Objective: In acromegaly, overproduction of GH and IGF-I causes abnormal extracellular matrix regulation. We hypothesized that this may predispose to the development of colonic diverticula. Because... Show moreObjective: In acromegaly, overproduction of GH and IGF-I causes abnormal extracellular matrix regulation. We hypothesized that this may predispose to the development of colonic diverticula. Because the relation between acromegaly and colonic diverticula is unknown, the study aim was to assess the prevalence of colonic diverticula in patients with cured acromegaly. Design: This was a case-control study. Methods: We screened reports of colonoscopies performed for the purpose of screening for polyps in 107 patients with cured or biochemically controlled acromegaly and in 214 age- and sex-matched controls for the presence of diverticula, dolichocolon, and polyps. In patients, the findings were related to GH/IGF-I concentrations at the time of diagnosis of acromegaly and to the duration of GH/IGF-I excess. Results: In acromegaly, colonic diverticula were present in 37% of patients, dolichocolon in 34%, and adenomatous polyps in 34%, which was increased compared with controls (odds ratio 3.6, 95% confidence interval 1.4, 5.7; 12.4, 95% confidence interval 6.8, 18.0; 4.1, 95% confidence interval 1.9, 6.4, respectively). The presence of colonic diverticula was associated with both GH and IGF- I concentrations at the time of diagnosis of acromegaly, when adjusted for the duration of active disease. The presence of dolichocolon and adenomatous polyps was associated with higher IGF-I concentrations at diagnosis. Conclusions: Acromegaly is associated with an increased prevalence of colonic diverticula. In addition to the known irreversible effect of GH excess on collagen of joints and cardiac valves, this observation indicates an irreversible effect of GH and/or IGF-I on the collagen in the colon. (J Clin Endocrinol Metab 95: 2073-2079, 2010) Show less
Background: Therapy with tyrosine kinase inhibitors is associated with thyroid dysfunction. Decreased serum thyroid hormone levels during tyrosine kinase inhibitors are also observed in athyreotic... Show moreBackground: Therapy with tyrosine kinase inhibitors is associated with thyroid dysfunction. Decreased serum thyroid hormone levels during tyrosine kinase inhibitors are also observed in athyreotic patients with thyroid carcinoma. We therefore hypothesized that tyrosine kinase inhibitors may influence thyroid hormone metabolism. Aim: The aim was to study the effects of sorafenib therapy on serum thyroid hormone concentrations and iodothyronine deiodination in athyreotic patients. Design: The design included a prospective open, single-center, single-arm 26-wk study. Methods: We measured serum thyroxine (T4), free T4, 3,5,3-triiodothyronine (T3), free T3, reverse T3 (rT3), and TSH concentrations at baseline and after 26 wk in 21 patients with progressive nonmedullary thyroid carcinoma treated with sorafenib. Ratios of T3/T4 and T3/rT3, which are independent of substrate availability and reflect iodothyronine deiodination, were calculated. Results: Serum free T4 and T3 levels, adjusted for levothyroxine dose per kilogram body weight, decreased by 11 and 18%, respectively, whereas TSH levels increased. The serum T3/T4 and T3/rT3 ratios decreased by 18 and 22%, respectively, which is compatible with increased type 3 deiodination. Conclusions: Sorafenib enhances T4 and T3 metabolism, which is probably caused by increased type 3 deiodination. Show less
Prolactinomas are a frequent cause of gonadal dysfunction and infertility, especially in women. Dopamine agonists are first-line therapy and their efficacy in the treatment of prolactinomas is well... Show moreProlactinomas are a frequent cause of gonadal dysfunction and infertility, especially in women. Dopamine agonists are first-line therapy and their efficacy in the treatment of prolactinomas is well established. Current challenges related to the management of prolactinomas remain in the recurrence of the disease after withdrawal of dopamine agonists, the potential of increased risk of cardiac valvulopathy, which is observed in patients treated with high-dose cabergoline for Parkinson's disease, the effects of pregnancy, and impaired quality of life associated with pituitary adenomas in general, and prolactinomas in particular. Although most prolactinomas are biochemically well controlled by pharmaceutical treatment, long-term follow-up is required. Show less
