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.
Alper Gürlek, Niki Karavitaki, Olaf Ansorge, and John A H Wass
Athanasios Fountas, Shu Teng Chai, Chrysoula Kourkouti, and Niki Karavitaki
The use of opioids has grown substantially over the past two decades reaching the dimensions of a global epidemic. These drugs have effects on multiple levels of the endocrine system through mechanisms which are still not fully elucidated, and awareness of their endocrine sequelae is vital for all specialists prescribing or managing patients on them. Hypogonadism is the most well-recognised consequence of opioid use (prevalence 21–86%) which, however, may remain undiagnosed with potential adverse outcomes for the patients. Although less frequent, cortisol deficiency can also be found. Furthermore, there is a negative impact on bone health (with reduced bone mineral density and increased fracture risk) and occasionally hyperprolactinaemia, whereas the clinical significance of alterations in other hormones remains to be clarified. Discontinuation or reduction of the opioid and, in cases of chronic pain, consideration of alternative therapies for pain relief are potential management options. Hormonal replacement, especially when the above measures are not practically feasible, needs to be considered. Further studies are needed to clearly establish the prevalence of hormonal abnormalities with various regimes, doses and routes of opioids and to address reliably the long-term benefits and risks of hormonal treatment in patients on opioids. Until evidence-based, safe and cost-effective clinical guidelines become available, periodical assessment of the gonadal and adrenal function (particularly when relevant clinical manifestations are present) and evaluation of the bone health status are advised.
Veronica A Preda, Jonathan Sen, Niki Karavitaki, and Ashley B Grossman
This review addresses the practical usage of intravenous etomidate as a medical therapy in Cushing's syndrome. We reviewed the relevant literature, using search terms ‘etomidate’, ‘Cushing's syndrome’, ‘adrenocortical hyperfunction’, ‘drug therapy’ and ‘hypercortisolaemia’ in a series of public databases. There is a paucity of large randomised controlled trials, and data on its use rely only on small series, case study reports and international consensus guideline recommendations. Based on these, etomidate is an effective parenteral medication for the management of endogenous hypercortisolaemia, particularly in cases with significant biochemical disturbance, sepsis and other serious complications such as severe psychosis, as well as in preoperative instability. We suggest treatment protocols for the safe and effective use of etomidate in Cushing's syndrome.
Veronica A Preda, Jonathan Sen, Niki Karavitaki, and Ashley B Grossman
The authors apologise for the publication of an error in Table 2 of this article published in the European Journal of Endocrinology 167 137–143. They wish to make clear in Table 2 that they are stipulating the dose of etomidate and that the corresponding dose of hydrocortisone for complete blockade should be 0.5–1.0 mg/h. The correct table is published in full below.
Treatment of hypercorticolism with etomidate: Recommendations.
|Infusion rate options||Blockade||Cortisol level||Biochemical monitoring||Other|
|Etomidate (IV) 0.04–0.05 m/kg per h=2.5–3.0 mg/h||Partial to complete depending on clinical circumstance of the patient||Titrate to serum cortisol 500–800 nmol/l in physiologically stressed patient, 150–300 nmol/l in non-physiologically stressed patient||Potassium level Cortisol level||Sedation scoring initially every two hours then every 12 hours after first 24 hours|
|Hydrocortisone IV 0.5–1.0 mg/h||Complete (will need steroid replacement)||<150 nmol/l||Potassium level Cortisol level|
This table could now be used as a practical guide for clinicians commencing infusions on the ward of etomidate and required hydrocortisone replacement.
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.
Metaxia Tampourlou, Raluca Trifanescu, Alessandro Paluzzi, Shahzada K Ahmed, and Niki Karavitaki
Microprolactinomas are the most common pituitary adenomas. In symptomatic patients, dopamine agonists are the first-line treatment of choice; when cabergoline is used, biochemical control rates between 85 and 93% have been reported. Long-term treatment is needed in most of the cases with compliance, patient convenience, and potential adverse effects representing areas requiring attention. Based on the literature published in the past 15 years, transsphenoidal surgery can lead to normal prolactin in the postoperative period in usually 71–100% of the cases with very low postoperative complication rates. Surgical expertise is the major determinant of the outcomes, and it may be a cost-effective option in young patients with life expectancy greater than 10 years (provided it is performed by experienced surgeons at high volume centers with confirmed optimal outcomes). Larger series of patients with adequate follow-up could further validate the place of transsphenoidal surgery (particularly through the endoscopic approach for which long-term results are currently limited) in the management algorithm of patients with microprolactinoma.
