Bruce D. Weintraub

Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.

BACKGROUND To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

A Mutation in the POU-Homeodomain of Pit-1 Responsible for Combined Pituitary Hormone Deficiency

Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Mutations in the gene encoding Pit-1 have been found in two dwarf mouse strains displaying hypoplasia of growth hormone, prolactin, and thyroid-stimulating, hormone-secreting cell types in the anterior pituitary. A point mutation in this gene was identified on one allele in a patient with combined pituitary hormone deficiency. Mutant Pit-1 binds DNA normally but acts as a dominant inhibitor of Pit-1 action in the pituitary.

Spectrum of Subclinical and Overt Hypothyroidism: Effect on Thyrotropin, Prolactin, and Thyroid Reserve, and Metabolic Impact on Peripheral Target Tissues

PURPOSE Subclinical hypothyroidism is found in about 7.5% of females and in about 3% of males. It appears to be a risk factor for atherosclerosis and for coronary heart disease and can affect various other target organs. The morbidity and clinical significance of subclinical hypothyroidism are controversial. Therefore, we evaluated the metabolic impact of progressive thyroid failure in patients with various degrees of hypothyroidism compared with control subjects. PATIENTS AND METHODS We investigated 86 female patients with the whole spectrum of subclinical hypothyroidism (n = 69) and of overt hypothyroidism (n = 17) and 52 euthyroid women as controls. All subjects underwent full medical and endocrine evaluations (including measurements of thyrotropin [TSH], TSH beta- and alpha-subunits, and prolactin before and after oral administration of thyrotropin-releasing hormone [TRH]) as well as lipid profiles and different tests of peripheral thyroid hormone action. All hypothyroid patients were divided into five categories according to disease severity: grades I to III (subclinical hypothyroidism, with normal thyroxine [T4] levels) and grades IV and V (overt hypothyroidism, with diminished T4). RESULTS In grade I subclinical hypothyroidism (basal TSH below 6 mU/L), we found significant changes in the clinical index (p less than 0.05), apoprotein A-I level (p less than 0.05), and stimulated prolactin level after oral TRH (p less than 0.001). The findings were similar in grade II (TSH 6 to 12 mU/L). Further changes could be demonstrated in grade III (TSH above 12 mU/L) with a definite elevation of ankle reflex time (p less than 0.001), serum myoglobin level (p less than 0.01), and, to a lesser extent, creatine kinase (p greater than 0.1). The mean low-density lipoprotein cholesterol (LDL-C) level showed an increase of 18%, which was not significant because of marked individual variations (p = 0.15). The frequency of elevated LDL-C levels was definitely higher in patients with grade III disease compared with the controls (42.9% versus 11.4%, p less than 0.05) and with patients with grades I and II disease. Total cholesterol, triglycerides, apoprotein B, and the systolic time intervals (pre-ejection period, corrected for heart rate [PEPc]) were clearly elevated only in overt hypothyroidism (grades IV and V) (p less than 0.01). CONCLUSION Subclinical hypothyroidism has significant effects on some peripheral target organs at an early stage (grades I and II), but affects LDL-C, skeletal muscle, and myocardial contractility only at a later stage (grades III, IV, and V). Our data of elevated LDL-C in grade III subclinical hypothyroidism provide a likely pathophysiologic explanation for the reported association of coronary heart disease with this syndrome. The impact of increased prolactin secretion, observed in subclinical hypothyroidism, on gonadal function and infertility has yet to be clarified. Therapy with thyroxine should be recommended in at least some patients with subclinical hypothyroidism. Patients with high TSH levels (above 12 mU/L) will require treatment because of the metabolic effects on several target organs. Before treatment is advocated in all patients with subclinical hypothyroidism, the benefits and long-term side effects of thyroid hormone therapy should be clarified by prospective studies in larger groups of patients.

