Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey.

CONTEXT: Population-based screening has been advocated for subclinical thyroid dysfunction in the elderly because the disorder is perceived to be common, and health benefits may be accrued by detection and treatment. OBJECTIVE: The objective of the study was to determine the prevalence of subclinical thyroid dysfunction and unidentified overt thyroid dysfunction in an elderly population. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey of a community sample of participants aged 65 yr and older registered with 20 family practices in the United Kingdom. EXCLUSIONS: Exclusions included current therapy for thyroid disease, thyroid surgery, or treatment within 12 months. OUTCOME MEASURE: Tests of thyroid function (TSH concentration and free T4 concentration in all, with measurement of free T3 in those with low TSH) were conducted. EXPLANATORY VARIABLES: These included all current medical diagnoses and drug therapies, age, gender, and socioeconomic deprivation (Index of Multiple Deprivation, 2004). ANALYSIS: Standardized prevalence rates were analyzed. Logistic regression modeling was used to determine factors associated with the presence of subclinical thyroid dysfunction. RESULTS: A total of 5960 attended for screening. Using biochemical definitions, 94.2% [95% confidence interval (CI) 93.8-94.6%] were euthyroid. Unidentified overt hyper- and hypothyroidism were uncommon (0.3, 0.4%, respectively). Subclinical hyperthyroidism and hypothyroidism were identified with similar frequency (2.1%, 95% CI 1.8-2.3%; 2.9%, 95% CI 2.6-3.1%, respectively). Subclinical thyroid dysfunction was more common in females (P < 0.001) and with increasing age (P < 0.001). After allowing for comorbidities, concurrent drug therapies, age, and gender, an association between subclinical hyperthyroidism and a composite measure of socioeconomic deprivation remained. CONCLUSIONS: Undiagnosed overt thyroid dysfunction is uncommon. The prevalence of subclinical thyroid dysfunction is 5%. We have, for the first time, identified an independent association between the prevalence of subclinical thyroid dysfunction and deprivation that cannot be explained solely by the greater burden of chronic disease and/or consequent drug therapies in the deprived population.

Successful treatment of amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a difficult management problem about which there are little published data. We examined whether continuing amiodarone or differentiating AIT into 2 subtypes affected outcome. METHODS AND RESULTS: The type and duration of antithyroid treatment and response were recorded in a consecutive series of 28 cases. Comparisons were made between those in whom amiodarone either was continued or stopped and between those with either possible type 1 or type 2 AIT. Of the 28 cases, 5 had spontaneous resolution of AIT; 23 received carbimazole (CBZ) alone as first-line therapy. Eleven achieved long-term euthyroidism off CBZ or on a maintenance dose. Five became hypothyroid and required long-term thyroxine. Five relapsed after stopping CBZ treatment and were rendered euthyroid with either long-term CBZ (n=3) or radioiodine (n=2). Four were intolerant of CBZ and received propylthiouracil (PTU), with good effect in 3. One was resistant to thionamide alone (CBZ then PTU) and responded to adjunctive steroids. No difference in presentation or outcome was noted between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 AIT. CONCLUSIONS: Continuing amiodarone has no adverse influence on response to treatment of AIT. First-line therapy with a thionamide alone is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. Differentiating between 2 possible types of AIT does not influence management or outcome.

Levothyroxine treatment and occurrence of fracture of the hip.

