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Plasma luteinizing hormone (LH) and testosterone (T) were measured by radioimmunoassay in nine pubertal boys and three sexually mature young men at 20-min intervals for 24 h. Plasma LH and T were also measured in one boy during a delayed sleep onset study. Polygraphic monitoring was carried out to identify precisely sleep onset. Wakefulness, and specific sleep stages. In all nine pubertal boys the plasma T concentration fluctuated and was significantly higher during normal nocturnal sleep as compared to daytime waking. This increased T secretion during sleep was temporally linked to the characteristic pubertal sleep augmentation of LH secretion. To define further the relationship of this increased T secretion to sleep, plasma LH and T were also measured in three of the pubertal boys after acute (1-day) reversal of the sleep-wake cycle. One of these boys was also studied after 3 days of sleep-wake cycle reversal. The results of these studies showed that plasma T was now augmented during the reversed daytime sleep period; the mean T concentrations during this period were significantly higher (P < 0.001) than during nocturnal waking in all four studies. Measurement of plasma LH and T in the three sexually mature young men showed episodic secretion of LH and T during both waking and sleep periods; there was no consistent significant augmentation of LH or T secretion during sleep. This study demonstrates that (a) in normal pubertal boys and sexually mature young men plasma T fluctuates episodically; (b) there is marked augmentation of T secretion during sleep in pubertal boys, which is dependent on increased LH secretion; (c) this pubertal LH-T secretory “program” is dependent on sleep, since it shifts with delayed sleep onset and reversal of the sleep-wake cycle; and (d) this demonstrable tropic effect of LH on T is evident only during puberty, since sexually mature young men fail to show any consistent relationship between LH and T secretion either awake or asleep.

Prolactin secretion in normal adults is characterized by periods of episodic secretion which increase in magnitude during sleep. In this study, we report the 24-h mean prolactin concentrations, prolactin secretory patterns, and associated pituitary hormone function in nine patients (seven women and two men) with hyperprolactinemia of diverse etiologies. Four of the women and one of the men had clinically demonstrable pituitary tumors, one boy had a hypothalamic tumor, and the three other women had “functional” hyperprolactinemia. The 24-h mean prolactin concentrations derived from averaging the 20-min interval samples for 24 h ranged from 28.6 to 1,220 ng/ml. The plasma prolactin patterns in these patients showed persistence of episodic secretion in all and loss of the normal sleep-wake difference in plasma prolactin in seven of nine. Three of the patients with galactorrhea and comparable 24-h mean prolactin concentrations (58.3, 59.7, and 64.3 ng/ml) showed similar prolactin secretory patterns despite different etiologic mechanisms. Evaluation of the secretory patterns of luteinizing hormone (LH) in these patients showed loss of normal pulsatile LH release and a low 24-h mean LH concentration in the patient with the pituitary tumor, while the two patients without clinically demonstrable pituitary tumors (“post-pill” galactorrhea and “idiopathic” galactorrhea) showed normal LH secretory patterns and 24-h mean LH concentrations. The 24-h mean cortisol concentrations and secretory patterns were normal in five of the seven patients who had these parameters measured. The patient with the hypothalamic tumor had a low 24-h mean cortisol concentration and production rate and absent response to metyrapone. The patient with “idiopathic” galactorrhea had an elevated 24-h mean cortisol concentration but normal cortisol production rate and urinary 17-hydroxycorticoid excretion. Growth hormone secretion was abnormal in four of the patients (one with the hypothalamic tumor and three with pituitary tumors). Thyrotropin-releasing hormone (TRH) administration in four patients resulted in normal TSH release in two patients (one of whom developed galactorrhea after the test), an absent response in the patient with the hypothalamic tumor, and a blunted response in one of the women with a pituitary tumor. The two men had low 24-h mean plasma testosterone concentrations (69 and 30 ng/100 ml) and symptoms of impotence and loss of libido. Five of the women (four with pituitary tumors and one with Chiari-Frommel syndrome) had either low 24-h mean LH concentrations, abnormal LH secretory patterns, or both. These data indicate that patients with hyperprolactinemia encompassing a varied etiological range frequently show loss of the normal sleep-associated increase in prolactin secretion as well as abnormalities in the regulation of the other hypothalamic pituitary-regulated hormones. The finding that the abnormalities in LH, growth hormone, thyrotropin, and cortisol (adrenocorticotrophic) secretion were almost uniformly confined to the patients with the clinically demonstrable hypothalamic or pituitary tumors suggests that the size of the lesion is the critical factor.

