Patients previously treated for nonfunctioning pituitary macroadenomas have disturbed sleep characteristics, circadian movement rhythm, and subjective sleep quality.

CONTEXT AND OBJECTIVE: Fatigue and excessive sleepiness have been reported after treatment of nonfunctioning pituitary macroadenomas (NFMA). Because these complaints may be caused by disturbed nocturnal sleep, we evaluated objective sleep characteristics in patients treated for NFMA. DESIGN: We conducted a controlled cross-sectional study. SUBJECTS AND METHODS: We studied 17 patients (8 women; mean age, 54 yr) in remission of NFMA during long-term follow-up (8 yr; range, 1-18 yr) after surgery (n = 17) and additional radiotherapy (n = 5) without comorbidity except for hypopituitarism and 17 controls matched for age, gender, and body mass index. Sleep was assessed by nocturnal polysomnography, sleep and diurnal movement patterns by actigraphy, and quality of life and subjective sleep characteristics by questionnaires. RESULTS: Compared to controls, patients had reduced sleep efficiency, less rapid eye movement sleep, more N1 sleep, and more awakenings in the absence of excessive apnea or periodic limb movements. Actigraphy revealed a longer sleep duration and profound disturbances in diurnal movement patterns, with more awakenings at night and less activity during the day. Patients scored higher on fatigue and reported impaired quality of life. CONCLUSION: Patients previously treated for NFMA suffer from decreased subjective sleep quality, disturbed distribution of sleep stages, and disturbed circadian movement rhythm. These observations indicate that altered sleep characteristics may be a factor contributing to impaired quality of life and increased fatigue in patients treated for NFMA.

Clinical osteoarthritis predicts physical and psychological QoL in acromegaly patients.

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 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 60 years (range 32-81 years), with strict biochemical control of acromegaly for a mean duration of 15 years. 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.

The exon-3 deleted growth hormone receptor polymorphism predisposes to long-term complications of acromegaly.

OBJECTIVE: The aim of the study was to evaluate the impact of the genomic deletion of exon 3 of the GH receptor (d3GHR) on long-term clinical outcome of acromegaly in a well-characterized cohort of patients with long-term remission of acromegaly. DESIGN: We conducted a cross-sectional study. METHODS: The presence of the d3GHR polymorphism was assessed in 86 acromegalic patients with long-term disease control and related to anthropometric parameters, cardiovascular risk factors, osteoarthritis, bone mineral density, colonic polyps and diverticulae, and dolichocolon. RESULTS: Fifty-one patients had two wild-type alleles (59%), whereas 29 patients (34%) had one allele and six patients (7%) had two alleles encoding for the d3GHR isoform. Carriers of the d3GHR isoform showed increased prevalence of osteoarthritis, especially of the hip [adjusted odds ratio (OR), 5.2; 95% confidence interval (CI), 3.2-7.1], of adenomatous polyps (adjusted OR, 4.1; 95% CI, 2.4-5.6), and dolichocolon (adjusted OR, 3.2; 95% CI, 1.8-4.6). Anthropometric parameters, cardiovascular risk factors, bone mineral density, and (non)vertebral fractures were not significantly different between patients with and without the d3GHR allele. CONCLUSION: In patients with long-term cured acromegaly, the d3GHR polymorphism is associated with an increased prevalence of irreversible comorbidities such as osteoarthritis, dolichocolon, and adenomatous colonic polyps, but not with other comorbidities such as cardiovascular risk factors.

Pretreatment insulin-like growth factor-I concentrations predict radiographic osteoarthritis in acromegalic patients with long-term cured disease.

OBJECTIVE: The aim of the study was to identify factors influencing the development of osteoarthritis during long-term control of acromegaly, focusing on disease-specific parameters, GH and IGF-I concentrations, and duration of disease, adjusted for the well-known determinants of primary osteoarthritis. DESIGN: We conducted a follow-up study. METHODS: We studied 67 patients with adequate biochemical control of acromegaly for a mean of almost 13 yr. Study parameters were the results of radiological assessment of the spine, hip, knee, and hand. Osteoarthritis was defined as radiological osteoarthritis using the scoring system developed by Kellgren and Lawrence. Correlations between potential factors of influence and osteoarthritis were performed by analysis of covariance and adjusted for age, gender, and body mass index. RESULTS: Patients with pretreatment IGF-I sd scores in the highest tertile had an almost 4-fold increased risk for radiological osteoarthritis of the hip when compared with patients in the lowest tertile. After adjustment for age, gender, BMI, and disease duration, pretreatment IGF-I sd scores predicted radiographic osteoarthritis in all joint sites. Osteoarthritis was not predicted by other factors, including pretreatment GH levels, type of treatment, and duration of follow-up. CONCLUSION: This is the first study to document pretreatment IGF-I concentration as a predictor of radiographic osteoarthritis in acromegalic patients with long-term disease control.

