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ABSTRACT: Background
The beneficial effects of recombinant human growth hormone (rhGH) therapy in growth hormone deficient (GHD) adults are well-established in the short-term. However, data documenting the effects during prolonged follow-up are relatively scarce.Objective
To evaluate the reported effects of rhGH replacement (≥5 years) in GHD adults on biochemical and anthropometric parameters, quality of life (QoL), bone metabolism, muscle strength, serious adverse events (SAEs), and mortality.Methods
We conducted a systematic literature search. Quality assessment of retrieved papers was performed using a quality assessment based on the modified STROBE statement.ResultsWe included 23 prospective studies with a rhGH treatment duration ranging from 5 to 15 years. Overall, beneficial effects were reported on QoL, body composition, lipid profile, carotid IMT and BMD. In contrast, the prevalence of the metabolic syndrome, glucose levels, BMI and muscle strength were not, or negatively influenced. Most of the studies were uncontrolled, lacked the presence of a control group (of non-treated GHD patients), and reported no data on lipid-lowering and anti-diabetic medication. Overall mortality was not increased.Conclusion
RhGH treatment in adult GHD patients is well-tolerated and positively affects QoL in the long-term. However, the metabolic and cardiovascular effects during long-term treatment are variable. The low numbers of long-term studies and studied patients and lack of control data hamper definite statements on the efficacy of prolonged treatment. Therefore, continuous monitoring of the effects of rhGH replacement to enable an adequate risk-benefit analysis that may justify prolonged, potentially life-long, treatment is advisable.
European Journal of Endocrinology 04/2013; · 3.42 Impact Factor
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ABSTRACT: Arthropathy is an invalidating complication of acromegaly. This arthropathy deteriorates radiographically despite long-term disease control. However, the clinical course and its relationship to the radiographic course are currently unknown. We aimed to investigate the clinical course of arthropathy during follow-up and its relationship to radiographic progression in long-term controlled acromegaly patients. Prospective follow-up study. We studied 58 patients (mean age 62 years, women 41 %) with controlled acromegaly for a mean of 17.6 years. Clinical progression of joint disease was defined at baseline and after 2.6 years, by the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and Australian/Canadian Osteoarthritis Index (AUSCAN) questionnaires for lower limb and hand OA, respectively, and performance tests. Potential risk factors for progression were assessed. The clinical course of arthropathy was related to the radiographic course. On average, hand and lower limb function deteriorated during follow-up, despite large interindividual variations. Joint pain was stable over time. High levels of pain and functional impairment at baseline were related to clinical progression of hand pain and functional limitations. High baseline BMI was a risk factor for functional deterioration in the lower limb. The changes in symptoms and radiographic progression during follow-up were not related. In treated acromegaly patients, joint function deteriorates during prolonged follow-up, despite biochemical disease control, although there was interindividual variation. Clinical and radiographic course of arthropathy were not related. Therefore, in clinical practice, a combination of clinical and radiographic assessment is necessary to evaluate the course of acromegalic arthropathy.
Pituitary 01/2013; · 1.83 Impact Factor
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ABSTRACT: Patients who are considered to have been successfully treated for pituitary disease because they are in long-term remission of functioning or non-functioning macroadenomas, still report reduced quality of life and persistent morbidity and have (slightly) increased mortality. It is likely that the causes are multi-factorial, including intrinsic imperfections of surgical or endocrine replacement therapy, but also of persistent effects of hormone excess on the central nervous system affecting personality and behaviour. In agreement, recent studies demonstrate that patients in long-term remission for acromegaly and Cushing's disease have a higher prevalence of psychopathology and more maladaptive personality traits, display different and less effective coping strategies, and experience more negative illness perceptions. These new findings are intriguing in view of the general impairments in health-related quality of life, suggesting that the effects of previous hormone excess on the central nervous system can be long-lasting and to a certain extent even be irreversible. This review aims to address the effects of the treatment of pituitary disease on quality of life and neuropsychological functioning. Further research is needed to gain more insight into irreversibility of hormone excess syndromes. However, since coping strategies are altered, it is tempting to speculate that quality of life might be improved by targeted interventions.
