Dopamine agonists and pituitary tumor shrinkage.

The primary aim of this review has been to clarify the tumor shrinking effects of dopamine agonists on pituitary macroadenomas of different cell types. Shrinkage is most dramatic for macroprolactinomas and is due to cell size reduction. Seventy-nine percent of 271 definite macroprolactinomas were reduced in size by at least 25%, and 89% shrank to some degree. Most shrinkage occurs during the first 3 months of treatment, although in a minority shrinkage is delayed. Dopamine agonist resistance during long-term therapy is exceptional. Drug withdrawal nearly always leads to a return of hyperprolactinemia, even after several years treatment, although early tumor reexpansion is unusual. About 10% of true macroprolactinomas do not shrink with dopamine agonists; the molecular mechanisms of such resistance have yet to be determined. Alternative formulations of BC and new dopamine agonists (CV 205-502 and cabergoline) are useful for the minority of patients unable to tolerate oral BC, but do not seem to further improve overall shrinkage rates. The risks of pregnancy have probably been overstated, and BC is suitable primary treatment for women with prolactinomas of all sizes; the drug can be used safely during pregnancy in the event of clinically relevant tumor expansion. The interpretation of different degrees of hyperprolactinemia is discussed and management strategies suggested. Most patients with macroprolactinomas now avoid surgery, but drug-induced, time-dependent tumor fibrosis should be remembered if surgery is contemplated. Nonfunctioning pituitary tumors are mostly of gonadotroph cell origin and may be associated with significant disconnection hyperprolactinaemia. Seventy-six of 84 well-characterized tumors showed no tumor shrinkage during dopamine agonist therapy. Possible explanations include abnormalities of dopamine receptor number and function. Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery. In contrast to macroprolactinomas, other functioning pituitary tumors (GH-, TSH-, and ACTH-secreting) rarely shrink during dopamine agonist therapy, although the number of tumors studied is small.

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.

An audit of the management of childhood-onset growth hormone deficiency during young adulthood in Scotland.

BACKGROUND: Adolescents with childhood onset growth hormone deficiency (CO-GHD) require re-evaluation of their growth hormone (GH) axis on attainment of final height to determine eligibility for adult GH therapy (rhGH). AIM: Retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition. PATIENTS: Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005 and 2013 were reviewed. Median (range) age at initial diagnosis of CO-GHD was 10.7 years (0.1-16.4) with a stimulated GH peak of 2.3 µg/l (0.1-6.5). Median age at initiation of rhGH was 10.8 years (0.4-17.0). RESULTS: Of the 130 CO-GHD adolescents, 74/130(57 %) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74 (82 %) remained GHD with 51/74 (69 %) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Of the remaining 56/130 (43 %) patients who were not re-tested, 34/56 (61 %) were transferred to adult services on rhGH without biochemical retesting and 32/34 of these had MPHD. The proportion of adults who were offered rhGH without biochemical re-testing in the four centres ranged between 10 and 50 % of their total cohort. CONCLUSIONS: A substantial proportion of adults with CO-GHD remain GHD, particularly those with MPHD and most opt for treatment with rhGH. Despite clinical guidelines, there is significant variation in the management of CO-GHD in young adulthood across Scotland.

Growth factors and pituitary tumors.

Growth within the anterior pituitary gland is probably controlled by several interacting extracellular messenger molecules, including hypothalamic peptides, target gland hormones, and several growth factors acting in autocrine or paracrine fashion. Adenoma formation may result from abnormal production of such factors or their specific cellular receptors, loss of local inhibitory influences, activation of the intracellular secondary message pathways conveying the mitogenic signal to the nucleus, or deregulation of the nuclear processes controlling mitosis.

Antithyroid drug regimen for treating Graves' hyperthyroidism.

