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)