BACKGROUND: Levothyroxine sodium is widely prescribed and has been implicated as a cause of reduction in bone mineral density and, therefore, suggested to be a major contributor to the risk of osteoporotic fractures. OBJECTIVE: To investigate whether levothyroxine use increases the risk of developing osteoporotic fractures. METHODS: We conducted a population-based, case-control analysis of the risk of a femur fracture in a large cohort of patients who had been prescribed levothyroxine. We used the United Kingdom General Practice (primary care) Research Database to identify 23,183 patients who had been prescribed long-term thyroid hormone therapy and to identify for each patient taking levothyroxine 4 controls matched for age, sex, primary care practice, and duration of registration on the database. The number of patients who had sustained a fracture of the proximal femur was ascertained for each group, together with drug therapies and medical diagnoses likely to affect fracture risk. RESULTS: Of the 23,183 patients prescribed thyroid hormone, a mean +/- SE of 1.61% +/- 0.08% had sustained a fracture of the femur, compared with 1.44% +/- 0.04% of 92,732 controls (P =.06). When analyzed according to sex, a significant difference in rate of fracture between patients taking levothyroxine and controls was found in males (P =.008). Compared with controls, patients taking levothyroxine had higher reported rates of medical diagnoses and therapies, potentially confounding the fracture risk. Independent predictors of the occurrence of fracture after adjustment for other factors were age (adjusted odds ratio [AOR], 1.11; 95% confidence interval [CI], 1.10-1.11; P<.001), medical diagnoses including rheumatoid arthritis (AOR in females, 1.69; 95% CI, 1.27-2.26; P<.001), excessive use of alcohol (AOR in females, 3.05; 95% CI, 1.94-4.76; P<.001), and prescription of drugs (eg, anticonvulsants; AOR in females, 2.49; 95% CI, 2.00-3.09; P<.001). Prescription of levothyroxine was an independent predictor of fracture occurrence in males (AOR, 1.69; 95% CI, 1.12-2.56; P =.01) but not females (AOR, 1.03; 95% CI, 0.92-1.16; P =.60). CONCLUSIONS: The lack of association between fracture and levothyroxine prescription in the whole cohort is reassuring, although an independent association between levothyroxine prescription and fracture occurrence in male patients suggests that levothyroxine may contribute to fracture risk in this specific group.

Thyroid function and mortality in patients treated for hyperthyroidism.

CONTEXT: Hyperthyroidism has been reported to cause excess all-cause and circulatory mortality. Whether this can be reversed is unknown, as is the influence of mild persisting thyroid dysfunction and treatment-induced hypothyroidism. OBJECTIVES: To determine whether radioiodine treatment is associated with increased mortality and to determine the influences of mild thyroid dysfunction and the development of overt hypothyroidism treated with thyroxine (T(4)). DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2668 individuals aged 40 years or older treated for overt hyperthyroidism with radioiodine in the West Midlands region of England from 1984-2002. MAIN OUTCOME MEASURES: Cause of death compared with age- and period-specific mortality in England and Wales and assessment of the influence of T(4) therapy for radioiodine-induced hypothyroidism and subclinical thyroid dysfunction on mortality. RESULTS: In 15,968 person-years of follow-up, 554 died vs 487 expected deaths (standardized mortality ratio [SMR], 1.14; 95% confidence interval [CI], 1.04-1.24, P=.002). Increased risks of all-cause and circulatory deaths vs age- and period-specific mortality were observed in follow-up in those not requiring, or prior to, T(4) therapy. These increased risks were not observed during follow-up on T(4) therapy (circulatory disease SMR prior to T(4), 1.33; 95% CI, 1.14-1.53 vs SMR, 0.91; 95% CI, 0.70-1.17 during T(4)). Patients receiving T(4) had decreased risk of mortality vs risk in the period not requiring, or prior to, T(4) therapy (all-cause mortality hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; circulatory mortality HR, 0.65; 95% CI, 0.48-0.87). Increased all-cause mortality vs the background population was observed in the period prior to T(4) therapy in follow-up associated with low, normal, and high serum thyrotropin. The SMR for ischemic heart disease increased slightly when analyzed by serum thyrotropin, high serum thyrotropin being the highest SMR (low thyrotropin SMR, 1.06; 95% CI, 0.75-1.45; normal thyrotropin SMR, 1.17; 95% CI, 0.76-1.71; high thyrotropin SMR, 1.48; 95% CI, 0.86-2.37). Comparison within the cohort showed that mild hypothyroidism prior to T(4) therapy was associated with increased risk of mortality from ischemic heart disease vs biochemical euthyroidism (HR, 2.08; 95% CI, 1.04-4.19). CONCLUSIONS: Patients treated with radioiodine for hyperthyroidism had increased mortality vs age- and period-specific mortality in England and Wales, a finding no longer evident during T(4) therapy. This supports treating hyperthyroidism with doses of radioiodine sufficient to induce overt hypothyroidism. The association within the cohort of mortality from ischemic heart disease with subclinical hypothyroidism suggests T(4) replacement should be considered should this biochemical abnormality develop after radioiodine therapy.

