End-organ Responsiveness Research Articles

Growth retardation in inflammatory bowel disease

Growth retardation and delay in sexual maturation complicate child-onset Crohn's disease in nearly 1 in 5 patients, with a somewhat lower complication rate in ulcerative colitis. Successful management of this complication requires an understanding of the appropriate definition of growth retardation in inflammatory bowel disease, and a critical assessment of its etiology and responses to therapy. This review of the experience at the University of Chicago and the experience reported from other centers indicate that to date no specific endocrine abnormalities can be implicated in the pathogenesis of growth retardation in inflammatory bowel disease. However, studies of end organ responsiveness to hormones in such patients are still rudimentary. A factor of considerable etiological prominence is that of calorie insufficiency superimposed on protein, vitamin, and mineral deficiencies. Therapy for growth retardation is usually successful when control of the disease is effective. Thus, when either medical or surgical therapy controls disease and permits oral nutritional restitution and adequate calorie and protein intake, growth and maturation are frequently reestablished. Usually, such nutritional restitution requires the use of oral formula supplements. Less commonly, adjunctive peripheral intravenous therapy with amino acids and lipid emulsions is required to initiate nutritional repletion. Rarely, total parenteral alimentation is indicated in patients in whom complete bowel rest is required. Surgery is indicated for complications such as obstruction, perforation, and fistula. Additionally, surgery should be considered for those whose growth retardation fails to respond to a maximal medical/ nutritional program as described here.

Specificity of initial synaptic contacts made on guinea-pig superior cervical ganglion cells during regeneration of the cervical sympathetic trunk.

1. Largely appropriate synaptic connexions are formed with neurones in the superior cervical ganglion at long intervals after interruption of the preganglionic nerve. In the present study we have assessed the accuracy of connexions during the early stages of re-innervation by observing end-organ responses to ventral root stimulation in vivo, and by recording intracellularly from ganglion cells during ventral root stimulation in isolated preparations. 2. Appropriate, but weak, end-organ responses were elicited by stimulation of the first and fourth thoracic ventral roots (T1 and T4) 15--30 days after freezing the cervical sympathetic trunk. 3. Intracellular recordings from ganglion cells during stimulation of the ventral roots C8--T7 in vitro showed that synaptic contacts are first re-established 8--11 days after freezing the preganglionic nerve. The proportion of re-innervated cells, and the strength of innervation of individual neurones, increased rapidly for up to about 3 months after nerve injury, but showed little change thereafter. Innervation remained weaker than normal even after 6 months. 4. Patterns of segmental innervation recorded intracellularly during the early stages of regeneration were similar to, but more restricted than normal. Even 13--19 days after interruption of the preganglionic nerve, neurones re-innervated by more than one spinal cord segment tended to be innervated by a contiguous subset of the spinal segments which contribute innervation to the ganglion. The incidence of neurones receiving innervation from a discontinuous segmental subset was about the same at early and late stages or re-innervation. 5. Throughout the course of nerve regeneration, re-innervated neurones tended to receive dominant synaptic input from axons arising at a particular spinal level, as do normal cells, with adjacent segments contributing a synaptic influence that diminished as a function of distance from the dominant segment. 6. The results of these experiments argue against the initial formation of imprecise connexions with subsequent retention of appropriate contacts and a loss of inappropriate ones. Rather our findings suggest that the re-innervation of ganglion cells proceeds by a gradual accumulation of synaptic connexions which are, from the outset, appropriate.

Vitamin-D-Dependent Rickets Type II

Studies were done to determine the cause for hypocalcemia, secondary hyperparathyroidism, osteomalacia and osteitis fibrosa cystica in a 22-year-old black woman. The patient had normal serum 25-hydroxyvitamin D (14 ng per milliliter) and markedly elevated serum 1,25-dihydroxyvitamin D (137 pg per milliliter). Vitamin D3, 4000 units per day for four weeks, increased the serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to as high as 29 and 297 pg per milliliter, respectively, and corrected the hypocalcemia and secondary hyperparathyroidism. The results suggest that the disorder results from impaired end-organ response to 1,25-dihydroxyvitamin D. We propose that the entity be called vitamin-D-dependent rickets Type II.