The Netherlands Journal of Medicine 08/2012; 70(6):255-60. · 2.07 Impact Factor
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ABSTRACT: Arthropathy is an invalidating complication of acromegaly, of which the prognosis and determinants are currently unknown in treated acromegaly. Therefore, the objective of the present study was to investigate the radiographic progression of arthropathy over a mean follow-up period of 2.6 years and determinants of outcome in patients with long-term, well-controlled acromegaly.
Prospective follow-up study.
In a prospective cohort study we studied 58 patients (mean age 62, women 41%) with controlled acromegaly for a mean of 17.6 years. Radiographic progression of joint disease was defined by the Osteoarthritis Research Society International classification as a 1-point increase in joint space narrowing (JSN) or osteophyte scores on radiographs of the hands, knees, and hips obtained at the first study visit and after 2.6 years. Potential risk factors for progression were assessed.
Progression of osteophytes and JSN was observed in 72 and 74% of patients respectively. Higher age predisposed for osteophyte progression. Patients with biochemical control by somatostatin (SMS) analogs had more progression of osteophytosis than surgically cured patients (odds ratio=18.9, P=0.025), independent of age, sex, BMI, baseline IGF1 SDS and exon 3 deletion of the GHR. This was also evident for JSN progression, as were higher age and higher baseline IGF1 SDS.
Acromegalic patients have progressive JSN and osteophytosis, despite long-term biochemical control. Parameters reflecting GH/IGF1 activity were associated with progressive joint disease. Remarkably, biochemical control by SMS analogs was associated with more progression than surgical cure. Although the present study is not a randomized controlled trial, this may indicate insufficient GH control according to current criteria and the need for more aggressive therapy.
European Journal of Endocrinology 05/2012; 167(2):235-44. · 3.42 Impact Factor
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ABSTRACT: To systematically evaluate the reported prevalence of hypopituitarism following radiotherapy of the head and neck for cerebral or nasopharyngeal tumours, and following total body radiation.
Systematic review and meta-analysis
PubMed, EMBASE, Web of Science, and the Cochrane Library were searched for articles about the prevalence of hypopituitarism in adults following cranial radiotherapy. The reference lists of key articles were searched to identify other relevant studies. A meta-analysis was performed with the aid of the exact likelihood approach using a logistic regression with a random effects model at study level.
18 studies were included, with a total of 873 patients. These included 608 patients treated for nasopharyngeal cancer and 265 for one or more cerebral tumours. The total radiation dose ranged from 14-83 Gy and 40-97 Gy for nasopharyngeal and cerebral tumours, respectively. The prevalence of any degree of hypopituitarism was 0.66 (95% CI: 0.48-0.76). The prevalence of growth hormone deficiency was 0.45 (95% CI: 0.27-0.55), of LH- FSH deficiency 0.3 (95% CI: 0.16-0.29), of TSH deficiency 0.25 (95% CI: 0.13-0.35), and of ACTH deficiency 0.22 (95% CI: 0.13-0.29), respectively. The prevalence of hyperprolactinaemia was 0.34 (95% CI: 0.11-0.38). There were no differences between the effects of radiotherapy between the two tumour groups. There was no difference in prevalence between studies with greater or lesser risk of bias.
Hypopituitarism is highly prevalent in adult patients following cranial radiotherapy for nasopharyngeal carcinoma and cerebral tumours. Therefore, all patients treated with cranial radiotherapy should have a long-term structured follow-up with regular assessment of pituitary function.
Nederlands tijdschrift voor geneeskunde 01/2012; 156(9):A4340.
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N R Biermasz,
R van 't Klooster,
M J E Wassenaar,
S H Malm,
K M J A Claessen,
R G H H Nelissen,
F Roelfsema,
A M Pereira,
H M Kroon,
B C Stoel,
J A Romijn,
M Kloppenburg
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ABSTRACT: Arthropathy is an invalidating complication of acromegaly. Although acromegalic arthropathy shares features with primary osteoarthritis, joint spaces are widened rather than narrowed in patients with long-term cure of acromegaly. The late effects of acromegaly on hand joints have not been characterized. Therefore, the objective of the current study was to assess joint space widths (JSWs) of hand joints in patients with long-term control of acromegaly and to identify factors associated with JSW.
A cross-sectional study was carried out in 89 patients (age 58 ± 12 years, 49% women) with long-term controlled acromegaly and 471 controls without hand symptoms (age 46 ± 12 years, 42% women). Radiological JSWs of individual hand joints were measured by automated image analysis.
