Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

Volume-outcome relationship for adrenalectomy: analysis of an administrative dataset for the Getting It Right First Time Programme.

BACKGROUND: A minimum volume threshold of at least six procedures per annum per surgeon has been set in UK and European guidelines for adrenal surgery. The aim of this study was to investigate outcomes for adrenal surgery in England relative to annual surgeon and hospital trust volume. METHODS: Data were extracted from the Hospital Episodes Statistics database for England. A 6-year period (January 2013 to December 2018 inclusive) for all adult admissions for unilateral adrenal surgery was used. The primary outcome measure was an emergency readmission within 30 days of discharge following surgery. Procedures were categorized as open or minimally invasive surgery for analysis. Multilevel modelling was used to adjust for hierarchy and potential confounders. RESULTS: Data for 4189 adrenalectomies were identified. Only one third of surgeons (who operated on just over a half of all patients) performed at least six procedures in the year prior to the index procedure. For open surgery, emergency readmission rates fell significantly from 15.2 to 6.4 per cent for surgeons and from 13.2 to 6.1 per cent for trusts between the lowest- and highest-volume categories. Significant, but less dramatic falls were also seen for minimally invasive surgery. CONCLUSION: A volume-outcome effect was identified for adrenal surgery in England. Minimum volume thresholds should be set, although these may need to be more ambitious than the current threshold if outcomes are to be optimized. LAY SUMMARY: Surgery for disease of the adrenal gland can be complex. In many cases the skill and experience of the surgeon and the wider surgical team is thought to be important in determining the success of the procedure. The relative rarity of adrenal surgery means that there is little evidence to support this view. This study looked at outcomes for all 4189 patients who underwent adrenal surgery in England over a 6-year period. There was evidence that outcomes were better for patents when the surgeon and hospital trust had performed a larger number of adrenal surgery procedures in the year prior to the procedure. This was, however, dependent on which patient outcomes were studied and the type of procedure. These findings will inform the ongoing debate as to whether adrenal surgery in England should only be performed in regional centres by experienced teams.

Surgery for disease of the adrenal gland can be complex. In many cases the skill and experience of the surgeon and the wider surgical team is thought to be important in determining the success of the procedure. The relative rarity of adrenal surgery means that there is little evidence to support this view. This study looked at outcomes for all 4189 patients who underwent adrenal surgery in England over a 6-year period. There was evidence that outcomes were better for patents when the surgeon and hospital trust had performed a larger number of adrenal surgery procedures in the year prior to the procedure. This was, however, dependent on which patient outcomes were studied and the type of procedure. These findings will inform the ongoing debate as to whether adrenal surgery in England should only be performed in regional centres by experienced teams.

Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency: Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK.

These guidelines aim to ensure that patients with adrenal insufficiency are identified and adequately supplemented with glucocorticoids during the peri-operative period. There are two major categories of adrenal insufficiency. Primary adrenal insufficiency is due to diseases of the adrenal gland (failure of the hormone-producing gland), and secondary adrenal insufficiency is due to deficient adrenocorticotropin hormone secretion by the pituitary gland, or deficient corticotropin-releasing hormone secretion by the hypothalamus (failure of the regulatory centres). Patients taking physiological replacement doses of corticosteroids for either primary or secondary adrenal insufficiency are at significant risk of adrenal crisis and must be given stress doses of hydrocortisone during the peri-operative period. Many more patients other than those with adrenal and hypothalamic-pituitary causes of adrenal failure are receiving glucocorticoids as treatment for other medical conditions. Daily doses of prednisolone of 5 mg or greater in adults and 10-15 mg.m-2 hydrocortisone equivalent or greater in children may result in hypothalamo-pituitary-adrenal axis suppression if administered for 1 month or more by oral, inhaled, intranasal, intra-articular or topical routes; this chronic administration of glucocorticoids is the most common cause of secondary adrenal suppression, sometimes referred to as tertiary adrenal insufficiency. A pragmatic approach to adrenal replacement during major stress is required; considering the evidence available, blanket recommendations would not be appropriate, and it is essential for the clinician to remember that adrenal replacement dosing following surgical stress or illness is in addition to usual steroid treatment. Patients with previously undiagnosed adrenal insufficiency sometimes present for the first time following the stress of surgery. Anaesthetists must be familiar with the symptoms and signs of acute adrenal insufficiency so that inadequate supplementation or undiagnosed adrenal insufficiency can be detected and treated promptly. Delays may prove fatal.

Nelson syndrome: definition and management.

Nelson syndrome is an important complication of treatment with total bilateral adrenalectomy (TBA) for patients with refractory Cushing's disease. Although early cases of Nelson syndrome often presented with the clinical features of large sellar masses, the modern face of Nelson syndrome has changed primarily due to earlier detection (with highly resolved magnetic resonance imaging (MRI) and sensitive ACTH assays) and greater awareness of the condition, resulting in reduced morbidity and mortality. Although lack of administration of neoadjuvant pituitary radiotherapy post-TBA surgery may predict future development of Nelson syndrome, other predictive factors remain controversial. Therefore, Nelson syndrome should be screened for closely and long-term in all patients with a history of Cushing's disease and TBA. The diagnosis of Nelson syndrome remains controversial, and the pathogenesis of this condition is incompletely understood. Current hypotheses include the "released negative feedback" mechansism (residual pituitary corticotropinoma cells are "released" from the negative feedback effects of cortisol following TBA), and the "aggressive corticotropinoma" mechanism (Nelson syndrome is most likely to develop in those patients with refractory treatments - including TBA - for an underlying aggressive corticotropinoma). Effective management of Nelson syndrome with pituitary surgery and radiotherapy is often a challenge. Other therapies (such as Gamma Knife surgery and temozolomide) play an important role and merit further research into their efficacy and placement in the management pathway of Nelson syndrome.

