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F Malgo, N A T Hamdy, T J Rabelink, H M Kroon, K M J A Claessen, A M Pereira, N R Biermasz and N M Appelman-Dijkstra

Objective

Acromegaly is a rare disease caused by excess growth hormone (GH) production by the pituitary adenoma. The skeletal complications of GH and IGF-1 excess include increased bone turnover, increased cortical bone mass and deteriorated microarchitecture of trabecular bone, associated with a high risk of vertebral fractures in the presence of relatively normal bone mineral density (BMD). We aimed to evaluate tissue-level properties of bone using impact microindentation (IMI) in well-controlled patients with acromegaly aged ≥18 years compared to 44 controls from the outpatient clinic of the Centre for Bone Quality.

Design and methods

In this cross-sectional study, bone material strength index (BMSi) was measured in 48 acromegaly patients and 44 controls with impact microindentation using the osteoprobe.

Results

Mean age of acromegaly patients (54% male) was 60.2 years (range 37.9–76.5), and 60.5 years (range 39.8–78.6) in controls (50% male). Patients with acromegaly and control patients had comparable BMI (28.2 kg/m2 ± 4.7 vs 26.6 kg/m2 ± 4.3, P = 0.087) and comparable BMD at the lumbar spine (1.04 g/cm2 ± 0.21 vs 1.03 g/cm2 ± 0.13, P = 0.850) and at the femoral neck (0.84 g/cm2 ± 0.16 vs 0.80 g/cm2 ± 0.09, P = 0.246). BMSi was significantly lower in acromegaly patients than that in controls (79.4 ± 0.7 vs 83.2 ± 0.7; P < 0.001).

Conclusion

Our data indicates that tissue-level properties of cortical bone are significantly altered in patients with controlled acromegaly after reversal of long-term exposure to pathologically high GH and IGF-1 levels. Our findings also suggest that methods other than DXA should be considered to evaluate bone fragility in patients with acromegaly.

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A A van der Klaauw, J A Romijn, N R Biermasz, J W A Smit, J van Doorn, O M Dekkers, F Roelfsema and A M Pereira

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.

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K M J A Claessen, S R Ramautar, A M Pereira, J W A Smit, F Roelfsema, J A Romijn, H M Kroon, M Kloppenburg and N R Biermasz

Objective

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.

Design

Prospective follow-up study.

Methods

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.

Results

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.

Conclusions

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.

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K M J A Claessen, A Navas Canete, P W de Bruin, A M Pereira, M Kloppenburg, H M Kroon and N R Biermasz

Background

Arthropathy is a prevalent and invalidating complication of acromegaly with a characteristic radiographic phenotype. We aimed to further characterize cartilage and bone abnormalities associated with acromegalic arthropathy using magnetic resonance imaging (MRI).

Methods

Twenty-six patients (23% women, mean age 56.8 ± 13.4 years), with active (n = 10) and controlled acromegaly (n = 16) underwent a 3.0 T MRI of the right knee. Osteophytes, cartilage defects, bone marrow lesions and subchondral cysts were assessed by the Knee Osteoarthritis Scoring System (KOSS) method. Cartilage thickness and cartilage T2 relaxation times, in which higher values reflect increased water content and/or structural changes, were measured. Twenty-five controls (52% women, mean age: 59.6 ± 8.0 years) with primary knee OA were included for comparison.

Results

Both in active and controlled acromegaly, structural OA defects were highly prevalent, with thickest cartilage and highest cartilage T2 relaxation times in the active patients. When compared to primary OA subjects, patients with acromegaly seem to have less cysts (12% vs 48%, P = 0.001) and bone marrow lesions (15% vs 80%, P = 0.006), but comparable prevalence of osteophytosis and cartilage defects. Patients with acromegaly had 31% thicker total joint cartilage (P < 0.001) with higher cartilage T2 relaxation times at all measured sites than primary OA subjects (P < 0.01).

Conclusions

Patients with active acromegaly have a high prevalence of structural OA abnormalities in combination with thick joint cartilage. In addition, T2 relaxation times of cartilage are high in active patients, indicating unhealthy cartilage with increased water content, which is (partially) reversible by adequate treatment. Patients with acromegaly have a different distribution of structural OA abnormalities visualized by MRI than primary OA subjects, especially of cartilage defects.

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O M Dekkers, N R Biermasz, J W A Smit, L E Groot, F Roelfsema, J A Romijn and A M Pereira

Objective: Quality of life (QoL) has become increasingly important in the evaluation of treatment of pituitary and hormonal diseases. A reduced QoL has been reported in childhood-onset craniopharyngioma; however, reports of QoL in adult craniopharyngioma patients are scarce. In the present study, we assessed QoL in adult patients successfully treated for craniopharyngioma in our centre.

Design: This was a case-control study.

Methods: In this study, we assessed QoL in 29 adult patients in remission during long-term follow-up after treatment for craniopharyngioma. Four validated health-related questionnaires (HADS, MFI-20, NHP and SF-36) were used, covering multiple aspects of physical, psychological and social functioning. Patient outcomes were compared to controls (n = 142) and to age-adjusted reference values derived from literature.

