Pituitary metastases: presentation and outcomes from a pituitary center over the last decade.

PURPOSE: Highlight and characterize manifestations, diagnostic/management approaches and outcomes in a contemporary cohort of patients with pituitary metastases (PM) from a large European pituitary center-over 10 years. METHODS: Retrospective review of PM cases between 1/2009 and 12/2018. Clinical, laboratory, imaging data at PM detection and during follow-up were analysed. RESULTS: 18 cases were identified (14 females; median age at diagnosis 61.5 years). Most common primary malignancies were lung (39%) and breast (32%). Most frequent presenting manifestation was visual dysfunction (50%). Gonadotrophin, ACTH, TSH deficiency were diagnosed in 85%, 67%, 46% of cases, respectively; diabetes insipidus (DI) was present in 17%. 33% of cases were detected during investigation for symptoms unrelated to PM. PM management included radiotherapy (44%), transsphenoidal surgery (17%), transsphenoidal surgery and radiotherapy (6%) or monitoring only (33%). One-year survival was 49% with median survival from PM detection 11 months (range 2-47). CONCLUSIONS: In our contemporary series, clinical presentation of PM has evolved; we found increased prevalence of anterior hypopituitarism, decreased rates of DI and longer survival compared with older literature. Increased availability of diagnostic imaging, improvements in screening and recognition of pituitary disease and longer survival of patients with metastatic cancer may be contributing factors.

Dopamine agonist resistant prolactinomas: any alternative medical treatment?

Consensus guidelines recommend dopamine agonists (DAs) as the mainstay treatment for prolactinomas. In most patients, DAs achieve tumor shrinkage and normoprolactinemia at well tolerated doses. However, primary or, less often, secondary resistance to DAs may be also encountered representing challenging clinical scenarios. This is particularly true for aggressive prolactinomas in which surgery and radiotherapy may not achieve tumor control. In these cases, alternative medical treatments have been considered but data on their efficacy should be interpreted within the constraints of publication bias and of lack of relevant clinical trials. The limited reports on somatostatin analogues have shown conflicting results, but cases with optimal outcomes have been documented. Data on estrogen modulators and metformin are scarce and their usefulness remains to be evaluated. In many aggressive lactotroph tumors, temozolomide has demonstrated optimal outcomes, whereas for other cytotoxic agents, tyrosine kinase inhibitors and for inhibitors of mammalian target of rapamycin (mTOR), higher quality evidence is needed. Finally, promising preliminary results from in vitro and animal reports need to be further assessed and, if appropriate, translated in human studies.

DIAGNOSIS OF ENDOCRINE DISEASE: Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview.

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

Surgery for Cushing's disease in pregnancy: our experience and a literature review.

Cushing's syndrome in pregnancy is a rare phenomenon and there is limited literature on its management. Cushing's disease in pregnancy is even less common and there is little guidance to help in the treatment for this patient group. Diagnosis of Cushing's syndrome in pregnancy is often delayed due to overlap of symptoms. In addition, there are no validated diagnostic tests or parameters documented. We present a case of a 30-year-old woman presenting to the antenatal clinic at 13 weeks of pregnancy with high suspicion of Cushing's disease. Her 21-week fetal scan showed a congenital diaphragmatic hernia and she underwent pituitary magnetic resonance imaging, which confirm Cushing's disease. She successfully underwent transsphenoidal adenomectomy with histology confirming a corticotroph adenoma. Tests following transsphenoidal surgery confirmed remission of Cushing's disease and she underwent an emergency caesarean section at 38 weeks. Unfortunately, her baby died from complications associated with the congenital abnormality 36 hours after birth. The patient remains in remission following delivery. To date, there have been no reported cases of congenital diaphragmatic hernia associated with Cushing's disease in pregnancy. In addition, we believe that this is only the eighth reported patient to have undergone successful transsphenoidal surgery for Cushing's disease in pregnancy.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline

"OBJECTIVE: To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults. PARTICIPANTS: The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline. EVIDENCE: The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries."

Management of craniopharyngiomas.

Craniopharyngiomas are rare epithelial tumours arising along the path of the craniopharyngeal duct. Their pathogenesis remains uncertain and they can present with a variety of manifestations attributed to pressure effects to surrounding structures. The optimal management of craniopharyngiomas remains challenging mainly due to their sharp, irregular borders and their tendency to adhere to vital neurovascular structures making surgical manipulations potentially hazardous to vital brain areas. Non-aggressive surgery followed by radiotherapy is currently the most widely used option possibly achieving the most optimal long-term outcome. Other treatment modalities including intracystic irradiation, intracystic instillation of antineoplasmatic agents and stereotactic radiotherapy are also available in our armamentarium. The long-term morbidities related with the craniopharyngiomas and their treatment remain significant, with hypothalamic damage playing the protagonist role and requiring further studies to identify measures that will improve the prognosis of the patients.

