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Objective Active acromegaly is associated with psychopathology, personality changes, and cognitive dysfunction. It is unknown whether, and to what extent, these effects are present after long-term cure of acromegaly. Aim The aim of the study was to assess psychopathology, personality traits, and cognitive function in patients after long-term cure of acromegaly. Design This was a cross-sectional study. Patients and Methods We studied 68 patients after long-term cure (13 ± 1 yr) of acromegaly and 68 matched controls. We compared these data with 60 patients treated for nonfunctioning pituitary macroadenomas (NFMAs) and 60 matched controls. Psychopathology was assessed using the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form and personality by the Dimensional Assessment of Personality Pathology short-form (DAPP). Cognitive function was assessed by 11 tests. Results Compared with matched controls, patients cured from acromegaly scored significantly worse on virtually all psychopathology questionnaires and on several subscales of the DAPP. Compared with NFMA patients, patients cured from acromegaly scored worse on negative affect (P = 0.050) and somatic arousal (P = 0.009) and seven of 18 subscales of the DAPP (P < 0.05). Cognitive function in patients cured from acromegaly did not differ from matched controls or patients treated for NFMA. Conclusion Patients with long-term cure of acromegaly show a higher prevalence of psychopathology and maladaptive personality traits but not cognitive dysfunction, compared with matched controls and patients treated for NFMA. These results suggest irreversible effects of previous GH excess, rather than effects of pituitary adenomas per se and/or their treatment, on the central nervous system.

Background/Objective: Sex steroid treatment to reduce final height of tall boys has been available since the 1950s. In women, it has been shown to interfere with fertility. In men, no such data are available. We therefore evaluated fertility and gonadal function in tall men who did or did not receive high-dose androgen treatment in adolescence.Methods: We conducted a retrospective cohort study of 116 tall men, of whom 60 had been treated. Reproductive and gonadal function was assessed by standardized interview, semen analysis, endocrine parameters, ultrasound imaging, and fatherhood. Mean age at treatment commencement was 14.2 yr, and mean follow-up was 21.2 yr.Results: Sixty-six men (36 treated and 30 untreated) had attempted to achieve fatherhood. The probability of conceiving their first pregnancy within 1 yr was similar in treated and untreated men (26 vs. 24; Breslow P = 0.8). Eleven treated and 13 untreated men presented with a left-sided varicocele (P = 0.5). Testicular volume, sperm quality, and serum LH, FSH, and inhibin B levels were comparable between treated and untreated men. However, treated men had significantly reduced serum T levels, adjusted for known confounders [mean (SD) 13.3 (1.8) vs. 15.2 (1.9) nmol/liter; P = 0.005). In addition, testicular volume and serum inhibin B and FSH levels in treated men were significantly correlated with age at treatment commencement.Conclusion: At a mean follow-up of 21 yr after high-dose androgen treatment, we conclude that fatherhood and semen quality in tall treated men are not affected. Serum testosterone levels, however, are reduced in androgen-treated men. Future research is required to determine whether declining testosterone levels may become clinically relevant for these men as they age. (J Clin Endocrinol Metab 95: 5233-5240, 2010)

Context: Twenty-four-hour TSH secretion profiles in primary hypothyroidism have been analyzed with methods no longer in use. The insights afforded by earlier methods are limited. Objective: We studied TSH secretion in patients with primary hypothyroidism (eight patients with severe and eight patients with mild hypothyroidism) with up-to-date analytical tools and compared the results with outcomes in 38 healthy controls. Design and Methods: Patients and controls underwent a 24-h study with 10-min blood sampling. TSH data were analyzed with a newly developed automated deconvolution program, approximate entropy, spikiness assessment, and cosinor regression. Results: Both basal and pulsatile TSH secretion rates were increased in hypothyroid patients, the latter by increased burst mass with unchanged frequency. Secretory regularity (approximate entropy) was diminished, and spikiness was increased only in patients with severe hypothyroidism. A diurnal TSH rhythm was present in all but two patients, although with an earlier acrophase in severe hypothyroidism. The estimated slow component of the TSH half-life was shortened in all patients. Conclusion: Increased TSH concentrations in hypothyroidism are mediated by amplification of basal secretion and burst size. Secretory abnormalities quantitated by approximate entropy and spikiness were only present in patients with severe disease and thus are possibly related to the increased thyrotrope cell mass. (J Clin Endocrinol Metab 95: 928-934, 2010)

