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Pia Burman, ÅsaLinda Lethagen, Krasnodar Ivancev, Leif Johansson and Anders Sundin

Context

Establishing the cause of Cushing's syndrome (CS) can be a considerable challenge, in particular in ectopic adrenocorticotropic hormone (ACTH) syndrome, and often requires a combination of biochemical tests and imaging procedures.

Subject

A 27-year-old man presented with signs of CS. P-ACTH levels were three times above the upper limit of normal (ULN) and free urinary cortisol around 2000 nmol/24 h. The work-up showed remarkable results.

Results

A 2-day low-dose dexamethasone suppression test demonstrated paradoxical increases in cortisol. Sampling from the bilateral inferior petrosal sinus sampling (BIPSS) showed a central to peripheral ACTH ratio of 4.7 after corticotrophin-releasing hormone (CRH) stimulation, i.e. indicated pituitary disease, but magnetic resonance imaging of the pituitary was normal. Computed tomography (CT) scan of the lungs showed two oval-shaped masses, 1.3×1.8 and 1.3×2 cm, in the middle lobe. Both were positive at somatostatin receptor scintigraphy, compatible with tumors or inflammatory lesions. Subsequently, 11C-5-hydroxytryptophan-PET showed distinct uptake in the tumors but not elsewhere. Two carcinoids situated 3 cm apart, both staining for ACTH, were removed at surgery.

Conclusion

This unique case with dual bronchial carcinoids inducing hypercortisolism illustrates the problems with identifying the source of ACTH in CS. Possibly, an abnormal regulation of ACTH production in response to dexamethasone, or steroid-induced tumor necrosis, explains the paradoxical outcome at dexamethasone suppression, and the false positive result at BIPSS reflects an unusual sensitivity of the pituitary corticotrophs to CRH in this patient. The work-up illustrates the great value of 11C-5-hydroxytryptophan-PET as a diagnostic procedure when other investigations have produced ambiguous results.

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Jens Bollerslev, Thor Ueland, Anders P Jørgensen, Kristian J Fougner, Ragnhild Wergeland, Thomas Schreiner and Pia Burman

Objective: GH deficiency is associated with an increased cardiovascular mortality. Fifty-five patients with adult-onset GH deficiency (AO-GHD) (24 female, 31 male, mean age 49 years) were enrolled in a placebo-controlled double-blind crossover study to investigate the effects of GH therapy on a variety of cardiovascular risk factors representing different aspects of atherogenesis, including apolipo-proteins (Apo A-1, Apo B), markers of subclinical inflammation (high-sensitivity C-reactive protein (CRP) and interleukin-6) and markers of endothelial function (intercellular adhesion molecule-1, von Willebrand factor and sCD40L (a pro-atherogenic factor and marker for plaque destabilization)).

Methods: GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. GH and placebo were administered for 9 months each, separated by a 4 month washout period.

Results: The final mean dose of GH was 50% higher for women and IGF-I increased to the same level in both sexes. Compared with placebo, substitution with GH showed a significant effect on Apo B (mean change −0.15 (−0.22 to −0.08) mg/l) and CRP (−1.8 (−3.3 to −0.3) mg/l). The baseline level of and change in IGF-I during treatment with GH contributed significantly to the improvement in both markers. No effects were found on interleukin-6 or Apo A-1, or on markers of endothelial function. No gender differences were observed for any of the markers at baseline or following intervention.

Conclusions: GH substitution to naïve patients with AO-GHD at a low, individually titrated dose aiming at normalizing IGF-I was followed by significant reductions in Apo B and CRP, indicating a positive effect of GH on cardiovascular risk.

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Mahesh Sathiavageeswaran, Pia Burman, David Lawrence, Alan G Harris, Marina G Falleti, Paul Maruff and John Wass

Objective: Young adults with childhood-onset GH deficiency (GHD) have reduced memory and attention, which can be improved by treatment with GH. Little information is available on cognitive function in elderly GHD patients.

Design: Single center, double-blind, randomized, placebo-controlled study of 52-week duration.

