Myxedematous Patient Research Articles

Henry Harrower and the turbulent beginnings of endocrinology.

The emergence of new medical science in the mid-19th century was usually greeted with derision by "practical men" who saw their academic colleagues as elitist intellectuals whose work bore little or no relation to the rough-and-tumble aspects of patient care. This schism, which was nowhere greater than in the field of endocrinology, widened in 1891 when a myxedematous patient was dramatically restored to health after the administration of a thyroid extract. On the one hand, academicians-who saw this result as a triumphal example of the transference of laboratory studies to the bedside--were encouraged to pursue further studies in endocrine pathophysiology and pharmacology. On the other hand, medical practitioners began to believe that crude extracts from glands or other organs, when prescribed as orally administered mixtures, were effective for the treatment of most human ailments. The organotherapeutic forces were ably championed by Henry R. Harrower, MD, a manufacturer as well as a dispenser of organotherapeutic products. For some years, the claims of the organotherapists remained unchallenged. Finally, in 1921, Harvey Cushing, pioneer neurosurgeon and endocrinologist, launched a crushing assault on the purveyors of pluriglandular therapy. These attacks continued over ensuing years, and organotherapy fell into disrepute. Nevertheless, the assertions of "practical men" have not subsided; rather, we are now confronted by insistent claims for a bewildering array of herbal remedies, over-the-counter hormonal products, and alternative therapies.

培養皮膚線維芽細胞におけるLDLリセプターに対する甲状腺ホルモンの影響

An inherited deficiency of low density lipoprotein (LDL) receptors in familial hypercholesterolemia (FH) is assumed to be the cause of the decreased catabolism of LDL. In contrast, in hyperthyroidism there is an increased rate of LDL catabolism. A 58-year-old female patient with heterozygous FH revealed a normal level of serum cholesterol (193mg/dl) in coexistence of hyperthyroidism. After the therapy of hyperthyroidism with radioiodine the patient's lipid profile revealed an increased concentrations of cholesterol (Whole serum 338, VLDL 68, LDL 199, HDL 42mg/dl). There was a significant inverse correlation between her serum cholesterol levels and her serum thyroxine levels (r=-0.815, p<0.01).Since LDL catabolism in vivo is thought to be mediated largely through the LDL receptor, the role of thyroid hormone in this receptor-mediated degradation of LDL was studied in human skin fibroblasts. Confluent cells were exposed to a medium containing 5% lipoprotein deficient serum prepared from a myxedematous patient by ultracentrifugation for 2 days with or without added triiodothyronine (T3). After 125I-LDL was added, the cells were incubated for 6 hours at 37°C for the determinations of 125I-LDL uptake and degradation. In the cells from 2 normal subjects, LDL uptake and degradation was enhanced 29% by preincubation with T3 (1.0μg/ml). In the cells from 2 heterozygous patients with FH, LDL uptake and degradation was enhanced 23% with T3(1.0μg/ml). While, in the cells from 2 homozygous patients with FH, no effect of T3 was observed. These results suggest that normal serum cholesterol levels in a heterozygous patient with FH result in part from an enhanced degradation of LDL by extrahepatic cells exposed to excess thyroid hormone.

Myxedema psychosis: Clinical and biochemical changes during recovery

A myxedematous patient with a panpsychotic reaction is described. Results of serial psychological testing, ankle reflex measurement and urinary catecholamine and 17-OHCS determinations are presented. As the patient gradually became euthyroid, mental disturbance, ankle reflex time, and urinary excretion of catecholamines and corticosteroids also gradually decreased. Thyroid hormone improved mental functioning before exerting major peripheral effects. Abnormally high urinary excretion of epinephrine and norepinephrine was similar to that described in psychotic depression and in acute schizophrenia and was apparently related to psychological distress. Normetanephrine levels were also elevated in contrast to the findings in psychotic depression. Corticosteroid levels were quite low despite severe psychological distress, probably as an effect of prolonged hypothyroidism on the adrenal cortex.

Failure of TSH Antisera To Neutralize Long-Acting Thyroid Stimulator

Rabbits were immunized against bovine pituitary TSH (Thytropar) and against human pituitary TSH. The antiserum to bovine TSH, at concentrations as low as 1 in 25, completely neutralized 1.0 mU/ml of U.S.P. Thyrotropin Reference Substance (bovine). Partial neutralization occurred with an antiserum concentration of 1 in 125. Similar concentrations of the antiserum to human pituitary TSH were effective against the TSH present in serum from a myxedematous patient. The bovine TSH antiserum had only weak action against the TSH in myxedema serum, partial neutralization occurring at an antiserum concentration of 1 in 2. Similarly, the human TSH antiserum was only weakly active against bovine TSH, partial neutralization occurring with an antiserum concentration of 1 in 5. Neither antiserum had any demonstrable action against long-acting thyroid stimulator present in serum from a thyrotoxic patient.