Re-innervation of guinea-pig superior cervical ganglion cells by preganglionic fibres arising from different levels of the spinal cord.

1. The ability of preganglionic axons to re-establish their normal pattern of synaptic connexions with superior cervical ganglion cells has been studied after section of the cervical sympathetic trunk.2. In vivo stimulation of the last cervical (C8) and the first seven thoracic ventral roots (T1-T7) 3-4 months after section of the trunk produced end-organ responses similar to those observed in normal animals.3. The pattern of innervation of individual neurones, determined by intracellular recording of synaptic potentials 4-9 months after cutting the sympathetic trunk, was also similar to that observed in normal neurones. Both normal and re-innervated ganglion cells were contacted by pre-ganglionic axons arising from C8 to T7, and each neurone was usually innervated by a contiguous subset of these segments.4. Re-innervated neurones, as normal cells, were typically dominated by the innervation from a particular spinal cord segment, with the adjacent segments contributing a synaptic influence that decreased as a function of distance from the dominant segment. This was true whether the amplitude of the post-synaptic potential, or the estimated number of contributing axons, was used as the criterion of segmental dominance.5. Re-innervated neurones, however, showed some abnormalities. The average number of ventral roots contributing innervation to each neurone was reduced from 4.1 to 3.0, and discontinuities in the sequence of innervating segments were more frequent than in normal neurones. Moreover, fewer preganglionic axons contacted each neurone after regeneration.6. A further difference between normal and re-innervated neurones during the period covered by these experiments was that axons from the more caudal spinal cord segments were less successful in re-establishing contacts with ganglion cells than those from the rostral segments. The more caudal the position of the preganglionic neurones, the more pronounced was this relative deficiency.7. Although anomalies of ganglion cell innervation were apparent, the basis for the restoration of normal functional effects appears to be the re-establishment of a pattern of innervation of individual neurones similar to that observed in normal ganglia.

Effects of thyroid hormone on plasma adenosine 3′,5′-monophosphate production in man

Thyroid hormone may nonspecifically modulate cAMP production and end-organ responsiveness to diverse hormonal stimuli. This hypothesis was tested in 18 hyperthyroid, 16 euthyroid, and 8 hypothyroid human subjects by measurement of cAMP in plasma and urine both in the basal state and following stimulation by epinephrine, parathyroid hormone, and glucagon—hormones known to act through cAMP. Supine fasting plasma cAMP (PcAMP) concentrations (mean ± SEM) were minimally elevated in the hyperthyroid patients (23.5 ± 1.3 n M, p < 0.001) when compared with the euthyroid (17.1 ± 0.6 n M) or hypothyroid (20.5 ± 1.7 n M) groups. Infusion of propranolol over 45 min failed to lower basal PcAMP concentrations in 5 hyperthyroid subjects. Epinephrine infusions (0.05 μg/kg/min) caused an exaggerated peak PcAMP response (58.7 ± 5.7 n M) in 5 hyperthyroid patients and a diminished response (27.3 ± 3.2 n M) in 5 hypothyroid patients when compared with 5 euthyroid subjects (42.3 ± 2.6 n M, p < 0.05). Administration of parathyroid hormone, 200 units intravenously, also caused significant differences in urinary cAMP excretion (μmole/hr) in the hyperthyroid (11.37 ± 0.96, p < 0.005) and hypothyroid patients (2.4 ± 0.58, p < 0.001) when compared to the euthyroid group (6.59 ± 0.74). Glucagon (1 mg intravenously) caused an enhanced peak PcAMP response in the hyperthyroid patients (514 ± 34 n M) compared with the euthyroid (240 ± 29 n M) or hypothyroid (223 ± 28 n M) groups ( p < 0.005). The PcAMP disappearance half-time following the peak response to glucagon was similar in all three groups, indicating that plasma sampling is probably a valid indicator of cAMP production. These studies demonstrate that thyroid hormone may modulate the response of multiple hormonal effects mediated by cAMP. The findings suggest a further cellular mode of action of thyroid hormone which may account for a number of the metabolic disturbances observed in patients with thyroid disease.