Objective: In patients with active Cushing's syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes... Show moreObjective: In patients with active Cushing's syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes reverse after successful treatment. We therefore evaluated the changes in cardiac structure and dysfunction after successful treatment of CS, using more sensitive echocardiographic parameters (based on two-dimensional strain imaging) to detect subtle changes in cardiac structure and function. Methods: In a prospective study design, we studied 15 consecutive CS patients and 30 controls (matched for age, sex, body surface area, hypertension, and left ventricular (LV) systolic function). Multidirectional LV strain was evaluated by two-dimensional speckle tracking strain imaging. Systolic (radial thickening, and circumferential and longitudinal shortening) and diastolic (longitudinal strain rate at the isovolumetric relaxation time (SRIVRT)) parameters were measured. Results: At baseline, CS patients had similar LV diameters but had significantly more LV hypertrophy and impaired LV diastolic function, compared to controls. In addition, CS patients showed impaired LV shortening in the circumferential (-16.5 +/- 3.5 vs -19.7 +/- 3.4%, P=0.013) and longitudinal (-15.9 +/- 1.9 vs -20.1 +/- 2.3%, P<0.001) directions and decreased SRIVRT (0.3 +/- 0.15 vs 0.4 +/- 0.2/s, P=0.012) compared to controls. After normalization of corticosteroid excess, LV structural abnormalities reversed, LV circumferential and longitudinal shortening occurred, and SRIVRT normalized. Conclusion: CS induces not only LV hypertrophy and diastolic dysfunction but also subclinical LV systolic dysfunction, which reverses upon normalization of corticosteroid excess. Show less
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... Show moreContext: 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) Show less
Wassenaar, M.J.E.; Biermasz, N.R.; Kloppenburg, M.; Klaauw, A.A. van der; Tiemensma, J.; Smit, J.W.A.; ... ; Romijn, J.R. 2010
OBJECTIVE: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess... Show moreOBJECTIVE: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess the impact of joint-specific complaints, clinical and radiological signs of arthropathy on different aspects of quality of life (QoL) in patients with acromegaly after long-term disease control. DESIGN: Cross-sectional study. METHODS: We studied 58 patients (31 males), mean age 60years (range 32-81years), with strict biochemical control of acromegaly for a mean duration of 15years. QoL was assessed by four health-related QoL questionnaires (HADS, MFI-20, NHP, SF-36) and one disease specific QoL questionnaire (AcroQoL). The outcomes of these questionnaires were compared with joint-specific self-reported complaints of pain/stiffness, clinical osteoarthritis based on American College of Rheumatology (ACR) and radiological osteoarthritis based on the Kellgren-Lawrence (KL) scoring method. RESULTS: Long-term cured acromegaly patients had high pain scores of the spine, knee, and hip which limited physical functioning (mean difference -27.0, 95%-CI -9.5, -41.0) and psychological well-being (mean difference -44.4, 95%-CI -26.1, -60.9) (SF-36). Clinical osteoarthritis of the spine was associated mostly with impaired QoL scores, on physical, social, and emotional functioning, and on anxiety and depression. Remarkably, radiological osteoarthritis was not associated with impaired QoL. CONCLUSION: These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control. Show less
Background: Carney complex (CNC) is a familial multiple neoplasia syndrome frequently associated with primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular... Show moreBackground: 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) Show less
CONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear... Show moreCONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE: The aim of the study was to assess the effect of dopamine agonist withdrawal in patients with idiopathic hyperprolactinemia and prolactinomas. DATA SOURCES: PubMed, the Cochrane Library, the Web of Science, and EMBASE were searched electronically. No restriction was made with respect to language. STUDY SELECTION: Studies reporting the proportion of normoprolactinemic patients after withdrawal of dopamine agonist or studies in which this proportion could be calculated were eligible. Both observational studies and clinical trials were eligible. Nineteen studies were included in the meta-analysis, with a total of 743 patients. DATA EXTRACTION: Data extraction was performed by two reviewers independently. DATA SYNTHESIS: The pooled proportion of patients with persisting normoprolactinemia after dopamine agonist withdrawal was 21% in a random effects model [95% confidence interval (CI), 14-30%; I(2) 81%). Stratified analysis showed higher proportions of treatment success in idiopathic hyperprolactinemia (32%; 95% CI, 5-80%), compared with both microprolactinomas (21%; 95% CI, 10-37%), and macroprolactinomas (16%; 95% CI, 6-36%). In a random effects meta-regression adjusting for cause of hyperprolactinemia, a longer treatment duration was associated with treatment success (P = 0.015), whereas the use of cabergoline showed a trend of effect (P = 0.07). CONCLUSIONS: This meta-analysis showed that hyperprolactinemia will recur after dopamine agonist withdrawal in a considerable proportion of patients. The probability of treatment success was highest when cabergoline was used for at least 2 yr. Show less
Objective: Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. These can partly be... Show moreObjective: Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. These can partly be explained by severity of trauma and timing of hormonal evaluation, but may also be dependent on endocrine tests and criteria used for diagnosis of hypopituitarism. Methods: Systematic review of studies reporting prevalence of hypopituitarism in adults >= 1 year after TBI focusing on used (dynamic) tests and biochemical criteria. Results: We included data from 14 studies with a total of 931 patients. There was considerable variation in definition of hypopituitarism. Overall, reported prevalences of severe GH deficiency varied between 2 and 39%. Prevalences were 8 20% using the GHRH-arginine test (cutoff < 9 mu g/l), 11-39% using the glucagon test (cutoff 1-5 mu g/l), 2% using the GHRH test (no cutoff), and 15-18% using the insulin tolerance test (ITT; cutoff < 3 mu g/l). Overall, the reported prevalence of secondary adrenal insufficiency had a broad range from 0 to 60%. This prevalence was 0-60% with basal cortisol (cutoff < 220 or < 440 nmol/l), 7-19% using the ACTH test, and 5% with the ITT as first test (cutoff < 500 or < 550 nmol/l). Secondary hypothyroidism was present in 0-19% (free thyroxine) or 5-15% (thyroid-releasing hormone stimulation). Secondary hypogonadism was present in 0-29%. Conclusion: The reported variations in the prevalence rates of hypopituitarism after TBI are in part caused by differences in definitions, endocrine assessments of hypopituitarism, and confounding factors. These methodological issues prohibit simple generalizations of results of original studies on TBI-associated hypopituitarism in the perspective of meta-analyses or reviews. Show less
Context: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear... Show moreContext: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. Objective: The aim of the study was to assess the effect of dopamine agonist withdrawal in patients with idiopathic hyperprolactinemia and prolactinomas. Data Sources: PubMed, the Cochrane Library, the Web of Science, and EMBASE were searched electronically. No restriction was made with respect to language. Study Selection: Studies reporting the proportion of normoprolactinemic patients after withdrawal of dopamine agonist or studies in which this proportion could be calculated were eligible. Both observational studies and clinical trials were eligible. Nineteen studies were included in the meta-analysis, with a total of 743 patients. Data Extraction: Data extraction was performed by two reviewers independently. Data Synthesis: The pooled proportion of patients with persisting normoprolactinemia after dopamine agonist withdrawal was 21% in a random effects model [95% confidence interval (CI), 14-30%; I-2 81%). Stratified analysis showed higher proportions of treatment success in idiopathic hyperprolactinemia (32%; 95% CI, 5-80%), compared with both microprolactinomas (21%; 95% CI, 10-37%), and macroprolactinomas (16%; 95% CI, 6-36%). In a random effects meta-regression adjusting for cause of hyperprolactinemia, a longer treatment duration was associated with treatment success (P = 0.015), whereas the use of cabergoline showed a trend of effect (P = 0.07). Conclusions: This meta-analysis showed that hyperprolactinemia will recur after dopamine agonist withdrawal in a considerable proportion of patients. The probability of treatment success was highest when cabergoline was used for at least 2 yr. (J Clin Endocrinol Metab 95: 43-51, 2010) Show less