Summary Utilizing a glucose oxidase analytical method, free glucose has been found to be virtually absent from human bile, both in the normoglycemic state and during induced hyperglycemia. In contrast, orally administered xylose appears in bile in concentrations similar to those of plasma. These results suggest a physiologically determined blood-bile barrier for glucose in man. Possible mechanisms for this phenomenon are discussed.

Coprostanol-C14, biosynthetically prepared, was administered orally to two patients, and cholestanol-4-C14 was administered to one of them 10 months later. At the time when radioactivity in the circulation was at a maximum, 3.6 and 3.5% of the administered labeled coprostanol was present in the plasma; the corresponding value after administration of cholestanol-C14 was 4.7%. The dynamic behavior of absorbed radioactive cholestanol was identical with that of orally ingested cholesterol-4-C14, including the esterification process; on the other hand, virtually no coprostanol ester was present in the circulation. It is suggested that the conformation of the A/B rings or configuration at C-3 are related to the esterification mechanism of sterols. After 5 days, over 50% of both compounds had been excreted in the feces. The conversion of coprostanol-C14 to coprostanone-C14 has been demonstrated.

Individual metabolites of steroid hormones were isolated and measured from the urine of patients with chronic myelogenous leukemia. The results were compared with earlier studies of patients with chronic lymphatic leukemia, men with prostatic cancer, women with breast cancer and normal men and women. The metabolites of hydrocortisone were in the normal range for the patients with chronic myelogenous leukemia but the amount of tetrahydrocortisol was generally greater than that of tetrahydrocortisone. There was no evidence for a sex difference in the production of these metabolites. The tentative conclusion was drawn that metabolites of the "adrenal androgens" were also in the normal range in chronic myelogenous leukemia. These results contrast with those in chronic lymphatic leukemia patients where a sex difference in production of hydrocortisone was evident and the metabolites of "adrenal androgens" were at low levels in both sexes.

Cumulative observations concerning the use of triamcinolone in 74 patients with rheumatoid arthritis and in 15 with related rheumatic syndromes are reported. Anti-inflammatory properties of this steroid were confirmed. Although disturbances in electrolyte metabolism were not observed, the usual undesirable effects resulting from the administration of glucocorticoids were noted. Es reportate observationes cumulative in re le uso de triamcinolona in 74 patientes con arthritis rheumatoide e in 15 patientes con syndromes rheumatic affin. Le qualitate anti-inflammatori de iste steroide esseva confirmate. Ben que disturbationes in le metabolismo electrolytic non esseva observate, le usual effectos adverse que resulta del administration de glucocorticoides esseva observate.

A highly polar metabolite, 3α-ureido-11β-hydroxy-Δ4-androsten-17-one (ureasterone), has been isolated from human urine. The structure was derived by infrared, nuclear magnetic resonance, and mass spectrometry, and by degradation of the compound with aqueous acetic acid to 11β-hydroxy-Δ3,5-androstadien-17-one and urea. Partial synthesis of the ureidosteroid was achieved by reaction of urea and the allylic alcohol, 3α,11β-dihydroxy-Δ4-androsten-17-one, in aqueous solution at pH 5. It was concluded that ureasterone was formed during the incubation of urine at pH 5 to cleave the conjugate of 3α,11β-dihydroxy-Δ4-androsten-17-one, a normal metabolite of 11β-hydroxy-Δ4-androstene-3,17-dione.