Neurologic manifestations of myxedema.

Headache Headache, a vague, subjective symptom, often encountered, but difficult to evaluate, seems to occur quite frequently in the myxedematous patient although the underlying mechanism is not clear. The headache is usually described as chronic, recurrent, bilateral and diffuse, and quite unlike sinusitis, migraine, eyestrain and the incidental headache. In the Georgetown series 14 per cent of 109 patients complained of headache. It is admitted that most of the studies incriminating headache and myxedema are purely clinical observations, lacking adequate controls, satisfactory diagnostic criteria and clear historical delineation from other types of headache.78 , 79 For example, Jones80 excluded all the usual . . .

Metabolic effects and therapeutic applications of triiodothyropropionic acid.

The effects of mare than sixty analogues of thyroxine have been investigated in animals, and more than thirty analogues have been studied in humans. Animal studies have shown that structural alterations of the thyroid hormone cause not only large variations in potency but also dissociation of the various hormonal effects of thyroxine. Dissociation of thyroid horrrwnal effects has also been demonstrated in the human with triiodothyropropionic acid.The drug is satisfactory as maintenance therapy in myxedema and appears to have definite advantages in maintaining the myxedematous patient with angina pectoris. Triiodothyropropionic acid effects a 15 to 20 per cent drop in the serum cholesterol of about 80 per cent of euthyroid individuals with either elevated or normal cholesterol levels. Its administration in the proper dosage decreases elevated serum uric acid levels in both myxedematous and euthyroid individuals.

Separation of human thyrotropin from plasma by ion exchange chromatography.

ABSTRACT Thyrotropic activity was recovered completely from dialyzed mixtures of 7–35 ml. of human plasma and crude human pituitary preparations by chromatography on pH 7.2–7.8 Amberlite IRC-50 columns, eluted with a gradient to 2 M sodium chloride. This procedure was successful over a range of 0.08–17u.s.p. milliunits per milliliter of plasma and separated thyrotropin from the nondiatyzable substances in plasma interfering with the bioassay method used. Endogenous thyrotropic activity (0.2 milliunit per milliliter) was measured in the plasma of a myxedematous patient by this method. The active fraction was in the same location in the elution chromatogram as the activity recovered from mixtures of human plasma and crude human pituitary thyrotropin, or from the latter alone.

Treatment of a lingual goiter with triiodothyronine.

ABSTRACT This report concerns a myxedematous patient, aged 55, with severe dysphagia produced by a large vascular tumor at the base of her tongue. Radioiodine was useful in establishing a diagnosis of lingual goiter. However, in dosages which could be tolerated by the patient, it could not be concentrated sufficiently for therapeusis. Since the gland was too vascular and large for easy surgical removal, the patient was given 75 μg. of triiodothyronine per day, both for treatment of the myxedema and for shrinkage of the goiter via suppression of pituitary thyrotropic activity. The goiter shrank remarkably within six weeks and the patient became asymptomatic. Desiccated thyroid was then substituted as maintenance therapy. Such treatment is recommended: 1) as preoperative preparation when surgery is necessary, or 2) as the sole treatment of large lingual goiters.

Effect of thyroid therapy on the tone and contractility of the urinary bladder in hypothyroidism.

INTRODUCTION IT IS a well known fact that in myxedema there is hypotonia of the heart (1), of the uterus (2), of the alimentary canal (manifested as megaduodenum (3) or megacolon (4, 5)), and of the gallbladder (6, 7). Evans (8) mentions the case of a myxedematous patient who had difficulty at the beginning of micturition and pollakiuria, and in whom volumes of residual urine ranging from 700 to 1,500 cc. were obtained by catheterization of the bladder. A similar case was observed by Escamilla (9). All these manifestations of hypotonia of the visceral muscles disappear after treatment with desiccated thyroid. These facts led us to make a graphic study of the tone of the urinary bladder in myxedema, employing the method which Alvarez and Caldeyro- Barcia (10) developed for the study of the tone of the pregnant uterus. In this report we present the results obtained in 3 patients with primary thyroid insufficiency.

Effect of phosphate in enhancing the action of triiodothyronine.