Mortality in Cushing's syndrome: systematic analysis of a large series with prolonged follow-up.

OBJECTIVE: In this study, we aim to assess the long-term survival and causes of death in a retrospective cohort study on patients with all aetiologies of endogenous Cushing's syndrome (CS) (except adrenal cancer), presenting to two large tertiary endocrine referral centres, and to identify variables predicting mortality. SUBJECTS AND METHODS: The records of all patients presenting with endogenous CS in the Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK and the Department of Endocrinology, 'Evangelismos' General Hospital, Athens, Greece between 1967-2009 (Oxford series) and 1962-2009 (Athens series) were reviewed. The standardised mortality ratio (SMR) was calculated for the Oxford series. RESULTS: In total, 418 subjects were identified (311 with Cushing's disease (CD), 74 with adrenal Cushing's (AC) and 33 with ectopic Cushing's (EC)). In CD, the probability of 10-year survival was 95.3% with 71.4% of the deaths attributed to cardiovascular causes or infection/sepsis. SMRs were significantly high overall (SMR 9.3; 95% CI, 6.2-13.4, P<0.001), as well as in all subgroups of patients irrespective of their remission status. In AC, the probability of 10-year survival was 95.5% and the SMR was 5.3 (95% CI, 0.3-26.0) with P=0.2. Patients with EC had the worst outcome with 77.6% probability of 5-year survival. CONCLUSIONS: In this large series of patients with CS and long-term follow-up, we report that in CD the mortality is significantly affected, even after apparently successful treatment. The SMR of patients with AC was high, but this was not statistically significant. The implicated pathophysiological mechanisms for these findings need to be further elucidated aiming to improve the long-term outcome.

A thyroxine absorption test followed by weekly thyroxine administration: a method to assess non-adherence to treatment.

OBJECTIVE: For patients who remain hypothyroid despite the administration of what would seem adequate doses of levothyroxine (L-T4), the underlying cause can be difficult to determine. The possibility of a biological cause should first be explored; however, in the majority of cases, poor adherence to medication is likely to be the main cause of treatment failure. When non-adherence is suspected but not volunteered, options to confirm the suspicion are limited. In this study, we identified patients for whom known drugs and pathological causes of L-T4 malabsorption were excluded, and despite often high doses of L-T4, the patients remained hypothyroid. DESIGN: Using a weight-determined oral L-T4 bolus administration, absorption was initially assessed in 23 patients. In nearly all patients, this was shown to be maximal at 120 min post-ingestion. This was then followed by the continued administration of a weekly T4 bolus for a 4-week period after which TSH and free T4 (fT4) levels were recorded. RESULTS: All patients showed a rise in fT4 at 120 min following the administration of the L-T4 bolus, with a mean increase of 54±3% from baseline. Following the treatment period, using an equivalent weekly L-T4 dose, which was significantly less than that of the daily dose taken by the patients before the test, TSH reduced from baseline in ~75% of cases. CONCLUSION: Using this combination of tests allows significant malabsorptive problems to be identified first and then potential non-adherence to be demonstrated. A management plan can then be implemented to increase adherence, aiming to improve treatment outcomes.

Pituitary apoplexy in non-functioning pituitary adenomas: long term follow up is important because of significant numbers of tumour recurrences.

OBJECTIVES: The frequency of pituitary tumour regrowth after an episode of classical pituitary apoplexy is unknown. It is thus unclear whether regrowth, if it occurs, does so less frequently than with non-apoplectic non-functioning pituitary macroadenomas that have undergone surgery without postoperative irradiation. This has important repercussions on follow up protocols for these patients. DESIGN: Retrospective cohort study of patients diagnosed with classical pituitary apoplexy in Oxford in the last 24 years. MEASUREMENTS: MRI/CT scans of the pituitary were performed post-operatively and in those patients who did not receive pituitary irradiation, this was repeated yearly for 5 years and 2 yearly thereafter. RESULTS: Thirty-two patients with non-functioning pituitary adenomas who presented with classical pituitary apoplexy were studied. There were 23 men and the mean age was 56·6 years (range 29-85). The mean follow up period was 81 months (range 6-248). Five patients received adjuvant radiotherapy within 6 months of surgery and were excluded from further analysis. In this group, there were no recurrences during a mean follow up of 83 months (range 20-150). In the remaining 27 cases there were 3 recurrences, with a mean of 79 months follow up (range 6-248) occurring 12, 51 and 86 months after surgery. This gives a recurrence rate of 11·1% at a mean follow up of 6·6 years post surgery. All recurrences had residual tumour on the post operative scan. CONCLUSIONS: Patients with classical pituitary apoplexy may show recurrent pituitary tumour growth and therefore these patients need continued post-operative surveillance if they have not had post-operative radiotherapy.