Pheochromocytomas and extra-adrenal paragangliomas detected by screening in patients with SDHD-associated head-and-neck paragangliomas.

Patients with SDHD-associated head-and-neck paragangliomas (HNP) are at risk for developing pheochromocytomas for which screening has been advised. To assess clinical, biochemical, and radiological outcomes of screening in a large single-center cohort of SDHD-positive patients with HNP and to address the necessity for repetitive follow-up, we evaluated 93 patients with SDHD-associated HNP (p.Asp92Tyr, p.Leu139Pro). Screening consisted of measurement of 24 h urinary excretion of catecholamines and/or their metabolites in duplicate, which was repeated with intervals of 2 years if initial biochemical screening was negative. In patients, in whom urinary excretion was above the reference limit, imaging studies with (123)I-MIBG (metaiodobenzylguanidine) scintigraphy and magnetic resonance imaging (MRI) and/or computed tomography (CT) were performed. Pheochromocytomas and extra-adrenal paragangliomas were treated surgically after appropriate blockade. Median follow-up was 4.5 years (range 0.5-19.5 years). Twenty-eight out of the 93 patients were included in our study and underwent additional imaging for pheochromocytomas/extra-adrenal paragangliomas. In 11 out of the 28 patients intra-adrenal pheochromocytomas were found. Extra-adrenal paragangliomas were discovered in eight patients. These tumors were detected during initial screening in 63% of cases, whereas 37% were detected after repeated biochemical screening. One patient was diagnosed with a biochemically silent pheochromocytoma. The high prevalence of pheochromocytomas/extra-adrenal paragangliomas in patients with SDHD-associated HNP warrants regular screening for tumors in these patients. Paragangliomas that do not secrete catecholamines might be more prevalent than previously reported. Future studies will have to establish whether routine imaging studies should be included in the screening of SDHD mutation carriers, irrespective of biochemical screening.

Short-term overt hypothyroidism induces discrete diastolic dysfunction in patients treated for differentiated thyroid carcinoma.

BACKGROUND: Thyroid hormone has important effects on the cardiovascular system. The consequences of episodes of acute hypothyroidism on cardiac function have been investigated in only a few studies, and their results are inconclusive. Our objective was to investigate the effects of acute hypothyroidism on cardiac function in patients with iatrogenically induced subclinical hyperthyroidism after treatment for differentiated thyroid carcinoma. MATERIAL AND METHODS: Fourteen patients with a history of differentiated thyroid carcinoma on thyroid-stimulating hormone (TSH)-suppressive thyroxine replacement therapy were studied. We assessed cardiac function before, and 1 and 4 weeks after withdrawal of thyroxine substitution. We measured serum levels of free thyroxine, triiodothyronine and TSH and used a new sophisticated Doppler echocardiography technique, tissue Doppler imaging (TDI), to assess detailed and quantitative assessment of systolic and diastolic cardiac function. Echocardiographic parameters in patients were compared to controls. RESULTS: Compared to controls, patients had higher left ventricular mass and wall thickness and decreased diastolic function during TSH-suppressive l-thyroxine substitution therapy. Thyroxine withdrawal resulted in a decrease in both early (E) and late (A) diastolic mitral inflow velocities, without impact on E/A ratio. Using TDI, late diastolic velocity (A') decreased without impact on E'/A' ratio. Left ventricular dimensions, wall thickness and mass did not change during thyroxine withdrawal. CONCLUSIONS: Subclinical hyperthyroidism is accompanied by diastolic dysfunction. Subsequent acute hypothyroidism induces only subtle changes in diastolic function.

High prevalence of arthropathy, according to the definitions of radiological and clinical osteoarthritis, in patients with long-term cure of acromegaly: a case-control study.

