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.

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.

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.

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.

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.

Turner's syndrome in adulthood.

Turner's syndrome is the most common chromosomal abnormality in females, affecting 1:2,500 live female births. It is a result of absence of an X chromosome or the presence of a structurally abnormal X chromosome. Its most consistent clinical features are short stature and ovarian failure. However, it is becoming increasingly evident that adults with Turner's syndrome are also susceptible to a range of disorders, including osteoporosis, hypothyroidism, and renal and gastrointestinal disease. Women with Turner's syndrome have a reduced life expectancy, and recent evidence suggests that this is due to an increased risk of aortic dissection and ischemic heart disease. Up until recently, women with Turner's syndrome did not have access to focused health care, and thus quality of life was reduced in a significant number of women. All adults with Turner's syndrome should therefore be followed up by a multidisciplinary team to improve life expectancy and reduce morbidity.

Wide variation in surgical outcomes for acromegaly in the UK.

OBJECTIVE: Unsuccessful surgery for acromegaly has major consequences for the patient as well as financial consequences for the National Health Service (NHS). Surgical expertise affects the outcome. We have used the UK National Acromegaly Register to assess surgical outcomes in different centres to investigate whether these match the previously published case series. DESIGN: Retrospective and prospective observational study by analysis of anonymized national computer register records derived from individual clinical case records from 22 UK endocrine units and their associated pituitary surgical services. PATIENTS: Cases of acromegaly, presenting in 1970-2004, with levels of GH or IGF-1 (785 and 430 cases, respectively) recorded prior to transsphenoidal adenomectomy and in the 12 months postsurgery, before any subsequent pituitary surgery or radiotherapy. GH-lowering pharmacological therapy was permitted only if suspended for biochemical testing. MEASUREMENTS: Percentage of cases with 'safe' mean postoperative GH levels (< 5 mU/l) and/or IGF-1 in the age- and sex-adjusted normal range. RESULTS: 'Safe' GH, normal IGF-1, or both was achieved for 26%, 29% and 20% of extrasellar macroadenomas (> 1 cm), respectively, 39%, 39% and 29% of intrasellar macroadenomas, 56%, 51% and 37% of microadenomas (< 1 cm) and 39%, 39% and 28% of cases overall. In centres contributing more than 10 patients' data, rates of safe GH levels ranged from 20% to 68% and IGF-1 from 19% to 55%. Success rates in attaining safe postsurgical levels of GH improved only slightly in the UK between 1974 and 1999 but markedly thereafter. CONCLUSIONS: Surgical outcomes for acromegaly in UK centres vary widely and historically have not, except in a few centres, matched those of large published series, which mostly have a success rate around 60%. Results have, however, improved substantially since 2000 and in the most successful units match those of the best published series. Experience is an important determinant of surgical success in acromegaly and the very recent improvement in surgical results in the UK coincides with a trend to concentrate pituitary surgery in the hands of a smaller number of specialists. Therefore, patients should be offered surgery by a dedicated pituitary surgeon with a caseload sufficient to offer the prospect of safe postsurgical GH and IGF-1 levels for the majority of cases.

Surgical debulking of pituitary macroadenomas causing acromegaly improves control by lanreotide.

