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Marleen Kars, Ferdinand Roelfsema, Johannes A Romijn and Alberto M Pereira

Pituitary carcinomas are extremely rare. In general, the initial clinical, biochemical, and histological characteristics are of minimal utility in distinguishing benign adenomas from pituitary carcinomas. We describe a 63-year-old woman with a macroprolactinoma, who presented with diplopia and blurred vision. This unusual initial presentation and the subsequent aggressive clinical course, with diffuse local and distant intramedulary metastases, prompted us in retrospect to make a detailed analysis of the therapeutic interventions and histology. In addition, we reviewed all available literature on published cases of malignant prolactinoma and detailed their epidemiological, clinical, and histopathological characteristics. In brief, it is postulated that pituitary carcinomas arise from the transformation of initially large, but benign, adenomas. Unusual and/or atypical clinical manifestations appear to occur more frequently. In vivo, the development of dopamine agonist resistance in invasive macroprolactinoma is indicative of malignancy and should prompt the clinician to perform a biopsy of the tumor. For pituitary tumors that exhibit high mitotic activity, increased Ki-67 and/or p53 immunoreactivity, it may be useful to denote these tumors as ‘atypical’ prolactinomas to raise the possibility of future malignant development.

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O M Dekkers, J M Timmermans, J W A Smit, J A Romijn and A M Pereira

Objectives

To compare the cortisol response of the 1 μg and the 250 μg ACTH test in a large study of patients with suspected adrenal insufficiency.

Design

Retrospective cohort study.

Methods

Single center study assessing patients tested for primary or secondary adrenal insufficiency between January 2004 and December 2007, who had both ACTH tests (1 μg and 250 μg; n=207) within a time interval of 6 weeks. Test results were compared with a Bland–Altman plot and McNemar's test.

Results

The mean difference between the cortisol responses in the two ACTH tests was 26 nmol/l (95% confidence interval (CI) 13, 40), showing a marginally higher response for the 250 μg test. The diagnostic performances of the two tests were similar (P=0.49) using a cut-off value for cortisol of 550 nmol/l. A normal cortisol response to the 1 μg ACTH test could be accompanied by an abnormal response to the 250 μg ACTH test, and vice versa.

Conclusion

This study shows that the 1 μg and the 250 μg ACTH tests have comparable cortisol responses in patients with suspected adrenal insufficiency. However, in individual patients, the difference in cortisol response to the two tests can be substantial, and the response in the 250 μg test is not invariably higher than the response in a 1 μg test.

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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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M Kars, A M Pereira, J J Bax and J A Romijn

The increased risk of cardiac valve disease in patients treated for Parkinson's disease with cabergoline has raised concerns about the safety of treatment with ergot-derived dopamine agonists in patients with endocrine diseases, especially prolactinoma. Six cross-sectional studies have been published recently, of which five studies do not show an association between the treatment of prolactinoma with cabergoline during 45–79 months and clinically relevant valvular regurgitation in a total of 413 patients. Nonetheless, concern is raised because the use of cabergoline was associated in one study with an increased prevalence of moderate tricuspid regurgitation, and in two other studies with mild tricuspid regurgitation. Furthermore, the use of cabergoline was associated with increased frequencies of valvular thickening, calcifications and increased mitral tenting area. At present, the clinical relevance of these findings is still uncertain, but concern is raised with respect to the safety of the use of cabergoline in the long-term treatment of prolactinomas. Echocardiographic evaluation should be considered in patients, who require long-term treatment with cabergoline, especially in high doses. There is a need for larger, preferably prospective, studies with careful echocardiographic assessment and with longer durations of follow-up than the currently available studies.

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R A Feelders, S J Pulgar, A Kempel and A M Pereira

Objective

Cushing's disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD.

Design

Studies published in English were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, health-related quality of life (HRQoL), treatment outcomes, mortality, prevalence of comorbidities at diagnosis, and reversibility of comorbidities following the treatment.

Methods

A two-stage literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD: i) articles published from 2000 to 2012 were identified and ii) an additional hand search (all years) was conducted on the basis of bibliography of identified articles.

Results

At the time of diagnosis, 58–85% of patients have hypertension, 32–41% are obese, 20–47% have diabetes mellitus, 50–81% have major depression, 31–50% have osteoporosis, and 38–71% have dyslipidemia. Remission rates following transsphenoidal surgery (TSS) are high when performed by expert pituitary surgeons (rates of 65–90%), but the potential for relapse remains (rates of 5–36%). Although some complications can be partially reversed, time to reversal can take years. The HRQoL of patients with CD also remains severely compromised after remission.

Conclusions

These findings highlight the significant burden associated with CD. As current treatment options may not fully reverse the burden of chronic hypercortisolism, there is a need for both improved diagnostic tools to reduce the time to diagnosis and effective therapy, particularly a targeted medical therapy.