OBJECTIVE: To evaluate the prevalence and rheumatological and radiological characteristics of arthropathy in patients after long-term cure of acromegaly in comparison with age-matched controls. DESIGN: Case-control study. PATIENTS: We compared 89 patients with adequate biochemical control of acromegaly (mean 14 years) and 67 age-matched controls. MEASUREMENTS: Study parameters were the results of symptom questionnaires, structured physical examination and radiographs of the spine, hip, knee and hand. The diagnosis of osteoarthritis was based on a) radiological osteoarthritis determined by Kellgren and Lawrence and b) clinical osteoarthritis determined by the American College of Rheumatology (ACR) criteria. For the radiological comparison with controls, a Dutch reference group was used. RESULTS: Pain/stiffness at > or =1 joint site was reported by 72% of patients, most frequently in the spine and hands. Radiological osteoarthritis at > or =1 joint site was present in 99% of patients, most frequently in the spine and hip, and increased at all joint sites in comparison with controls (odds ratios: 2-20). Despite long-term cure of acromegaly, the characteristic widening of joint spaces was still present. In addition, severe osteophytosis was present. Representative radiographs of these typical features are included in the manuscript. According to the ACR criteria, clinical osteoarthritis at > or =1 joint site was present in 63% of patients, most frequently in the spine and hand. Patients had a higher prevalence of osteoarthritis than controls at all joint sites according to all scoring methods and at a younger age. CONCLUSIONS: Prior GH excess has irreversible, deleterious late effects on the clinical and radiological aspects of joints in patients with long-term cure of acromegaly.

Reduced quality of life in patients with head-and-neck paragangliomas.

OBJECTIVE: The objective of this study was to assess the quality of life (QoL) in patients with head-and-neck paragangliomas ('glomus tumors'). DESIGN: We conducted a case-control study. METHODS: We assessed QoL in 82 patients with head-and-neck paragangliomas using four validated health-related questionnaires: Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index (MFI-20), Short Form-36 (SF-36), and Nottingham Health Profile (NHP). Patient outcomes were compared with controls provided by the patients and with a large age- and sex-adjusted control group. RESULTS: The QoL scores in the paraganglioma patients were significantly reduced in 12 out of the 21 subscales compared with own controls, and in 18 out of the 21 subscales compared with age- and sex-adjusted values derived from the previous studies. In the MFI-20 questionnaire, patients reported more general fatigue, physical fatigue, mental fatigue, and a reduction in activity and motivation. The scores in the NHP showed a difference in energy, emotional reaction, and social isolation. General health perception, pain, and physical functioning were reported to be worse in the paraganglioma patients on the SF-36 scale. Although anxiety and depression did not reveal any significant differences between patients and their own controls, an increased score on both anxiety and depression was seen when compared with the extended control group. Especially, dysphonia contributes to a reduced QoL. CONCLUSION: QoL is considerably reduced in patients with head-and-neck paragangliomas.

Quality of life is decreased in female patients treated for microprolactinoma.

OBJECTIVE: Most studies on treatment of microprolactinoma have focused on clinical and biochemical outcome rather than on functional and mental well-being. We evaluated this topic in female patients with microprolactinoma, because other pituitary adenomas are associated with decreased quality of life. DESIGN: We conducted a cross-sectional study. PATIENTS AND METHODS: To assess the impact of treatment for microprolactinoma on subjective well-being, quality of life was investigated in 55 female patients (mean age 45 +/- 10 years), treated for microprolactinoma in our center, using four validated, health-related questionnaires: Short-Form-36 (SF-36), Nottingham Health Profile (NHP), Multidimensional Fatigue Inventory (MFI-20), and Hospital Anxiety and Depression Scale (HADS). Patient outcomes were compared with those of 183 female controls with equal age distributions. RESULTS: Anxiety and depression scores were increased when compared with controls for all subscales as measured by HADS, and fatigue for all but one subscale as measured by MFI-20. Patients treated for microprolactinoma had worse scores on social functioning, role limitations due to physical problems (SF-36), energy, emotional reaction, and social isolation (NHP) when compared with control subjects. Important independent predictors of quality of life were reproductive status and anxiety and depression scores according to the HADS. CONCLUSION: Quality of life is impaired in female patients treated for microprolactinoma, especially due to increased anxiety and depression. These increased anxious and depressive feelings might be due to possible effects of hyperprolactinemia on the central nervous system. Failure to recognize this association may adversely affect patient-doctor relationships.