Clinical review 142: cardiac dysrhythmias and thyroid dysfunction: the hidden menace?

Thyrotoxicosis is often perceived as a reversible disorder without long-term consequences, perhaps because of the availability of effective treatments, but recent evidence suggests that there may, in fact, be adverse outcomes. Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in those with a past history of overt hyperthyroidism treated with radioiodine as well as in those with subclinical hyperthyroidism indicated by a low serum TSH concentration. Thyroid hormones exert direct effects on the myocardium as well as the systemic vasculature predisposing to dysrhythmias, especially supraventricular. Effects of thyroid hormones on the autonomic nervous system may also contribute to arrhythmogenesis. Atrial fibrillation is a recognized complication of hyperthyroidism that predisposes to embolic events. Development of atrial fibrillation, together with other supraventricular dysrhythmias (both clinically obvious and those detected only by Holter monitoring) in those with hyperthyroidism may account for increased vascular mortality. Improved detection of supraventricular dysrhythmias and therapeutic intervention (e.g. anticoagulants, antiarrhythmics) may improve the long-term vascular prognosis, but their role remains to be established in large therapeutic trials.

Long-term safety and efficacy of depot long-acting somatostatin analogs for the treatment of acromegaly.

Depot somatostatin analogs are now increasingly being prescribed as adjuvant and primary therapy for the treatment of acromegaly. Previous studies have shown them to be both effective and safe, suppressing GH levels to less than 2 micro g/liter in 50-65% of cases and normalizing serum IGF-I levels in 65%. However, published data on their long-term efficacy and safety is scanty. We analyzed data from 22 patients (16 female and 6 male) treated with Sandostatin LAR or Lanreotide for an average of 41 months (range 12-89). Three patients had previously been treated with surgery, two with radiotherapy, and seven with both. Ten patients had received primary medical therapy. Mean pretreatment GH levels were 13.1 +/- 3.4 micro g/liter, and IGF-I levels were 592.9 +/- 53.9 micro g/liter. Results after 12 months of therapy indicated reduction in GH (3.2 +/- 0.7 micro g/liter; P < 0.0001) and IGF-I (321.9 +/- 33.9 micro g/liter; P < 0.001) concentrations, and this was sustained at latest follow-up. Using GH criteria (serum GH < 2 micro g/liter), 46% of subjects achieved a cure at 12 months, and 36% achieved a cure long-term. Fifty-two percent achieved normal IGF-I values at 12 months, and 67% long-term. Mean fasting and 2-h plasma glucose concentrations were similar at latest follow-up and at 12 months to baseline values. Three patients developed impaired glucose tolerance within 12 months of treatment, one going on to develop frank diabetes mellitus. However, glucose tolerance improved in five patients. Five patients developed gallstones while on treatment. In summary, this study reports the long-term efficacy of the depot somatostatin analogs as either adjuvant or primary therapy. Although overall glucose tolerance did not change, the development of impaired glucose tolerance in three patients at a time when GH levels were not changing highlights the ongoing need to monitor the long-term safety of these preparations.

Heart rate variability and turbulence in hyperthyroidism before, during, and after treatment.

Patients with subclinical and treated overt hyperthyroidism have an excess vascular mortality rate. Several symptoms and signs in overt hyperthyroidism suggest abnormality of cardiac autonomic function that may account in part for this excess mortality rate, but few studies have examined cardiac autonomic function in untreated and treated hyperthyroidism. We assessed heart rate turbulence (HRT) and time-domain parameters of heart rate variability in a large, unselected cohort of patients with overt hyperthyroidism referred to our thyroid clinic (n = 259) and compared findings with a group of normal subjects with euthyroidism (n = 440). These measures were also evaluated during antithyroid therapy (when serum-free thyroxine and triiodothyronine concentrations returned to normal but thyrotropin remained suppressed (i.e., subclinical hyperthyroidism, n = 110) and when subjects were rendered clinically and biochemically euthyroid (normal serum thyrotropin, free thyroxine and triiodothyronine concentrations, n = 219). We found that overall measures of heart rate variability and those specific for cardiac vagal modulation were attenuated in patients with overt hyperthyroidism compared with normal subjects; measurements of overall heart rate variability remained low in those with low levels of serum thyrotropin but returned to normal in patients with biochemical euthyroidism. Measurements of HRT (onset and slope) were also decreased in patients with overt hyperthyroidism, but HRT slope returned to normal values with antithyroid treatment. This study is the first to evaluate HRT in overt and treated hyperthyroidism.