Attention Deficit-Hyperactivity Disorder in People with Generalized Resistance to Thyroid Hormone

BACKGROUND Attention deficit-hyperactivity disorder is a well-recognized psychiatric disorder of childhood. Its cause is unknown, but there is evidence of a familial predisposition. Symptoms suggestive of this disorder have been reported in subjects with generalized resistance to thyroid hormone, a disease caused by mutations in the thyroid receptor-beta gene and characterized by reduced responsiveness of peripheral and pituitary tissues to the actions of thyroid hormone. We systematically evaluated the presence and severity of attention deficit-hyperactivity disorder in 18 families with a history of generalized resistance to thyroid hormone. METHODS We studied 49 affected and 55 unaffected family members; 52 were adults, and 52 were children. All subjects were evaluated with structured psychiatric questionnaires by interviewers who were unaware of the medical diagnosis. The number of symptoms of attention deficit-hyperactivity disorder was calculated for each subject. RESULTS Among the adults, 11 of 22 subjects with generalized resistance to thyroid hormone (50 percent) and 2 of 30 unaffected subjects (7 percent) had met the criteria for attention deficit-hyperactivity disorder as children (P < 0.001). Among the children, 19 of 27 subjects resistant to thyroid hormone (70 percent) and 5 of 25 unaffected subjects (20 percent) met the criteria for the disorder (P < 0.001). The odds of having attention deficit-hyperactivity disorder were 3.2 times higher for affected male subjects than for affected female subjects and were 2.7 times higher for unaffected male subjects than for unaffected female subjects. The mean symptom score was 2.5 times higher in the affected group than in the unaffected group (7.0 vs. 2.8, P < 0.001). The frequency of other psychiatric diagnoses was similar in the two groups. CONCLUSIONS In our study sample, attention deficit-hyperactivity disorder is strongly associated with generalized resistance to thyroid hormone.

Decreased Receptor Binding of Biologically Inactive Thyrotropin in Central Hypothyroidism: Effect of Treatment with Thyrotropin-Releasing Hormone

Previous studies have suggested that certain cases of idiopathic central hypothyroidism of hypothalamic origin may result from the secretion of biologically inactive thyrotropin. To investigate this possibility and to define the mechanism of defective hormone action, we measured the adenylate cyclase-stimulating bioactivity (B) and receptor-binding (R) activity of purified immunoreactive serum thyrotropin (I) from seven patients with hypothalamic hypothyroidism. We found a strikingly decreased R/I ratio (less than 0.15) in patients as compared with controls (0.6 to 2.7) and a similarly decreased B/I ratio (less than 0.2 vs 2.8 to 5.6). After acute injection of thyrotropin-releasing hormone (TRH, 200 micrograms intravenously), the R/I ratio increased in two of three patients, but the B/I ratio became normal in only one. After administration of TRH for 20 to 30 days, an increase in immunoreactive serum thyrotropin was observed in all patients. Moreover, both ratios returned to normal in all but one patient, who had apparent desensitization. The increase in the amount and bioactivity of secreted thyrotropin after long-term TRH therapy resulted in enhanced secretion of serum thyroid hormones in all patients studied. We conclude that in certain cases of hypothalamic hypothyroidism, secreted thyrotropin lacks biologic activity because of impaired binding to its receptor; TRH treatment can correct both defects. These data suggest that TRH regulates not only the secretion of thyrotropin but also its specific molecular and conformational features required for hormone action.

Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain.

Genetic analysis in our laboratory of families with generalized thyroid hormone resistance (GTHR) has demonstrated tight linkage with a locus, c-erbA beta, encoding a nuclear T3 receptor. Three point mutations and two deletions in this locus have previously been reported in affected individuals in unrelated families as potential molecular bases for this disorder. In the present study, we have used direct sequencing of polymerase chain reaction-amplified exons of the c-erbA beta gene to rapidly identify novel point mutations from seven previously uncharacterized kindreds with GTHR. Six single base substitutions and one single base insertion were identified and found to be clustered in two regions of exons 9 and 10 in the ligand binding domain of the receptor: in the distal ligand-binding subdomain L2 and across the juncture of the taui and dimerization subdomains. Reduction of T3-binding affinity in each of four mutations tested as well as segregation of all mutations to clinically affected individuals strongly supports the hypothesis that these changes are the cause of GTHR in these kindreds. In view of the diversity of clinical phenotypes manifested, the distinct topographic clustering of the mutations provides an invaluable genetic tool for the molecular dissection of thyroid receptor function.