Summary Forty-seven serial rectal mucosal biopsy specimens were obtained on nine patients receiving 5-FU. Correlations of histopathological findings with the total dose of 5-FU and toxic symptoms were made. The earliest specific change in the rectal mucosa was loss of nuclear polarity in the crypt epithelium with evidence of nuclear debris and cytoplasmic vacuolization. Six of the patients developed histopathological changes in the nucleus. Two patients went on to develop glandular mucosal atrophy. The mucosa returned to normal in all patients after cessation of therapy. The sequence of events and correlation with toxic symptoms are discussed.

The metabolism of estradiol, its production rate and the urinary excretion rate of its metabolites were studied in 5 women patients with breast cancer, 2 of whom were postmenopausal and 3 were ovariectomized, both before and after a period of 7beta,17alpha-dimethyltestosterone (calusterone) therapy. In all cases calusterone caused a profound decrease in the transformation to estriol and an increase in the formation of estrone and 2-hydroxyestrone. The production rate of estrogens was diminished by calusterone in the three overiectomized patients but not in the postmenopausal subjects. The possible participation of the above changes in the chemotherapeutic action of calusterone is discussed.

The production and peripheral metabolism of cortisol have been studied in 10 cirrhotics and 11 controls after i.v. tracers of cortisol-(14)C. The findings were as follows: (a) Total urinary excretion of radioactivity was normal (81% of the dose) but a decreased fraction was present as glucosiduronates: 18-47% of the dose (average 34%) compared to a normal average of 54%. (b) There was a distinctively abnormal pattern of cortisol metabolites, not previously observed in other illnesses: tetrahydrocortisone was decreased to 14% of the enzyme hydrolysate (normal 26%); cortolones were increased to 34% (normal 19%), owing entirely to an increase in cortolone (20alpha) formation, since beta-cortolone (20beta) was not significantly increased; Reichstein's substances U and epi-U were increased, averaging 2.6% for the former and 4.7% for the latter; tetrahydrocortisol, allotetrahydrocortisol and cortols were normal. This pattern was independent of the degree of decreased glucosiduronate formation and also independent of the presence or absence of a portacaval shunt. (c) Cortisol production, determined by isotope dilution, was normal in each of six cirrhotic patients. From these data, taken in conjunction with our previously reported findings concerning the influence of norethandrolone on cortisol metabolism, the following conclusions were drawn: (a) Cirrhotic patients have decreased A-ring reduction of cortisone to tetrahydrocortisone and correspondingly increased 20-ketone reduction of cortisone to Reichstein's substances U and epi-U and then to the cortolones. (b) Intrahepatic cholestasis, a regular pathophysiological feature of cirrhosis, may be responsible for the observed abnormal cortisol metabolite pattern in this disease. (c) The slowed metabolic turnover rate of cortisol in cirrhosis may be due to decreased transport and/or binding of cortisol to its intracellular metabolic sites rather than to abnormalities of any specific metabolizing enzymes.

Abnormal estrogen metabolism has been found in cirrhosis after administration of intravenous tracers of estradiol-(3)H to 6 patients and 23 healthy controls. The major abnormalities observed involved estrogen metabolites other than the 3 "classic" ones, i.e., estrone (E1), estradiol (E2), and estriol (E3). Urinary recovery of radioactivity was regularly elevated in the patients, to an average of 71% of the dose compared to 51% in normals. This is considered to reflect the component of intrahepatic cholestasis in cirrhosis. The per cent dose recovered as urinary glucosiduronates (42%) was normal in cirrhotics in contrast to impaired glucuronidation of cortisol metabolites in this disease. E1 and E2 were present in normal amounts, and E3 was slightly elevated to 21% of the extract compared to 14% in controls. There were strikingly decreased excretion of 2-hydroxyestrone (3% compared with normal 20%) and 2-methoxyestrone (2% compared with 5%) and increased excretion of 16alpha-hydroxyestrone (12% compared with normal 6%). Thus cirrhosis, too, is characterized by the reciprocal relationship between decreased 2-hydroxylation and increased 16alpha-hydroxylation previously described in hypothyroidism and male breast cancer. However, unlike these latter, the increase of 16alpha-hydroxy metabolites was less than the decrease of 2-hydroxy metabolites. The data indicate clearcut impairment of 2-hydroxylation, suggestive impairment of 16alpha-hydroxylation, and a definite depression of the reaction 16alpha-hydroxyestrone--estriol, the latter finding so far unique to cirrhosis. Demonstration of abnormal peripheral metabolism of estrogen in cirrhosis provides a new approach to the origin of the hyperestrogenic syndrome in this disease.

