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  • Author: A A van der Klaauw x
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Quality of life is decreased in female patients treated for microprolactinoma

M Kars, A A van der Klaauw, C S Onstein, A M Pereira, and J A Romijn

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.

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

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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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

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

B Havekes, A A van der Klaauw, H C Hoftijzer, J C Jansen, A G L van der Mey, A H J T Vriends, J W A Smit, J A Romijn, and E P M Corssmit

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.

Free access

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

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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Increased aortic root diameters in patients with acromegaly

Agatha A van der Klaauw, Jeroen J Bax, Johannes W A Smit, Eduard R Holman, Victoria Delgado, Gabe B Bleeker, Nienke R Biermasz, Ferdinand Roelfsema, Johannes A Romijn, and Alberto M Pereira

Objective

The clinical manifestations of acromegalic cardiomyopathy include arrhythmias, valvular regurgitation, concentric left ventricular (LV) hypertrophy, and LV systolic and diastolic dysfunction. At present, it is unknown whether acromegaly also affects the aortic root.

Design

Aortic root diameters were prospectively 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 observation period of 1.9 years (range 1.5–3.0 years). Baseline parameters were compared with healthy controls.

Results

The diameters of the aortic root at the sino-tubular junction and the ascending aorta were increased in patients with acromegaly: 30±4 vs 26±3 mm (P=0.0001) and 33±5 vs 30±4 mm (P=0.006) respectively. The diameter of the aortic root at the aortic annulus and aortic sinus were not different from controls. During follow-up, the aortic root diameters increased at the levels of the annulus and the sinotubular junction (P=0.025 and P=0.024 respectively), whereas there was no change in the diameters at the levels of the sinus and the ascending aorta during follow-up. Baseline aortic root diameters were not influenced by disease duration, current disease activity, or blood pressure. When patients with active and inactive disease were analyzed separately, only the diameter of the sinotubular junction increased in patients with inactive acromegaly during follow-up (P=0.031).

Conclusion

Aortic root diameters are increased in patients with acromegaly compared with healthy controls.

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Cardiac manifestations of GH deficiency after treatment for acromegaly: a comparison to patients with biochemical remission and controls

Agatha A van der Klaauw, Jeroen J Bax, Gabe B Bleeker, Eduard R Holman, V Delgado, Johannes W A Smit, Johannes A Romijn, and Alberto M Pereira

Objective

Both GH excess and GH deficiency (GHD) lead to specific cardiac pathology. The aim of this study was to evaluate cardiac morphology and function in patients with GHD after treatment for acromegaly.

Design

Cross-sectional study.

Patients and methods

Cardiac parameters were studied by conventional two-dimensional echocardiography and tissue Doppler imaging in 53 patients with acromegaly (16 patients with GHD, 20 patients with biochemical remission, and 17 patients with active disease). Patients with GHD were also compared with age- and gender-matched controls.

Results

Left ventricular (LV) dimensions, wall thickness, and mass did not differ between the three groups, or between the patients with GHD and healthy controls. Systolic function, assessed by LV ejection fraction, tended to be lower in patients with GHD compared with patients with biochemical remission (65.9±7.3% vs 72.4±8.5%, P=0.070), but was higher when compared with active acromegaly (58.8±9.3%, P=0.047). No differences were found with healthy controls. Diastolic function, measured with early diastolic velocity (E′), was lower in patients with GHD when compared with both patients with biochemical remission (6.0±2.1 cm/s vs 8.3±1.5 cm/s, P=0.005) and healthy controls (8.1±1.9 cm/s, P=0.006).

Conclusion

GHD after acromegaly results in a specific decrease in diastolic function compared with patients with biochemical remission of acromegaly and healthy controls. In addition, systolic function tends to be decreased in patients with GHD compared with patients with biochemical remission, but was higher than that in patients with active acromegaly.

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Administration route-dependent effects of estrogens on IGF-I levels during fixed GH replacement in women with hypopituitarism

Agatha A van der Klaauw, Nienke R Biermasz, Pierre M J Zelissen, Alberto M Pereira, Eef G W M Lentjes, Johannes W A Smit, Sjoerd W van Thiel, Johannes A Romijn, and Ferdinand Roelfsema

Objective

GH-deficient women using oral estradiol treatment require higher doses of recombinant human GH (rhGH) to achieve similar IGF-I levels when compared with men and women on transdermal estradiol replacement. The aim of this study was to evaluate the effects of oral versus transdermal estrogen administration at similar plasma estradiol levels on IGF-I, IGF-binding protein-3, and sex hormone-binding globulin (SHBG) concentrations.