Methods: Elderly GH therapy naïve GHD patients (n=34; age range 60–77 years) were enrolled and randomized to receive placebo or GH therapy which was titrated to achieve a target IGF-I level of +1 to +2 s.d. of the normal mean for age. Cognitive function was assessed at baseline and after 24 and 52 weeks, using a computerized psychometric test package (Neurobehavioral Examination System-2).

Results: The mean GH dose was 0.16±0.06 mg/day; mean IGF-I increased from 135±59 ng/ml at baseline to 213±77 ng/ml during active treatment. The GH-treated group had better mean serial digit learning scores compared with placebo group (P<0.05). Assessment of effect sizes showed that improvements in memory occurred with GH after 24 weeks. The overall adverse event rates were similar in the GH and the placebo group.

Conclusion: This study indicates that GH replacement may be accompanied by improvement in certain measures of cognitive function in elderly patients with GHD.

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Britt Edén Engström, Pia Burman, Camilla Holdstock, Margareta Öhrvall, Magnus Sundbom and F Anders Karlsson

Objective: Overfeeding suppresses GH secretion and makes evaluation of a suspected GH deficiency (GHD) difficult. In normal weight subjects, gender is known to influence GH concentrations, which is most apparent in the ambulatory, morning-fasted state. In this study, we examined the GH/IGF-I axis in obese men and women and the effect of surgically induced weight loss.

Design: Sixty-three subjects (body mass index (BMI) 45 ± 6 kg/m2; 54 women, 9 men) were studied prior to, and 6 and 12 months following Roux-en-Y gastric bypass (RYGBP) surgery. Fifty-four patients with classic GHD (BMI 27 ± 6 kg/m2; 35 men, 19 women) were included for comparison. Methods: Hormones were analysed in fasting morning serum samples.

Results: RYGBP resulted in a decreased BMI to 35 ± kg/m2 at 6 months and 32 ± 6 kg/m2 at 12 months. GH and IGF-I increased at 6 months in the women and at 12 months in both sexes by ≥ 300 and 11% respectively. Prior to RYGBP, GH concentrations were low in the obese men and similar to those of GHD men (mean 0.09 mU/l). Obese women had tenfold higher values than obese men and sevenfold higher than GHD women. IGF-I levels were in the low reference range in the obese and below −2 s.d. for age in 13%.

Conclusions: Surgically induced weight loss partially restores GH secretion. Despite a marked suppression of GH values, a gender influence is maintained in severe obesity. In obese women, single morning GH and IGF-I values seem sufficient to exclude a suspicion of classic GHD.

Free access

Jacqueline Trouillas, Pia Burman, Ann McCormack, Stephan Petersenn, Vera Popovic, Olaf Dekkers and Gerald Raverot

The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC.

Free access

Pia Burman, Britt Edén-Engström, Bertil Ekman, F Anders Karlsson, Erik Schwarcz and Jeanette Wahlberg

Context and objective

The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after ≥1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD.

Design

Twenty patients (19 naïve and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5–5 mg/week over 6 weeks.

Methods

Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end.

Results

At study end, the median cabergoline dose was 5 mg, range 2.5–5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study.

Conclusions

Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.

Free access

Olaf M Dekkers, Pia Burman and On behalf of the ESE Clinical Committee

Free access

Jens Bollerslev, Jostein Hallén, Kristian J Fougner, Anders Palmstrøm Jørgensen, Cybele Kristo, Hans Fagertun, Ola Gudmundsen, Pia Burman and Thomas Schreiner

Fifty-five patients with adult-onset GH deficiency (mean age, 49 years) were enrolled in a placebo-controlled, crossover study to investigate the effects of GH therapy on exercise capacity, body composition, and quality of life (QOL). GH and placebo were administered for 9 months each, separated by a 4-month washout period. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. The final mean daily dose of GH was 1.2 IU/day for men and 1.8 IU/day for women. Mean IGF-I concentration at baseline was higher in men than in women (95±33 vs 68±41 μg/l respectively; P < 0.04) and increased to a similar level on GH therapy. Body fat mass was reduced by 1.9±2.9 kg and lean body mass was increased by 1.8±2.8 kg (P = 0.0001 for each) with GH treatment. Total and low-density cholesterol levels decreased. Absolute maximal oxygen uptake increased by 6% (P = 0.01), relative to body weight by 9% (P = 0.004), and there was a trend toward increased endurance performance by 7% (P = 0.07). There were no significant effects on QOL. In conclusion, treatment with a low, physiologic dose of GH produced positive effects on body composition and lipids and improved exercise capacity, likely to be of clinical relevance. No changes in QOL were seen, possibly because of a good QOL at baseline.

