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Cristina Capatina, Warrick Inder, Niki Karavitaki and John A H Wass

Pituitary tumour apoplexy (PA) is a rare clinical syndrome that occurs as a result of acute haemorrhage and/or infarction within a frequently undiagnosed pituitary tumour. The sudden enlargement of the pituitary mass undergoing PA is responsible for a wide range of acute symptoms/signs (severe headache, visual loss, diplopia, hypopituitarism, impaired consciousness) which, together with the radiological evidence of a pituitary lesion, establish the diagnosis. The optimal care of PA requires involvement of a multidisciplinary team including endocrinologist, neurosurgeon, neuroophthalmologist and the management strategy that depends on the clinical manifestations, as well as the presence of co-morbidities. Prompt surgical decompression is initially indicated in cases with severe or progressive impairment of the visual acuity or the visual fields or with altered mental state and leads to visual and neurological recovery in most of the patients. The patients with mild, stable clinical picture (including those with isolated ocular palsies) can be managed conservatively (support of fluid and electrolyte balance and stress doses of steroids in most cases) with favourable visual and neurological outcome. Frequent reassessment is mandatory because the clinical course can be unpredictable; if progression of symptoms occurs, later elective surgery is indicated and is beneficial, especially in terms of visual outcome. The endocrinological outcome is less favourable, irrespective of the treatment option, with many patients remaining on long-term replacement therapy. Despite the above guidelines, clear proof of optimal outcomes in the form of randomised controlled trials is lacking. Regrowth of the pituitary tumour years after a PA episode is possible and patients require long-term surveillance.

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Alper Gürlek, Niki Karavitaki, Olaf Ansorge and John A H Wass

Prolactinoma is the most common pituitary tumour in adults. Macroprolactinomas, particularly in men, may occasionally exhibit a very aggressive clinical course as evidenced by progressive growth, invasion through bone into the sphenoid sinus, cavernous sinus, suprasellar region or the nasopharynx. Some may even progress to pituitary carcinoma with craniospinal or systemic metastases. Aggressive tumours have low cure rates despite appropriate medical and surgical treatment. The mechanisms underlying this aggressive biological behaviour have not yet been fully clarified. Recent immunohistochemical, molecular and genetic studies have provided some insight in this respect. Invasive prolactinomas may be associated with a high Ki-67/MIB-1 labelling index indicating increased cell proliferation, although this is not a universal finding. The AA polymorphism in the cyclin adenine (A)/guanine (G) gene is more frequently detected in invasive prolactinomas. Increased expression of the polysialylated neural cell adhesion molecule (NCAM) and reduced expression of the E-cadherin/catenin complex implies a contribution of altered cell-to-cell adhesion and cellular migration. Extracellular matrix components (ECM), matrix metalloproteinases (MMPs) and their inhibitors play important roles in the context of angiogenesis and invasion. The induction of fibroblast growth factor and vascular endothelial growth factor via oestrogen-induced overexpression of novel genes (PTTG, hst and Edpm5) enhance cell growth, proliferation and angiogenesis contributing to invasiveness in prolactinomas. Although mutations in proto-oncogenes like Ras are uncommon, loss of tumour suppressor genes at loci 11q13, 13q12–14, 10q and 1p seem to be associated with invasiveness. Of the described mechanisms, only reduced E-cadherin/catenin expression and overexpression of hst gene seem to be relatively specific markers for prolactinoma invasiveness compared with other pituitary adenomas. Further research is needed to clarify the molecular mechanisms behind the aggressive course of some prolactinomas to predict those with a potentially poor clinical outcome, and to devise treatments that will eventually enable the cure of these challenging tumours.

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Raghava Reddy, Simon Cudlip, James V Byrne, Niki Karavitaki and John A H Wass

Background

Non-functioning pituitary adenomas (NFAs) are slow-growing tumours with reported re-growth rates following surgical resection alone of up to 50% at 10 years. Currently, the desired length of follow-up surveillance imaging in un-irradiated patients is unclear.

Aim

To clarify the timing of re-growth in patients with NFAs, treated solely by surgery without post-operative pituitary radiotherapy, and also to clarify whether continued imaging is necessary in these patients.

Methods

A case note analysis of all patients who underwent surgery alone for NFA between January 1984 and December 2007 was undertaken. Patients were followed for a minimum of 1 year. Re-growth was diagnosed on the basis of radiological appearances with or without associated manifestations.