Enhanced end-organ responsiveness of the uremic kidney to the natriuretic factor

In chronic renal disease, the addition of a fixed quantity of Na to the extracellular fluid (ECF) will evoke a natriuretic response per nephron which is inversely proportional to the glomerular filtration rate (GFR). One factor that could contribute to this "magnification" phenomenon is an increased sensitivity of residual nephrons to physiologic natriuretic forces. The present studies were designed to examine this possibility. Natriuretic urine fractions from uremic patients, infused into one renal artery of normal rats, produced a small but significant unilateral natriuresis. Infusion of the same fractions in identical amount into remnant kidneys of stage II nonuremic rats (i.e., rats with a contralateral normal kidney in situ) produced a natriuresis in the remnant kidney only which was equivalent to that observed in the normal kidneys. The i.v. infusion of natriuretic fractions into stage II rats produced comparable increments in the fractional excretion of sodium (FENa) bilaterally. However, when the natriuretic fractions were infused into remnant kidneys of stage III rats (no contralateral kidney), deltaFENa was significantly greater than in the foregoing groups. Because stage III rats have increased control values for FENa, baseline FENa was increased to an equivalent level in normal rats by unilateral renal denervation. Natriuretic factor was administered into the ipsilateral renal artery. Although the natriuretic response was increased, it was significantly less than in the stage III remnant kidneys. The data support the view that the uremic state per se is associated with an enhanced responsiveness of the residual nephrons to the natriuretic factor found in the urine (and blood) of uremic patients.

Impaired Release of Parathyroid Hormone in Magnesium Deficiency

Parathyroid hormone release and end-organ responsiveness to parathyroid extract (PTE) were evaluated in a 25-year-old woman with magnesium deficiency associated with hypocalcemia and inappropriately low levels of serum immunoreactive parathyroid hormone (iPTH). End-organ responsiveness to PTE was demonstrated by increases in serum calcium and in urinary phosphorus, cyclic AMP, and hydroxyproline. When the serum calcium was increased from a baseline of 6.9 mg/100 ml to levels of 8.0 mg/100 ml and higher by calcium infusion, the serum iPTH decreased from the low normal range to below the limits of detectability. The intravenous administration of 3 mg/kg of body weight of magnesium led to an abrupt and striking increase in circulating iPTH with a 2-fold increase in one minute, a 6-fold increase in two minutes, and an 8-fold increase in five minutes. The very rapid increase in serum iPTH produced by magnesium infusion in this study suggests an effect of magnesium on hormone secretion rather than an effect on hormone synthesis. The evidence provided by this investigation indicates that the release of parathyroid hormone is impaired in magnesium deficiency and that the level of circulating calcium required for the suppression of parathyroid hormone secretion is lower than that in normal subjects.

Nephrology: An Annotated Bibliography of Recent Literature

Nephrology: An Annotated Bibliography of Recent Literature

In vivo aspects of progesterone distribution and metabolism

The end-organ response of any hormone is the result of many factors which precede the event, including biosynthesis, secretion, transport, distribution, and metabolism. These factors vary among different species. The metabolic clearance rate (MCR) of progesterone varies between 40 and 180 L./day/Kg. in man (60 to 70), monkey (40 to 50), rabbit (55 to 60), sheep (110), rat (120), and guinea pig (180). Major sites of clearance include liver, brain, and uterus. Specific metabolites of progesterone include 20 α-hydroxypregn-4-en-3-one (20αOHP) and 5 α-pregnan-3,20-dione (5α-DPH). Liver, brain, and uterine clearances, extractions, and conversions of progesterone to these metabolites have been studied in various species under apparent steady-state conditions. A specific hormone action of progesterone, the appearance of uteroglobin in the rabbit clerus, has also been studied in varying horomonal states (estrogen, estrogen plus progesterone, and progesterone alone). These have all been used as examples of progesterone distribution and metabolism.

