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M A E M Wagenmakers, R T Netea-Maier, J B Prins, T Dekkers, M den Heijer and A R M M Hermus

Objective

The determinants that cause impaired quality of life (QOL) in patients in long-term remission of Cushing's syndrome (CS) are unknown. The aim of this study was to get more insight into the patient and disease characteristics related to impaired QOL in these patients.

Design

Cross-sectional study.

Methods

The QOL of 123 patients in remission of CS (age 52.2±12.0 years, 106 women, duration of remission 13.3±10.4 years, 80% pituitary CS), assessed with seven validated questionnaires, was compared with the QOL of an age- and sex-matched control group (n=105). To investigate the influence of the aetiology of CS on QOL, patients in remission of pituitary and adrenal CS were compared. Furthermore, the influence of hormonal deficiencies, treatment strategy, duration of remission, gender and age on QOL was investigated.

Results

QOL in the total patient group and each patient subgroup was significantly worse on practically all dimensions of questionnaires compared with the control group (P<0.05), except for patients in remission of pituitary CS without hormonal deficiencies who had an impaired QOL on 50% of the QOL dimensions. Subgroup analysis revealed no difference in QOL between different patient groups, especially no difference between patients in remission of adrenal and pituitary CS. Female gender and a shorter duration of remission had a negative influence on QOL in the patient group.

Conclusions

QOL remains impaired in patients in long-term remission of CS regardless of aetiology, presence of hormonal deficiencies and treatment strategies. More research is needed to establish the causes.

Free access

J A A Meijer, L E H Bakker, G D Valk, W W de Herder, J H W de Wilt, R T Netea-Maier, N Schaper, E Fliers, P Lips, J T Plukker, T P Links and J A Smit

Objective

Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients.

Design

Retrospective multicenter study in eight University Medical Centers in The Netherlands.

Methods

Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease.

Results

In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification.

Conclusions

Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC.

Free access

Mark R Postma, Romana T Netea-Maier, Gerrit van den Berg, Jens Homan, Wim J Sluiter, Margreet A Wagenmakers, Alfons C M van den Bergh, Bruce H R Wolffenbuttel, Ad R M M Hermus and André P van Beek

Objective

To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly.

Design

This is a cross-sectional study in two tertiary referral centers in The Netherlands.

Patients and methods

One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS.

Results

IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85±1.52 vs 0.25±1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44±0.72 vs SSTA−, n=44, IGF1 SDS 0.41±0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA.

Conclusion

QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels.

Free access

R T Netea-Maier, E J van Lindert, M den Heijer, A van der Eerden, G F F M Pieters, C G J Sweep, J A Grotenhuis and A R M M Hermus

Objective and design: The endoscopic technique has been recently introduced in the field of transsphenoidal pituitary surgery. This technique allows inspection of sellar, supra- and parasellar structures and removal of the tumor under direct visualization, is minimally traumatic and permits easier reoperations. This is the first report on the results of endoscopic surgery for patients with Cushing’s disease. Our aim was to retrospectively analyze the results of pituitary surgery in 35 consecutive patients with Cushing’s disease operated in our hospital after the introduction of the endoscopic technique (1998–2004).

Methods: Remission was defined as suppression of plasma cortisol (≤50 nmol/L) after 1 mg dexamethasone overnight determined in the first 3 months after surgery and disappearance of clinical signs and symptoms of hypercortisolism. The patients were followed for an average of 27 months (range 4 to 81 months, median 20 months).

Results: Pituitary MRI showed a macroadenoma in 6 patients, a microadenoma in 17 patients and no adenoma in 12 patients. After the initial surgery 27 patients (77%) were in remission. None of the patients had a relapse during follow-up. In the remaining 8 patients hypercortisolemia persisted after surgery. Three of them had a second endoscopic pituitary surgery resulting in remission in two patients. In one patient a second endoscopic pituitary surgery will soon follow. The remaining four patients were treated with radiotherapy postoperatively. Two of them were at the time of data collection in remission. One patient from the remission group had a serious epistaxis and three patients had cerebrospinal fluid leakage, one requiring an external lumbar drain, shortly after surgery. No complications were recorded in the failure group. Postoperatively 34% of all patients required substitution with levothyroxine, 40% required substitution with glucocorticoids, 17% received estrogens or testosterone and 6% still required desmopressin.