BACKGROUND: Antithyroid drugs are widely used in the therapy of hyperthyroidism. There are wide variations in the dose, regimen or duration of treatment used by health professionals. OBJECTIVES: To assess the effects of dose, regimen and duration of antithyroid drug therapy for Graves' hyperthyroidism. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Central), MEDLINE, EMBASE, BIOSIS, CINAHL, HEALTHSTAR, Current Controlled Trials and reference lists. We contacted investigators and hand searched conference abstracts. Most recent search: July 2004. SELECTION CRITERIA: Randomised and quasi-randomised trials of antithyroid medication for Graves' hyperthyroidism were used. DATA COLLECTION AND ANALYSIS: Trial allocation to included, excluded and awaiting assessment categories was made by consensus. Two reviewers independently extracted data and assessed trial quality. Pooling of data for primary outcomes, and select exploratory analyses were undertaken. MAIN RESULTS: Twenty-three randomised trials involving 3115 participants were included. Overall the quality of trials as reported was poor; specifically in terms of allocation concealment, assessor blinding and loss to follow-up. Four trials examined the effect of duration of therapy on relapse rates of Graves' hyperthyroidism. In one trial using the Titration regimen, longer duration therapy (18 months) had significantly fewer relapses (37% versus 58%) than six month therapy (Odds ratio (OR) 0.42, 95% confidence interval (CI) 0.18 to 0.96). In one quasi-randomised trial using the Block-Replace regimen, there was no significant difference between the six and 12 month (relapses rates 41% versus 35%) arms of the study. Extending the duration of therapy to over 18 months was not associated with improved relapse rates (Peto OR 0.75, 95% CI 0.39 to 1.43). Twelve trials examined the effect of Block-Replace versus Titration regimen. The relapse rates were similar in both groups at 51% in the Block-Replace group and 54% in the Titration group (Peto OR 0.86, 95% CI 0.68 to 1.08). Participants reporting rashes (10% versus 5%) and withdrawing due to side effects (16% versus 9%) were significantly higher in the Block-Replace group compared to the Titration group respectively. Three studies considered the addition of thyroxine with continued low dose antithyroid therapy after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups were not significant (Odds ratio 0.58, 95% CI 0.05 to 6.21). Four studies considered the addition of thyroxine alone after initial therapy with antithyroid drugs. There was no significant difference in the relapse rates between the groups after 12 months follow-up with relapse rates being 31% (88/282) with thyroxine and 29% (82/284) with placebo (Peto OR 1.15, 95% CI 0.79 to 1.67). AUTHORS' CONCLUSIONS: The evidence (based on four studies) suggests that the optimal duration of antithyroid drug therapy for the Titration regimen is 12 to 18 months. The six month Block-Replace regimen was found to be as effective as the 12 month treatment in one quasi-randomised study. The Titration (low dose) regimen had fewer adverse effects than the Block-Replace (high dose) regimen and was no less effective in trials (based on 12 trials) of equal duration. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. The incidence of hypothyroidism was not reported and there were no deaths reported in the study populations.

Cushing's syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin.

Adrenal phaeochromocytoma rarely causes ectopic ACTH syndrome. We describe a 44-yr-old hypertensive woman who was Cushingoid and markedly pigmented. Laboratory studies indicated severe hypokalaemia, abnormal liver function tests, and random serum cortisols greater than 1660 nmol/L. Urinary catecholamines were markedly increased. An abdominal computed tomography scan showed a 4-cm left adrenal mass and an hypertrophied right adrenal. ACTH levels were elevated at 200 pmol/L, but ACTH precursors, which cross-react in the ACTH assay, were more highly elevated at 1625 pmol/L. The tumor cells cultured in vitro also secreted ACTH precursors, whereas ACTH levels were undetectable. Because the patient was highly pigmented, we measured circulating concentrations of alpha-MSH, which were undetectable and certainly insufficient to stimulate melanogenesis, suggesting that tumorderived ACTH precursors or ACTH were responsible for the pigmentation. A laparoscopic adrenalectomy resulted in remission of the Cushing's syndrome and dramatic reduction in the pigmentation. Before operation, treatment of the patient with metyrapone and replacement dexamethasone decreased cortisol from more than 1660 to less than 20 nmol/L. Surprisingly, this resulted in a decrease in ACTH precursors to 100 pmol/L and ACTH to 9.0 pmol/L. In vitro treatment of the tumor cells with dexamethasone for 24 or 40 h increased ACTH precursor secretion. In summary, this phaeochromocytoma causing Cushing's syndrome secreted primarily ACTH precursors, which seemed to cause the marked pigmentation. In vivo and in vitro evidence suggests that glucocorticoids induced ACTH precursor secretion.