IT HAS been reported from our laboratories that the intravenous administration of triiodothyronine (T-3) to a myxedematous patient was followed by a marked rise in oxygen consumption within seven hours. The intravenous administration of triiodothyronine in comparable, or even greater doses, to intact dogs has not in our hands been observed to cause any acute elevation in oxygen consumption. However, during the course of studies in dogs designed to determine the effect of triiodothyronine on the oxygen consumption of kidney tissue, it was observed that the intravenous administration of triiodothyronine to animals receiving a continuous infusion of phosphate produced a marked and rapid increase in oxygen consumption and death from what appeared to be a thyroid storm. These observations suggested that a phosphate load enhanced the action of this thyroid hormone.

Proteinuria and Hypothyroidism

SINCE both hypothyroidism and renal disease may have in common the findings of periorbital edema, lassitude, weakness and anemia, it is of some interest to know whether albuminuria is also encountered in both disorders. Although current textbooks of medicine seem unanimous in stating that albuminuria may often be found in hypothyroidism1 2 3 4 5 a careful review of the literature does not definitely substantiate this. The description of hypothyroidism by Sir William Gull in 1873 reported the urine as normal in the 2 cases described.6 In Murray's review of the life history of the first myxedematous patient treated with thyroid, as quoted by . . .

Therapeutic activity of desiccated thyroid substance, sodium L-thyroxine and D,L-triiodothyronine: A comparative study

T HE development of a commercially practical method for synthesizing thyroxine,’ the identification of 3,5,3’-L-triiodothyronine in human plasma2 and the recognition of its physiologic importance 3,4 have stimulated considerable interest in the re-evaluation of thyroid hormone therapy. Several reports have already appeared describing the oral or intravenous use of sodium L-thyroxine,617 L-triiodothyroninell1a,16--20 and D,L-triiodothyronine16*17 in patients with myxedema. That desiccated thyroid substance, thyroxine and triiodothyronine are all hormonally active in such trials is universally agreed. However, reported investigations with the best human test subject, the myxedematous patient, are not yet of sufficient number to settle completely the relative intensity, speed and duration of action, as well as the variations in responsiveness. The present report deals with experiences with twelve patients suffering from adult myxedema. The manner of approach differs in one respect from most if not all of the other studies of human subjects. In the present work, following attainment of a euthyroid state under therapy, the patient has been allowed to lapse into a measurable degree of hypothyroidism prior to the beginning of therapy with the same or a second thyroid preparation. This has afforded us repeated comparisons under conditions as nearly identical as possible for us to achieve. average age of fifty-three and a half years, were the subjects of this study. Each had the classical symptoms and signs of myxedema. The diagnosis was further confirmed by determination of the basal metabolic rate, serum cholesterol and, in some instances, the serum protein-bound iodine, thyroidal uptake of radioactive iodine and the twenty-four hour excretion of creatine of a person on a meat-free diet. Manifestations of myxedema had been present for periods varying from six months to twelve years prior to recognition, with an average duration of 3.7 years. In seven subjects the development of myxedema was spontaneous; in three it followed thyroidectomy; in one radiation therapy, and in the remaining one the prolonged use of an antithyroid compound. The initial basal metabolic rates of the group ranged from minus 16 to minus 47 per cent, with an average of minus 34.9 per cent. Serum cholesterol values, performed by the method of Pearson, Stern and McGavack,23 varied from 291 to 443 mg. per 100 cc. with an average of 358.4 mg. per 100 cc. The serum protein-bound iodine, carried out by the method of O’Neal and Simmsz4 was initially 3.9 pg. per 100 cc. or less. Because of the changes initially present, serial determinations were made throughout the study, as well as repeated estimations of the urinary 17-ketosteroids, blood counts, electrocardiograms and cardiac roentgenograms.

The tolerance of patients with myxedema for thyroid.

THE myxedematous patient is said to be less tolerant than the normal subject to the administration of desiccated thyroid. Although this concept has long prevailed, objective support is meager. It has been suggested that the tolerance of the euthyroid patient derives from inactivation of the exogenous thyroid by the functioning thyroid gland (1, 2, 3). Others (4, 5) have observed in rat, dog and rabbit that thyroidectomy enhances the metabolic response to large doses of thyroid. The studies of Means and Lerman (6) indicate that the patient with myxedema has a striking initial response of the metabolic rate to desiccated thyroid, but that as the metabolic rate approaches normal, further response is comparable to that seen in normal subjects having similar metabolic rates. More recently Greer (7), after studying the radioiodide uptake of the human thyroid gland as influenced by administration of thyroid, suggested that the myxedematous and the euthyroid patient might be comparable in their responses, and that there is no inactivation of the administered thyroid by the gland. Riggs has recently expressed himself as being in complete agreement with Greer (8). Whether, in fact, there is any gross difference in response has been tested in the present study by the administration of desiccated thyroid to patients with myxedema in increasing doses until the point of drug-induced thyrotoxicity was reached.