Conclusions: Endoscopic transsphenoidal pituitary surgery resulted in our series of patients with Cushings disease in an excellent postoperative remission rate. A randomized clinical trial, comparing endoscopic and conventional pituitary surgery in patients with Cushings disease, is needed to determine the pros and cons of both techniques.

Free access

Annenienke C van de Ven, Romana T Netea-Maier, Femmie de Vegt, H Alec Ross, Fred C G J Sweep, Lambertus A Kiemeney, Johannes W Smit, Ad R Hermus and Martin den Heijer

Objective

The aim of this study was to investigate the influence of age on the association between thyroid function and mortality.

Design

The Nijmegen Biomedical Study is a population-based study, comprising 5816 randomly selected adults of all age groups without previously known thyroid disease.

Methods

TSH, free thyroxine (FT4) and peroxidase antibodies were measured in 2002–2003. The number of deaths were established in 2012 (median follow-up time 9.4 years).

Results

Subclinical thyrotoxicosis was associated with mortality in subjects aged <65 years (hazard ratio (HR) 2.5, 95% CI 1.1–5.7), but not in subjects aged >65 years. As for thyroid function within the normal range: in the 493 participants aged 80 years or older, an FT4 level in the high-normal range (18.5–22 pmol/l) was associated with a higher mortality in comparison with FT4 levels in the middle range (11.5–15.0 pmol/l): HR 1.7 (95% CI 1.0–2.9). In these elderly, TSH levels within the high-normal range (3.0–4.0 mIU/l) were also associated with a higher mortality in comparison with TSH levels within the middle range (1.0–2.0 mIU/l): HR 1.8 (95% CI 1.0–3.1).

Conclusions

The relationship between thyroid function and mortality differs according to age. This finding might (partially) explain the discrepant results of previous studies examining the relationship between thyroid function and mortality in different age groups.

Restricted access

T L C Wolters, S H P P Roerink, R B T M Sterenborg, M A E M Wagenmakers, O Husson, J W A Smit, A R M M Hermus and R T Netea-Maier

Objective

Acromegaly has a negative influence on health-related quality of life (HRQoL). Previous studies provide limited information on the course of HRQoL during treatment. This study aims to assess the effect of treatment on the course of HRQoL at six predefined time points.

Design

This prospective study examines HRQoL in treatment-naive patients before and during the first 2.5 years of acromegaly treatment.

Methods

Therapy-naive acromegaly patients completed three validated questionnaires (RAND-36, AcroQoL, and the Appearance Self-Esteem (ASE)) at six predetermined time points before, during, and after treatment. Outcomes were correlated to IGF1 levels and disease control status.

Results

Twenty-seven acromegaly patients completed the questionnaires at all time points. After treatment, all patients had controlled acromegaly. Scores of RAND-36 domains General health, Vitality and Health change, and all AcroQoL dimensions (except for Relations) improved during treatment (P ≤ 0.003); the largest changes were detected during the first year. Gender influenced HRQoL scores, since AcroQoL scores significantly improved in males but not in females. Over time, IGF1 levels were negatively correlated with HRQoL. After 2.5 years of follow-up, HRQoL of controlled patients was still lower than in the general population.

Conclusion

HRQoL of acromegaly patients was considerably reduced at diagnosis. Disease control was associated with an improvement of HRQoL scores. Males showed a more pronounced improvement than females. The largest changes were detected in the first year of treatment. However, HRQoL during and after treatment remained impaired in acromegaly patients, emphasizing the need of additional support.

Free access

Mark R Postma, Thalijn L C Wolters, Gerrit van den Berg, Antonius E van Herwaarden, Anneke C Muller Kobold, Wim J Sluiter, Margreet A Wagenmakers, Alfons C M van den Bergh, Bruce H R Wolffenbuttel, Ad R M M Hermus, Romana T Netea-Maier and André P van Beek

Objective

To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery.

Design

A retrospective study in two large tertiary referral centers in The Netherlands.

Methods

Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit.

Results

In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006).

Conclusions

Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.