Outcome in surgically treated Rathke's cleft cysts: long-term monitoring needed.

OBJECTIVE: To clarify the outcome of all cases of Rathke's cleft cysts (RCC) treated surgically and followed up in Oxford during a long-term period. SUBJECTS AND METHODS: The records of all patients with RCC seen in the Department of Endocrinology between January 1978 and June 2009 were reviewed. RESULTS: A total of 33 patients (20 females, median age 43 years) were identified. At presentation, major visual field defects were detected in 58% of patients and gonadotrophin, ACTH and TSH deficiency in 60, 36 and 36% of patients respectively. Desmopressin treatment was required in 18% of patients. Treatment consisted of cyst evacuation combined with or without biopsy/removal of the wall. Post-operatively, visual fields improved in 83% of patients with impairment, whereas there was no reversal of ACTH or TSH deficiency or of diabetes insipidus. All but one subject had imaging follow-up during a mean period of 48 months (range 2-267). Cyst relapse was detected in 22% of patients at a mean interval of 29 months (range 3-48 months); in 57% of them, the recurrence was symptomatic. Relapse-free rates were 88% at 24-months and 52% at 48-months follow-up. At last assessment, at least quadrantanopia was reported in 19% of patients, gonadotrophin, ACTH and TSH deficiency in 50, 42 and 47% of patients respectively. Desmopressin treatment was required in 39% of patients. CONCLUSIONS: In this study of patients with RCC and long-term follow-up, we showed a considerable relapse rate necessitating long-term monitoring. Surgical intervention is of major importance for the restoration of visual field defects, but it does not improve endocrine morbidity, which in the long-term affects a substantial number of patients.

Nelson's syndrome.

Nelson's syndrome is a potentially life-threatening condition that does not infrequently develop following total bilateral adrenalectomy (TBA) for the treatment of Cushing's disease. In this review article, we discuss some controversial aspects of Nelson's syndrome including diagnosis, predictive factors, aetiology, pathology and management based on data from the existing literature and the experience of our own tertiary centre. Definitive diagnostic criteria for Nelson's syndrome are lacking. We argue in favour of a new set of criteria. We propose that Nelson's syndrome should be diagnosed in any patient with prior TBA for the treatment of Cushing's disease and with at least one of the following criteria: i) an expanding pituitary mass lesion compared with pre-TBA images; ii) an elevated 0800 h plasma level of ACTH (>500 ng/l) in addition to progressive elevations of ACTH (a rise of >30%) on at least three consecutive occasions. Regarding predictive factors for the development of Nelson's syndrome post TBA, current evidence favours the presence of residual pituitary tumour on magnetic resonance imaging (MRI) post transsphenoidal surgery (TSS); an aggressive subtype of corticotrophinoma (based on MRI growth rapidity and histology of TSS samples); lack of prophylactic neoadjuvant pituitary radiotherapy at the time of TBA and a rapid rise of ACTH levels in year 1 post TBA. Finally, more studies are needed to assess the efficacy of therapeutic strategies in Nelson's syndrome, including the alkylating agent, temozolomide, which holds promise as a novel and effective therapeutic agent in the treatment of associated aggressive corticotroph tumours. It is timely to review these controversies and to suggest guidelines for future audit.

An e-mail GP advisory service: a more efficient way of dealing with clinical enquiries.

Good communication between primary and secondary care is vital for patient management. This article describes how an e-mail enquiry service for endocrinology and diabetes was established within one hospital and the potential benefits that it offers.

The value of the oral glucose tolerance test, random serum growth hormone and mean growth hormone levels in assessing the postoperative outcome of patients with acromegaly.