Patients had wider mean joint spaces than controls: metacarpo-phalangeal (MCP) joints were ~24%, proximal interphalangeal joints ~21%, and distal interphalangeal joints were ~20% wider (patients vs controls; P < 0.001 for all joints). Mean JSW exceeded the 95th percentile of the values obtained in controls in 64% of patients. Higher IGF1 and GH concentrations at diagnosis were associated with larger JSWs (adjusted β for pretreatment GH in tertiles: 0.09 (95% confidence interval (CI) 0.03-1.84) and for IGF1 in tertiles: 0.14 (95% CI 0.05-0.23) at the MCP joints in acromegalic patients. In male patients, but not in female patients, increased JSWs were associated with more self-reported pain (P = 0.02).
Using a new semi-automated image analysis of hand radiographs, acromegalic patients with long-term disease control appeared to have increased joint spaces of all hand joints. JSWs were positively related to disease activity at diagnosis, but not to duration of follow-up, suggesting irreversible cartilage hypertrophy. Irreversible cartilage hypertrophy may partly explain persisting hand complaints despite long-term disease control.
European Journal of Endocrinology 12/2011; 166(3):407-13. · 3.42 Impact Factor
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ABSTRACT: To evaluate the association between radiographic osteoarthritis (OA) and either serum insulin-like growth factor-1 (IGF-1) levels or IGF-1 gene polymorphisms in patients with primary OA.
We conducted a systematic review of reported associations between circulating IGF-1 and/or IGF-1 gene polymorphisms and radiographic OA. Studies were eligible when: (1) investigating serum IGF-1 and/or IGF-1 gene polymorphisms in relation to prevalent or incident radiographic OA; (2) written in English; (3) full-text article or abstract; (4) patients had primary OA in knee, hip, hand or spine; (5) longitudinal, case-control or cross-sectional design. Quality assessment was done using a standardized criteria set. Best-evidence synthesis was performed based on guidelines on systematic review from the Cochrane Collaboration Back Review Group, using five evidence levels: strong, moderate, limited, conflicting and no evidence.
We included 11 studies with more than 3000 primary OA cases. Data on the relationship between serum IGF-1 and radiographic OA were inconsistent. Adjustment for body mass index (BMI) was often omitted. Of four high-quality studies, three studies reported no association, one study found significantly higher IGF-1 levels in OA patients compared to controls. Patients with IGF-1 gene promoter polymorphisms and a genetic variation at the IGF-1R locus had an increased OA prevalence compared to controls.
Observational data showed no association between serum IGF-1 and occurrence of radiographic OA (moderate level of evidence), and a positive relationship between IGF-1 gene polymorphisms and radiographic OA (moderate level of evidence); however the confounding effect of BMI was insufficiently addressed. Future well-designed prospective studies should further elaborate the role of the complex GH/IGF-1 system in primary OA.
Osteoarthritis and Cartilage 11/2011; 20(2):79-86. · 3.90 Impact Factor
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ABSTRACT: Hypothalamus-pituitary-adrenal-axis activity is suggested to be involved in the pathophysiology of the metabolic syndrome. In diet-induced obesity mouse models, features of the metabolic syndrome are induced by feeding high fat diet. However, the models reveal conflicting results with respect to the hypothalamus-pituitary-adrenal-axis activation. The aim of this review was to assess the effects of high fat feeding on the activity of the hypothalamus-pituitary-adrenal-axis in mice. PubMed, EMBASE, Web of Science, the Cochrane database, and Science Direct were electronically searched and reviewed by 2 individual researchers. We included only original mouse studies reporting parameters of the hypothalamus-pituitary-adrenal-axis after high fat feeding, and at least 1 basal corticosterone level with a proper control group. Studies with adrenalectomized mice, transgenic animals only, high fat diet for less than 2 weeks, or other interventions besides high fat diet, were excluded. 20 studies were included. The hypothalamus-pituitary-adrenal-axis evaluation was the primary research question in only 5 studies. Plasma corticosterone levels were unchanged in 40%, elevated in 30%, and decreased in 20% of the studies. The effects in the peripheral tissues and the central nervous system were also inconsistent. However, major differences were found between mouse strains, experimental conditions, and the content and duration of the diets. This systematic review demonstrates that the effects of high fat feeding on the basal activity of the hypothalamus-pituitary-adrenal-axis in mice are limited and inconclusive. Differences in experimental conditions hamper comparisons and accentuate the need for standardized evaluations to discern the effects of diet-induced obesity on the hypothalamus-pituitary-adrenal-axis.
