Reduction of anti-thyroid hormone autoantibodies through plasma exchange and corticosteroid therapy.

Anti-thyroid hormone autoantibodies are occasionally found in Hashimoto's disease. They can interfere with thyroid hormone assays. The authors report the case of a 35-year-old hypothyroid (TSH between 29 and 46 microIU/ml) female patient with Hashimoto's disease and surprisingly high free and total levels of plasma T4 and T3 assayed with different solid phase radio-immunologic kits. Two immunoenzymologic assay kits gave a T4 level close to the one expected. The presence of circulating anti-T4, T3 and reverse T3 autoantibodies was demonstrated by precipitating the corresponding tracers with the patient's serum in the presence of polyethylene glycol without heterologous antibodies. The replacement treatment of 150 micrograms l-thyroxine allowed normalization of TSH at 3.4 microIU/ml, but the patient remained tired and anxious, with headaches and tachycardia. After discontinuing treatment for one month a series of four plasma exchanges was carried out in six days. After the first exchange the binding percentages were already much lower and went even lower after the other exchanges. After the fourth one, the free T4 and T3 levels were closer to the expected levels:7.3 pmol/l (N:10-30 pmol/l) and 4.3 pmol/l (N:3-9 pmol/l). Treatment by prednisone made it possible to maintain the percentages of binding to the three tracers for two weeks at the levels reached after the fourth plasma exchange. Two months after discontinuing corticosteroid treatment they returned to the initial levels and were again interfering with the free T4 and T3 assays. This finding suggests that usefulness of the thyroid hormone immuno-enzymologic assay, which apparently is not affected by the anti-thyroid hormone autoantibody interference.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid stimulating antibodies in sarcoidosis.

OBJECTIVES: Thyroid disorders, particularly euthyroid goiters and hyperthyroidism, can be observed in sarcoidosis. The aim of this study was to analyze the presence of thyroid stimulating antibodies (TSAb) in 21 patients with sarcoidosis. 12 patients out of 21 had simultaneous euthyroid goiter. The others were euthyroid and free of goiter. METHODS: The TSAb testing was carried out using the rat thyroid fragment perifusion technique. Thyroid response to IgG was determined by the mean rate of T4 release (R) during a 30-min perifusion and the secretion peak (Imax). Antibodies inhibiting TSH binding to its receptors were also looked for. RESULTS: Ten patients were TSAb+ and eleven were TSAb-. There was no difference between the TSAb+ and TSAb- groups in the clinical parameters for sarcoidosis, nor in the number of goiters found (n = 6 for both groups). In 5 out of the 6 cases where goiter was present in the TSAb+ group it was homogeneous and diagnosed at the same time as or after the first signs of sarcoidosis, whereas in 5 out of the 6 cases of goiter in TSAb- patients, it was nodular, diagnosed before sarcoidosis in 3 of them, endemic in one of them, and familial in another. The search for antibodies inhibiting TSH binding to its receptors was negative in 10 out of 21 patients tested. CONCLUSION: Although the presence of thyroid-stimulating antibodies in the serum of patients with sarcoidosis, found here for the first time, remains to be explained, it pleads in favor of the immunologic nature of the association of sarcoidosis with thyroid disorders.

Leydig cell tumor estrogen secretion: suppression by a gonadotropin releasing hormone agonist.

A 35-year-old patient and a 48-year-old patient with a benign feminizing Leydig cell tumor were treated just before orchiectomy with a GnRH agonist, respectively buserelin, administered subcutaneously for 7 days (500 micrograms/8 h) and intranasally for the following 7 days (400 micrograms/8 h), and long acting détryptoréline in a single im injection of 3.75 mg. After 10 days of treatment, breast pain was relieved. In the first patient, serum immunoassayable FSH and LH first rose and reached a peak by the first day, then decreased to nearly basal values; they unexpectedly rose again and the second peak was as high as the first one; they again decreased just before orchiectomy. The bioassayable to immunoassayable LH ratio rose and reached a peak on day 3; then it decreased and reached a nadir before orchiectomy. In the second patient, after the initial increase, FSH and LH decreased regularly with no subsequent increase. In both patients, an increase in plasma testosterone (T) and estradiol (E2) followed the first gonadotropin peak, then T and E2 decreased progressively and reached castration levels. It was thus possible to strongly inhibit both E2 tumoral secretion and T secretion. Our findings suggest that E2 tumoral secretion inhibition by GnRH agonists might be proposed as an alternative treatment to surgery, i.e. for patients who refuse orchiectomy or for whom surgery is contraindicated.