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.

A consensus on the diagnosis and treatment of acromegaly complications.

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.

Risedronate in adults with osteogenesis imperfecta type I: increased bone mineral density and decreased bone turnover, but high fracture rate persists.

UNLABELLED: Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. INTRODUCTION: Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. METHODS: Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. RESULTS: Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm(2), p = 0.007; mean Z-score, -1.93 vs. -1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. CONCLUSIONS: Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

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.

Hypopituitarism following envenoming by Russell's vipers (Daboia siamensis and D. russelii) resembling Sheehan's syndrome: first case report from Sri Lanka, a review of the literature and recommendations for endocrine management.

Russell's vipers (Daboia russelii and D. siamensis) inhabit 10 South and South East Asian countries. People envenomed by these snakes suffer coagulopathy, bleeding, shock, neurotoxicity, acute kidney injury and local tissue damage leading to severe morbidity and mortality. An unusual complication of Russell's viper bite envenoming in Burma (D. siamensis) and southern India (D. russelii) is hypopituitarism but until now it has not been reported elsewhere. Here, we describe the first case of hypopituitarism following Russell's viper bite in Sri Lanka, review the literature on this subject and make recommendations for endocrine investigation and management. A 49-year-old man was bitten and seriously envenomed by D. russelii in 2005. He was treated with antivenom but although he recovered from the acute effects he remained feeling unwell. Hypopituitarism, with deficiencies of gonadal, steroid and thyroid axes, was diagnosed 3 years later. He showed marked improvement after replacement of anterior pituitary hormones. We attribute his hypopituitarism to D. russelii envenoming. Russell's viper bite is known to cause acute and chronic hypopituitarism and diabetes insipidus, perhaps through deposition of fibrin microthrombi and haemorrhage in the pituitary gland resulting from the action of venom procoagulant enzymes and haemorrhagins. Forty nine cases of hypopituitarism following Russell's viper bite have been described in the English language literature. Patients with acute hypopituitarism may present with hypoglycaemia and hypotension during the acute phase of envenoming. Those with chronic hypopituitarism seem to have recovered from envenoming but present later with features of hypopituitarism. Over 85% of these patients had suffered acute kidney injury immediately after the bite. Steroid replacement in acute hypopituitarism is life saving. All 11 patients with chronic hypopituitarism in whom the outcome of treatment was reported, showed marked improvement with hormone replacement. Unrecognized acute hypopituitarism is potentially fatal while chronic hypopituitarism can be debilitating. Physicians should therefore be aware of this complication of severe envenoming by Russell's vipers, especially in Burma and South India, so that the diagnosis may be made without delay and replacement started with essential hormones such as hydrocortisone and thyroxine.

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.

Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome.

AIMS/HYPOTHESIS: Variants in the fat-mass and obesity-associated gene (FTO) influence susceptibility to type 2 diabetes via an effect on adiposity/obesity. Given the important role of obesity in the aetiology of both polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus, our aim was to establish whether FTO variants are also implicated in PCOS susceptibility. METHODS: We performed a genetic association study of FTO variant rs9939609 using case-control analyses, conducted in 463 PCOS patients (geometric mean BMI 27.5 kg/m(2)) and 1,336 female controls (geometric mean BMI 25.3 kg/m(2)) of UK British/Irish origin. We also sought evidence for associations between FTO variation and circulating testosterone levels in 324 UK PCOS patients and 1,000 women from the Northern Finland Birth Cohort of 1966. Outcome measures included FTO rs9939609 genotype frequencies by participant group and androgen measures (testosterone, free androgen index) by genotype. RESULTS: There was a significant association between FTO genotype and PCOS status in the UK case-control analysis, which was attenuated by adjustment for BMI (Cochran-Armitage test, odds ratio [per minor allele copy] 1.30 [95% CI 1.12, 1.51], p = 7.2 x 10(-4) [unadjusted], p = 2.9 x 10(-3) [adjusted]). This association was most evident in obese PCOS patients (PCOS patients below median BMI vs UK controls, p = 0.11; above median BMI vs controls, p = 2.9 x 10(-4)). No relationship between FTO genotype and androgen levels was seen. CONCLUSIONS/INTERPRETATION: We provide the first evidence that variants that predispose to common obesity also result in altered susceptibility to PCOS, confirming the mechanistic link between these conditions. The predominant effect of FTO variants on PCOS susceptibility is probably mediated through adiposity.

Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

Collision lesions of the sella: co-existence of craniopharyngioma with gonadotroph adenoma and of Rathke's cleft cyst with corticotroph adenoma.

Collision lesions of the sellar region are relatively uncommon. Most contributions include a pituitary adenoma or a cyst/cystic tumor, particularly a Rathke cleft cyst. The association of craniopharyngioma with an adenoma is particularly rare. Among reported cases, some have included secondary prolactin cell hyperplasia due to pituitary stalk section effect. Herein, we report two collision lesions, including a gonadotroph adenoma with adamantinomatous craniopharyngioma and a corticotroph adenoma with Rathke's cleft cyst. Clinicopathologic correlation and a review of the literature are undertaken.