Maria Fleseriu, Olaf M Dekkers, and Niki Karavitaki
Patients with pituitary tumours, ensuing hormonal abnormalities and mass effects are usually followed in multidisciplinary pituitary clinics and can represent a management challenge even during the times of non-pandemic. The COVID-19 pandemic has put on hold routine medical care for hundreds of millions of patients around the globe, while many pituitary patients’ evaluations cannot be delayed for too long. Furthermore, the majority of patients with pituitary tumours have co-morbidities potentially impacting the course and management of COVID-19 (e.g. hypopituitarism, diabetes mellitus, hypertension, obesity and cardiovascular disease). Here, we summarize some of the diagnostic and management dilemmas encountered, and provide guidance on safe and as effective as possible delivery of care in the COVID-19 era. We also attempt to address how pituitary services should be remodelled in the event of similar crises, while maintaining or even improving patient outcomes. Regular review of these recommendations and further adjustments are needed, depending on the evolution of the COVID-19 pandemic status. We consider that the utilization of successful models of pituitary multidisciplinary care implemented during the COVID-19 pandemic should continue after the crisis is over by using the valuable and exceptional experience gained during these challenging times.
Kirstie Lithgow, Ruchika Batra, Tim Matthews, and Niki Karavitaki
Visual dysfunction is an important element in the morbidity encountered in patients with pituitary adenoma leading to functional impairment and compromised quality of life. It consists of many parameters (even in the absence of reported symptomatology) as a result of tumour growth in proximity to structures critical for vision (anterior visual pathway, cranial nerves within cavernous sinuses), and as an adverse consequence of therapeutic interventions. Adenoma resection leads to high rates of visual improvement and possibly continues beyond a year post surgery, but the exact timing of maximum effect requires elucidation. Retinal nerve fibre layer measurement may be a reliable, objective parameter predicting favourable visual outcomes, although its prognostic value when pathological, needs to be confirmed. For compromised vision after pituitary apoplexy, early surgical decompression remains usual practice until evidence-based guidance becomes available. The risk of radiation-induced visual toxicity is mainly influenced by total and per fraction dose of radiation and treatment modality. Careful selection of cases and of radiotherapy technique/planning are of major importance in minimising this risk. Dopamine agonists lead to visual recovery in a considerable number of prolactinoma patients. Visual morbidity should be considered a vital indicator in the metrics of quality of service/care in pituitary disease making regular, full ophthalmic examination an essential component of modern management of pituitary pathology at all time points of patient pathway. Well-designed studies minimising effects of bias and using tools and scoring systems reliably reflecting visual status will provide robust evidence on valid prognostication and patient stratification guiding clinical decision making.
Raghava Reddy, Simon Cudlip, James V Byrne, Niki Karavitaki, and John A H Wass
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.
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.
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.
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).
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.
Agata Juszczak, Avinash Gupta, Niki Karavitaki, Mark R Middleton, and Ashley B Grossman
Ipilimumab (Yervoy; Medarex and Bristol-Myers Squibb) is a human MAB against cytotoxic T-lymphocyte antigen 4, which enhances co-stimulation of cytotoxic T-lymphocytes, resulting in their proliferation and an anti-tumour response. It is licensed for the treatment of unresectable or metastatic malignant melanoma, while multiple clinical trials using this medication in the treatment of other malignancies are ongoing. As a clinical response to ipilimumab results from immunostimulation, predictably it generates autoimmunity as well, causing immune-related adverse events in the majority of patients. Of those, endocrinopathies are frequently seen, and in particular, autoimmune lymphocytic hypophysitis with anterior panhypopituitarism has been reported a number of times in North America. We present a case of a male referred to our department with manifestations of anterior panhypopituitarism after his third dose of ipilimumab for metastatic malignant melanoma, and we discuss the management of his case in the light of previous reports. We also review the published literature on the presenting symptoms, time to presentation, investigations, imaging, treatment and follow-up of ipilimumab-induced autoimmune lymphocytic hypophysitis.