Genetic and Clinical Features of 42 Kindreds with Resistance to Thyroid Hormone: The National Institutes of Health Prospective Study

Resistance to thyroid hormone, first described by Refetoff and coworkers in 1967 [1], is characterized by decreased pituitary and tissue responsiveness to thyroid hormone. Patients typically have elevated serum free and total triiodothyronine (T3) and thyroxine (T4) levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) levels. The phenotype is heterogeneous; classic features include attention-deficit hyperactivity disorder, growth delay, and tachycardia [2, 3]. Resistance to thyroid hormone is usually transmitted in an autosomal dominant manner, but sporadic de novo cases are common, and recessive inheritance is rare [1, 4]. Linkage between resistance to thyroid hormone and the thyroid hormone receptor (TR ) gene was shown in 1988 [5]. Since then, about 100 mutations have been found in that gene [6], clustered primarily in two hot spots in the T3-binding domain (exons 9 and 10), respecting the integrity of the dimerization domain [7]. Mutant receptors have normal DNA binding, but T3 binding and transactivation are impaired to varying degrees [8, 9]. Moreover, the abnormal receptors antagonize the function of normal receptors in a dominant negative manner [10, 11]. Thyroid hormone action is mediated through two types of nuclear receptors, (TR ) and TR [12, 13], which have different organ distributions. Thus, resistance to thyroid hormone provides an exciting opportunity to study the in vivo, tissue-specific action of thyroid hormone. The prevalence of resistance to thyroid hormone is unknown but is thought to be low. The phenotype is heterogeneous and ranges from highly symptomatic to subclinical [2, 3, 14]. Resistance to thyroid hormone is traditionally defined as generalized resistance and, more rarely, as pituitary resistance [15]. In generalized resistance, pituitary and peripheral tissues are not always involved to the same degree, and this creates a mosaic of hypothyroid and hyperthyroid symptoms in the patient. If the degree of resistance is similar in pituitary and peripheral tissues, high levels of thyroid hormone result in compensation, and patients are euthyroid. Patients with pituitary resistance are predominantly hyperthyroid and have hypermetabolism and tachycardia [16]. A single case of isolated peripheral resistance has been reported [17]. Since 1976, 104 patients with resistance to thyroid hormone from 42 unrelated kindreds have been studied prospectively at the National Institutes of Health (NIH), along with 114 of their unaffected relatives, who serve as a control group with environmental and genetic back-grounds similar to those of the patients. Here, we report the results of their initial evaluation. Our goals were to analyze the resistance-to-thyroid-hormone phenotype, including its newly recognized features; to assess the organ specificity of resistance to thyroid hormone; and to define factors contributing to the heterogeneity of the phenotype. Methods Patients and Controls Data collected at the time of initial hospitalization at the NIH were analyzed for 218 persons (104 with and 114 without resistance to thyroid hormone, including 29 persons who had married into families that had resistance to thyroid hormone) from 42 unrelated families. Patients were referred to the NIH for the evaluation of inappropriate TSH secretion. Appropriate informed consent was obtained as approved by the National Institute of Diabetes and Digestive and Kidney Diseases institutional review board. Participants younger than 16 years of age were considered to be children. A full personal and family history was taken from each participant, and specific information about goiter; cardiac symptoms; speech; ear, nose, and throat infections; and hearing problems was collected through interviews. Resting pulse (taken while participants were sleeping or after at least 10 minutes of rest) and goiter were recorded from physical examination, and height (an average of 10 measurements with a stadiometer), weight, and weight-for-height were plotted using charts adapted from Hamill and colleagues [18]. Diagnostic Criteria Resistance to thyroid hormone was diagnosed on the basis of elevated free and total thyroid hormone levels in the presence of normal or elevated TSH levels. Blood was analyzed for levels of T3 (Quanticoat TM, Kallesad Diagnostic, Chasco, Minnesota), T4 (fluorescein polarization immunoassay, Abbott TDx, Abbott Park, Illinois), free T4 (Gammacoat TM two-step RIA, INC-STAR, Stillwater, Minnesota), free T3 (RIA, Becton Dickinson kit, SmithKline Beecham Laboratories, Van Nuys, California), TSH (MAIAclone, Serono Diagnostics, Walpole, Massachusetts), -subunit of TSH (RIA, Hazelton-Washington, Vienna, Virginia), prolactin (TOSOH AIA-1200, Hazelton), and thyroxine-binding globulin (TBG) (Cornings Immunophase, TBG125 I, Corning Medical, Norwood, Massachusetts). Thyroid uptake of 123I was measured at 24 hours. Diagnosis was confirmed by