BACKGROUND: Macroadenomas causing acromegaly are cured surgically in only around 50% of patients. Primary medical treatment with somatostatin analogues has been suggested to be a means of treating patients with a potentially poor surgical outcome. Previous retrospective studies have also suggested that surgical debulking of pituitary tumours causing acromegaly improves control by somatostatin analogues. No prospective study using lanreotide has been carried out thus far to assess whether this is the case. OBJECTIVE: We carried out a prospective study to assess whether surgical debulking of pituitary macroadenomas causing acromegaly improved the subsequent control of acromegaly by the somatostatin analogue lanreotide. PATIENTS AND METHODS: We treated 26 consecutive patients [10 males and 16 females--median age 53.5 years (range 22-70)] with macroadenoma causing acromegaly unselected for somatostatin response for 16 weeks with lanreotide, maximizing GH and IGF-I suppression, if necessary, by incremental dosing. Surgical resection was carried out and the patients were re-assessed off medical treatment at 16 weeks following surgery. Those with nadir GH > 2 mU/l in the oral glucose tolerance test (OGTT) and a mean GH in the GH day curve (GHDC) > 5 mU/l were subsequently restarted on lanreotide and the responses were assessed at the same time points as during the preoperative lanreotide treatment. RESULTS: GH values fell on lanreotide treatment and prior to surgery they were considered 'safe' (mean GH in GHDC < 5 mU/l) in eight patients (30.7%). After surgery, they were 'safe' in 18 patients (69.2%). The figures for normal IGF-I were 11 (42.3%) before surgery and 23 (88.5%) after surgery. After surgery, six patients had nadir GH > 2 mU/l in the OGTT and 'unsafe' GH levels (mean GH in GHDC > 5 mU/l); on re-exposure to lanreotide, GH levels fell in all patients and at the end of 16 weeks postsurgery, they were 'safe' in three of them (50%) (P < 0.05). Pituitary tumour volume was also assessed prospectively, preoperatively on lanreotide and showed a mean fall of 33.1%. Eighty-three percent of patients had > 20% shrinkage. CONCLUSIONS: In this first prospective study using lanreotide, surgical debulking of pituitary tumours causing acromegaly improved subsequent postoperative control by the somatostatin analogue lanreotide. Surgery should, therefore, be considered in patients with macroadenoma causing acromegaly, even if there is little prospect of surgical cure. Lanreotide causes significant pituitary tumour shrinkage in the majority of patients.

Home administration of lanreotide Autogel by patients with acromegaly, or their partners, is safe and effective.

OBJECTIVE: The introduction of ready-to-use lanreotide Autogel has presented the possibility of patients receiving their acromegaly treatment at home. The objective of this study was to assess the ability of patients (or their partners) to administer repeat, unsupervised, injections of lanreotide Autogel without compromising efficacy or safety. DESIGN: Multicentre (10 UK regional endocrine centres), open-label, nonrandomised, controlled study. Patients elected either to receive/administer unsupervised home injections after injection technique training (Test group) or continued to receive injections from a healthcare professional (Control group). Patients received monthly injections of lanreotide Autogel at their established dose. Effects were monitored for up to 40 weeks. PATIENTS: Thirty patients (15 per treatment group) with acromegaly treated with a stable dose of lanreotide Autogel (60, 90 or 120 mg) for > or = 4 months before screening. Measurements The main outcome measure was the proportion of patients/partners who successfully administered injections throughout the study. RESULTS: All Test group patients/partners qualified to administer injections. Fourteen of 15 patients fulfilled all criteria for successful administration of unsupervised injections (95% confidence interval, 70%-99%). Fourteen of 15 Test and 14/15 Control patients maintained growth hormone and IGF-1 control. Local injection tolerability was good for both treatment groups, and safety profiles were similar. All Test group patients continued with unsupervised injections after the study. CONCLUSIONS: Patients with acromegaly or their partners were able to administer lanreotide Autogel injections with no detrimental effect on efficacy and safety; therefore, unsupervised home injections are a viable alternative to healthcare professional injections for suitably motivated patients.

Nonsurgical cerebrospinal fluid rhinorrhea in invasive macroprolactinoma: incidence, radiological, and clinicopathological features.

CONTEXT: Macroprolactinomas (MPRLs) may result in nonsurgical (spontaneous or dopamine agonist induced) cerebrospinal fluid (CSF) rhinorrhea; however, the incidence of and mechanisms underlying this phenomenon are poorly understood. OBJECTIVE: The objective of the study was to determine the incidence of nonsurgical rhinorrhea and identify biochemical, radiological, and histopathological factors associated with leakage. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of MPRL patients (n = 114) was compared with patients with nonfunctioning pituitary adenoma (NFA) (n = 181) seen over a 19-yr period (1985-2004). MAIN OUTCOME MEASURES: Incidence of CSF rhinorrhea, factors predictive of leakage, and differential expression of candidate markers of invasiveness were measured. RESULTS: Nonsurgical CSF rhinorrhea occurred in 8.7% of MPRLs (10 of 114) [2.6% spontaneous (three of 114), 6.1% dopamine agonist induced (seven of 114)], whereas no NFAs developed nonsurgical rhinorrhea. There was a clear male preponderance in MPRLs with nonsurgical rhinorrhea (males to females, 9:1, P = 0.008). Dopamine agonist resistance was more frequent in MPRLs with rhinorrhea than with MPRLs without rhinorrhea [30% (n = 10) vs. 5% (n = 104) P = 0.003]. Baseline prolactin levels, rate of prolactin decline in response to dopamine agonists, and tumor volume at diagnosis did not predict CSF leakage. Candidate markers of invasiveness, specifically the protease-activated receptor 1 and e-cadherin expression scores and tumor macrophage density, were not significantly different between groups; MPRL+CSF rhinorrhea (n = 6), MPRL without CSF rhinorrhea (n = 9), and NFAs (n = 9). CONCLUSIONS: The incidence of nonsurgical CSF rhinorrhea in MPRL patients (8.7%) is higher than expected. Dopamine agonist resistance is more common in MPRLs with CSF rhinorrhea; however, whether this is a mechanistic relationship requires further study. Protease-activated receptor 1 expression, e-cadherin expression, and macrophage infiltration rates do not distinguish tumors with from those without CSF rhinorrhea.