Hormone and Metabolic Research 11/2011; 43(13):899-906. · 2.19 Impact Factor
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W Y Kwok,
J Bijsterbosch,
S H Malm, N R Biermasz,
K Huetink,
R G Nelissen,
I Meulenbelt,
T W J Huizinga,
R van 't Klooster,
B C Stoel,
M Kloppenburg
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ABSTRACT: To investigate the validity of joint space width (JSW) measurements in millimeters (mm) in hand osteoarthritis (OA) patients by comparison to controls, grading of joint space narrowing (JSN), and clinical features.
Hand radiographs of 235 hand OA patients (mean age 65 years, 83% women) and 471 controls were used. JSW was measured with semi-automated image analysis software in the distal, proximal interphalangeal and metacarpal joints (DIPJs, PIPJs and MCPJs). JSN (grade 0-3) was assessed using the osteoarthritis research society international (OARSI) atlas. Associations between the two methods and clinical determinants (presence of pain, nodes and/or erosions, decreased mobility) were assessed using Generalized Estimating Equations with adjustments for age, sex, body mass index (BMI) and mean width of proximal phalanx.
JSW was measured in 5631 joints with a mean JSW of 0.98 mm (standard deviation (SD) 0.21), being the smallest for DIPJs (0.70 (SD 0.25)) and largest for MCPJs (1.40 (SD 0.25)). The JSN=0 group had a mean JSW of 1.28 mm (SD 0.34), the JSN=3 group 0.17 mm (SD 0.23). Controls had larger JSW than hand OA patients (P-value<0.001). In hand OA, females had smaller JSW than men (β -0.08, (95% confidence interval (95% CI) -0.15 to -0.01)) and lower JSW was associated with the presence of pain, nodes, erosions and decreased mobility (adjusted β -0.21 (95% CI -0.27, -0.16), -0.37 (-0.40, -0.34), -0.61 (-0.68, -0.54) and -0.46 (-0.68, -0.24) respectively). These associations were similar for JSN in grades.
In hand OA the quantitative JSW measurement is a valid method to measure joint space and shows a good relation with clinical features.
Osteoarthritis and Cartilage 09/2011; 19(11):1349-55. · 3.90 Impact Factor
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ABSTRACT: Illness perceptions pertain to the pattern of beliefs patients develop about their illness. Illness perceptions are determinants of quality of life (QoL). Factors contributing to persisting impaired QoL after Cushing's syndrome (CS) remain largely unknown. Therefore, the objective of this study was to explore illness perceptions, as potentially modifiable psychological factors, in relation to QoL in patients with long-term remission of CS.
Cross-sectional study.
We included patients with long-term remission of CS (n=52). Illness perceptions were evaluated using the Illness Perception Questionnaire (IPQ)-Revised, and QoL was measured using the physical symptom checklist, EuroQoL-5D (EQ-5D), and the CushingQoL. Reference data were derived from recent studies and included patients with vestibular schwannoma (n=80), acute (n=35) or chronic (n=63) pain, and chronic obstructive pulmonary disease (COPD; n=171).
Illness perceptions showed a strong correlation with QoL. Patients with CS scored distinctively more negative on the IPQ compared with patients with vestibular schwannoma and patients with acute pain, and also reported more illness-related complaints (all P<0.01). There were also some differences in illness perceptions between patients with CS and patients with chronic pain and patients with COPD, but there was no distinct pattern.
Patients after long-term remission of CS report more negative illness perceptions compared with patients with other acute or chronic conditions. Further research is needed to assess whether QoL in CS can be improved by addressing these illness perceptions, for example, by a self-management intervention program.
European Journal of Endocrinology 07/2011; 165(4):527-35. · 3.42 Impact Factor
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N E Kokshoorn,
J W A Smit,
W A Nieuwlaat,
J Tiemensma,
P H Bisschop,
R Groote Veldman,
F Roelfsema,
A A M Franken,
M J E Wassenaar, N R Biermasz,
J A Romijn,
A M Pereira
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ABSTRACT: Hypopituitarism after traumatic brain injury (TBI) is considered to be a prevalent condition. However, prevalence rates differ considerably among reported studies, due to differences in definitions, endocrine assessments of hypopituitarism, and confounding factors, such as timing of evaluation and the severity of the trauma. Aim To evaluate the prevalence of hypopituitarism in a large cohort of TBI patients after long-term follow-up using a standardized endocrine evaluation. Study design Cross-sectional study.