Attenuated pulse size, disorderly growth hormone and prolactin secretion with preserved nyctohemeral rhythm distinguish irradiated from surgically treated acromegaly patients.

BACKGROUND: Radiation induces time-dependent loss of anterior pituitary function, attributed to damage of the pituitary gland and hypothalamic centres. The development of growth hormone deficiency (GHD) in irradiated acromegaly patients is not well defined. OBJECTIVE: Detailed analysis of spontaneous 24-h GH and prolactin (PRL) secretion in relation to other pituitary functions and serum IGF-I concentrations in an attempt to find criteria for GHD in acromegalic patients with a GH response < 3 microg/l during the insulin tolerance test (ITT). DESIGN: Plasma hormone profiles obtained by 10 min sampling for 24 h in postoperatively irradiated acromegalic patients, compared with patients cured by surgery only and matched healthy controls. SETTING/PARTICIPANTS: University setting. Fifteen subjects in each group. OUTCOME MEASURES: GH and PRL secretory parameters quantified by deconvolution, cluster, cosinor and approximate entropy (ApEn) analyses, IGF-I concentrations. RESULTS: Irradiation attenuated pulsatile secretion of GH and PRL, but total PRL secretion was unchanged. GH and PRL secretory regularity were diminished. Circadian timing remained intact. Pulsatile GH secretion and IGF-I were correlated (R = 0.30, P = 0.04). Criteria of pulsatile GH secretion = 12 microg/l/24 h and ApEn = 0.800 separated 12 of 15 irradiated patients from all others. CONCLUSION: Irradiated acromegaly patients with a subnormal GH response to ITT have very limited spontaneous GH secretion, with specific attenuation of the size of GH bursts and a highly irregular pattern, but with retained diurnal properties. These patients are thus likely GH-deficient and might benefit from GH replacement.

Sustained effects of recombinant GH replacement after 7 years of treatment in adults with GH deficiency.

CONTEXT: The goal of GH replacement with recombinant human GH (rhGH) is to ameliorate symptoms, signs, and complications of adult GH deficiency (GHD) in the long term. To determine whether the observed short-term beneficial effects of rhGH treatment are sustained in the long term, we evaluated biochemical and anthropometric parameters after 7 years of rhGH replacement. PATIENTS AND METHODS: After 2, 5, and 7 years of rhGH replacement, 63 adult GHD patients (30 men, 52 adult-onset GHD) were assessed. IGF-I increased during rhGH replacement, and a stable dose of rhGH was reached within 1 year of rhGH substitution. Thereafter, this individualized dose was continued. RESULTS: Plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased even after 5 years of rhGH replacement (11% decrease, P < 0.001; 22% decrease, P < 0.001 respectively). High-density lipoprotein cholesterol levels increased during 7 years of rhGH replacement (1.4 +/- 0.5 mmol/l at baseline vs 1.7 +/- 0.5 mmol/l after 7 years, P < 0.001), whereas triglyceride concentrations remained unchanged. Fasting glucose levels increased during follow-up, mainly during the first 2 years of rhGH replacement (4.4 +/- 0.7 mmol/l to 5.0 +/- 1.0 mmol/l, P < 0.001). Body mass index increased during follow-up, whereas waist circumference and waist-to-hip ratio remained unchanged. Diastolic blood pressure decreased (P = 0.002), but when patients using antihypertensive medication were excluded this decrease did not reach significance (P = 0.064). Systolic blood pressure remained unchanged. CONCLUSION: The beneficial effects of rhGH replacement, described after short-term rhGH replacement, are sustained in the long term up to 7 years.

Quality of life is decreased after treatment for nonfunctioning pituitary macroadenoma.