DNA analysis using traditional methods in 14 families [7] or using a new strategy, a modification of single-stranded conformational polymorphism, to screen [19] and identify the other mutations [20]. We used the new consensus [6] for exon, codon, and nucleotide designation. Parents of affected persons were screened if possible; if both parents tested negative, patients were considered to have sporadic cases. Magnetic resonance imaging (MRI) of the pituitary gland was done to rule out a TSH-secreting pituitary adenoma. Parameters of Thyroid Hormone Action Assessment of Pituitary Resistance In patients with no history of thyroidectomy who were not receiving thyroid medication (untreated patients), TSH-releasing hormone tests (Relefact, Ferring Laboratory, Suffern, New York) were done. Levels of TSH, -subunit of TSH, and prolactin were measured 0 and 30 minutes after intravenous injection of 500 g (for adults) or 7 g/kg body weight (for children) of TSH-releasing hormone. Assessment of Peripheral Resistance Attention-deficit hyperactivity disorder and IQ were assessed using previously described methods [21, 22]. Briefly, a neuropsychologist, blinded to the diagnosis of resistance to thyroid hormone assessed IQ by using age-appropriate Wechsler intelligence tests. Attention-deficit hyperactivity disorder was diagnosed by psychiatrists, also blinded to the diagnosis of resistance to thyroid hormone, using appropriate structured psychiatric interviews. Right-ankle reflex was measured with an achillometer (Polymed GmbH, Polymed Medical Center, Medizintechnik, Glattbugg ZH, Switzerland) connected to a 1511B electrocardiograph (Hewlett-Packard, Waltram, Massachusetts) in untreated persons. Results given are each an average of three measurements. Audiologic evaluation included threshold tests of pure tones and speech stimuli and biochemical studies of middle-ear function (tympanometry and acoustic reflexes). Significant hearing loss was defined as a speech threshold greater than 20 decibels. Bone age was determined in children by using a hand-wrist radiograph according to the method of Greulich and Pyle [23]. Standard deviations were calculated using the Brush foundation table [23]. Basal metabolic rate was measured at Georgetown University Hospital in Washington, D.C., in untreated persons by using a Sensor Medics 2900 metabolic cart (Sensor Medics Corp., Yorba Linda, California). Results are expressed as a ratio between observed and theoretical basal metabolic rate adjusted for age, sex, height, and weight. Pulsed and continuous echocardiography assessed cardiac dimension and cardiac cycle intervals in 36 untreated adults with resistance to thyroid hormone and 15 untreated adults without resistance. Indices of thyroid hormone actionlevels of cholesterol, ferritin (Abbott Diagnostics), testosterone-binding globulin (TeBG) (Hazelton, Washington, Virginia), and carotene (SmithKline Beecham Clinical Laboratories)were measured [24-27] in fasting, untreated patients. Levels of IgG, IgA, and IgM were also measured. Criteria for Organ Assessment of Thyroid Hormone Action Table 1 shows the variables that were selected to assess end-organ action of thyroid hormone, and it defines the hypothyroid, euthyroid, and hyperthyroid ranges. For basal metabolic rate and for cholesterol, ferritin, and TeBG levels, normal ranges were those validated at our center; for resting pulse, normal values were adapted from Cole [28]; for bone and brain, ranges were based on clinical observation in persons with congenital hypothyroidism. Table 1. Criteria for Tissue Assessment of Thyroid Hormone Action Statistical Analysis Continuous variables are expressed as mean SE, and binary variables are expressed as proportion SE. We estimated SE for all variables (continuous and binary) using a bootstrap approach [29] by resampling the 42 families (not the individual persons) with replacement 1000 times and estimating the distribution of means or proportions from the 1000 replicates. Specifically, we estimated the mean (or proportion) in each replicate and estimated the SE from the sample of 1000 means (or proportions). This procedure allowed us to take into account correlations among persons within families, because we used families rather than individual persons as resampling units. Similarly, we did statistical tests that took correlations within families into account and yielded P values that discriminated between the factor being studied [such as whether a person had resistance to thyroid hormone] and familial traits. We did four sets of statistical tests that compared 1) persons who had resistance to thyroid hormone with persons who did not; 2) persons with resistance to thyroid hormone who had exon 9 mutations with persons with resistance to thyroid hormone who had exon 10 mutations; 3) persons with resistance to thyroid hormone who had an affected mother with persons with resistance who did not have an affected mother, separately in children and in adults; and 4) children with adults, separately acco

