Metabolism of steroid hormones by human endocrine tumors

119

Southern Society for Clinical Research P. Eliel, * William 0. Smith, Carl Thomsen and Josephine Hawrylko. Oklahoma Medical Research Foundation, Medical Service, Veterans Hospital, and Dept. of Medicine, Univ. of Oklahoma School of Medicine, Oklahoma City, Okla. The effects on magnetism metabolism of parathormone, acetazolamide, calcium and phosphate loading, protein deprivation, and vitamin D have been studied in man, using the metabolic balance technic. Two of four patients with hypoparathyroidism exhibited hypomagnesemia. The administration of parathormone resulted in: (1) disappearance of hypomagnesemia and hypocalcemia, and (2) parallel changes in urine magnesium and calcium, i.e., an initial drop followed by rises to values exceeding control levels. Administration of vitamin D likewise produced parallel urine changes in a hypoparathyroid patient with normal serum magnesium. Acetazolamide caused disappearance of tetany and prompt phosphorus diuresis, but only minor changes in serum and urinle calcium and magnesium. Severe tetany appeared soon afterwards in association with a marked drop in serum magnesium. Intravenous calcium and phosphate loads were followed by falls in serum magnesium attributed to intracellular migration of this ion. Intestinal absorption of magnesium was decreased by dietary protein deprivation. These studies suggest that: (1) the blood level and renal excretion of magnesium are governed directly or indirectly by parathyroid activity, (2) hypomagnesemia may facilitate the appearance of hypoparathyroid tetany, (3) the serum magnesium concentration may share in the same physical-chemical relationships governing calcium and phosphorus concentrations, and (4) intestinal absorption of magnesium, like calcium, is affected by protein intake. SIGNIFICANCE ACTIONS

OF THE EXTRA-ADRENAL

OF CORTICOTROPIN

METABOLIC

PEPTIDES.

Frank L.

Dept. of Medicine and Physiology, Division of Endocrinology, Duke Univ., Durham, N. C.

Engel.*

The pituitary tropic hormones are generally assumed to act exclusively on their target glands. However, we and others have found that oxycel and pure peptide ACTH share certain metabolic activities with growth hormone (STH) and melanophore-stimulating hormone (MSH) in both intact and adrenalectomized animals. Studies of products of chemical inactivation (alkali, HzOz and cysteine) and of JULY,

1958

pepsin and chymotrypsin digestion as well as comparative metabolic potency measurements of ACTH, STH, TSH and MSH eliminate mutual contaminations as the basis for common activities. Correlations with structure indicate that the N-terminal serine of ACTH is necessary for adrenal ascorbic acid depletion (AAAD) and metabolic but not melanophore activities. Removal of ten “tail” amino acids by pepsin eliminates ketogenic but not AAAD or MSH activities. P-MSH with a seven amino acid sequence in common with fi-ACTH but no Nterminal serine lacks AAAD and ketogenic activities. The hypothesis is proposed that the specificity of ACTH is related more to its affinity for the adrenal than to its ability to stimulate specific metabolic reactions (steroidogenesis). When administered or secreted in excess or perhaps when modified chemically as a peptide it may stimulate metabolism of other cells in a manner analogous to its action on the adrenal cortex, with results determined by the specific functions of the cell. METABOLISM ENDOCRINE

OF

STEROID

TUMORS.

HORMONES

BY

HUMAN

Lewis L. Engel and Silly

Baggett. The John Collins Warren

Laboratories of the Huntington Memorial Hospital of Harvard Univ. at the Massachusetts General Hospital and the Dept. of Biological Chemistry, Harvard Medical School, Boston, Mass. and Ralph I. Dorfman and Kenneth Savard. Worcester Foundation for Experimental Biology, Shrewshury, Mass.

The availability of isotopically-labeled steroid hormones and their precursors makes possible direct experimentation on isolated human tissues. The findings obtained in this fashion may be correlated with data obtained from a study of urinary excretion patterns. This approach has been applied to the study of steroid hormone metabolism by two human testicular tumors of widely differing cell types. In the first, an interstitial cell tumor of the testis in a five year old boy, it was possible to demonstrate the formation from radioactive acetate of 4-androstene-3,17-dione, 1 l/I-hydroxy-4-androstene-3,17-dione, 17c+hydroxyprogesterone, testosterone, adrenosterone and dehydroepiandrosterone. The formation of nineteen carbon steroids bearing oxygen substituents was wholly unexpected in view of the histological characterization of the tissue. In the second tumor, a highly malignant,

Southern

120

Society for Clinical

undifferentiated tumor of the testis in a three year old boy, the formation from acetate-l-Cl4 of labeled hydrocortisone, *l l&hydroxy-4-androstene-3,17-dione has been demonstrated. Hydrocortisone synthesis was consistent with the clinical picture and demonstrated the remarkable biochemical capacities of this undifferentiated tissue. INTRACARDIAC

DIMENSIONS,

ANATOMIC

AND

DY-

Doris J. W. Escher. Montefiore Hospital, Divisions of Medicine and Diagnostic Radiology, New York, N. Y. NAMIC.