Design

Parallel crossover study in which two groups of hypogonadal and GH-deficient women with fixed and stable rhGH replacement passed through four different estradiol treatment schemes (2 and 4 mg oral, and 50 and 100 μg transdermal estradiol) with a duration of four cycles each to ensure a new steady state. Group I (18 patients using oral estradiol prior to the study) was treated with oral followed by transdermal estradiol and group II (five patients with transdermal estradiol prior to inclusion) with transdermal followed by oral estradiol.

Results

Estradiol concentrations were lowest during 50 μg transdermal and highest during 4 mg oral estradiol treatment. Estradiol concentrations did not differ during 100 μg transdermal and 2 mg oral treatment. Nevertheless, IGF-I levels were significantly higher during 100 μg transdermal when compared with 2 mg oral treatment (P=0.005 in group I and 0.02 in group II), while SHBG levels were significantly lower (P=0.002 in group I and P=0.004 in group II). SHBG and IGF-I concentrations were negatively correlated (R=−0.41, P=0.0001).

Conclusion

During fixed GH replacement, the route of estrogen administration is a determinant of IGF-I levels in hypogonadal GH-deficient women.

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Recombinant human GH replacement increases CD34+ cells and improves endothelial function in adults with GH deficiency

Agatha A van der Klaauw, Alberto M Pereira, Ton J Rabelink, Eleonora P M Corssmit, Anton-Jan Zonneveld, Hanno Pijl, Hetty C de Boer, Johannes W A Smit, Johannes A Romijn, and Eelco J P de Koning

Objective

Adult patients with GH deficiency (GHD) are at increased risk for cardiovascular morbidity and mortality. Endothelial function, vascular stiffness, and loss of circulating CD34+ cells are considered biomarkers for cardiovascular disease. The aim of this study was to assess vascular structure and function in relation to circulating CD34+ cells in adults with GHD before and during 1 year of recombinant human GH (rhGH) replacement.

Design

One-year intervention with rhGH.

Patients and methods

Vascular function (flow-mediated dilatation (FMD)) and structure (pulse wave velocity (PWV) and analysis) were assessed in 14 adult patients (nine men) with GHD (mean age 57 years, range 27–71 years). In addition, the number of CD34+ cells was evaluated using flow cytometric analysis. Study parameters were analyzed at baseline, and after 6 months and 1 year of rhGH replacement.

Results

rhGH replacement increased IGF-I levels from 10.4±4.5 mmol/l at baseline to 18.4±10.1 mmol/l, and 20.5±8.0 mmol/l, at 6 months, and 1 year respectively (P=0.001). FMD increased from 3.5±1.8% to 6.0±2.5% and 5.1±2.5% during 1 year of rhGH replacement (P=0.008). There was no beneficial effect on PWV, central pulse pressure, central systolic pressure, and augmentation index. The number of CD34+ cells increased from 794.9±798.8 to 1270.7±580.1 cells/ml and to 1356.9±759.0 cells/ml (P=0.010).

Conclusion

One year of rhGH replacement in adults with GHD improves endothelial function and increases the number of circulating CD34+ cells.

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The prevalence of the metabolic syndrome is increased in patients with GH deficiency, irrespective of long-term substitution with recombinant human GH

Agatha A van der Klaauw, Nienke R Biermasz, Edith J M Feskens, Marieke B Bos, Johannes W A Smit, Ferdinand Roelfsema, Eleonora P M Corssmit, Hanno Pijl, Johannes A Romijn, and Alberto M Pereira

Objectives: Many reports demonstrate improvements in cardiovascular risk factors during GH replacement (rhGH) in adult GH deficiency (GHD). However, it remains to be determined to what extent these changes translate into a reduction of increased cardiovascular morbidity and mortality. The aim of this study was to evaluate the effects of long-term rhGH replacement on the prevalence of the metabolic syndrome (MS).

Design, settings, main outcome measures: The MS was scored by the National Cholesterol Education Program-Adult Treatment Panel III definition in 50 consecutive GHD patients (45 ± 9 years of age), before and after 2 and 5 years of rhGH replacement, and the data of untreated patients were compared with the general population using data from a Dutch population-based study (n = 1062, 44 ± 8 years of age).

Results: Hypertriglyceridaemia (46.0 vs 18.5%, P < 0.0001), hypertension (66.0 vs 35.5%, P < 0.0001) and abdominal obesity (38.0 vs 23.4%, P = 0.0178) were more prevalent in untreated patients when compared with controls, resulting in a higher prevalence of the MS in patients (38.0 vs 15.7%, P < 0.0001). During rhGH replacement at a mean dose of 0.5 ± 0.2 mg/day resulting in IGF-I concentrations in the normal age-adjusted reference range, mean high-density lipoprotein cholesterol level increased compared with baseline (P < 0.001). However, the prevalence of (components of) the MS did not change after 2 or 5 years of treatment with rhGH.

Conclusion: In this study, the prevalence of the MS in patients with GHD is increased compared with healthy controls, irrespective of rhGH replacement.