Octreotide Therapy for Thyroid-Stimulating Hormone-Secreting Pituitary Adenomas: A Follow-up of 52 Patients

Table. SI Units, Drug, and Abbreviation Thyroid-stimulating hormone (TSH)-secreting adenomas are rare, constituting fewer than 1% of all pituitary adenomas in large neurosurgical series [1-3]. The inappropriate secretion of TSH by these tumors can result in hyperthyroidism [1-5], but diagnosis may be delayed because symptoms are often attributed to more common causes of thyrotoxicosis. This delay, coupled with the usually aggressive nature of these tumors, allows tumors to become large and invasive. In most cases, surgical removal is incomplete, and, even after additional pituitary irradiation, only about 40% of patients can be cured [1, 6]. The use of dopamine agonists has proved to be generally unsuccessful [1, 4, 5]. Because native somatostatin inhibits TSH secretion in healthy persons [7, 8] and in patients with TSH-secreting adenomas [9], treatment with the long-acting somatostatin analog octreotide has been proposed for such patients. Studies of octreotide in a limited number of patients with TSH-secreting adenomas have shown a favorable effect of this drug on TSH secretion, thyroid function, and, in rare cases, pituitary adenoma size [2,10-36]. To assess the efficacy of octreotide therapy in patients with TSH-secreting adenomas, we reviewed outcomes in 15 new cases and 37 previously reported cases. Methods Patients Twenty-seven men and 25 women who were 16 to 84 years old (median age, 44 years) and had a TSH-secreting adenoma were evaluated. Studies were done at 24 medical centers in nine countries (Appendix). Data were collected from reports published in the English or French language between 1987 and 1991 [2,10-36]. The list of published articles and abstracts of papers presented at various national and international meetings was provided by the Centre de Documentation of Laboratoires Sandoz, Rueil-Malmaison, France. The authors of these studies were asked to provide us, when possible, with follow-up information on their patients [2, 10-36]. In 6 of these patients (patients 30 to 35), available data were too imprecise or incomplete, particularly regarding TSH levels, to allow pertinent evaluation [29-32]. However, some data on these patients were analyzed. Data on 15 additional patients (patients 38 to 52) whose studies were done in various centers (see Appendix) and not previously reported were included in the final analysis. In all patients, the diagnosis of thyrotropinoma had been made on the basis of an inappropriate secretion of TSH (that is, the coexistence of increased serum thyroid hormone levels and an increased or normal [but at least unsuppressed] TSH serum level [3]. In all but 5 patients, who had surgically proven microadenoma, macroadenoma generally associated with suprasellar or laterosellar extension was shown by computed tomographic (CT) scan or magnetic resonance imaging (MRI). Before octreotide therapy, 23 patients had undergone pituitary adenomectomy; 9 of these patients had also had radiotherapy of the pituitary area without resolution of hyperthyroidism. At the time octreotide therapy was initiated, some patients were receiving antithyroid medication because of hyperthyroidism or thyroid hormone replacement because of previous thyroidectomy or radioiodine treatments, and only fragmentary information could be obtained in these cases. In all but 4 of the remaining patients (90%), hyperthyroidism was present before treatment. Basal serum TSH levels were increased (5.2 to 129 mU/L) in 23 of 49 patients and normal (but inappropriately unsuppressed in the presence of high thyroid hormone levels) in the remaining patients. Thirty patients had increased serum levels (1.5 to 311 g/L) of free -subunitthe uncombined subunit of glycoprotein hormones often secreted in excess together with TSH by TSH-secreting adenomas [3]whereas 4 of the 37 patients studied had normal levels. Nine of the patients had mixed growth hormone-TSH-secreting adenoma and also had the classic features of acromegaly. Treatment Regimen The initial dose of octreotide (Sandostatin, Sandoz Pharma, Ltd., Basel, Switzerland) ranged from 50 to 100 g subcutaneously two or three times per day. The dosage was increased according to individual biochemical responses to a maximum level of 500 g three times per day. The median octreotide dose at the final evaluation was 300 g/d. In 25 patients, treatment was extended beyond 3 months (range, 3 to 61 months; mean, 20 17 months). Evaluation Patients were evaluated at various intervals determined by the protocol of the medical center at which they were treated. Data from the pretherapeutic evaluation were available in 49 patients. The response to the first injection of octreotide (50 or 100 g), although assessed in 40 patients, was provided in 35. Evaluation of TSH levels was done after 1 to 2 weeks of octreotide therapy in 33 patients. Evaluation was done again after 1 month of therapy in 23 patients. In the 25 patients