Results

One hundred and fifty-five patients (94 males, mean age at diagnosis 57.9 (range 18.3–88) years) were included. Twenty-nine were followed up for more than 10 years. The mean follow-up following surgery was 6.1 years (median 4.3 (range 1–25.8)). Re-growth was documented in 54 (34.8%) cases and 20.4% of these cases showed relapse/re-growth 10 or more years after the initial surgery. Kaplan–Meier analysis showed relapse rates of 23.1, 46.7 and 67.9% at 5, 10 and 15 years respectively. There was a significant increase in the re-growth rates if there was either pituitary tumour remnant observed on the first post-operative scan (P≤0.001) or a younger age at initial surgery (P=0.034).

Conclusion

These results suggest that patients with NFAs need to be closely monitored following surgery, particularly those with post-operative tumour remnants. With 20% of relapse occurring after 10 years, follow-up surveillance needs to be continued beyond this time.

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Susan M. Webb, John A. H. Wass, Erica Penman, M. Murphy, José Serrano, Jaume Binimelis and Carlos Pavía

Abstract. Plasma immunoreactive somatostatin (IRS) levels were measured fasting at 09.00 h in groups of adult individuals and children of different ages, as well as in pregnant women, in patients with pernicious anaemia documented to be achlorhydric, and in children with growth hormone deficiency.

There was a gradual rise in the mean level of IRS from the third decade (mean 35.8 ± 3.8 pg/ml), which reached significance at the seventh (61.1 ± 8.4 pg/ml), eighth (66.7 ± 5 pg/ml) and ninth decade (82.6 ± 13.8 pg/ml). No change was observed in the second 28.3 ± 3.8 pg/ml) and third (31.1 ± 3.2 pg/ml) trimester of pregnancy when compared with matched, non-pregnant controls (29.7 ± 2.2 pg/ml); however, the children aged under 2 years (69.6 ± 11.2 pg/ml) had significantly higher values than the eldest group (12 to 16 years old) (46.3 ± 7.2 pg/ml) (P < 0.05). In achlorhydric patients, basal (27.2 ± 3.7 pg/ml; P < 0.01) and postprandial IRS (42.8 ± 7.7 pg/ml; P < 0.001) was significantly lower than in a matched, normal control group (basal 59.4 ± 7.2; postprandial 132.1 ± 26.3 pg/ml). Growth hormone deficiency was not associated with any differences in circulating IRS, basally or after insulin hypoglycaemia, when compared with values in normal children.

These results would suggest, 1) that age has a significant effect on plasma IRS, and should be considered in the interpretation of fasting plasma levels of IRS; 2) that pregnancy and growth hormone deficiency is not accompanied by any changes in circulating IRS and presumably, somatostatin binding proteins; 3) that gastric acid is necessary for a normal release of IRS from the gastrointestinal tract to the circulation.

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Thomas M Barber, Felipe F Casanueva, Fredrik Karpe, Mary Lage, Stephen Franks, Mark I McCarthy and John A H Wass

Objective

Abnormal ghrelin regulation may influence the development of obesity-associated conditions including polycystic ovary syndrome (PCOS). Our aim was to compare ghrelin regulation between PCOS cases and controls.

Design

We compared serum ghrelin (total) levels, fasting and 30-min post-oral (75 g) glucose load, between 50 PCOS cases and 28 female controls, including 22 body mass index (BMI)/fat mass-matched pairs. All subjects were of UK British/Irish origin.

Methods

Measurements included serum ghrelin (RIA technique (LINCO Research, St Charles MO, USA)), fat mass, serum testosterone, fasting serum insulin and plasma glucose levels. Insulin sensitivity was calculated as the homeostasis model assessment of insulin resistance (HOMA2 IR).

Results

Fasting serum ghrelin levels were significantly lower in PCOS cases versus BMI/fat mass-matched controls (geometric mean (s.d. range), 1104 pg/ml (764–1595) vs 1756 pg/ml (1314–2347) respectively; P=2.3×10−4). Ghrelin suppression following oral glucose load was significantly blunted in PCOS cases versus BMI/fat mass-matched controls (geometric mean ghrelin suppression (s.d. range), 160 pg/ml (88–289) vs 424 pg/ml (220–818) respectively; P=2.0×10−4). Whole-group comparisons (50 PCOS cases versus 28 controls) adjusted for fat mass and age revealed similar results. In PCOS cases, there was a significant negative correlation between fasting serum ghrelin and HOMA2 IR (r 2=−0.40, P=5.7×10−3). Following adjustment for HOMA2 IR, fat mass and age, comparisons between the whole groups of PCOS cases and controls revealed attenuated but significant differences in fasting serum ghrelin (P=1.3×10−3) and ghrelin suppression (P=1.8×10−3).