Preliminary characterization of growth factors secreted by human pituitary tumors.

To investigate the secretion of mitogenic factors by human pituitary tumors we have cultured cells from 54 adenomas in serum-free medium. Conditioned media from 28 (52%) elicited dose-dependent stimulation of [3H]thymidine incorporation into rat GH3 cells (22-338% above control), while 14 (26%) inhibited GH3 proliferation. Stimulating activity was observed more frequently in nonfunctional tumor-conditioned medium (73%; n = 22) than in secretory tumor-conditioned medium (37%; n = 32). Of 10 tumour-conditioned media with mitogenic activity for GH3 cells, only 4 produced modest stimulation of HEp2 (human laryngeal carcinoma) cells. In contrast, [3H]thymidine incorporation into A431 (human squamous carcinoma) and PC12 (rat adrenal pheochromocytoma) cells was enhanced by each of 15 tumor-conditioned media (up to 342% and 275%, respectively), 8 of which had shown stimulatory and 2 inhibitory effects on GH3 cells. Gel filtration of pooled conditioned media from 10 nonfunctional tumors showed significant growth-promoting activity for GH3 cells in fractions corresponding to mol wt of 2-3 and 11-18 kDa. Proliferative activity on A431 cells also eluted in two positions; one corresponded to the higher mol wt peak seen with GH3 cells, while the other, not observed with GH3 cells, was in the 3- to 6-kDa range. These findings suggest that cells derived from human pituitary adenoma tissue synthesize and secrete several growth factors, each of which may have its own target cell specificities. These factors have yet to be characterized, but we suggest that they may have a role in stimulating the development or maintenance of human pituitary adenomas.

Reversible adrenocorticotropin deficiency due to probable autoimmune hypophysitis in a woman with postpartum thyroiditis.

The natural history and pathogenesis of lymphocytic hypophysitis remain poorly understood. We describe a 34-yr-old woman with postpartum thyroiditis and ACTH deficiency, studied at monthly intervals for 18 months after pregnancy. A significant titer of thyroid peroxidase autoantibodies was detected at 16 weeks gestation, and she was recruited into a prospective study of postpartum thyroid function. Four months postpartum she developed mild hyperthyroidism [free T4 (fT4), 27 pmol/L; TSH, less than 0.2 mU/L] and showed a rise in thyroid peroxidase and thyroglobulin autoantibodies. At 9 months postpartum, serum fT4 and fT3 levels were low normal (8.0 and 1.7 pmol/L, respectively), but TSH was not raised (0.4 mU/L). Subsequent investigation showed a low basal plasma cortisol level (28 nmol/L) in association with undetectable ACTH, and subnormal cortisol responses to depot Synacthen (535 nmol/L at 6 h) and hypoglycemia (peak, 145 nmol/L). FSH, LH, GH, and PRL function and computerized tomography of the pituitary were normal. Retrospective analysis of serum samples taken throughout the postpartum year showed developing hypocortisolemia between 3-9 months postpartum. Each sample was also tested for pituitary autoantibodies using a specific indirect immunofluorescent assay; none was detected. The ACTH deficiency recovered spontaneously, with normal cortisol responses to depot Synacthen (greater than 1380 at 6 h) and hypoglycemia (peak, 590) 14 and 18 months postpartum, respectively. This case illustrates that postpartum pituitary deficiencies are potentially reversible. The pattern of pituitary deficit and postpartum thyroiditis supported a diagnosis of autoimmune hypophysitis.

Effect of bromocriptine treatment on the fibrous tissue content of prolactin-secreting and nonfunctioning macroadenomas of the pituitary gland.

We performed a quantitative study using a point-counting technique at the light microscope level of the fibrous tissue content of PRL-secreting and nonfunctioning pituitary macroadenomas from patients treated or untreated with bromocriptine (BC) before surgery. There was a significant increase in the fibrous tissue content of PRL-secreting, but not nonfunctioning, tumors after BC treatment. The extent of the increase in fibrous tissue in prolactinomas correlated with the duration of treatment with BO.