receiving long-term therapy (> 3 months), evaluation was done at 3-month intervals during the first year and thereafter at 6-month intervals. For each evaluation, we attempted to retrieve measurements of serum TSH, free -subunit, and thyroid hormone levels done on blood samples collected in the morning or, when available, hourly during a 3- to 12-hour profile; mean values were used for analysis. Levels of TSH, -subunit and thyroid hormone (generally as free thyroxine, free triiodothyronine, or both) were measured by immunoradiometric assay or radioimmunoassay using commercially available kits at the individual study centers. In consideration of the different assays used, the normal ranges for TSH and free thyroxine levels were set at 0.1 to 5 mU/L and 10 to 20 pmol/L, respectively. Methods of serum free -subunit determination were too heterogeneous to allow within-group comparison. Thus, the individual course of -subunit was assessed according to the normal reference range indicated by the individual medical center. In general, hormonal responses are indicated as a percentage decrease in hormone levels or expressed in terms of whether they returned to within the normal range (as defined by the investigators). Serial anatomic evaluation of the pituitary gland by either CT scan or MRI was available in 26 patients. In 7 patients, the percentage change in tumor volume was calculated. Abdominal ultrasound examinations were done at regular intervals and at the final evaluation in 19 of the 25 patients receiving long-term therapy. Statistical Analysis Statistical analysis was done using a Wilcoxon test for paired data. Results are expressed as mean SD. Results Hormonal Effects The acute response of serum TSH levels to the first injection of octreotide (50 to 100 g) was evaluated in 35 patients (Figure 1). The TSH level decreased in all but 2 of these patients (mean decrease for the whole group, 55.8% 27%), the nadir occurring between 3 and 6 hours after injection. The -subunit level decreased in 15 of the 19 patients assessed (mean decrease, 37.5% 24%). Figure 1. Individual levels of thyroid-stimulating hormone (TSH) and free -subunit during single-dose octreotide studies in patients with TSH-secreting adenomas. Thirty-three patients were evaluated for the short-term effect of octreotide (Figure 2). The mean pretreatment TSH concentration was 14.7 25.9 mU/L. Reduction of TSH levels after 1 to 2 weeks of octreotide therapy (50 or 100 g two or three times daily) was observed in 30 patients (mean decrease for the whole group, 74.1%). Serum TSH levels decreased to a mean level of 3.8 7.4 mU/L (P < 0.01). Among patients whose basal serum TSH levels were supranormal, 88% showed a reduction of more than 50% in the TSH level; in 72%, the TSH level returned to normal. The -subunit levels, assessed in 19 patients, showed a similar pattern, with a mean reduction of 64.3% (24%). In about two thirds of the patients, the TSH response after 1 to 2 weeks was better than after the first dose; this analysis included 5 patients who did not respond to acute injection with a reduction in TSH level of more than 50%. Thyroid hormone levels decreased in all patients and returned to normal in 73% of patients. Patients had similar TSH and thyroid hormone responses to octreotide, regardless of whether they had a pure TSH-secreting adenoma or a mixed growth hormone-TSH-secreting adenoma. After 1 month of treatment, serum TSH (n = 23) and -subunit (n = 11) levels were similar to those seen after 1 week of treatment (data not shown). In 3 patients, despite the lack of normalization of serum TSH levels, thyroid hormone levels returned to normal after 1 week of therapy [10, 17]. The relation between individual dosage and the hormonal response was impossible to assess because of the different octreotide doses used (ranging from 100 to 300 g/d). Although 2 of the patients studied showed persistently suppressed TSH levels, thyroid hormone levels that initially returned to normal demonstrated an escapedefined as the re-increase in serum levels despite increasing dosageearly between weeks 2 and 4 of treatment. This led to the discontinuation of treatment in these two patients. Figure 2. Individual levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) during short-term (1 to 2 weeks) octreotide therapy in patients with TSH-secreting adenomas. Octreotide therapy was continued beyond 3 months (range, 3 to 61 months; mean, 20 17 months) in 25 patients, with daily doses ranging from 100 to 1500 g. Overall, the response to treatment, as assessed by TSH and -subunit levels, was better than or similar to that after short-term treatment. Based on the persistence of normal thyroid hormone levels, efficacy was maintained in 21 of the 25 patients (84%) as long as the treatment was continued. Tachyphylaxisdefined as the necessity to increase doses to maintain normal TSH levelswas observed in 5 of the 21 patients. Thyroid hormone levels did not increase, however, and, in fact, remained normal in 4 of these pati