Epinephrine-Induced Alterations in Urinary Cyclic AMP in Hyper- and Hypothyroidism

Although ratios of urinary cyclic AMP (cAMP) to creatinine were found in this study to be elevated in hyperthyroidism, as previously reported, this elevation appears to result primarily from a decrease in the rate of urinary creatinine excretion associated with the hyperthyroid state and not to be due to an increase in the urinary cAMP production rate. Indeed, there was no significant alteration observed in the urinary cAMP excretion found in 15 hyper-, 12 eu-, and 5 hypothyroid subjects. However, a slight, but significant increase in the 24-hour urinary cAMP excretion was noted in ambulating hyperthyroid subjects (8.5 +/- 2.4 muMol/day; normal 5.2 +/- 1.6 muMol/day; P less than .05). In contrast, the effect of the infusion of 0.05 mug/kg/min of epinephrine over a 2-hour period, resulted in a significantly greater rise in urinary cAMP excretion in hyperthyroid patients (0.83 +/- 0.07 muMol/h) compared to euthyroid subjects (0.53 +/- 0.4 muMol/h; P less than .005). Furthermore, hypothyroid subjects had no significant rise in urinary cAMP excretion after epinephrine infusion (P less than .001). Cardiovascular end-organ response to the epinephrine infusion was also greater in the hyperthyroid subjects and virtually absent in the hypothyroid group. These results suggest that there may be a significant alteration in the cAMP generating systems in states of thyroid hormone excess or insufficiency, and that provocative stimuli, such as epinephrine, may have its end-organ response modified by thyroid hormone effects on adenylate cyclase-cyclic AMP generating systems.

AGE-DEPENDENT VARIATION IN CARTILAGE RESPONSE TO SOMATOMEDIN

The role of variation in end-organ cartilage response to somatomedin (SM) as a significant determinant of growth velocity has been investigated.The response of costal cartilage of foetal and post-natal rabbits to SM has been assessed by simultaneously measuring 35S and 3H-thymidine uptake in vitro. Cartilage from rabbits of known growth rate at 23 and 30 days after conception (gestation 33 days), and at 1, 7, 17, 28, 39, 64, 90 and more than 200 days after birth, was studied. An excellent correlation between thymidine uptake and the growth velocity of the costal cartilage was shown. The uptake of 35S was also closely related to growth velocity and the 3H/35S ratio declined as growth rate slowed.Serum SM of each age group was measured by the porcine cartilage technique of Van den Brande. The post-natal serum SM increased progressively with age to an adult plateau.This study suggests that the growth velocity of costal cartilage is determined by the combined effects of end-organ response and serum SM stimulus.

Effects of catheterization of renal artery on renal function in the rat.

ArticleEffects of catheterization of renal artery on renal function in the rat.L G Fine, H Lee, D Goldsmith, H Weber, and M D BlaufoxL G Fine, H Lee, D Goldsmith, H Weber, and M D BlaufoxPublished Online:01 Dec 1974https://doi.org/10.1152/jappl.1974.37.6.930MoreSectionsPDF (939 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByActivation of renal vascular smooth muscle TRPV4 channels by 5-hydroxytryptamine impairs kidney function in neonatal pigsMicrovascular Research, Vol. 148A vibrator prevents streaming during close-arterial infusion into the kidneyShereen M. Hamza, and Susan Kaufman1 April 2004 | American Journal of Physiology-Renal Physiology, Vol. 286, No. 4Urineless estimation of glomerular filtration rate and renal plasma flow in the ratJournal of Pharmacological and Toxicological Methods, Vol. 36, No. 3Stereospecific evaluation of sotalol pharmacokinetics in a rat model: Evidence suggesting an enantiomeric interactionBiopharmaceutics & Drug Disposition, Vol. 15, No. 2Natriuretic activity of digoxin-like immunoreactive substance extracted from cord bloodLife Sciences, Vol. 42, No. 3The effect of water deprivation on the osmotic release of reninKidney International, Vol. 22, No. 4Improved techniques for acute and chronic cannulation of renal artery in the ratKidney International, Vol. 22, No. 1MorphophysiologyThe effects of aortic infusion of ethylene oxide on renal function in the ratToxicology and Applied Pharmacology, Vol. 38, No. 2Enhanced end-organ responsiveness of the uremic kidney to the natriuretic factorKidney International, Vol. 10, No. 5 More from this issue > Volume 37Issue 6December 1974Pages 930-3 https://doi.org/10.1152/jappl.1974.37.6.930PubMed4436227History Published online 1 December 1974 Published in print 1 December 1974 Metrics