Conclusions

In women with PCOS, serum ghrelin levels are suppressed, showing a negative relationship with HOMA2 IR and a blunted response to oral glucose.

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Georgia Ntali, Cristina Capatina, Violet Fazal-Sanderson, James V Byrne, Simon Cudlip, Ashley B Grossman, John A H Wass and Niki Karavitaki

Objective

Non-functioning pituitary adenomas (NFAs) have a prevalence of 7–22/100 000 people. A significant number of patients suffer from morbidities related to the tumor, possible recurrence(s), and treatments utilized. Our aim was to assess mortality of patients with macroNFA and predictive factors.

Design

Retrospective cohort study in a tertiary referral center in the UK.

Methods

A total of 546 patients operated for a macroNFA between 1963 and 2011 were studied. Mortality data were retrieved through the National Health Service Central Register and hospital records and recorded as standardized mortality ratio (SMR). Mortality was estimated for the total and various subgroups with clinical follow-up data.

Results

Median follow-up was 8 years (range: 1 month–48.5 years). SMR was 3.6 (95% CI, 2.9–4.5), for those operated before 1990, 4.7 (95% CI, 2.7–7.6) and for those after 1990, 3.5 (95% CI, 2.8–4.4). Main causes of death were cardio/cerebrovascular (33.7%), infections (30.1%), and malignancy (28.9%). Cox regression analysis demonstrated that only age at diagnosis remained an independent predictor of mortality (hazard ratio 1.10; 95% CI, 1.07–1.13, P<0.001), whereas sex, presentation with acute apoplexy, extent of tumor removal, radiotherapy, recurrence, untreated GH deficiency, FSH/LH deficiency, ACTH deficiency, TSH deficiency, and treatment with desmopressin had no impact.

Conclusions

Despite the improvement of treatments over the last three decades, the mortality of patients with NFAs in our series remains high. Apart from age, factors related with the management/outcome of the tumor are not independent predictors, and pituitary hormone deficits managed with the currently-used substitution protocols do not adversely affect mortality.

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Elena Valassi, Alicia Santos, Maria Yaneva, Miklós Tóth, Christian J Strasburger, Philippe Chanson, John A H Wass, Olivier Chabre, Marija Pfeifer, Richard A Feelders, Stylianos Tsagarakis, Peter J Trainer, Holger Franz, Kathrin Zopf, Sabina Zacharieva, Steven W J Lamberts, Antoine Tabarin and Susan M Webb

Objective

The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS).

Design and methods

Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%).

Results

Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups.

Conclusions

The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

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Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Antoine Tabarin, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, John A H Wass, Peter J Trainer and for the ERCUSYN Study Group

Objective

To evaluate which tests are performed to diagnose hypercortisolism in patients included in the European Registry on Cushing’s syndrome (ERCUSYN), and to examine if their use differs from the current guidelines.

Patients and methods

We analyzed data on the diagnostic tests performed in 1341 patients with Cushing’s syndrome (CS) who have been entered into the ERCUSYN database between January 1, 2000 and January 31, 2016 from 57 centers in 26 European countries. Sixty-seven percent had pituitary-dependent CS (PIT-CS), 24% had adrenal-dependent CS (ADR-CS), 6% had CS from an ectopic source (ECT-CS) and 3% were classified as having CS from other causes (OTH-CS).

Results

Of the first-line tests, urinary free cortisol (UFC) test was performed in 78% of patients, overnight 1 mg dexamethasone suppression test (DST) in 60% and late-night salivary cortisol (LSaC) in 25%. Use of LSaC increased in the last five years as compared with previous years (P < 0.01). Use of HDDST was slightly more frequent in the last 5 years as compared with previous years (P < 0.05). Of the additional tests, late-night serum cortisol (LSeC) was measured in 62% and 48-h 2 mg/day low-dose dexamethasone suppression test (LDDST) in 33% of cases. ACTH was performed in 78% of patients. LSeC and overnight 1 mg DST supported the diagnosis of both PIT-CS and ADR-CS more frequently than UFC (P < 0.05).

Conclusions

Use of diagnostic tests for CS varies across Europe and partly differs from the currently available guidelines. It would seem pertinent that a European consensus be established to determine the best diagnostic approach to CS, taking into account specific inter-country differences with regard to the availability of diagnostic tools.

Free access

Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, Peter J Trainer, John A H Wass, Antoine Tabarin and for the ERCUSYN Study Group

Background

Surgery is the definitive treatment of Cushing’s syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial.

Objective

(1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS).

Patients and methods

1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS).

Results

Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups.

Conclusions

PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.