Response of Thyrotropin-Secreting Pituitary Adenomas to a Long-Acting Somatostatin Analogue

Thyrotropin-secreting pituitary adenomas are aggressive, invasive tumors that respond poorly to available surgical and medical treatments. Inappropriate release of thyrotropin by these tumors can result in hyperthyroidism. We treated five patients who had thyrotropin-secreting pituitary adenomas with the long-acting somatostatin analogue SMS 201-995, which was administered by subcutaneous injection in doses of 50 to 100 micrograms every 8 to 12 hours. Serum levels of thyrotropin were dramatically reduced by treatment in four of the five patients, and levels of another tumor marker, the alpha-subunit of thyrotropin, were reduced in all five. In two patients with hyperthyroidism due to production of excess thyrotropin by the tumor, treatment with the somatostatin analogue resulted in a sustained euthyroid state. One patient who was treated for more than 16 months had a persistent reduction in serum levels of thyrotropin and iodothyronines. We conclude that SMS 201-995 is an effective means of controlling hypersecretion of thyrotropin and the associated hyperthyroidism due to thyrotropin-secreting pituitary tumors.

Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin beta gene.

We have investigated ligand‐dependent negative regulation of the thyroid‐stimulating hormone β (TSHβ) gene. Thyroid hormone (T3) markedly repressed activity of the TSHβ promoter that had been stably integrated into GH3 pituitary cells, through the conserved negative regulatory element (NRE) in the promoter. By DNA affinity binding assay, we show that the NRE constitutively binds to the histone deacetylase 1 (HDAC1) present in GH3 cells. Significantly, upon addition of T3, the NRE further recruited the thyroid hormone receptor (TRβ) and another deacetylase, HDAC2. This recruitment coincided with an alteration of in vivo chromatin structure, as revealed by changes in restriction site accessibility. Supporting the direct interaction between TR and HDAC, in vitro assays showed that TR, through its DNA binding domain, strongly bound to HDAC2. Consistent with the role for HDACs in negative regulation, an inhibitor of the enzymes, trichostatin A, attenuated T3‐dependent promoter repression. We suggest that ligand‐dependent histone deacetylase recruitment is a mechanism of the negative‐feedback regulation, a critical function of the pituitary–thyroid axis.