We included 112 patients with TBI, hospitalized for at least 3 days and duration of follow-up >1 year after TBI from five (neurosurgical) referral centers. Evaluation of pituitary function included fasting morning hormone measurements and insulin tolerance test (n=90) or, when contraindicated, ACTH stimulation and/or CRH stimulation tests and a GH releasing hormone-arginine test (n=22). Clinical evaluation included quality of life questionnaires.
We studied 112 patients (75 males), with median age 48 years and mean body mass index (BMI) 26.7±4.8 kg/m(2). Mean duration of hospitalization was 11 (3-105), and 33% of the patients had a severe trauma (Glasgow Coma Scale <9) after TBI. The mean duration of follow-up was 4 (1-12) years. Hypopituitarism was diagnosed in 5.4% (6/112) of patients: severe GH deficiency (n=3), hypogonadism (n=1), adrenal insufficiency (n=2). Patients diagnosed with pituitary insufficiency had significantly higher BMI (P=0.002).
In this study, the prevalence of hypopituitarism during long-term follow-up after TBI was low. Prospective studies are urgently needed to find reliable predictive tools for the identification of patients with a significant pre-test likelihood for hypopituitarism after TBI.
European Journal of Endocrinology 06/2011; 165(2):225-31. · 3.42 Impact Factor
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N R Biermasz,
S D Joustra,
E Donga,
A M Pereira,
N van Duinen,
M van Dijk,
A A van der Klaauw,
E P M Corssmit,
G J Lammers,
K W van Kralingen,
J G van Dijk,
J A Romijn
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ABSTRACT: 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.
We conducted a controlled cross-sectional study.
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.
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.
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.
The Journal of clinical endocrinology and metabolism 03/2011; 96(5):1524-32. · 6.50 Impact Factor
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ABSTRACT: To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the pathophysiological process of growth hormone (GH) and insulin-like growth factor type I (IGF-I)-mediated osteoarthritis.
We utilised radiographs of the knee and hip joints of 84 patients with controlled acromegaly for a mean of 14.0 years with 189 patients with primary generalised osteoarthritis. Hips and knees with with doubtful or definite osteoarthritis (Kellgren-Lawrence score of ≥ 1) were compared in the current study. For a semiquantitative assessment of radiological osteoarthritis (range 0-3) osteophytes and JSN of the medial and lateral tibiofemoral and hip joints were scored according to the Osteoarthritis Research Society International atlas. Logistic regression analysis was performed with adjustment for age, sex, body mass index and intrapatient effect.
Knee and hip osteoarthritis in patients with cured acromegaly was characterised by more osteophytosis (OR 4.1-9.9), but less JSN (OR 0.3-0.5) in comparison with patients with primary osteoarthritis. Patients with acromegaly and osteoarthritis had significantly less self-reported functional disability than patients with primary osteoarthritis (p < 0.001). Self reported functional disability was associated with JSN rather than with osteophytosis.
Arthropathy caused by GH oversecretion results in osteophytosis and to a lesser extent in JSN. This observation suggests that the GH-IGF-I system is mainly involved in bone formation resulting in osteophytosis, but may possibly protect against cartilage loss.
Annals of the rheumatic diseases 02/2011; 70(2):320-5. · 8.11 Impact Factor
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ABSTRACT: 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.
This was a case-control study.
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.
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.
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.
The Journal of clinical endocrinology and metabolism 03/2010; 95(5):2073-9. · 6.50 Impact Factor
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ABSTRACT: 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.
Cross-sectional study.
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.
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.
These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 02/2010; 20(3):226-33. · 2.35 Impact Factor
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M J E Wassenaar, N R Biermasz,
A M Pereira,
A A van der Klaauw,
J W A Smit,
F Roelfsema,
T van der Straaten,
M Cazemier,
D W Hommes,
H M Kroon,
M Kloppenburg,
H-J Guchelaar,
J A Romijn
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ABSTRACT: 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.
We conducted a cross-sectional study.
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.
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.
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.