High dose androgen therapy in male pseudohermaphroditism due to 5 alpha-reductase deficiency and disorders of the androgen receptor.

We describe the clinical and biochemical features of six men with male pseudohermaphroditism due to androgen resistance. Each of the subjects had male-gender behavior but incomplete virilization. The underlying defects in androgen metabolism were defined by studies of the 5 alpha-reductase enzyme and the androgen receptor in fibroblasts cultured from biopsies of genital skin. Four of the six have 5 alpha-reductase deficiency, and two have defects of the androgen receptor (the Reifenstein syndrome). The responses of these men to androgen treatment were assessed by monitoring nitrogen balance, plasma luteinizing hormone (LH) values, and clinical parameters of virilization including penile growth, potency and ejaculatory volume, muscle bulk, and growth of body and facial hair. In all of the subjects with 5 alpha-reductase deficiency and one man with the Reifenstein syndrome significant response occurred, as evidence by nitrogen retention, lowered plasma LH levels, and improved virilization, with doses of parenteral testosterone esters that raised plasma testosterone levels above the normal male range and brought plasma dihydrotestosterone levels into the normal male range. The subject who did not respond with clinical virilization nevertheless showed nitrogen retention in response to acute testosterone administration. This patient had a profound deficiency of the androgen receptor, whereas the man with a receptor defect who did respond clinically to therapy had normal amounts of a qualitatively abnormal receptor. We conclude that high dose androgen therapy may be of benefit in improving virilization, self-image, and sexual performance in subjects with 5 alpha-reductase deficiency who have male-gender behavior and in some subjects with defects of the androgen receptor.

What is the natural history of nonoperated nonfunctioning pituitary adenomas?

BACKGROUND: Series of patients systematically investigating the outcome of clinically nonfunctioning pituitary adenomas (NFAs) not treated by surgery or radiotherapy during long follow-up periods are limited. Most reports involve the follow-up of selected cases of incidentally found lesions, rendering their results unreliable on the assessment of the pros and cons of a 'watch and wait' policy. OBJECTIVE: To investigate the outcome of a series of consecutive patients with presumed NFA (microadenoma or macroadenoma), who were not offered treatment at presentation (for a number of reasons) and were regularly followed up, and to identify possible factors predicting subsequent increase in tumour size. PATIENTS AND METHODS: All patients presenting to the Department of Endocrinology in Oxford between 1989 and 2005 with presumed NFA were studied retrospectively. Inclusion criteria were: (i) imaging features suggestive of a pituitary adenoma, (ii) no clinical and/or biochemical evidence of hormonal hypersecretion by the tumour, (iii) monitoring being the initial choice of management, and (iv) at least one repeat scan during the follow-up period. Subjects presenting with acute apoplexy were excluded. Follow-up management included clinical evaluation, assessment of the visual acuity and fields and imaging at regular intervals. The duration of observation was estimated from the dates of first and last scan. RESULTS: Forty subjects were included in the study [18 males/22 females, median age 52 years (range 18-89), 16 with microadenoma/24 with macroadenoma]. The mean follow-up period was 42 months (range 8-128). During the observation interval, 12.5% of the microadenomas and 50% of the macroadenomas increased in size. The 48-month probability for enlargement was 19% for the microadenomas and 44% for the macroadenomas. Among the subjects with tumour enlargement, 57% showed new or worse visual field defects (all had macroadenomas) and 21% showed chiasmatic involvement on imaging without visual deterioration (all had macroadenomas). New or worse visual field defects were found in 67% of the macroadenomas showing increase in size. No microadenoma enlarged to cause visual deterioration. In microadenomas, sex and age at presentation were not predictors of enlargement. In macroadenomas, sex, age, visual field defects or cavernous sinus invasion at presentation were not predictors of enlargement. CONCLUSIONS: The 'watch and wait' policy seems reasonable for microadenomas but is probably not a safe approach for macroadenomas, which appear to have a significant growth potential; in these cases, given the lack of established medical treatment, the decision for surgical intervention should balance the presence of significant comorbidities and the anaesthetic/peri-operative risks at presentation against the probability of tumour enlargement and its consequences, as well as the possible loss of advantages associated with early operation.

Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour.

The role of angiogenesis and lymphangiogenesis in thyroid cancer pathogenesis has not been elucidated. Patterns for tumour behaviour and metastasic spread vary according to tumour type and whether differences in the angiogenic or lymphangiogenic phenotype influence the route for tumour metastases or determine a more aggressive behaviour has not been fully explored. The angiogenic and lymphangiogenic phenotypes of a large cohort of thyroid proliferative lesions (n=191) were studied. Using immunohistochemistry for CD34, lymphatic vessel endothelial receptor-1 (LYVE-1) (specific markers for vascular and lymphatic endothelium respectively), vascular endothelial growth factor (VEGF-A), VEGF-C and fibroblast growth factor-2 (FGF-2), this study analyses microvascular density (MVD), lymphatic vascular density (LVD), and expression of angiogenic and lymphangiogenic factors in normal thyroid (NT; n=19), multinodular goitre (n=25), toxic multinodular goitre (n=8), Graves' hyperplasia (n=22), follicular adenoma (n=54), papillary carcinoma (PC; n=27), incidental papillary microcarcinoma (PMC; n=8), follicular carcinoma (FC; n=20) and medullary carcinoma (MC; n=8). MVD was decreased in proliferative lesions, benign and malignant, compared with NT (P<0.0001). In contrast, VEGF-A expression was increased in thyroid carcinomas (PC, FC and MC) when compared with PMC, benign lesions and NT (P<0.0001). LVD was higher in PC and PMC (P=0.001), and VEGF-C expression was increased in PC (P<0.0001). Despite higher LVD and increased expression of VEGF-A and VEGF-C in thyroid cancers, these markers were not related to poor prognosis in terms of tumour size, multifocality and/or presence of lymphatic or distant metastases. In conclusion, angiogenesis is reduced in thyroid proliferative lesions compared with NT tissue. However, VEGF-A expression is upregulated in thyroid cancers. Lymphangiogenesis and VEGF-C expression are increased in thyroid tumours prone to lymphatic metastases. This may be an important mechanism underlying the differences in metastatic behaviour between papillary and follicular thyroid cancer.

Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly.

BACKGROUND: There has been recent controversy as to the effectiveness of conventional pituitary irradiation in reducing circulating GH levels to less than 2.5 ng/ml and/or normalization of serum IGF-I. OBJECTIVES: Our objectives were to determine the effects of conventional pituitary irradiation on 1) lowering of serum GH and IGF-I levels, 2) the proportion of patients who achieve a GH level less than 2.5 ng/ml and a normal age-corrected IGF-I and the time taken to achieve this, and 3) the incidence of hypopituitarism and other adverse effects. DESIGN: We conducted retrospective data collection from 14 centers throughout the United Kingdom. PATIENTS: We studied 1840 patients with acromegaly, of whom 884 had received conventional pituitary irradiation. MEASUREMENTS: We assessed circulating GH and IGF-I levels and pituitary function at intervals after irradiation. RESULTS: Mean GH levels declined from 13.5 to 5.3 ng/ml at 2 yr after irradiation, to 2.0 ng/ml by 10 yr, and to 1.1 ng/ml at 20 yr. Twenty-two percent of patients achieved a level less than 2.5 ng/ml by 2 yr, 60% by 10 yr, and 77% by 20 yr. The interval to achieve this depended on the preirradiation GH level. IGF-I levels fell in parallel to those of GH with 63% of patients having a normal level by 10 yr. The proportions of patients with new pituitary hormone deficiencies 10 yr after irradiation were 18% for LH/FSH, 15% for ACTH, and 27% for TSH. No other side effects were noted. CONCLUSIONS: In this, the largest series reported, conventional pituitary irradiation is shown to be an effective and safe means of reducing both serum GH and IGF-I concentrations in patients with acromegaly.