BACKGROUND: The nadir GH value following an oral glucose tolerance test (OGTT) and the mean GH levels obtained from a GH day curve (GHDC) are among the tools currently used for assessing therapeutic end-points in surgically treated acromegaly. The latter test, however, is cumbersome and costly. OBJECTIVES: To evaluate, by using a modern, two-site chemiluminescent immunometric GH assay, the degree of discordance between the nadir GH following an OGTT and the mean GH obtained from a GHDC after surgical treatment of acromegaly and to check whether the OGTT can replace reliably the GHDC for the assessment of the disease status postoperatively. PATIENTS AND METHODS: Forty-nine patients [25 males/24 females, median age 52 years (range 18-70)] with a GH-secreting pituitary adenoma who had been surgically treated previously underwent hormonal evaluation of their disease status. The GHDC comprised of 9 x 30-min samples for GH collected in the morning after an overnight fast and rest. RESULTS: Seven per cent of patients with mean GH <1.7 mug/l (5 mU/l) in the GHDC had nadir GH >0.7 mug/l (2 mU/l) in the OGTT, and 10% of those with mean GH >1.7 mug/l had nadir GH <0.7 mug/l in the OGTT (all cases with discrepancies had normal IGF-I). GH value at time 0 min <0.6 mug/l in the OGTT had positive predictive value 100% and negative predictive value 75% in predicting nadir GH <0.3 mug/l (1 mU/l) in the OGTT. Nadir GH <0.8 mug/l in the OGTT had positive predictive value 97% and negative predictive value 95% in predicting mean GH <1.7 mug/l in the GHDC. Mean GH in the OGTT <1.4 mug/l had a positive predictive value 90% and negative predictive value 95% in predicting mean GH <1.7 mug/l in the GHDC. Mean GH in the OGTT <2.5 mug/l had positive predictive value 100% and negative predictive value 81% in predicting normal IGF-I. GH at time 0 min in the GHDC <2.1 mug/l had positive predictive value 90% and negative predictive value 90% in predicting mean GH <1.7 mug/l in the GHDC. CONCLUSIONS: The hormonal data obtained from an OGTT (mean and nadir GH) can provide comprehensive information on the status of acromegaly following surgery and can replace the GHDC cost-effectively. Furthermore, a morning fasting GH sample has an excellent positive predictive value in predicting biochemical cure and an optimal prognostic profile in predicting "safe" mean GH levels.

GH replacement in patients with non-functioning pituitary adenoma (NFA) treated solely by surgery is not associated with increased risk of tumour recurrence.

BACKGROUND: Subjects with non-functioning pituitary adenomas (NFAs) frequently develop GH deficiency due to tumour expansion or as a consequence of tumour therapy. The safety of GH replacement (GHR) in these individuals remains unclear. OBJECTIVE: To assess the effect of GHR on tumour recurrence in patients with NFAs solely treated by surgical removal. PATIENTS AND METHODS: The study involved all patients with NFA who presented to the Department of Endocrinology in Oxford between January 1989 and July 2005 and were treated solely by surgical removal of the tumour. Patients with follow up < 1 year were excluded. Recurrence was diagnosed on the basis of radiological appearances (detectable tumour after gross total removal or regrowth of pre-existing residue) on regular imaging surveillance. RESULTS: One hundred and thirty patients were included in the study, and were followed up for a mean period of 6.8 +/- 4.2 years (median 5.7, range 1.2-17.6). Twenty-three patients received GHR [16 male, 7 female, mean age at tumour diagnosis 53.7 +/- 14.6 years (range 20-80)]. The mean duration of GHR was 4.6 +/- 2.5 years (median 5.3, range 0.4-8.7). One hundred and seven subjects did not receive GH therapy [61 male, 46 female, mean age at tumour diagnosis 56.2 +/- 14.0 years (range 20-87)]. Tumour regrowth occurred in 38 non-GH treated subjects (36%) and 8 GHR subjects (35%). Regrowth was detected at a mean of 4.8 +/- 2.8 years (range 1-11 years) in the non-GH treated group, and at 6.5 +/- 2.3 years in the GHR group. In the GHR group, recurrence occurred after a mean of 2.9 +/- 2.2 years (range 0.4-5.9 years) following commencement of GH treatment. The Cox regression analysis showed that after adjusting for sex, age at tumour diagnosis, cavernous sinus invasion at diagnosis and type of tumour removal (partial or complete based on postoperative scan), GH treatment was not a significant independent predictor of recurrence (P = 0.09; hazard ratio = 0.51; 95% CI, 0.24-1.12). CONCLUSION: GH replacement in patients with NFA treated by surgery alone is not associated with an increased risk of tumour recurrence.

Radiotherapy of other sellar lesions.

Radiotherapy has been used as primary or adjuvant treatment in a number of non-adenomatous masses arising from within the sella. It is particularly important in the therapeutic algorithm of craniopharyngiomas and meningiomas and has also been used in chordomas/chordosarcomas and less commonly, in other lesions. This review describes the place of irradiation in the management of these masses.