The Journal of clinical endocrinology and metabolism 10/2009; 94(12):4671-8. · 6.50 Impact Factor
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ABSTRACT: The exon-3 deleted GH receptor (GHR(d3)) polymorphism is associated with an increased growth response to recombinant human GH (rhGH) therapy in some, but not all, studies in GH-deficient (GHD) and non-GHD children with short stature.
The aim of the study was to assess the effects of GHR(d3) on baseline height and the first year's growth response to rhGH treatment in prepubertal GHD and non-GHD children with short stature.
We conducted a systematic review and meta-analysis.
Fifteen studies reporting the effect of GHR(d3) on growth parameters were included. Principal outcomes were baseline height sd score (SDS) and the weighted average of change in growth velocity (Delta cm/yr) and height gain (Delta height SDS) after 1 yr of rhGH.
In GHD, not in non-GHD, baseline height SDS was 0.159 sd higher [95% confidence interval (CI), 0.020, 0.298] in GHR(d3) compared with GHR(wt-wt). In GHR(d3), rhGH therapy resulted in a higher increase in growth velocity (0.521 cm/yr; 95% CI, 0.196, 1.015) and height gain (0.075 sd; 95% CI, 0.007, 0.143) compared with GHR(wt-wt). Meta-regression demonstrated a larger difference between GHR(d3) and GHR(wt-wt) in studies using lower rhGH doses and carried out at a higher age, independently of the cause of short stature.
This meta-analysis in prepubertal children with short stature indicates that GHR(d3) is associated with increased baseline height in GHD, but not in non-GHD. Furthermore, GHR(d3) stimulates growth velocity by an additional effect of approximately 0.5 cm during the first year of rhGH treatment, and this effect is more pronounced at lower doses of rhGH and higher age.
The Journal of clinical endocrinology and metabolism 08/2009; 94(10):3721-30. · 6.50 Impact Factor
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ABSTRACT: 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.
We conducted a follow-up study.
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.
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.
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.
The Journal of clinical endocrinology and metabolism 04/2009; 94(7):2374-9. · 6.50 Impact Factor
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ABSTRACT: To evaluate the long-term outcome of transsphenoidal resection of pituitary adenomas at the Leiden University Medical Center (LUMC), The Netherlands.
Retrospective, descriptive.
416 consecutive patients undergoing surgery for pituitary adenoma at the LUMC between 1978 and 2004 were included; 174 patients with non-functioning macroadenomas (NFMA), 164 patients with acromegaly and 78 patients with Cushing's disease.
Biochemical remission was achieved in 66% of patients with acromegaly, and 72% of patients with Cushing's disease; incidence of pituitary failure was low in these patients (5% and 18% respectively). In 82% of the patients with NFMA visual function improved whereas the percentage with any degree of pituitary failure increased from 85% (preoperatively) to 95% (postoperatively). During follow-up of 10-15 years, the recurrence rate for acromegaly and Cushing's disease was 9% and for NFMA it was 15%.
Transsphenoidal resection is an effective treatment in most, but not all, patients with pituitary adenomas. The surgical results at the LUMC are comparable with those obtained in important international centres. All patients cured by surgery need lifelong follow-up, because of the real risk of recurrent disease.
Nederlands tijdschrift voor geneeskunde 12/2008; 152(47):2565-70.
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ABSTRACT: Several studies have assessed mortality risk in patients treated for acromegaly. All studies found a mortality that was higher than expected for the general population, but most of these increases were not statistically significant. For this reason, it is not formally established whether mortality in acromegaly is different from the general population.
The objective of the study was to address the all-cause mortality risk in patients with acromegaly.
The study was a metaanalysis.
Sixteen studies on mortality in patients with acromegaly were included. The principal outcome of the metaanalysis was the weighted average of the standardized mortality ratio (SMR) of all studies. In addition, we performed a subgroup analysis of studies in which more than 80% of the patients were treated by transsphenoidal approach.
The weighted mean of the SMR from all 16 studies was 1.72 (95% confidence interval 1.62-1.83). In studies with transsphenoidal surgery as the primary therapy, the weighted mean of the SMR was 1.32 (95% confidence interval 1.12-1.56).
This metaanalysis shows increased all-cause mortality in acromegalic patients, compared with the general population, even after transsphenoidal surgery.
Journal of Clinical Endocrinology & Metabolism 02/2008; 93(1):61-7. · 6.50 Impact Factor
