Gilbert S. Gordan

Some thoughts on the nature of ectopic parathyroid hormones

Abstract Immunologic differences between the parathyroid hormone (PTH) in the serum of patients with primary hyperparathyroidism and that in the serum of some patients with ectopic hyperparathyroidism are described. This divergence of immunologic activity suggests that some tumors elaborate hormonal peptides different from the normal PTH.

Osteolytic Sterol in Human Breast Cancer

Eleven of twelve human breast cancers contained a lipid which increased urinary 45Ca and 40Ca excretion of 45Ca-labeled, parathyroidectomized rats receiving a low Ca diet. The lipid has mobility on thin-layer chromatography and gas-liquid chromatography close to, but not identical with, that of 7-dehydrocholesterol. Authentic 7-dehydrocholesterol has osteolytic activity similar to that of the extracted sterol. Fluorescence and Lieberman-Burchard reactions of the extracted sterol are similar to those of 7-dehydrocholesterol. The lipid was found by thin-layer chromatography in the extracts which had osteolytic activity. Neither the lipid nor osteolytic activity was found in extracts of tissue from two normal human breasts.

Dissociation of growth-stimulating and skeleton-maturing actions of the synthetic androgen, fluoxymesterone

Summary 1. Fluoxymesterone, usually 5 mg. daily, was given by mouth for 6 to 41 months to 12 boys and 4 girls with short stature and retarded skeletal age from various causes. 2. During treatment the average growth rate was 3.2 inches per year, while skeletal age advanced an average of 0.83 year per chronologic year. Phallic enlargement in both sexes was the only androgenic effect observed. 3. Prognosis for adult height increasedan average of 1.9 inches during treatment.

Direct Measurement of Osteolysis in Man

Precise, direct measurement of bone calcium release (v(o-)) has been accomplished using a continuous tracer administration (CTA) technique. Dietary calcium (96.97% (40)Ca) is replaced by (40)Ca (99.991% (40)Ca) and blood levels of the naturally occuring isotope (48)Ca are monitored by neutron activation analysis as a function of time. (48)Ca abundance falls as this isotope is excreted and only partially replaced by release from bone. After a suitable period, an asymptotic abundance of (48)Ca in serum, E, is approached which is the fraction of the turnover rate of the rapidly exchangeable calcium pools coming from the skeleton (E = v(o-)/v(t)). E is determined with a standard error of 2%, providing a precise, sensitive index of v(o-). 13 studies in three normal men and one postmenopausal woman receiving maintenance estrogen show large intersubject variations in parameters of calcium metabolism using both CTA and pulse tracer administration (PTA) plus balance techniques. Induced hypercalcemia results in a prolonged decrease in v(o-). Glucocorticoid therapy initially and consistently induces a marked hypercalciuria while effects on most other parameters of calcium kinetics are variable. In two men E fell when testosterone was added to glucocorticoid treatment, consistent with the known antiosteolytic effect of androgens, despite the short period of study.

No Risk from Vitamin D in Pregnancy

Excerpt To the editor: In 1966 the ANNALSpublished an article by Dr. Helen Taussig (1), in which she expressed concern that vitamin D, if given to pregnant women, might cause congenital cardiovascu...

Calcium and phosphorus dynamics in pregnancy.

Abstract 1. The renal handling of calcium and of phosphorus was studied in 24 women in the sixth, seventh, or eighth month of pregnancy. 2. Serum calcium levels were lower than in nongravid women; the reduction of serum calcium was quantitatively accounted for by a decrease in serum albumin. Protein-binding was not altered by pregnancy. 3. The filtered calcium load, tubular resorption of calcium, and urinary excretion of calcium were not significantly altered by pregnancy. 4. Phosphate filtration and net tubular reabsorption were likewise not altered by pregnancy. 5. Effects of 2 Gm. of calcium taken by mouth varied with the preparation used: (a) calcium lactate produced hypercalcemia with the increment of serum calcium being normally distributed between the protein-bound and free fractions; (b) nonfat milk increased urinary calcium excretion but not the serum calcium level; (c) calcium sulfate and dicalcium phosphate effected no change in serum or urine calcium content; (d) all of the oral calcium preparations raised serum phosphate levels and decreased phosphaturia, with the most potent compound being calcium lactate; and (e) the cause of the phosphate antidiuresis without discernible hypercalcemia at a time when phosphaturia is normally maximal is unknown.