Increased capillary permeability to albumin and diabetic neuropathy.

An increase in the capillary permeability to albumin (CPA) has been reported in diabetic patients. We observed this frequently with a non-invasive isotopic test derived from the Landis method, using 99mTc-albumin and measuring residual radioactivity externally after removal of forearm venous compression. Evidence of the independent effects of hypertension and microangiopathy on CPA has already been found. The present work was designed to investigate CPA using the same test on diabetic patients without retinopathy and clinical proteinuria. Some of these patients had objective clinical distal and symmetrical polyneuropathy. Neuropathy was clearly present in 10 of the 11 patients with an abnormal test unexplained by causes other than diabetes and in only one of the 17 patients with a normal test. The most frequent abnormality affected the late radioactivity disappearance curve, which probably reflects an impaired lymphatic wash-out of interstitial albumin. These results strongly suggest a link between peripheral neuropathy and diabetic functional microangiopathy. An elevated blood flow secondary to sympathetic nerve failure may induce an increase in CPA and a saturation of lymphatic pumping which could also be deficient due to impaired lymphatic innervation.

[Preoperative localization of parathyroid adenoma with technetium and thallium double-labeling scintigraphy. Difficulties related to associated thyroid lesions]. / Localisation préopératoire des adénomes parathyroïdiens par la scintigraphie en double marquage, technétium et thallium. Difficulties liées aux lésions thyroïdiennes associées.

Technetium and thallium double-labeling scintigraphy with image subtraction was carried out on 63 patients suspected of having primary hyperparathyroidism, with or without thyroid involvement. Forty-four patients had a normal thyroid image with technetium. The positive foci located by double-labeling in patients who were to undergo surgery always coincided with parathyroid adenoma. In the 16 cases where the initial diagnosis of hyperparathyroidism was not substantiated, the double-labeling test was normal. Thus for these 44 patients, scintigraphy sensitivity was 75% and specificity was 100%. Nineteen patients had an abnormal thyroid image with technetium. In 7 cases, image subtraction following double-labeling yielded uninterpretable data. In 12 other patients, the positive foci located outside the thyroid by double-labeling coincided with a parathyroid adenoma, whereas this was true for only one patient whose positive foci were located inside the thyroid; a parathyroid adenoma was not detected preoperatively in 4 patients. This double-labeling test is thus useful in locating parathyroid adenomas when technetium scintigraphy of the thyroid is normal; when it is abnormal, double-labeling is advantageous only in cases of extra-thyroid foci.

Influence of starvation on hormonal control of hypophyseal secretion in rats.

The reduction of hypophyseal hormone secretion during starvation is not completely understood. A previous study showed that the concomitant reduction of plasma TSH and T3 may be related to an increased sensitivity of the thyrotrope cell to T3. This suggests that regulation of hypophyseal secretion by peripheral hormones may be altered in starved rats. As GH and PRL secretion are under the control of thyroid and steroid hormones, the aim of the present study was to investigate the modification of feed-back control by T3 or E2 on hypophyseal secretion during starvation. For this purpose, pituitary GH, PRL and TSH contents and their plasma responses to TRH injection were measured in euthyroid, thyroidectomized (Tx), T3-supplemented Tx and E2-treated male Wistar rats before and after a 3-day starvation. TRH (0.25 micrograms/100 g) was injected iv through a chronically-implanted catheter. Our results show that GH content and GH plasma response to TRH are dramatically increased in T3-treated Tx starved rats, suggesting that starvation also increases the effectiveness of T3 influence on somatotrope cell secretion. By contrast, effects of T3 on PRL secretion remain unchanged during starvation. Furthermore, starvation in E2-treated rats is associated with a marked rise in the PRL and GH responsiveness to TRH without any significant change of hormonal pituitary content. This suggests that, in starved rats, E2 increases the effects of TRH on lactotrope and somatotrope secretion. No significant effect on TSH secretion could be demonstrated. Thus, starvation seems to act differentially on the feed-back mechanisms controlling the hormonal secretion of the three adenohypophyseal target cells to TRH.