OBJECTIVE: Although a reduced quality of life (QoL) has been reported after long-term cure of functioning pituitary adenomas, the effect of successful treatment of nonfunctioning pituitary macroadenoma (NFMA) on QoL has not been fully addressed. Therefore, we evaluated a broad spectrum of QoL parameters in patients successfully treated for NFMA in our center. DESIGN: We conducted a case-control study. PATIENTS AND METHODS: We assessed QoL in 99 adult patients (mean age, 61.9 yr; range, 24-86 yr) in remission during long-term follow-up after surgical (n = 99) and additional radiotherapeutic (n = 37) treatment for NFMA by four validated health-related questionnaires (Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index, Nottingham Health Profile, and Short Form-36). Patient outcomes were compared with 125 controls and with age-adjusted reference values derived from the literature. RESULTS: NFMA patients reported significantly impaired QoL in all questionnaires compared with the 125 controls and the age-adjusted reference values. All subscales of fatigue, assessed using the Multidimensional Fatigue Index (general fatigue, physical fatigue, reduction in activity, reduction in motivation, and mental fatigue) were impaired. The scores in the Nottingham Health Profile pointed toward reduced energy and affected emotional reaction. In several subscales of the Short Form-36 (social functioning, role limitations due to physical problems, role limitations due to emotional problems, and general health perception), NFMA patients reported a reduced QoL. CONCLUSION: QoL is considerably reduced in patients after successful treatment of NFMA.

GH deficiency in patients irradiated for acromegaly: significance of GH stimulatory tests in relation to the 24 h GH secretion.

BACKGROUND: Radiotherapy for pituitary adenomas frequently leads to GH deficiency (GHD). The characteristics of GH secretion in GHD induced by postoperative radiotherapy for acromegaly are not known. HYPOTHESIS: In the long term, stimulated and spontaneous GH release is not different between patients with GHD treated by postoperative radiotherapy for acromegaly or for other pituitary adenomas. DESIGN/SUBJECTS: We compared the characteristics of basal and stimulated GH secretion in patients with GHD, who had previously received adjunct radiotherapy after surgery for GH-producing adenomas (n=10) vs for other pituitary adenomas (n=10). All patients had a maximal GH concentration by insulin tolerance test (ITT) of 3 microg/l or less, compatible with severe GHD. Mean time after radiation was 17 and 18.7 years, respectively. Stimulated GH release was also evaluated by infusion of growth hormone-releasing hormone (GHRH), GHRH-arginine and arginine, and spontaneous GH by 10 min blood sampling for 24 h. Pulse analyses were performed by Cluster and approximate entropy. OUTCOMES: There were no differences between both patient groups in stimulated GH concentrations in any test. Spontaneous GH secretion was not different between both patient groups, including basal GH release, pulsatility and regularity. Pulsatile secretion was lost in two acromegalic and three non-acromegalic patients. Insulin-like growth factor-I (IGF-I) was below -2 s.d. score in nine patients in each group. CONCLUSION: Acromegalic patients treated by surgery and postoperative radiotherapy with an impaired response to the ITT do not differ, in the long term, in GH secretory characteristics from patients treated similarly for other pituitary tumors with an impaired response to the ITT. The ITT (or the GHRH-arginine test) is therefore reliable in establishing the diagnosis of GHD in patients treated for acromegaly by surgery and radiotherapy.

Uncontrolled acromegaly is associated with progressive mitral valvular regurgitation.

INTRODUCTION: Recent cross-sectional studies have documented an association between acromegaly and regurgitant valvular heart disease. The aim of this study was to evaluate the change in prevalence of valvular heart disease in relation to the clinical activity, because the natural history of valvular changes in acromegaly is unknown. PATIENTS AND METHODS: Valvular regurgitation was assessed in 37 acromegalic patients (18 patients with active disease, and 19 with controlled disease) by conventional two-dimensional and Doppler echocardiography before and after an interval of 1.9 years (range 1.5-3.0 years). RESULTS: At baseline, valvular regurgitation (mitral and aortic sites combined) was present in 46% of the patients and increased to 67% at follow-up (P=0.008). Mitral regurgitation increased significantly from 32% to 60% (P=0.002), but no change was noted for the aortic valve (27% vs. 31%, NS). In patients with active disease, valvular regurgitation increased significantly from 56% at baseline to 88% at follow-up (P=0.031) due to a significant increase of mitral regurgitation from 39% to 78% at follow-up (P=0.016). In contrast, no increase in valvular regurgitation was found in patients with controlled disease. CONCLUSION: The prevalence of mitral, but not aortic, valvular regurgitation increased in patients with active acromegaly during follow-up. Patients with acromegaly require adequate cardiac evaluation and follow-up to establish the extent and progression of valvular involvement.