HYPER- AND HYPOCALCEMIA: PATHOGENESIS AND TREATMENTS

Historically. calcium abnormalities in cancer have a respectable beginning; they were noted by Virchow in 1855.’ In this report, he describes his experience with a calcium disturbance in metastatic breast cancer. Virchow tells us that he “was asked to do an autopsy on the body of a young woman. the course of whose disease had put the diagnostic and therapeutic art of her physicians to shame.” She had an occult carcinoma of the breast and widespread metastatic calcification. In looking over his experience, Virchow found metastatic calcification in other cases of breast carcinoma. Of course, because serum calcium and phosphate levels are both elevated in disseminated breast cancer, this is a probable complication. This is sometimes overlooked in some of the therapies used in the hypercalcemia of breast cancer today. Several isolated reports appeared after Virchow’s paper. In 1889, Stephen Paget. the son of Sir James Paget. described another Paget’s disease of bone.2 This is a condition that we have also ~ b s e r v e d , ~ in which patients with breast cancer have skeletal lesions that radiologically appear like cysts. Histologically, the lesions do not contain tumor, but only fihrous tissue. From this and subsequent information, one might deduce that breast cancers exert a humoral effect upon remote portions of the skeleton. In 1923, Zondek described a man with symptoms of hypercalcemia, whose serum calcium level was 13 and nonprotein nitrogen 116 mg/100 m1.4 Autopsy showed carcinoma of the gall bladder with local extension. No abnormality of the parathyroid glands or of the bones was noted. This was probably the first description of hypercalcemia in cancer. In 1936, Gutman noted that a 57-year-old man with incidental Paget’s disease of the femur had serum calcium levels of 16-18 mg/100 ml. Serum phosphate was 2.1-2.4, until the patient became uremic whereupon it rose. This patient was determined to have a bronchogenic carcinoma. In 1941, Albright characteristically condensed these data when he discussed P. Z., a 50-year-old Greek bootblack with a known renal cell carcinoma and metastasis to the i l i ~ m . ~ J This patient had severe hypercalcemia that had been attributed to skeletal metastasis. Albright pointed out, however, that if the metastasis were liberating calcium by breaking down bone, it should also liberate phosphate and the serum phosphate level should be elevated. In fact, the patient’s hypercalcemia was associated with hypophosphatemia. Parathyroid exploration both in life and at autopsy failed to show any abnormality. Albright made the highly original suggestion that the renal carcinoma might have elaborated a parathyroid hormone-like substance. He sent some of the tumor to the Canadian biochemist, Collip, for assay, but the methods of the time were inadequate to show parathyroid hormone (PTH) . A quarter of a century later, Albright’s suggestion was confirmed in three laboratories: those of Tashjian at Haward,* Sherwood and associates at the National Institutes of Health,g and Berson and Yalow at the Bronx Veterans Administration Hospital.lo Berson and Yalow also indicated that many patients with bronchogenic carcinoma have elevated serum parathyroid hormone levels without hypercalcemia. The reasons for this peculiarity will be discussed shortly. First, however, I think we should discuss hypercalcemia of metastatic breast

Cerebral Metabolism of Glutamic Acid in Multiple Sclerosis

CURRENT STUDIES concerning the pathogenesis of multiple sclerosis are increasingly being directed toward altered metabolic processes. The present investigation deals with cerebral metabolism in multiple sclerosis, and particularly with the metabolism of glutamic acid and its amide glutamine in patients suffering from varying stages of the disease. There is now available a suitable method for measuring the rate of cerebral blood flow (CBF) that permits a computation of the rate of utilization or liberation by the brain of any substance that can be accurately analyzed in blood.’ By means of this technic, the rates of CBF and the cerebral metabolic rates (CMR) for oxygen, carbon dioxide, glucose, lactic acid, pyruvic acid, as well as for glutamic acid and its amide glutamine have been measured in patients with multiple sclerosis and in a series of normal control subjects. A total of 32 patients with multiple sclerosis have been studied. The patients for the most part were admitted to the University of California Hospital, where a complete investigation of their clinical status was made and where they were independently examined by several members of the departments of neurology and neurosurgery. No patient was included in the study unless the clinical findings and subsequent course established the diagnosis of multiple sclerosis. The patients were divided into three groups: 1. Those in an acute active exacerbation of the disease, or patients in an initial attack who subsequently were shown to have multiple sclerosis. 2. Those with advanced multiple sclerosis who, at the time of the study, evinced no signs of active progression of the disease. The disease in this stage has been termed “indolent multiple sclerosis.’’ 3. Those who were either improving from an active exacerbation or recovering from an initial attack of the disease. The average age of the patients with multiple sclerosis was 31 years (range

Inhibition of Aerobic Respiration of Rat Brain by Desoxycorticosterone in vitro.

Summary (1) The concentration-action relationships of DC and DCG upon aerobic respiration of rat brain cell suspensions indicate: (a) Increasing amounts of DC and DCG produce increasing amounts of inhibition This relationship is reasonably linear plotting the logarithm of the amount of DC against per cent of inhibition produced. (b) With increasing amounts of DC a longer period of time is required to attain maximal inhibition while a comparable effect is more rapidly attained with equimolar amounts of the water-soluble conjugate, DCG. The effect, once attained, remains constant without further increase or release of the inhibition. (c) By this bio-assay the water-solubility of DC at 37.2°C is approximately 3.6×10-3 Molar. (2) These data suggest that, under the conditions used, the relatively large amounts of steroid necessary to produce inhibition of aerobic respiration in vitro entirely penetrate or are adsorbed by the affected system. These amounts exceed the concentrations of steroid which will affect other systems in vitro or that occur in living organisms. This does not necessarily exclude the possibility that steroidal inhibition of aerobic respiration may be of significance in the intact organism.

High-dosage Δ1-testololactone therapy of disseminated carcinoma of the breast

Δ1‐Testololactone, a nonvirilizing testosterone derivative, effective in the treatment of disseminated mammary carcinoma, was administered in a dosage larger than previously reported, in an attempt to obtain better control of the disease. Increasing the dose caused no improvement in the objective regression rate. Prolonged objective regressions were achieved in 4 of 32 women (12.5%) who previously had received one or more courses of hormone therapy. The drug did not cause virilization or other undesirable effects. During therapy there was a fall in urine calcium, calculated to result from an increase in tubular reabsorption. There was no hepatic, renal or other toxicity, no change in serum high‐density lipoprotein lipids and no hypercalcemia caused by therapy.