Glandular end organ deficiency associated with secretion of biologically inactive pituitary peptides.

ABSTRACT A 23-yr-old man who had been treated 8 yr previously with radiotherapy and o,p′-DDD for rapidly progressive Cushing's syndrome associated with a suprasellar mass, presented with clinical evidence of hypothyroidism and laboratory evidence of hypoadrenalism and hypothyroidism. Immunoassayable plasma ACTH and TSH levels were elevated, but there was adequate end organ responsiveness to exogenous ACTH and TSH. Plasma ACTH levels exhibited a normal circadian variation, and responded markedly to insulin induced hypoglycemia and to Pitressin® administration, with no associated change in plasma cortisol levels. Plasma TSH levels increased following TRH administration, with no change in serum T3 levels. In contrast to immunoassay results, bioassay demonstrated markedly diminished levels of plasma ACTH and absent TSH, indicating that the target organ deficiencies were secondary to lack of stimulation by biologically active hormone. Following trypsinization of the patient's plasma, levels of bioassayable ACT...

Vitamin-D-Resistant Idiopathic Hypoparathyroidism

A patient with idiopathic hypoparathyroidism was resistant to the usual doses of ergocalciferol. She developed acute renal failure as a consequence of ureteral ligation with secondary renal parenchymal inflammation, and hypercalcemia was noted during the diuretic phase of renal failure. On complete recovery from that renal failure, she became sensitive to doses of ergocalciferol that had previously been ineffective. The occurrence of hypercalcemia in this patient with hypoparathyroidism suggests that the hypercalcemia of acute renal failure may not necessarily be dependent on parathyroid hormone, and in some cases may be related to alterations in vitamin D metabolism or end-organ responsiveness.

The short cardiac pre-ejection period: an index to thyrotoxicosis.

Systolic time intervals (STI) were determined from simultaneous records of the electrocardiogram, carotid pulse and phonocardiogram in 17 consecutive patients with thyrotoxicosis and sinus rhythm. None of the patients had clinical evidence of congestive heart failure. Intervals measured included electromechanical systole (Q-S 2 ), heart sound interval (S 1 -S 2 ) and left ventricular ejection time (LVET). From these, the pre-ejection period (PEP), isovolumetric contraction time (ICT) and Q-S 1 intervals were derived. Deviations (ΔSTI) of observed values from expected values (Weissler equations) for the same heart rate were obtained by subtraction. The mean deviation of the thyrotoxic patients ± sem from the normal population were ΔQ- S 2 * = –37.8 ± 4.2; ΔLVET = –4.0 ± 4.1; ΔPEP * = –33.8 ± 1.8. The shortening of PEP was due largely to a shortened ICT (ΔICT * = –27.2 ± 1.1). In eight patients studied serially during treatment the short PEP returned to the normal range concurrently with serum T 4 measurements. This study indicates that the PEP is a unique noninvasive measurement of biological end organ responsiveness with thyroid dysfunction; a short PEP is characteristic of uncomplicated thyrotoxicosis and serial changes in PEP may be a useful index of therapeutic response. * P &lt; .001.

Letter: Digitalis: digoxin availability, toxicity.