Growth hormone--from molecule to mortality.

Growth hormone (GH) acts predominantly via insulin-like growth factor-I (IGF-I) expression. Acromegaly is associated with an increased mortality which can be reversed by optimal treatment. Somatostatin analogues are effective adjunctive therapies in patients treated with surgery and/or radiotherapy and result in tumour shrinkage in many patients. Pegvisomant is a GH analogue which inhibits functional dimerization of GH receptors, inhibits GH activity and normalizes IGF-I in over 90% of subjects. Adult GH deficiency is associated with changes in body composition, insulin status, lipid profile and Quality of Life measures. Hypopituitarism is associated with an increased mortality. Replacement with GH has clinically beneficial effects but there are no data on effects on mortality. Taller individuals are at a 20-60 percent increased risk of a range of cancers, an effect that may be mediated via IGFs. These observations suggest that there is an optimal level of circulating GH and IGF-I required to maintain normal health.

A paradigm shift in the monitoring of patients with acromegaly: last available growth hormone may overestimate risk.

CONTEXT: Acromegaly is associated with reduced life expectancy, which has been reported to be normalized if treatment is successful in controlling GH/IGF-I levels. OBJECTIVE: Most previous studies have invariably used the last available GH/IGF-I, which may be biased as it only assesses exposure at a single point in time. We compared the last available GH/IGF-I analysis to a "time-dependent" and cumulative method, during follow-up to assess risk of mortality in the West Midlands Acromegaly study (n = 501). RESULTS: Using the last available GH, there was a statistically significant increase in mortality comparing groups as low as GH ≤ 1 µg/L vs >1 µg/L (relative risks [RR] 1.8, P = .03). This was not the case when using the "time-dependent method," where only comparisons of GH values of GH ≤5 µg/L vs >5 µg/L were suggestive of being associated with an increased risk of mortality (RR = 1.5, P = .08). When the time-dependent GH method of analysis was used, the RR of mortality at each level was lower and the associated P value was less significant. Irrespective of using the last available or time-dependent method, when IGF-I was divided into levels according to quartile or arbitrary cutoffs, there was no significant increase in mortality with higher levels. CONCLUSIONS: This study emphasizes the potential bias of using the latest available GH/IGF-I levels to predict mortality. Our study again highlights the limitations of IGF-I in predicting mortality.

Medical therapy in acromegaly.

Acromegaly is a rare disease characterized by excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. The disease is associated with increased morbidity and premature mortality, but these effects can be reduced if GH levels are decreased to <2.5 µg/l and IGF-1 levels are normalized. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, radiotherapy and medical therapies, such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant. Medical therapy is currently most widely used as secondary treatment for persistent or recurrent acromegaly following noncurative surgery, although it is increasingly used as primary therapy. This Review provides an overview of current and future pharmacological therapies for patients with acromegaly.

Mortality in patients with pituitary disease.

Pituitary disease is associated with increased mortality predominantly due to vascular disease. Control of cortisol secretion and GH hypersecretion (and cardiovascular risk factor reduction) is key in the reduction of mortality in patients with Cushing's disease and acromegaly, retrospectively. For patients with acromegaly, the role of IGF-I is less clear-cut. Confounding pituitary hormone deficiencies such as gonadotropins and particularly ACTH deficiency (with higher doses of hydrocortisone replacement) may have a detrimental effect on outcome in patients with pituitary disease. Pituitary radiotherapy is a further factor that has been associated with increased mortality (particularly cerebrovascular). Although standardized mortality ratios in pituitary disease are falling due to improved treatment, mortality for many conditions are still elevated above that of the general population, and therefore further measures are needed. Craniopharyngioma patients have a particularly increased risk of mortality as a result of the tumor itself and treatment to control tumor growth; this is a key area for future research in order to optimize the outcome for these patients.

Does acromegaly enhance mortality?