Background: Carney complex (CNC) is a familial multiple neoplasia syndrome frequently associated with primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular adrenal hyperplasia that leads to Cushing's syndrome (CS). Germline PRKAR1A mutations cause CNC and only rarely isolated PPNAD. Patients and Methods: PRKAR1A mutation analysis in two large families with CS and no other CNC manifestations demonstrated a M1V germline mutation; a total of 21 asymptomatic individuals were screened, and mutation carriers were evaluated for CNC. The mutation was expressed in vitro and functionally tested for its effects on protein kinase A function. Results: Presymptomatic testing identified five first-degree relatives who were M1V carriers and who were all diagnosed with subclinical, mild CS at ages ranging from 20-56 yr. There were no other signs of CNC. In a cell-free system, we detected a shorter compared with the wild-type type 1 alpha regulatory subunit of protein kinase A (PRKAR1A) protein (43 kDa). This was not identified in cell lines from the patients or in transfection experiments in HEK293 cells that showed no detectable PRKAR1A protein from the M1V-bearing constructs. In these cells, the mutant mRNA was expressed in a 1: 1 ratio. Conclusion: In two large families, the M1V PRKAR1A mutation resulted in a PPNAD-only phenotype with significant variability both in terms of age of onset and clinical severity. Expression studies showed a unique effect of this sequence change. This study has implications for genetic counseling of carriers of this PRKAR1A mutation and patients with CNC and PPNAD and for the study of PRKAR1A-related tumorigenesis. (J Clin Endocrinol Metab 95: 338-342, 2010)

Context: Hormone secretion by somatotropinomas, corticotropinomas, and prolactinomas exhibits increased pulsatility and basal secretion, accompanied by greater disorderliness. Objective: Our objective was to evaluate TSH secretion by thyrotropinomas with up-to-date analytical and mathematical tools. Design: Twenty-four hour blood samplings at 10-min intervals in a clinical research laboratory in five patients with a thyrotropinoma and 10 healthy age- and gender-matched controls were performed. The obtained serum TSH profiles were analyzed with a new deconvolution method, approximate entropy, Cosinor analysis, and by quantification of spikiness. Results: TSH burst frequency and basal secretion were increased in patients compared with controls. TSH secretion patterns in patients were more irregular than in controls, but the diurnal rhythm was preserved at a higher mean in all patients, although with a 2-h phase delay. Conclusion: TSH secretion by thyrotropinomas shares many characteristics with other pituit...

Context: An association has been suggested between elevated plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride (TG) accumulation, and myocardial function.Objective: Our objective was to investigate the effects of an elevation of plasma NEFA by a high-fat, high-energy (HFHE) diet on hepatic and myocardial TG accumulation, and on myocardial function.Design: There were 15 healthy males (mean ± sd age: 25.0 ± 6.6 yr) subjected to a 3-d HFHE diet consisting of their regular diet, supplemented with 800 ml cream (280 g fat) every day.Methods: 1H-magnetic resonance spectroscopy was performed for assessing hepatic and myocardial TGs. Furthermore, left ventricular function was assessed using magnetic resonance imaging.Results: The HFHE diet increased hepatic TGs compared with baseline (from 2.01 ± 1.79 to 4.26 ± 2.78%; P = 0.001) in parallel to plasma TGs and NEFA. Myocardial TGs did not change (0.38 ± 0.18 vs. 0.40 ± 0.12%; P = 0.7). The HFHE diet did not change myocardial systolic function. Diastolic function, assessed by dividing the maximum flow across the mitral valve of the early diastolic filling phase by the maximum flow of the atrial contraction (E/A ratio), decreased compared with baseline (from 2.11 ± 0.39 to 1.89 ± 0.33; P = 0.031). This difference was no longer significant after adjustment for heart rate (P = 0.12).Conclusions: Short-term HFHE diet in healthy males results in major increases in plasma TG and NEFA concentrations and hepatic TGs, whereas it does not influence myocardial TGs or myocardial function. These observations indicate differential, tissue-specific partitioning of TGs and/or fatty acids among nonadipose organs during HFHE diet.