Comments and Corrections1 December 1973Digitalis: Digoxin Availability, ToxicityGORDON M. TRENHOLME, M.D.GORDON M. TRENHOLME, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-79-6-908_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In his article, "Digitalis Glycosides" (Ann Intern Med79:229-238, 1973) Dr. Doherty recommends adjustment of digitalis dosage in patients with thyroid disorders. He attributes the alteration in digitalis requirements in these patients to an altered end-organ responsiveness to digoxin. The data he presents in Figure 8 of his article, however, show significant differences in serum concentrations of tritiated digoxin in hypothyroid, hyperthyroid, and euthyroid patients given the same dose of digoxin. The differences in serum digoxin concentrations adequately explain the increased requirement for digoxin in hyperthyroid patients and the decreased requirement for digoxin in hypothyroid patients, without...Reference1. FORDOWENSCURD RJG: Kidney function in various thyroid states. J Clin Endocrinol Metab 21:548-553, 1961 CrossrefMedlineGoogle Scholar1. DOHERTYPERKINS JW: Digoxin metabolism in hypo- and hyperthyroidism. Studies with tritiated digoxin in thyroid disease. Ann Intern Med 64:489-507, 1966 LinkGoogle Scholar1. WAGNERCHRISTENSENSAKMAR JME: Equivalence lack in digoxin plasma levels. JAMA 224:199-204, 1973 CrossrefMedlineGoogle Scholar2. LINDENBAUMMELLOWBLACKSTONE JMM: Variation in biologic availability of digoxin from four preparations. N Engl J Med 285:1344-1347, 1971 CrossrefMedlineGoogle Scholar3. WOTMANBIGGERMANDEL SJI: Salivary electrolytes in the detection of digitalis toxicity. N Engl J Med 285:871-876, 1971 CrossrefMedlineGoogle Scholar4. SWANSONCACACECHUN MLG: Saliva calcium and potassium concentrations in the detection of digitalis toxicity. Circulation 47:736-743, 1973 CrossrefMedlineGoogle Scholar1. DOHERTY J: Digitalis assay by salivary electrolytes (editorial). N Engl J Med 285:1540-1541, 1971 CrossrefGoogle Scholar2. GOULDRAMANA REDDYGOMPRECHT LCR: Evaluation of digitalis toxicity by salivary electrolytes (letter). N Engl J Med 286:47, 1972 CrossrefMedlineGoogle Scholar3. FOGELMANLA MONTFINKLESTEIN AJS: Fallibility of plasma-digoxin in differentiating toxic from non-toxic patients. Lancet 2:727-729, 1971 CrossrefMedlineGoogle Scholar4. JOHNSONGREERMCCRERIE BH: Rate of dissolution of digoxin tablets as a predictor of absorption. Lan cet 1:1473-1475, 1973 CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: GORDON M. TRENHOLME, M.D.Affiliations: Walter Reed Army Institute of Research Duty Station: Laboratory for Tropical Diseases Joliet, Illinois PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 December 1973Volume 79, Issue 6Page: 908-910KeywordsAttentionGlycosidesThyroid diseasesToxicity ePublished: 1 December 2008 Issue Published: 1 December 1973 PDF downloadLoading ...

Mechanisms in the suppression of delayed hypersensitivity in the guinea pig by 6-mercaptopurine.

The mechanism of suppression, of delayed hypersensitivity to tuberculoprotein by 6-mercaptopurine (6-MP) was studied in guinea pigs. Under the conditions of the protocol, suppression of tuberculin delayed skin test reactivity was not associated with a significantly altered end-organ response to mediators of permeability. No significant alteration of in vivo lymphoid activity, as measured by reconstitution studies, was found. In addition, lymphoid cells from 6-MP-treated animals reacted in a fashion similar to those of placebo-treated animals with respect to (a) antigen-induced lymphocyte proliferation, (b) antigen-induced liberation of macrophage inhibitory factor activity, (c) direct inhibition by antigen of peritoneal exudate cell migration. Conversely, suppression was seen in levels of blood monocytes and in vitro function of macrophages from 6-MP-treated animals in several respects: (a) adherence to glass, (b) migratory rate, (c) phagocytic capacity. Therefore, it would appear that a ma]or mechanism of 6-MP-induced suppression of delayed hypersensitivity is through its action on effector cells.