Cholesterol-3-(3)H,4-(14)C was injected intravenously in man and its transformation to cholestanol was studied. From the (3)H: (14)C ratios in cholestanol isolated from blood, evidence for the participation of a ketonic intermediate in the conversion was obtained. In a second subject given cholestanol-3-(3)H,4-(14)C the (3)H: (14)C ratios in blood sterols remained unchanged for as long as 1 wk after the injection, which showed that cholestanol did not lose tritium by interconversion with cholestanone.

The concentration of glucose(G) and insulin(I) was measured every 20 rain for 24 hrs in 3 pts receiving only 18% glucose and 3.3% casein hydrolysate in order to evaluate the G & I response to total parenteral nutrition. Pt 1 received 4L by gravity drip. G was 16-158mg% and I was 0-372μU/ml. Peaks of G and I occurred whenever a new bottle of infusate was started. In pt 2 who received 5L, G was 31-210, I:0-216 and rate of flow 100-240ml/hr. Peaks of G and I corresponded to peaks of the rate of flow. In pt 2 5L of 10% glucose alone was later administered using a pump. Flow was 140-180ml/hr, G:49-93 and I:0-25. Pt 3 received 3L during a 12 hr gravity drip and a 12 hr pumped period. During the gravity drip, flow was 30-180ml/hr, G:50-123 and I:0-78. During the pumped period flow was 120ml/hr,G:66-101 and I:0-24. Urinary excretion of G was < 2% of the amount infused in all pts. The main factor controlling the conc. of G and I seems to be the rate of flow. During gravity drips marked changes in flow rate cause parallel marked changes in G and I which were eliminated during pumped periods. When the conc. of G is held relatively constant, little I is secreted, and complete utilization of nutrients takes place. These data suggest that constant infusion of hypertonic fluids will minimize fluctuations in G and I and prevent both hyperand hypoglycemia.

Intermediate values of hGH (2-7ng/ml) may occur in response to stimulatory tests. Patients with hGH responses less than 2ng/ml are probably hGH deficient while those with responses greater than 7ng/ml are probably not hGH deficient. 16 patients, in whom all other causes of growth failure have been excluded, were given insulin 0.1 units/kg IV, arginine 0.5gm/kg IV, or glucagon 1mg IM in order to evaluate their hGH responses. In 4 subjects who were found to have intermediate hGH responses, the concentration of hGH in plasma was measured every 20 minutes for 24 hours. In these subjects the maximum concentration of hGH during the 24 hour study was 13.3 12.9, 12.2 and 27.2ng/ml. These 4 subjects were treated with hGH 2 IU 3 times a week for 3-5 months. Growth in 3 of 4 subjects was 3.4cm, 4.1cm and 3.0cm/yr. The fourth subject grew 9.2cm/yr despite a maximum hGH of 13.3ng/ml during the 24 hour study. Our results indicate that the 24 hour study method of evaluating hGH responses is not more helpful than stimulatory tests in the diagnosis of hGH deficiency. Since the 24 hour study is more difficult to do, the usual stimulation tests are preferable and a trial of hGH treatment may be necessary.