Results: General fatigue, physical fatigue, energy, physical condition and physical mobility were significantly impaired, compared with controls. The main independent predictors for decreased QoL were visual field defects (depression, total HADS score, activity, motivation and energy), female gender (depression, motivation and pain), repeat surgery (role limitations due to emotional problems) and radiotherapy (mental fatigue) (the last two predictors to a lesser extent).

Conclusion: Adult patients treated for craniopharyngioma show persistent impairment in QoL, especially in the physical subscales.

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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 and A M Pereira

Objective

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.

Patients and methods

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.

Results

We studied 112 patients (75 males), with median age 48 years and mean body mass index (BMI) 26.7±4.8 kg/m2. 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).

Conclusion

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.

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M J E Wassenaar, N R Biermasz, N van Duinen, A A van der Klaauw, A M Pereira, F Roelfsema, J W A Smit, H M Kroon, M Kloppenburg and J A Romijn

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 ≥1 joint site was reported by 72% of patients, most frequently in the spine and hands. Radiological osteoarthritis at ≥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 ≥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.

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K M J A Claessen, N M Appelman-Dijkstra, A M Pereira, S D Joustra, R de Mutsert, K B Gast, M den Heijer, J W A Smit, O M Dekkers and N R Biermasz

Background

Adult GH deficiency (GHD) is associated with increased cardiovascular mortality. Recombinant human GH (rhGH) replacement has beneficial short-term metabolic effects. Although these positive effects sustain during longer follow-up, the prevalence of the metabolic syndrome (MS) remains increased in comparison with population data not adjusted for the higher mean BMI in GHD adults.

Objective

To explore whether middle-aged patients with proposed physiological rhGH replacement have been normalized with respect to MS and its individual components in comparison with the general population, adjusted for age, sex, and BMI.

Methods

One hundred and sixty-one GHD patients (aged 40–70 years) were studied before the start and after 5 years of rhGH replacement, and were compared with 1671 subjects (aged 45–66 years) from the general population (NEO Study).

Results

MS proportion in GHD patients was 41.0% before the start of rhGH suppletion, increasing to 53.4% after 5 years (P=0.007). Despite chronic rhGH replacement, GHD patients had a 1.3-times higher MS proportion than the general population, independently of age, sex, and BMI (95% CI 1.1–1.5, P=0.008). The GHD population showed a different metabolic profile than the general population with similar BMI: an increased risk of hypertriglyceridemia (adjusted prevalence ratio (PR) 2.0, 95% CI 1.7–2.3) and low HDL-C (adjusted PR 1.8, 95% CI 1.5–2.2), but less hyperglycemia (adjusted PR 0.5, 95% CI 0.4–0.7).

Conclusions

Despite 5 years of rhGH replacement, GHD patients still have a different metabolic profile and more frequently MS than the general population. These differences were independent of BMI, and resemble the unfavorable metabolic profile of untreated GHD patients, pointing to question the long-term benefits of rhGH replacement.

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A A van der Klaauw, A M Pereira, S W van Thiel, J W A Smit, E P M Corssmit, N R Biermasz, M Frolich, A Iranmanesh, J D Veldhuis, F Roelfsema and J A Romijn

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 μg/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.

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S D Joustra, R D Thijs, R van den Berg, M van Dijk, A M Pereira, G J Lammers, E J W van Someren, J A Romijn and N R Biermasz

Objective

Patients treated for nonfunctioning pituitary macroadenomas (NFMAs) have fatigue and alterations in sleep characteristics and sleep–wake rhythmicity frequently. As NFMAs often compress the optic chiasm, these complaints might be related to dysfunction of the adjacent suprachiasmatic nucleus (SCN). We aimed to explore whether indirect indices of SCN functioning are altered in the long term after surgery for NFMAs.

Methods

We studied 17 NFMA patients in long-term remission after transsphenoidal surgery, receiving adequate and stable hormone replacement for hypopituitarism, and 17 control subjects matched for age, gender, and BMI. Indirect indices of SCN function were assessed from 24-h ambulatory recordings of skin and core body temperatures, blood pressure, and salivary melatonin levels. Altered melatonin secretion was defined as an absence of evening rise, considerable irregularity, or daytime values >3 pg/ml. We additionally studied eight patients treated for craniopharyngioma.

Results

Distal–proximal skin temperature gradient did not differ between NFMAs and control subjects, but proximal skin temperature was decreased during daytime (P=0.006). Core body temperature and non-dipping of blood pressure did not differ, whereas melatonin secretion was often altered in NFMAs (OR 5.3, 95% CI 0.9–30.6). One or more abnormal parameters (≥2.0 SDS of control subjects) were observed during nighttime in 12 NFMA patients and during daytime in seven NFMA patients. Similar patterns were observed in craniopharyngioma patients.

Conclusion

Heterogeneous patterns of altered diurnal rhythmicity in skin temperature and melatonin secretion parameters were observed in the majority of patients treated for NFMAs. On a group level, both NFMA and craniopharyngioma patients showed a lower daytime proximal skin temperature than control subjects, but other group averages were not significantly different. The observations suggest altered function of central (or peripheral) clock machinery, possibly by disturbed entrainment or damage of the hypothalamic SCN by the suprasellar macroadenoma or its treatment.