Scleroderma-like lesions and the carcinoid syndrome.

Patients with scleroderma-like lesions secondary to metastatic secreting carcinoid tumors are different in several ways from patients with progressive systemic sclerosis. Scleroderma resulting from a carcinoid does not have an acrosclerotic distribution but develops first in dependent regions of the body following pronounced pitting edema. Raynaud's phenomenon is absent. Results of serological tests are negative. The typical internal organ changes of systemic sclerosis are not seen. Differences in end-organ (skin) response to exogenous serotonin creatinine sulfate suggest metabolic differences as well. It is probable that scleroderma arises by a different mechanism when associated with the carcinoid syndrome than when seen independently, and that this mechanism involves capillary permeability and tissue edema induced by serotonin or other active tumor metabolites.

Pathogenesis of hypocalcemia in primary hypomagnesemia: normal end-organ responsiveness to parathyroid hormone, impaired parathyroid gland function.

Hypocalcemia is a frequent feature of hypomagnesemia in man and several other species. To elucidate the cause of this hypocalcemia, we have studied a child with primary hypomagnesemia and secondary hypocalcemia during magnesium supplementation when he was normomagnesemic and normocalcemic and after magnesium restriction for 16 days when he quickly became hypomagnesemic (0.5 meq/liter) and hypocalcemic (3.4 meq/liter) and had positive Chvostek's and Trousseau's signs. Whether in the normomagnesemic or hypomagnesemic state, intravenous bovine parathyroid extract (PTE) 8 U. S. P. U/kg promptly caused transient increases in the urinary phosphate excretion, renal phosphate clearance and cyclic AMP excretion. The magnitudes of these responses were similar in the two states, and similar to those observed in a hypoparathyroid patient. When the patient was hypomagnesemic and hypocalcemic, intramuscular PTE, 8 U/kg at 8-h intervals for four doses promptly caused hypercalcemia. The findings indicate that the end-organs were responsive to parathyroid hormone. The concentrations of serum parathyroid hormone (PTH) were normal in the normomagnesemic state ranging from 0.15 ng/ml to 0.40 ng/ml. Serum PTH did not increase in the hypomagnesemic state in spite of hypocalcemia. Indeed, PTH became unmeasurable in four consecutive samples at the end of the period of magnesium restriction. The concentrations of serum calcitonin remained unmeasurable (< 0.10 ng/ml) throughout the study, implying that excess calcitonin was not the cause of hypocalcemia in magnesium depletion. The findings in this study support our thesis that magnesium depletion causes impaired synthesis or secretion of parathyroid hormone. This impairment would account for the hypocalcemia observed in the hypomagnesemic state.

Hypocalcemia in infants of diabetic mothers: Studies in calcium, phosphorus, and magnesium metabolism and parathormone responsiveness

Since infants of diabetic mothers are often delivered prematurely, it has been uncertain whether the hypocalcemia reported in them is related to maternal diabetes or to prematurity. In this study of 28 infants of diabetic mothers and 28 prospectively matched infants born to nondiabetic mothers, the incidence of hypocalcemia was significantly increased in the infants of diabetic mothers, even when gestational age and perinatal complications were taken into consideration. Renal studies demonstrated no differences in excretion of calcium, magnesium, and phosphorus between infants of diabetic mothers and control infants. Serum calcium levels were higher in diabetic mothers than in nondiabetic control subjects. Lower serum calcium levels and higher serum phosphate levels were present in infants of diabetic mothers postnatally. End organ responsiveness was shown by a calcemic and phosphaturic response to exogenous parathormone. It is speculated that relative maternal hyperparathyroidism leading to fetal hypoparathyroidism may be a factor in the pathogenesis of neonatal hypocalcemia in infants of diabetic mothers.