The increased mortality associated with acromegaly was first demonstrated in early epidemiological studies. Since the seminal paper by Wright et al. in 1970, nearly 20 studies have analyzed mortality rates in over 5,000 patients with acromegaly. Overall standardized mortality rates are approximately two times higher than in the general population, relating to an average reduction in life expectancy of around 10 years. The excess deaths are due predominantly to cardiovascular, cerebrovascular and respiratory disease. Malignancy deaths have been high in some studies but not others; in the largest series looking at cancer mortality in acromegaly, overall cancer deaths were not increased, but colon cancer mortality was higher than expected. In 1993, Bates et al. first demonstrated that outcome was related to the latest measurable growth hormone (GH), and treatment to reduce GH levels led to improved outcomes. Other factors predicting poor outcome include the presence of hypertension and diabetes. On the basis of current evidence, a latest GH of less than 2-2.5 mug/L is a better predictor of good outcome than a normal insulin-like growth factor-1 (IGF-1), possibly due to discrepancy between GH and IGF-1 at low GH levels. There is some evidence to suggest a more stringent GH cut-off (less than 1 mug/L) may yield additional benefit but further studies are required to investigate any added risk of increased mortality from hypopituitarism. Radiotherapy has been linked specifically to cerebrovascular mortality and its use in patients with acromegaly must involve a careful risk-benefit analysis in each case.

Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study.

OBJECTIVES: This study sought to prospectively evaluate the prevalence of cardiovascular abnormalities in patients with overt hyperthyroidism before and after antithyroid therapy. BACKGROUND: Overt hyperthyroidism is associated with recognized cardiovascular effects believed to be reversed by antithyroid therapy; however, increasing data suggest significant long-term cardiovascular mortality. METHODS: A total of 393 (312 women, 81 men) consecutive unselected patients with overt hyperthyroidism were recruited and compared with 393 age- and gender-matched euthyroid control subjects. Hyperthyroid patients were re-evaluated after antithyroid therapy. Findings in patients and matched control subjects were compared at presentation, after treatment when patients had subclinical hyperthyroidism biochemically, and when patients were rendered biochemically euthyroid. All had a structured cardiovascular history and examination, including measurements of blood pressure (BP) and pulse rate. All had resting 12-lead electrocardiogram and 24-h digital Holter monitoring of cardiac rhythm. RESULTS: A higher prevalence of cardiovascular symptoms and signs, as well as abnormal hemodynamic parameters, was noted among hyperthyroid patients at recruitment compared with control subjects. Cardiac dysrhythmias, especially supraventricular, were more prevalent among patients than among control subjects. Palpitation and dyspnea, postural decrease in systolic pressure, and atrial fibrillation (AF) remained more prevalent in treated hyperthyroid subjects with subclinical hyperthyroidism compared with control subjects, and remained more prevalent after restoration of euthyroidism. Predictors for successful reversion to sinus rhythm in those with AF associated with hyperthyroidism were lower BP measurements at recruitment and an initial hypothyroid state induced by antithyroid therapy. Mortality was higher in hyperthyroid subjects than in control subjects after a mean period of follow-up of 66.6 months. CONCLUSIONS: Cardiovascular abnormalities are common in patients with overt hyperthyroidism at presentation, but some persist despite effective antithyroid therapy.

Primary medical therapy for acromegaly.

There is now considerable evidence that the clinical outcome in patients with acromegaly can be improved very substantially by means of better surgical expertise and effective medical therapies used in a flexible and innovative manner. Medical therapy alone in patients who have not undergone surgery or radiotherapy (primary medical therapy) offers the prospect of near normalisation of GH/IGF-I levels together with substantial tumour shrinkage in a significant number of patients.

The role of growth hormone-receptor antagonism in relation to acromegaly.

Acromegaly is a rare but disabling condition associated with reduced life expectancy. It is caused almost invariably by a growth hormone-secreting pituitary adenoma. Transsphenoidal surgery and/or radiotherapy are still considered to be the treatment of choice, but despite recent advances in both these forms of treatment, the overall surgical cure rate remains approximately 60%, and radiotherapy is characterised by delayed effect and a high incidence of hypopituitarism. Medical therapy in the form of dopamine agonists and somatostatin analogues has traditionally been used as an adjunct to surgery and/or radiotherapy, but is increasingly being used as first line therapy in the treatment of acromegaly. Recently, a third form of medical therapy, the growth hormone receptor antagonist, pegvisomant, has been licensed for use in acromegaly. This article examines the design, properties, clinical efficacy and safety of pegvisomant.