Preterm birth is associated with postnatal growth failure, abdominal fat accumulation, insulin resistance, and hypertension, resembling increased glucocorticoid bioactivity. We tested the effects of the R23K and N363S polymorphisms in the glucocorticoid receptor gene, associated with decreased and increased sensitivity to cortisol, respectively, on linear growth and the adult metabolic profile in a cohort (n = 249) of men and women born less than 32 gestational weeks and followed up prospectively from birth until 19 yr of age. This was a birth cohort study that included 249 19-yr-old survivors born at a gestational age less than 32 wk from the Dutch Project on Preterm and Small-for-Gestational-Age Infants cohort. This project was a nationwide multicenter follow-up study. Linear growth and adult body composition, fasting cortisol, glucose, insulin, and cholesterol concentrations, and blood pressure were measured. The 23K variant (n = 24) was associated with lower fasting insulin levels [mean difference after log transformation: -0.09 (95% confidence interval -0.16, -0.01) mU/liter] and a lower homeostatic model assessment for insulin resistance index [mean difference after log transformation: -0.09 (95% confidence interval -0.16, -0.01)] as well as with a taller stature departing from the age of 1 yr onward. 23K carriers showed complete catch-up growth between the ages of 3 months and 1 yr, and attained height was similar to the population reference mean, whereas stature in noncarriers was on average 0.5 sd below this mean. In contrast, the N363S polymorphism was not associated with any of the outcomes. Carriers of the 23K variant are, at least in part, protected against postnatal growth failure and insulin resistance after preterm birth

Introduction: Malignant paragangliomas have been well described in carriers of mutations of the succinate dehydrogenase B (SDHB) gene, but have rarely been associated with mutations in the succinate dehydrogenase D (SDHD) gene. Aim: The aim of the study was to report the different clinical expression patterns of malignant paragangliomas in five patients with SDHD (D92Y) mutations observed in approximately 200 SDHD (D92Y) mutation carriers followed in our institution. Results: Metastasis and/or local tumor invasion was documented 0 (n = 2), 1, 18, and 30 yr after the initial diagnosis of paraganglioma. Malignancy was proven by paraganglioma bone metastases (n = 2), intrathoracic paraganglioma with lymph node metastases, locally invasive head-and-neck paraganglioma with destruction of the petrosal bone, and locally invasive paraganglioma of the bladder with lymph node metastases. Four of the five patients developed catecholamine excess during follow-up due to intraadrenal paraganglioma (pheochromocytoma) (n = 1), extra adrenal paraganglioma (n = 2), and presumed subclinical disease (n = 1). Conclusion: SDHD mutations (D92Y) are associated with malignant paragangliomas and catecholamine excess with remarkable interindividual variations despite the same mutation. We estimate that the prevalence of malignancy in carriers of D92Y mutations is at least 2.5%.