This paper presents a new technic for demonstrating and clarifying the complex anatomy of the intact heart. Chambers, valve positions and lines of blood flow are presented on the basis of their natural three dimensional, torsioned relationship and these views are then related to the four standard roentgen exposures in which the heart is normally positioned for clinical study. Use is made in this demonstration of a semiradiolucent normal heart model which is catheterized and x-rayed, as is done during cardiac catheterization. Comparison is made between views of the model, in which areas are selectively opacified for delineation and similar views of clinical material in which flow tracts and valve positions were established during cardiac catheterization. In addition to the main consideration of a dynamically normal heart, some elucidation of the blood flow patterns in interarterial and interventricular septal defect has also been undertaken. CHLOROTHIAZIDE

IN THE MANAGEMENT

OF

EDEM-

M. Jeanne Fairweather, John M. Lewis, Ralph V. Ford* and Don W. Chapman. * Baylor Univ. College of Medicine, Houston, Texas. ATOUS

STATES.

To determine the diuretic properties of orally administered chlorothiazide (diurol@) as compared with parenteral thiomerin, the following study was initiated. A series of twenty edemeither cardiacs or cirrhotics, atous patients, were studied. They were at bedrest, given 800 mg. sodium diet with a controlled water intake of 3,000 ml. each twenty-four hours. The dosage of digitalis and antihypertensive drugs remained constant throughout in those who were previously receiving them. The serum electrolyte levels and the ,twenty-four hour urinary volume and excretion of sodium were determined. Teleroentgenograms and electrocardio-

Research

grams were obtained at the onset and completion of the study. Daily weights were recorded. After a three-day control period ten patients received 2,000 mg. of chlorothiazide orally each day for three days; the other ten patients received 2 cc. of thiomerin parenterally initially for three days. Another three-day control period followed, then the diuretics were reversed. Serum sodium, potassium, chloride, bicarbonate, blood urea nitrogen and hematocrit were analyzed on control day three, and drug day two of each threeday period. The natriuresis and water diuresis is greater following the administration of chlorothiazide than thiomerin. In one patient with cirrhosis totally refractory to thiomerin a twenty-pound diuresis was obtained with chlorothiazide. Continued administration of chlorothiazide may lead to hypokalemia, hypochloremia and an elevation of CO,; however, this is reversible with potassium chloride. Chlorothiazide potentiates the effect of hypotensive agents. Chlorothiazide has thus been found to be an effective relatively non-toxic oral diuretic. 17-21

HYDROXYCORTICOSTEROIDS

IN LABOR

AND

Lee L. Farris, M. D. Turner, James D. Hardy * and Michael Newton. Dept. of Surgery and of Obstetrics & Gynecology, Univ. of Mississippi Medical Center, Jackson, Miss. DELIVERY.

Previous studies of plasma 17-21 hydroxycorticosteroid levels in obstetrical patients have shown a rise in the antepartal period and return to normal after delivery. The object of this investigation was to determine the plasma levels of 17-21 hydroxycorticosteroids at specific times during and after the physiological stress of labor and delivery. Fifteen normal women were selected at random for this study. All had normal, spontaneous labor; minimal analgesia and anesthesia were necessary. Blood samples were drawn from an antecubital vein at about the thirty-sixth week of pregnancy, during active labor, at delivery of the baby, immediately after delivery of the placenta, and one, four and twenty-four hours postpartum. Determination of 17-21 hydroxycorticosteroid material in the plasma was made by the methods of Nelson and Samuels and Bongiovanni. The following mean values for free and glucuronide conjugates of 17-21 hydroxycorticosteroids, expressed in pg./ 100 cc. were obtained, late pregnancy, 10.63; active labor, 14.71; delivery, 21.16; end of third stage, 26.50; one hour postpartum, 27.01; four AMERICAN

JOURNAL

OF

MEDICINE