Efficacy of Sandostatin LAR (long-acting somatostatin analogue) is similar in patients with untreated acromegaly and in those previously treated with surgery and/or radiotherapy.

BACKGROUND AND OBJECTIVES: Somatostatin analogues have been used as an adjunct to surgery and radiotherapy in the treatment of acromegaly for over 15 years, but debate surrounds their use as primary therapy. Newman suggested that octreotide was equally effective as primary or adjuvant therapy, but the effects of previous surgery/radiotherapy may have led to a preselection bias. In an attempt to eliminate this bias, the efficacy of the depot somatostatin analogue Sandostatin LAR as primary and adjuvant therapy has been assessed using GH and IGF-I levels at diagnosis as baseline values. DESIGN: We retrospectively analysed the GH and IGF-I data from a large multicentre study in which patients' biochemical response to treatment with the depot somatostatin analogue Sandostatin LAR as primary and adjuvant therapy was assessed. We used GH and IGF-I levels at diagnosis as baseline values to eliminate any preselection bias. PATIENTS AND RESULTS: In 91 patients (42 male) studied, mean serum GH fell from 36.2 +/- 3.3 micro g/l (SEM) at diagnosis to 2.2 +/- 0.2 micro g/l after 48 weeks of treatment (P < 0.0001). In the primary (n = 34) and adjuvant (n = 57) therapy groups, mean GH fell from 30.7 +/- 5.7 to 2.6 +/- 0.4 micro g/l (P < 0.0001) and from 39.5 +/- 4.1 to 2.0 +/- 0.2 micro g/l (P < 0.0001), respectively. Sixty-two percent of patients in the primary therapy group and 70% in the adjuvant therapy group achieved GH < 2 micro g/l. Serum IGF-I levels were available in 67 patients (34 male). In the primary therapy group (n = 25) mean IGF-I fell from 764 +/- 68 to 414 +/- 31 micro g/l (P < 0.0001) at 48 weeks. In the adjuvant therapy group (n = 42) mean IGF-I was 666 +/- 50 micro g/l, falling to 384 +/- 30 micro g/l (P < 0.0001) at 48 weeks. 72% of patients achieved normal age-related IGF-I-values. There were no statistically significant differences in GH or IGF-I levels between the primary and adjuvant therapy groups at diagnosis, pre Sandostatin LAR or after 48 weeks of treatment. CONCLUSION: This retrospective study demonstrates that in a group of patients with similar diagnostic GH and IGF-I levels, Sandostatin LAR was equally effective as primary therapy in acromegalic patients as in patients previously treated with surgery and/or radiotherapy.

Isolation and characterization of human thyroid endothelial cells.

From collagenase digests of human thyroid, endothelial cells were separated from follicular cells by their greater adherence to gelatin-coated plates. Endothelial cells were further purified using fluorescence-activated cell sorting, selecting for cells expressing factor VIII-related antigen. Isolated cells were negative for thyroglobulin and calcitonin when examined by immunostaining. The receptor for the angiopoietins, Tie-2, was expressed by the cells, and expression was increased by agents that elevate cAMP. Nitric oxide synthase (NOS) 3, the endothelial form of NOS, was expressed by the cells and similarly regulated. Cells responded strongly to the mitogen fibroblast growth factor (FGF)-2 in growth assays but only weakly to vascular endothelial growth factor (VEGF). VEGF was, however, able to stimulate nitric oxide release from the cells consistent with their endothelial origin. The FGF receptor (FGFR1) was full length (120 kDa) and immunolocalized to the cytosol and nucleus. Thyrotropin (TSH) did not regulate FGFR1, but its expression was increased by VEGF. Thrombospondin, a product of follicular cells, was a growth inhibitor, but neither TSH nor 3,5,3'-triiodothyronine had direct mitogenic effects. Thyroid follicular cell conditioned medium contained plasminogen activator activity and stimulated the growth of the endothelial cells, but when treated with plasminogen to produce the endothelial-specific inhibitor, angiostatin, growth was inhibited. Human thyroid endothelial cell cultures will be invaluable in determining the cross talk between endothelial and follicular cells during goitrogenesis.