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Jitske Tiemensma, Alberto M Pereira, Johannes A Romijn, Elizabeth Broadbent, Nienke R Biermasz and Adrian A Kaptein

Context and objective

Patients with acromegaly have persistent complaints despite long-term biochemical control. Drawings can be used to assess patients' perceptions about their disease. We aimed to explore the utility of the drawing test and its relation to illness perceptions and quality of life (QoL) in patients after long-term remission of acromegaly.

Design

A cross-sectional study was conducted to evaluate the utility of the drawing test.

Methods

A total of 50 patients after long-term remission (mean±s.e.m., 16±1.2 years) of acromegaly were included in this study. Patients completed the drawing test (two retrospective drawings of their body perception before acromegaly and during the active phase of acromegaly, and one drawing on the current condition after long-term remission), Illness Perception Questionnaire-Revised, Physical Symptom Checklist, EuroQoL-5D, and AcroQoL.

Results

Patients perceived a dramatic change in body size during the active state of the disease compared with the healthy state before the awareness of acromegaly. Patients reported that their body did not completely return to the original proportions after long-term remission. In addition, larger drawings indicated more negative consequences (P<0.05), a higher score on emotional representations (P<0.05), and more perceived symptoms that were attributed to acromegaly (P<0.01). Larger drawings also indicated more impaired QoL, especially disease-specific QoL (all P<0.05).

Conclusion

There are strong correlations among the drawing test, illness perceptions, and QoL. The drawing test appears to be a novel and relatively easy tool to assess the perception of patients after long-term remission of acromegaly. The assessment of drawings may enable health care providers to appreciate the perceptions of patients with long-term remission of acromegaly, and enable discussion of symptoms and remission.

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Nienke R Biermasz, Neveen A T Hamdy, Alberto M Pereira, Johannes A Romijn and Ferdinand Roelfsema

Introduction: The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established.

Patients and methods: In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57±1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2±7 years.

Results: Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck.

Conclusion: Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.

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John M Felt Jr, Sarah A Depaoli, Alberto M Pereira, Nienke R Biermasz and Jitske Tiemensma

Context

Impaired quality of life (QoL) is common in patients after long-term remission of acromegaly. The acromegaly QoL (AcroQoL) is a disease-specific QoL questionnaire for patients diagnosed with acromegaly. The summed total score is the most frequently used scoring method of the AcroQoL. However, the total score does not capture all of the aspects of QoL that are outlined by the World Health Organization (WHO).

Objective

The aim of the present study was to use novel and sophisticated confirmatory methods to identify the optimal number of subscales for the AcroQoL.

Design and patients

Patients in remission from acromegaly were recruited from the Leiden University Medical Center and were asked to complete the AcroQoL (Dutch version) questionnaire (n=72).

Results

The three-subscale version of the AcroQoL consisted of subscales reflecting Physical Complaints, Appearance Issues, and Personal Relations Issues related to QoL. Model fit indices (i.e., comparative fit index and root mean square error of approximation) indicated that the three-subscale version represented the data better than the total score and two-subscale models did. A χ 2 difference test indicated that the three-subscale model was a significantly better fit than the total score and two-subscale models were (P<0.05).

Conclusion

Model fit and comparison statistics indicate that the three-subscale model is a better scoring method than the total score and two-subscale versions of the AcroQoL are. The three-subscale version also better reflected the WHO's recommendation of using a multidimensional measure of QoL than the total score and two-subscale methods did. Therefore, it is recommended that values from the three-subscales of the AcroQoL be reported in future research.

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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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Alberto M Pereira, Victoria Delgado, Johannes A Romijn, Johannes W A Smit, Jeroen J Bax and Richard A Feelders

Objective

In patients with active Cushing's syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes reverse after successful treatment. We therefore evaluated the changes in cardiac structure and dysfunction after successful treatment of CS, using more sensitive echocardiographic parameters (based on two-dimensional strain imaging) to detect subtle changes in cardiac structure and function.

Methods

In a prospective study design, we studied 15 consecutive CS patients and 30 controls (matched for age, sex, body surface area, hypertension, and left ventricular (LV) systolic function). Multidirectional LV strain was evaluated by two-dimensional speckle tracking strain imaging. Systolic (radial thickening, and circumferential and longitudinal shortening) and diastolic (longitudinal strain rate at the isovolumetric relaxation time (SRIVRT)) parameters were measured.

Results

At baseline, CS patients had similar LV diameters but had significantly more LV hypertrophy and impaired LV diastolic function, compared to controls. In addition, CS patients showed impaired LV shortening in the circumferential (−16.5±3.5 vs −19.7±3.4%, P=0.013) and longitudinal (−15.9±1.9 vs −20.1±2.3%, P<0.001) directions and decreased SRIVRT (0.3±0.15 vs 0.4±0.2/ s, P=0.012) compared to controls. After normalization of corticosteroid excess, LV structural abnormalities reversed, LV circumferential and longitudinal shortening occurred, and SRIVRT normalized.

Conclusion

CS induces not only LV hypertrophy and diastolic dysfunction but also subclinical LV systolic dysfunction, which reverses upon normalization of corticosteroid excess.