Context: Increased mortality in patients with pituitary tumors after surgicaltreatmenthasbeenreported.However,itisunknowntowhat extent excess mortality is caused by pituitary tumors and their treatment in general and to what extent by previous exposure to hormonal overproduction. Objective: The aim of the study was to compare mortality between patients treated for Cushing’s disease and nonfunctioning pituitary macroadenomas (NFMAs). Design: This was a follow-up study. Patients: We included 248 consecutive patients with pituitary adenomas treated by transsphenoidal surgery in our hospital for NFMAs (n 174) and ACTH-producing adenomas (n 74). The mean durationoffollow-upaftersurgerywas10.17.2yrforthewholecohort. Outcome Measures: The standardized mortality ratio (SMR) was calculated for the whole cohort and also for the two diseases separately. Cox regression analysis was used to compare mortality in patients with Cushing’s disease with NFMA patients. Results: Patients with Cushing’s disease (39.1 16.1 yr) were significantly younger at time of operation than NFMA patients (55.3 13.4 yr). The SMR for the whole cohort was 1.41 [95% confidence interval (CI), 1.05–1.86]. The SMR in NFMA patients was 1.24 (95% CI, 0.85–1.74) vs. 2.39 (95% CI, 1.22–3.9) in patients with Cushing’s disease. In patients with Cushing’s disease, compared with NFMAs, the age-adjusted mortality was significantly increased: hazard ratio 2.35 (95% CI, 1.13–4.09, P 0.008). Conclusions: Mortality in patients previously treated for Cushing’s disease is increased, compared with patients treated for NFMAs. This implies that previous, transient overexposure to cortisol is associated with increased mortality. (J Clin Endocrinol Metab 92: 976–981, 2007) P ITUITARY ADENOMAS ARE benign neoplasms associated with considerable morbidity due to mass effects, hormonal overproduction, and pituitary insufficiency. In nonfunctioning pituitary macroadenomas (NFMAs), morbidity is caused by mass effects of the tumor leading to visual field defects, decreased visual acuity, and pituitary insufficiency in the majority of patients (1). In functioning pituitary adenomas, morbidity is caused by hormonal overproduction, in addition to tumor mass effects in cases of macroadenomas. In Cushing’s disease, cortisol excess causes central obesity, insulin resistance, hypertension, hyperlipidemia, and osteoporosis (2, 3). Moreover, cortisol overproduction is associated with increased cardiovascular risk, continuing even after remission of the disease (4, 5). In addition to increased morbidity, a number of studies have reported increased mortality in patients with pituitary tumors (6–10) and associated conditions such as hypopituitarism (11–13). In the majority of these studies the general population was used as a control group to assess mortality risk in patients with pituitary adenomas. However, this approach is not able to make a distinction between the effects of hormone overproduction per se vs. the general aspects of the pituitary tumor and their treatment, on mortality. We performed a single-center study to assess mortality rates during long-term follow-up after transsphenoidal surgery in patients with nonfunctioning pituitary macroadenomas and Cushing’s disease. Mortality in pituitary adenomas is associated with general aspects of pituitary tumors and their treatment but also with disease-specific morbidity due to overproduction of pituitary hormones. To answer the question to which extent previous exposure to hormonal overproduction per se is associated with increased mortality, we compared mortality in patients operated for Cushing’s disease to mortality in patients operated for NFMAs because patients treated for NFMAs lack cortisol excess specific for Cushing’s disease.

Survival studies in differentiated thyroid carcinoma (DTC) may be biased because they have been performed in heterogeneous populations. In addition, specific death causes in DTC have not been documented well in the literature. The aim of our study was to investigate survival and specific death causes in a homogeneous cohort of DTC patients. Patients included 366 consecutive patients with DTC who had all been treated according to the same protocol for initial therapy and follow-up. Prognostic factors for DTC-related death were analyzed by univariate Cox regression analysis, followed by stepwise multivariate Cox regression analysis. Standardized mortality rates (SMR) were calculated using normal mortality rates for the entire Dutch population. During follow-up of 8.3 +/- 4.6 yr, 82 patients (22.4%) died. At multivariate Cox-regression analysis, tumor stage T4, distant metastases, and advanced age were associated with an increased relative risk for DTC-related death. SMR for the entire group was 2.32. This could be explained by increased SMR in patients with stage T4, distant metastases, or advanced age. Death causes could be verified in 80 patients: 52 died of DTC, 28 due to other causes. Ten of the 20 patients with stage T1-3M0 died from thyroid carcinoma. Relative risk for thyroid cancer-related death and SMR are significantly increased in patients with stage T4 and M1 or advanced age. Although death risk is not increased in T1-3 M0 patients, DTC contributed significantly to mortality in all patient categories

Subclinical hyperthyroidism has been reported to affect systolic and diastolic cardiac function. However, the reversibility of these effects is not well established. Our objective was to investigate the presence and reversibility of cardiac abnormalities in patients with long-term exogenous subclinical hyperthyroidism. We conducted a prospective, single-blinded, placebo-controlled randomized trial of 6 months duration with two parallel groups. The study occurred at the Leiden University Medical Center, a tertiary referral center for thyroid carcinoma. As a model for subclinical hyperthyroidism, 25 patients with a history of differentiated thyroid carcinoma with more than 10 yr of TSH suppressive therapy with L-T4 were studied. L-T4 dose was replaced by study medication containing L-T4 or placebo. Medication was titrated in a single-blinded fashion to establish continuation of TSH suppression (low-TSH group) or euthyroidism (euthyroid group). We assessed serum levels of free T4 and TSH and used echo Doppler cardiography including tissue Doppler to establish left ventricular (LV) dimensions and function as well as diastolic function. Baseline echocardiography data were compared with 24 controls. There were no differences in baseline cardiac parameters and TSH levels between the two groups. Although mean LV mass index was increased as compared with 24 controls, only four patients had LV hypertrophy at baseline. This was not improved by restoration of euthyroidism. At baseline, diastolic function was impaired in all patients as indicated by abnormal values for the peak flow of the early filling phase (E, 55.3 +/- 9.5 mm/sec), the ratio of E and the peak flow of the atrial filling phase (E/A ratio, 0.87 +/- 0.13), the early diastolic velocity obtained by tissue Doppler (E', 5.7 +/- 1.3 cm/sec), and the peak atrial filling velocity obtained by tissue Doppler (A', 6.8 +/- 1.4 cm/sec), prolonged E deceleration time (234 +/- 34 msec), and isovolumetric relaxation time (121 +/- 15 msec). After 6 months, significant improvements were observed in the euthyroid group in the E/A ratio (+41%; P