Free access

M A E M Wagenmakers, H D Boogaarts, S H P P Roerink, H J L M Timmers, N M M L Stikkelbroeck, J W A Smit, E J van Lindert, R T Netea-Maier, J A Grotenhuis and A R M M Hermus

Context

Although the endoscopic technique of transsphenoidal pituitary surgery (TS) has been widely adopted, reports on its results in Cushing's disease (CD) are still scarce and no studies have investigated long-term recurrence rates. This is the largest endoscopic series published till now.

Objective

To gain insight into the role of endoscopic TS as a primary treatment option for CD, especially in patients with magnetic resonance imaging (MRI)-negative CD and (invasive) macroadenomas.

Design

Retrospective cohort study.

Patients and methods

The medical records of 86 patients with CD who underwent endoscopic TS were examined. Data on preoperative and postoperative evaluation, perioperative complications, and follow-up were collected. Remission was defined as disappearance of clinical symptoms with a fasting plasma cortisol level ≤50 nmol/l either basal or after 1 mg dexamethasone.

Results

The remission rate in different adenoma subclasses varied significantly: 60% in MRI-negative CD (n=20), 83% in microadenomas (n=35), 94% in noninvasive macroadenomas (n=16), and 40% in macroadenomas that invaded the cavernous sinus (n=15). The recurrence rate was 16% after 71±39 months of follow-up (mean±s.d., range 10–165 months).

Conclusions

Endoscopic TS is a safe and effective treatment for all patients with CD. Recurrence rates after endoscopic TS are comparable with those reported for microscopic TS. Our data suggest that in patients with noninvasive and invasive macroadenomas, the endoscopic technique of TS should be the treatment of choice as remission rates seem to be higher than those reported for microscopic TS, although no comparative study has been performed.

Free access

Kim Freriks, Theo C J Sas, Maaike A F Traas, Romana T Netea-Maier, Martin den Heijer, Ad R M M Hermus, Jan M Wit, Janiëlle A E M van Alfen-van der Velden, Barto J Otten, Sabine M P F de Muinck Keizer-Schrama, Martin Gotthardt, Philippe H Dejonckere, Gladys R J Zandwijken, Leonie A Menke and Henri J L M Timmers

Objective

Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment.

Design and methods

During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition.

Results

Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency.

Conclusion

Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.

Free access

Annenienke C van de Ven, Romana T Netea-Maier, H Alec Ross, Teun A E van Herwaarden, Suzanne Holewijn, Jacqueline de Graaf, Bart L A Kiemeney, Doorlène van Tienoven, Jack F M Wetzels, Johannes W Smit, Fred C G J Sweep, Ad R M M Hermus and Martin den Heijer

Objective

Several cross-sectional studies on populations with iodine deficiency showed that TSH-levels are negatively associated with age, while in populations with high iodine intake TSH is positively associated with age. The question is whether such an age-thyroid function relation is an ongoing process apparent also in longitudinal studies and whether it reflects an actual iodine deficiency or an iodine insufficiency in the past.

Methods

In an area with a borderline iodine status in the past, we studied 980 participants of the Nijmegen Biomedical Study. We measured serum TSH, free thyroxine (FT4), total triiodothyronine (T3), peroxidase antibodies, and the urine iodine and creatinine concentration 4 years after our initial survey of thyroid function, in which we reported a negative association between TSH and age.

Results

Within 4 years, TSH decreased by 5.4% (95% CI 2.5–8.3%) and FT4 increased by 3.7% (95% CI 2.9–4.6%). Median urinary iodine concentration was 130 μg/l. Estimated 24-h iodine excretion was not associated with TSH, T3, change of TSH, or FT4 over time or with the presence of antibodies against thyroid peroxidase. Only FT4 appeared to be somewhat higher at lower urine iodine levels: a 1.01% (95% CI 0.17–1.84%) higher FT4 for each lower iodine quintile.

Conclusions

In this longitudinal study, we found an ongoing decrease in TSH and increase in FT4 in a previously iodine insufficient population, despite the adequate iodine status at present. This suggests that low iodine intake at young age leads to thyroid autonomy (and a tendency to hyperthyroidism) that persists despite normal iodine intake later in life.