Pregnancy in a patient with myxedema

Pregnancy in a myxedematous patient, before treatment with thyroid hormone, is recorded. The course and outcome of the pregnancy were uneventful. Other examples of normal pregnancy occurring in patients with myxedema and cretinism are cited.

A STUDY OF THE MECHANISM OF THE INHIBITION OF THE THYROID GLAND INDUCED BY INGESTION OF THYROID SUBSTANCE*†

THE ingestion of thyroid hormone depresses the activity of the thyroid gland. Farquharson and Squires (1) reported that, upon cessation of ingestion of thyroid substance by normal individuals, the basal metabolic rate (BMR) fell to below pretreatment control levels. In a myxedematous patient, the BMR fell to pretreatment levels and not below. Riggs et al. (2) and Winkler et al. (3) illustrated the same phenomenon by demonstrating a fall of serum protein-bound iodine (PBI) to below normal levels in euthyroid subjects after discontinuance of thyroid medication. Recently, Greer (4) found that the uptake of radioactive iodine (I131 uptake) by the thyroid gland of normal persons was markedly inhibited by the ingestion of desiccated thyroid; it returned to normal within four weeks after cessation of the thyroid ingestion. He noted that the daily ingestion of 60–180 mg. of thyroid depressed the I131 uptake in over 90 per cent of his subjects. Last year, a patient with a functioning struma ovarii was studied in t...

THE DURATION OF ACTION OF SINGLE DOSES OF THYROID HORMONE1

REPORTS on the duration of action of thyroid compounds vary considerably. As early as1904, Magnus-Levy reported that the effects on the basal metabolic rate of thyroid feeding in myxedematous patients lasted 80 days. Kendall (1917), probably the first to inject pure thyroxin intoanimals, compared the effects of small daily doses and a single large dose. A goat receiving 9 mg.daily was dead at the end of 11 days; the single injection of 150 mg. in another goat produced changes in the electrocardiographic tracings which returned to normal in 2 or 3 days. In contrast to-these results, Kendall (1923) reported that a single dose of thyroxin in a myxedematous patient would exert its physiologic effect for 5 to 6 weeks. Boothby, Sandiford, Sandiford, and Slosse (1925) showed that the rate of decline of the basal metabolism following withdrawal of thyroid administration in myxedematous patients was a straight line, when plotted on semilogarithmic paper.

Management of the myxedematous patient with symptoms of cardiovascular disease

1. 1. In myxedema, variations in blood proteins are of no value in following the results of therapy. 2. 2. In myxedema with cardiac failure, variations in the weight of the patient, his basal metabolic rate, and his circulation time are of no value in ascertaining his thyroid status at any particular moment. 3. 3. When taken in conjunction with the initial level, i.e., before treatment, the total blood cholesterol has been a very reliable method of ascertaining the degree of thyroid sufficiency in myxedema with cardiac failure, for it is uninfluenced by the latter in the absence of signs of liver damage. 4. 4. An increase in capillary permeability is a constant feature of myxedema. A decrease from the initially high permeability is one of the earliest and most constant signs of improvement. 5. 5. Thyroid therapy must be used cautiously in myxedema with cardiac failure. The dose should be sufficiently small to avoid an aggravation of the cardiac phenomena, but, no matter how severe the failure is, some hormone should be used. An effort should be made to make the initial dose sufficiently large to effect a decrease in capillary permeability. 6. 6. Satisfactory initial daily doses of thyroid hormone, as desiccated thyroid substance, have ranged from 0.05 to 1 grain. In thirteen cases, stabilization was attained through the daily use of amounts varying from 0.5 to 3 grains.

THE EFFECT OF THYROID THERAPY ON CHILDREN

Thyroid extracts are known for their effect on metabolism. Not only is the weight curve affected, but there is a greater excretion of water, salts and nitrogen, and growth and regeneration are promoted. This is most strikingly seen in the cretin or myxedematous patient. Associated with these metabolic changes is the elevation of the basal metabolic rate from a low to a normal level. Before the advent of tests of basal metabolism, the effects of thyroid action were judged more or less clinically; that is, by improved mentality, increased irritability, decreased sluggishness and alterations in growth phenomena. Today, however, the association between studies of basal metabolism and of thyroid disease is so close that many consider scientific proof of thyroid disease lacking unless an abnormal basal metabolic rate has been demonstrated.¹ As a corollary to this close association, the general impression has been that even in normal persons, exhibition