Active acromegaly is associated with significant comorbidity and reduced quality of life. However, the prevalence of comorbidity after long-term remission is not established. Therefore, we assessed the presence of comorbidity in 118 patients in long-term remission after surgery, radiotherapy, and/or somatostatin analog treatment according to strict biochemical criteria of serum GH and IGF-I concentrations and evaluated the impact of comorbidity on quality of life. The mean duration of remission was 12.0 +/- 7.4 yr, and mean actual IGF-I sd scores were 0.6 +/- 1.7. Self-reported joint problems occurred in 77% of patients, hypertension in 37%, a history of myocardial infarction in 9%, and diabetes mellitus in 11%. The presence of joint problems was not related to GH and IGF-I levels, active disease duration, or age. Joint complaints had significant negative impact on quality of life. Patients with a history of myocardial infarction had reduced scores for general health, depression, and fatigue, and diabetes mellitus was associated with reduced scores for anxiety and sleep. In conclusion, acromegalic patients had a high prevalence of joint-related comorbidity and hypertension despite long-term control of GH excess. Especially, joint complaints contributed to a reduced perceived quality of life in these patients.

After successful transsphenoidal surgery for acromegaly, life-long follow-up is required, because 10-15% of patients develop recurrence of disease. We assessed whether it is safe to perform postoperative follow-up with only biochemical evaluation in acromegalic patients initially cured by transsphenoidal surgery. We studied 32 patients cured after transsphenoidal surgery for acromegaly during a follow-up of 8.7 +/- 6.4 yr (mean +/- sd). Serial measurements of serum GH during glucose tolerance test and magnetic resonance imaging (MRI) scans were performed. Serial MRI scans were reevaluated by three independent neuroradiologists, who were blinded for the clinical and biochemical data, for growth of suspected tumor tissue. Twenty-three patients remained biochemically cured in the long term, whereas nine of the 32 patients developed recurrence of disease, indicated by elevated serum GH concentrations during glucose tolerance test and clinical symptoms/signs. None of the 23 patients with long-term biochemical cure showed growth of tumor tissue according to two neuroradiologists, whereas the third neuroradiologist assessed three of 23 patients as having tumor growth despite continuing biochemical cure. In the nine patients with biochemical recurrence, no tumor growth was found in the series of postoperative MRI scans, according to two of the three independent radiologists, whereas the third radiologist found tumor growth in four patients with recurrent disease. In conclusion, in patients with acromegaly, initially cured by transsphenoidal surgery, it appears safe to check for recurrent disease during long-term follow-up of these patients by biochemical markers only.

Combination antiretroviral therapy for the treatment of human immunodeficiency virus type 1-infected patients is associated with development of the lipodystrophy syndrome (LD). We previously showed that plasma levels of free fatty acids are higher in patients with lipodystrophy. The purpose of this study was to evaluate the postabsorptive rate of lipolysis, using [(2)H(5)]glycerol infusion, the resting energy expenditure (REE) measured by indirect calorimetry, and the responses of both to epinephrine infusion ( approximately 15 ng/kg.min) in patients with LD. Results were compared with those obtained in five matched human immunodeficiency virus type 1-infected patients. The postabsorptive rate of appearance of glycerol did not differ between the two groups. There was no difference in the lipolytic response to epinephrine, although the response in the LD group was delayed (P < 0.001). The postabsorptive REE adjusted for lean body mass was lower and remained lower during epinephrine infusion in the LD group. Postabsorptive norepinephrine concentrations were higher and remained elevated during epinephrine infusion in the LD group. We conclude that the lipolytic response to epinephrine in the LD group was normal, albeit delayed. Norepinephrine concentrations were increased in patients with lipodystrophy, indicating increased sympathetic activity. Postabsorptive REE was lower in the patients with lipodystrophy. Our data suggest that highly active antiretroviral therapy-associated lipodystrophy normalizes the REE, but has only minor effects on lipolysis as a result of concomitant sympathetic stimulation of adipose tissue.