Free access

Etienne Delgrange, Gerald Raverot, Marie Bex, Pia Burman, Bénédicte Decoudier, France Devuyst, Ulla Feldt-Rasmussen, Marianne Andersen and Dominique Maiter

Objective

To characterise distinctive clinical features of giant prolactinomas in women.

Design

A multicentre, retrospective case series and literature review.

Methods

We collected data from 15 female patients with a pituitary tumour larger than 4 cm and prolactin levels above 1000 μg/l and identified 19 similar cases from the literature; a gender-based comparison of the frequency and age distribution was obtained from a literature review.

Results

The initial PubMed search using the term ‘giant prolactinomas’ identified 125 patients (13 women) responding to the inclusion criteria. The female:male ratio was 1:9. Another six female patients were found by extending the literature search, while our own series added 15 patients. The median age at diagnosis was 44 years in women compared with 35 years in men (P<0.05). All cases diagnosed before the age of 15 years were boys. In women (n=34), we observed a minor peak incidence during the third decade of life and a major peak during the fifth decade. Amenorrhoea was a constant feature with seven cases of primary amenorrhoea. In eight women with onset of secondary amenorrhoea before the age of 40 years, the diagnosis was made 2–31 years later (median 9 years) and in all but one because of tumour pressure symptoms. The prolactin levels were above 10 000 μg/l in 15/34 and misdiagnosis due to ‘hook effect’ occurred in two of them. Eighteen patients were treated with cabergoline; standard doses (<2.0 mg/week) were able to normalise prolactin in only 4/18 patients, and 7/18 patients were resistant to weekly doses ranging from 3.0 to 7.0 mg.

Conclusion

Giant prolactinomas are rare in women, often resistant to dopamine agonists and seem to be distributed in two age groups, with a larger late-onset peak.

Free access

Camilo Jimenez, Pia Burman, Roger Abs, David R Clemmons, William M Drake, Kent R Hutson, Michael Messig, Michael O Thorner, Peter J Trainer and Robert F Gagel

Objective

We examined pituitary tumor volumes in patients treated with pegvisomant for 18 months or longer, and in whom the tumors were monitored for at least 3 years. We present details on 9 of 304 patients in clinical trials with pegvisomant who experienced tumor growth within the first year of treatment.

Method

Magnetic resonance images prior to start of pegvisomant and at last follow-up were examined in 43 patients (14% of participating patients). Twenty-nine had received prior radiation therapy (18% of irradiated patients) and all but five received somatostatin analogs between periods of pegvisomant treatment.

Results

At follow-up, the median tumor volume was 0.6 cc (range 0.0–19.7 cc), in comparison with 1.6 cc (0.0–19.7 cc) at baseline (P<0.001). Twenty-five patients, of which 23 received radiation therapy, had tumor volume reduction. Seventeen patients had no significant change. One patient, who had not received radiation therapy, had an increase in tumor volume from 1.61 to 1.93 cc. Of the nine patients with tumor growth, six had progressive growth before initiating pegvisomant. Two patients with stable tumors while on octreotide experienced enlargement after octreotide discontinuation but remained stable on long-term pegvisomant therapy.

Conclusion

The present data indicate that pegvisomant does not promote tumor growth and suggest that the nine observed cases of tumor progression, which occurred within 8 months after commencing pegvisomant, are likely rebound expansions after discontinuation of somatostatin analogs and/or the natural history of aggressively growing pituitary tumors. Continued long-term surveillance of tumor volume, particularly in non-irradiated patients, is recommended.