Asymptomatic diabetic cardiomyopathy: a noninvasive study.

Forty-nine diabetic patients (26 type I and 23 type II), free of cardiovascular disease symptoms, were compared with 32 controls in a noninvasive study of left ventricular (LV) function. Absence of ischemic cardiopathy was confirmed by routine investigations and an exercise electrocardiogram using 12 leads with a thallium-201 myocardial scintigraphy. Diabetic patients had (1) a significantly prolonged mean isovolumetric relaxation time (IVRT) assessed by M-mode echocardiography and phonomechanography; (2) a significantly reduced E-F slope; (3) an increased mean Weissler index (pre-ejection period/LV ejection time). The IVRT and E-F slope abnormalities reflect increased myocardial stiffness and impaired LV compliance. The increased Weissler index reflects impaired myocardial contractility. These abnormalities were not related to sex, age, duration of diabetes or to the presence or extent of complications. No significant difference was found between diabetic patients and controls for mean diastolic and systolic LV diameters, thickness of the posterior wall or of the interventricular septum, assessed by echocardiography, or for the ejection fraction, determined by radionuclide angiocardiography. Finally, more than half of the patients with a frankly abnormal IVRT, Weissler index and E-F slope had had diabetes for less than 5 years, some even less than 2 years, without complications. These data show: (1) evidence of LV dysfunction specific to diabetes and unrelated to ischemic cardiopathy and hypertension; (2) the possible involvement of a metabolic factor in this early asymptomatic LV abnormality rather than microangiopathy.

Isotopic test of capillary permeability to albumin in diabetic patients: effects of hypertension, microangiopathy, and duration of diabetes.

Capillary permeability to albumin (CPA) was studied by performing an isotopic noninvasive test with venous compression on 87 nonselected diabetics with no edema, no cardiac failure, and no peripheral vascular disease. Excessive albumin retention (AR greater than or equal to 8%) ten minutes after removal of the compression was found in 27 patients (31%). The radioactivity disappearance curve was then analyzed using the Fast Fourier Transform (FFT). An abnormal isotopic CPA test was thus found in at least 45 out of the 87 patients. The prevalence of an abnormal test was not different in type 1 and type 2 diabetics. We studied the independent effects of hypertension, presence of specific clinical signs of microangiopathy (retinopathy and/or significant proteinuria), and duration of diabetes. Among diabetics free of specific clinical signs of microangiopathy, the prevalence of an AR greater than or equal to 8% was significantly higher in those with hypertension (11/19) than in those with normal blood pressure (2/28) and in nondiabetic hypertensive patients (0/16). Among normotensive diabetics, the prevalence of an abnormal test was higher, but not significantly, in patients with specific clinical signs of microangiopathy (8/11) than in those free of them (7/18). Seven normotensive diabetics without specific clinical signs of microangiopathy had an abnormal test; five of them had had diabetes for more than five years. The prevalence of diabetes of more than five years duration was significantly higher in patients with an abnormal test (35/45) than in normotensive diabetics free of specific clinical signs of microangiopathy with a normal test (4/11).(ABSTRACT TRUNCATED AT 250 WORDS)

Is thyrotropin-releasing hormone receptor involved in thyrotrope adaptation to starvation?

The aim of the present study was to delineate the involvement of TRH receptors in the thyrotrope adaptation to starvation (i.e. plasma TSH and thyroid hormone decrease, increased sensitivity to T3) by measuring [3H]TRH binding in euthyroid, hypothyroid and T3-substituted rats (175 ng/100 g body weight). Our results show that in euthyroid rats, starvation does not significantly modify either the affinity or the number of pituitary binding sites. In hypothyroid and T3-substituted rats, starvation does not alter the negative control exerted by T3 on the number of TRH binding sites. Our data indicate that the adaptation of thyrotrope to starvation does not primarily result from alterations of TRH binding sites.