To evaluate glucose kinetics in children with falciparum malaria, basal glucose production and gluconeogenesis and an estimate of the flux of the gluconeogenic precursors were measured in Kenyan children with uncomplicated falciparum malaria before (n = 11) and during infusion of alanine (1.5 mg/kg·min; n = 6). Glucose production was measured by [6,6-2H2]glucose, gluconeogenesis by mass isotopomer distribution analysis of glucose labeled by [2-13C]glycerol. Basal plasma glucose concentration ranged from 2.1–5.5 mmol/L, and basal glucose production ranged from 3.3–7.3 mg/kg·min. Glucose production was largely derived from gluconeogenesis (73 ± 4%; range, 52–93%). During alanine infusion, plasma glucose increased by 0.4 mmol/L (P = 0.03), glucose production increased by 0.8 mg/kg·min (P = 0.02), and gluconeogenesis increased by 0.8 mg/kg·min (P = 0.04). We conclude that glucose production in children with uncomplicated falciparum malaria is largely dependent on gluconeogenesis. However, gluconeogenesis is potentially limited by insufficient precursor supply. These data indicate that in children with falciparum malaria, gluconeogenesis fails to compensate in the presence of decreased glycogen flux to glucose, increasing the risk of hypoglycemia.

Interferon-alpha (IFN alpha) concentrations are increased in conditions associated with tissue injury. To investigate the endocrine and metabolic actions of IFN alpha in vivo, we studied eight healthy controls on two occasions, once after administration of 5 million units/m2 rhIFN alpha and once after administration of saline (control). Rates of appearance (Ra) of glucose and glycerol in plasma were measured by infusion of [3-3H]glucose and D5-glycerol, respectively. Energy expenditure and substrate oxidation were determined by indirect calorimetry. IFN alpha induced increases in plasma concentrations of norepinephrine (225 +/- 93%; P0.02 vs. control), epinephrine (272 +/- 80%; P0.05), cortisol (353 +/- 63%; P0.02), glucagon (50 +/- 12%; P0.05), free fatty acids (223 +/- 61%; P0.02), and glycerol (68 +/- 21%; P0.02) and in resting energy expenditure (36 +/- 50%; P0.03). The Ra of glycerol (169 +/- 39%; P0.02) and fat oxidation (104 +/- 23%, P0.02) were also increased after IFN alpha treatment. The Ra of glucose was higher at the end of the recombinant human IFN alpha treatment day than in the control experiment (12.83 +/- 1.08 vs. 9.34 +/- 0.46 mumol/kg.min; P0.03). It is concluded that IFN alpha administration induces, directly or indirectly, major endocrine and metabolic changes and is probably part of the cytokine network mediating the endocrine and catabolic reactions to tissue injury.

Both hyper- and hypothyroidism have been reported during prolonged recombinant human interferon-alpha (rhIFN alpha) therapy. To assess the short term effects of IFN alpha therapy on thyroid hormone metabolism, we measured thyroid hormone concentrations in eight healthy volunteers for 24 h after sc administration of rhIFN alpha and, on another occasion, after sc administration of saline (control study). There were no effects of rhIFN alpha on plasma T4 and free T4 or on thyroid hormone binding index. However, rhIFN alpha induced a significant decrease in the plasma concentrations of TSH (P < 0.03) and T3 (P < 0.02) compared with those in the control study, associated with an increase in rT3 concentrations (P < 0.02). IFN alpha induced a moderate increase in interleukin-6 (IL-6) concentrations (P < 0.02 vs. control study), whereas IL-1 and tumor necrosis factor concentrations remained below the detection limit in all subjects. It is concluded that IFN alpha administration induces major changes in thyroid hormone metabolism, possibly mediated in part by IL-6. The acute effects of rhIFN alpha mimic the euthyroid sick syndrome and appear to be different from the effects of chronic rhIFN alpha treatment on thyroid hormone metabolism.