, which is a secondary manifestation of androgen resistance. This differs from the situation in the male pseudohermaphrodites with 5a-reductase deficiency, where the defect affects hepatic and peripheral 5a-reduction with a marked decrease in both 5a C-19 and C-21 metabolites. (J Clin EndocrinolMetab 54: 931, 1982)

Zondek (1) as early as 1934 demonstrated that enzymes of the liver destroyed the biological activity of the estrogens. Since then both in tivo and in vitro studies have provided much evidence to show that the liver is the organ primarily responsible for the catabolism of the steroid hormones: estrogens, androgens, progesterone, and the corticosteroids (2). However, not until the development of improved methods for measurement of certain of the adrenocortical steroids and their metabolites, and the availability of labeled radioactive cortisol, corticosterone, and aldosterone has it been possible accurately to evaluate the influence of liver disease on the rate of degradation and synthesis of the steroids in man. The studies here reported are based on the use of certain of these newer techniques.On incubation with rat liver tissue, cortisol and cortisone are rapidly metabolized, but only very slowly with other tissues (3-5). Perfusion studies have demonstrated a very rapid metabolism of the steroids by the liver but not by other organs (6-8). Hechter, Frank, Caspi and Frank (9) found that the major portion of the cortisone and cortisol administered into the portal vein in dogs was not recovered as unaltered steroid from the hepatic venous blood. Bradlow, Dobriner and Gallagher (10) found that 70 per cent of a dose of tritium-labeled cortisone administered to mice was found in the liver within five minutes after intravenous administration. Administered cortisol also disappears rapidly from the circulation in rats (11), and this rapid metabolism can be prevented by hepatectomy but not by nephrectomy (12).The liver in man has a high capacity for metabolizing the circulating blood cortisol, as demonstrated by the fact that the level of 17-hydroxycorticosteroids in the hepatic vein blood is lower than the level in the arterial blood (13,14). Adrenocortical steroids administered intravenously

The evidence is quite conclusive from animal studies that an excess of circulating thyroid hormone results in adrenal enlargement, and hypothyroidism produced by surgical thyroidectomy or by administration of antithyroid drugs results in adrenal atrophy. This subject has been extensively reviewed by Money (1). Studies of adrenal size in patients with thyroid disease coming to autopsy have yielded conflicting reports. Means (2) reported no change in adrenal size in hyperthyroidism, Marine (3) and LeCompte (4) reported a decrease in size of the adrenal, and Holst (5) found enlarged adrenals in some patients with hyperthyroidism. Berkheiser (6) reported an advanced case of hypothyroidism, with atrophy of the adrenals and lipoid depletion.Measurements of adrenal size may not, however, always represent a completely satisfactory "yardstick" for evaluation of adrenal cortical secretory activity (7,8). In the past few years, several investigators have reported measurements of various plasma and urinary steroid fractions in hyper-and hypothyroidism in man. Several investigators have reported on the levels of free urinary corticoids (9-12) in hyperthyroidism, and in myxedema (9, 10). Because of the relatively nonspecific methods of assay used these data are difficult to interpret. Urinary 17-ketosteroids have usually been found to be low in both hyperand hypothyroidism (9-18). Plasma 17,21-dihydroxy-20-ketosteroids have been reported to be normal in these diseases (19)(20)(21). Guinea pigs, which excrete a large fraction of the cortisol metabolites as free 17,21-dihydroxy-20-ketosteroids, show an increased excretion of free urinary corticoids after administration of thyroxine (20). In patients with clinical myxedema, the urinary level of the total free and glucuronide conjugated 17,21-dihydroxy-20-keteosteroids has been found to be decreased, whereas in hyperthyroidism the level of these urinary steroids is either normal or slightly increased (20).Thyroidectomized rats (22) and cats (23) are reported to survive adrenalectomy better than animals with an intact thyroid, and administration of thyroid to the adrenalectomized cats produced sudden death of the animals. Also, in patients with Addison's disease, acute adrenal cortical failure may be precipitated if thyroid hormone is administered (24, 25). Primary myxedema has been observed in which the presenting findings were those of adrenal cortical insufficiency, and adrenal function returned to normal following thyroid hormone therapy (26).With the advent of new and improved methods for the measurement of certain of the adrenal cortical hormones, and the availability of cortisol-4-C14, it has become possible to further study the relationship of the thyroid hormone to adrenal cortical function. These techniques have been applied to a study of the rate of degradation and the rate of synthesis of cortisol in myxedema and thyrotoxicosis, before and after therapy. In this manner, much new information has been gained regarding the state of activity of the adrenal cortex in these ...