Endocrine investigations in two cases of feminizing Leydig cell tumour.

Two patients, aged 32 and 35 years, presented with gynaecomastia and a unilateral testicular tumour which proved to be a Leydig cell tumour. Pre-operative samples taken at 08.00 h on different days showed marked elevation of plasma oestradiol in the first patient, and very slight irregular oestradiol elevation in the second, plasma oestrone within the normal range in both patients, reduced plasma testosterone in the first patient and reduced or normal testosterone in the second, and low or low-normal serum LH and FSH in both patients. One of the patients received an oral dose of 100 mg of clomiphene citrate for 3 consecutive days which induced a rise in LH and FSH and a decrease in the 17-hydroxyprogesterone/androstenedione ratio. These data suggest the inhibiting effect of endogenous hyperoestrogenism on testicular steroidogenesis owing to both the reduction of gonadotropin secretion and a direct local negative effect on C 17,20-lyase. After human chorionic gonadotropin stimulation, oestradiol response was increased and abnormally prolonged, a finding which may be helpful when diagnosing a feminizing Leydig cell tumour; testosterone reached normal values. After removal of the tumoural testis, gynaecomastia regressed within a few days, gonadotropins increased, oestrogens dropped, testosterone and 5 alpha-dihydrotestosterone normalized in one patient but remained low in the other at day 30. The Leydig cells outside the tumour appeared morphologically normal, but the count gave evidence of juxtatumoural Leydig cell hyperplasia in areas where the tumour was well encapsulated while showing a significant reduction at a distance from the tumour and in the contralateral testis by comparison with control testes.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative value of 24-hour ECG monitoring and standardized maneuvers in the detection and exploration of cardiac autonomic neuropathy in diabetics]. / Intérêt comparé de l'enregistrement ECG des 24 heures et des manoeuvres standardisées dans la détection et l'exploration de la neuropathie autonome cardiaque chez le diabétique.

24-hour continuous electrocardiographic ECG monitoring and standardized tests were performed to detect cardiac autonomic neuropathy in diabetic patients. Thirty-eight patients, with a mean duration of diabetes of 10 years, twenty-five IDDM and thirteen NIDDM, and thirty-two controls, with no illness or treatment which could alter the heart rate (HR), were studied. Five standardized tests were performed. Three tests investigated parasympathetic function: variations of HR during Valsalva manoeuvre, deep breathing and standing. The other two tests investigated sympathetic function: detection of orthostatic hypotension and blood pressure response to sustained handgrip. Parasympathetic HR control was impaired in twenty-nine patients, together with impaired sympathetic cardiovascular control in seven. According to the 6 indices studied, 24-hour ECG monitoring detected abnormalities in only eight patients. Mean minimum 24-hour HR and mean sleeping HR were elevated in the group of patients whose five standardized tests were normal and in the group of patients with impairment of both parasympathetic and sympathetic cardiovascular control, but not in the group of patients with only impaired parasympathetic HR control. This study suggests that 24-hour ECG monitoring is a less sensitive test of cardiac autonomic neuropathy than standardized tests. Moreover, it shows HR abnormalities that are not specific to cardiac autonomic neuropathy.

Feminizing Leydig cell tumor: endocrine and incubation studies.

A 32-year-old patient with a history of surgery for left gynecomastia four years previously presented with right gynecomastia; a tumor in the left testis proved to be a Leydig cell tumor. Preoperative investigations showed elevated but variable levels of plasma estradiol (E2) and estrone (E1), and reduced serum LH and FSH and plasma testosterone (T). After hCG stimulation, E2 response was increased and abnormally prolonged; T reached normal values, which has predictive value for a return to normal of post-operative T level. After left orchiectomy, gynecomastia regressed within a few days, gonadotropins increased by day 2, estrogens dropped by day 2 and were normal at day 7, T and 5 alpha-dihydrotestosterone dropped at day 2 but reached normal levels at day 16. Pathophysiology of these hormonal data are discussed. An incubation procedure with 3H testosterone showed an aromatase activity 21 times greater in the tumor than in normal peritumoral tissue, while the percentage of the volume occupied by Leydig cells was 34 times higher. This suggests that the aromatase activity of a single tumor cell is very similar to that of a normal Leydig cell. Furthermore, evidence of juxtatumoral Leydig cell hyperplasia in areas where the tumor was well encapsulated suggests the existence of a factor stimulating Leydig cell multiplication.

Detection of thyroid-stimulating antibodies in thyroid diseases, employing rat thyroid fragment perifusion.

The technique of perifusing rat thyroid fragments was used to investigate the presence of thyroid-stimulating antibodies (TSAb) in the sera of 48 patients. Response to IgG was measured by determining the mean rate of release of T4 (R) during a 30-min perifusion and the secretion peak (Imax) by means of samples taken every 5 min. Values found to be above the mean + 2 SD of the control values of R or Imax were considered to be positive. TSAb were found in all the 17 patients with untreated Graves' disease (GD) and in the 2 treated with antithyroid drugs, but not in the 3 who had undergone surgery or 131I treatment or in the 2 on corticosteroid treatment. TSAb were also found in 2 out of 3 patients with untreated nodular toxic goiter (UNTG) and in 6 out of 8 with diffuse nontoxic goiter (DNG) but at lower levels. In the untreated GD group, R and Imax correlated significantly with the corresponding IgG concentrations (from 90 to 800 micrograms/ml), suggesting TSAb activity which can be compared from one patient to another. TSAb activity did not correlate with thyroid function tests in any group. In all the groups it induced an early secretion peak followed by a decreasing response throughout the stimulation period, as was previously found with 65 mIU/ml TSH. The specificity of this technique was verified by five different control methods: the perifusion technique was checked by using KRBG buffer alone; sera were studied from a group of healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of prolactin involvement in corticosteroid secretion.

In mammals prolactin can modify adrenal steroidogenesis. Its trophic effect on adrenal cells where prolactin receptors have been identified suggest a direct impact upon corticosteroid biosynthesis. In man, this role of prolactin remains controversial. The purpose of our study was to investigate the effects of chronic hyperprolactinemia on basal and stimulated corticosteroid hormone secretion. Seven women with untreated chronic hyperprolactinemia (HPRL) were included in the study. In each of them, a beta 1-24 ACTH test was performed on a normal and low Na+ diet for 4 days. Basal and ACTH-stimulated cortisol, aldosterone, deoxycorticosterone and 17 hydroxyprogesterone secretion were not significantly different in HPRL and NPRL women. These results do not support evidence for any significant role of prolactin upon corticosteroid biosynthesis in man. They also suggest that prolactin is not the pituitary factor which modulates ACTH or low Na+ diet stimulated corticosteroid secretion.

Sensitivity of thyrotropin (TSH) secretion to 3,5,3'-triiodothyronine and TSH-releasing hormone in rat during starvation.

The mechanisms by which plasma T3 and TSH decrease after a 3-day starvation period are not completely understood. In this study we tested the hypothesis of a possible modification in the sensitivity of thyrotroph cell to T3 and/or TRH. For that purpose, TRH tests were performed before and after a 3-day starvation in euthyroid, thyroidectomized, and T3-treated (75 or 175 ng/100 g BW) thyroidectomized male Wistar rats. TRH (10 to 500 ng/100 g BW) was injected iv through a chronically-implanted catheter. In another set of experiments, hypophyseal TSH content was also determined. Our results showed that after a 3-day-starvation plasma TSH decreased in all except hypothyroid rats; TSH responsiveness to TRH was unchanged in euthyroid rats but was increased in hypothyroid rats; and the T3-dependent increase in TSH responsiveness to TRH was significantly amplified. Moreover, there was a significant positive correlation between TSH responsiveness to TRH and hypophyseal TSH content. These results suggest that starvation induces an increased sensitivity of thyrotroph cell to T3.