Impaired processing of proopiomelanocortin in corticotroph macroadenomas.

The regulation and secretion of the ACTH precursors POMC and pro-ACTH were assessed directly using a 2-site immunoradiometric assay in six patients with pituitary macroadenomas (> or = 1.2 cm in diameter) and 27 patients with Cushing's disease due to a microadenoma. ACTH precursor levels were elevated in patients with macroadenomas (150-3690 pmol/L; normal range, < 5-40 pmol/L) and significantly higher than those in microadenoma patients (median, 29 pmol/L; range, 9-104 pmol/L; P < 0.001). Patients with macroadenomas also had increased ACTH precursor/ACTH ratios (15-181:1) compared with microadenoma patients (median, 5:1, range, 0.7-18.5:1; P < 0.001). ACTH precursors were unresponsive to high dose dexamethasone in patients with macroadenomas, whereas ACTH and cortisol responses varied. After CRH administration, ACTH precursors were unchanged, whereas cortisol increased significantly, suggesting the release of biologically active ACTH. This study clearly demonstrates reduced processing of POMC to ACTH in large pituitary tumors, a characteristic usually associated with tumors causing the ectopic ACTH syndrome, and provides evidence for differential regulation of ACTH precursors and ACTH by glucocorticoid and CRH. Variation in the clinical symptoms of patients with corticotroph macroadenomas may be attributable to differences in biological potency between the ACTH precursors and ACTH.

Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families.

Familial glucocorticoid deficiency is an autosomal recessive syndrome of adrenal unresponsiveness to ACTH characterized by glucocorticoid deficiency, high plasma ACTH levels, and a normal renin-aldosterone axis. Defects of the ACTH receptor have been suggested as a possible cause, and we have previously reported a number of novel mutations of the ACTH receptor gene in some, but not all, cases, suggesting that familial glucocorticoid deficiency may have a heterogeneous molecular etiology. Here we report the clinical features and ACTH receptor gene analysis in four patients from different families. We found that two patients were compound heterozygotes for the S74I and R128C mutations (patient A) and I44M and L192fs frame shift mutations (patient B). The other two patients (C and D) were of different ethnic ancestry, but were both homozygous for a R146H mutation. Segregation studies within families revealed heterozygosity in the parents and several other family members. Human CRH tests in the parents of patients A and B showed normal cortisol and ACTH responses in the S74I, R128C, and I44M heterozygotes and exaggerated cortisol and ACTH responses in the L192fs heterozygote, suggesting that the physiological ACTH increment induced in this test did not reveal evidence of subclinical ACTH resistance, and that this test may not be of value in ascertaining heterozygosity.

Primary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size.

Conventional surgery and radiotherapy for acromegaly have limitations. There are few data on the use of the somatostatin analog octreotide (Oct) as primary medical therapy. An open prospective study of 27 patients with newly diagnosed acromegaly was conducted in nine endocrine centers in the United Kingdom. Twenty patients had macroadenomas, and 7 had microadenomas. For the first 24 wk (phase 1), patients received sc Oct in an initial dose of 100 microg, 3 times daily, increased to 200 micro g three times daily after 4 wk in the 13 patients whose mean serum GH remained greater than 5 mU/liter (2 microg/liter). Five-point GH profiles were performed at 0, 4, 12, and 24 wk, and high resolution pituitary imaging using a standard protocol was performed at 0, 12, and 24 wk (magnetic resonance imaging in 25 patients and computed tomography in 2). Tumor dimensions and volumes were calculated by a central, reporting neuroradiologist, and the results were audited by a second, independent neuroradiologist. After 24 wk, 15 patients proceeded to phase 2 of the study with a direct switch to monthly injections of the depot formulation of Oct, Sandostatin long-acting release (Oct-LAR). Further GH profiles were performed at 36 and 48 wk, and pituitary imaging was performed at 48 wk. The median pretreatment serum GH concentration was 30.7 mU/liter (range, 6.7-141.4). During sc Oct, serum GH fell to less than 5 mU/liter in 9 patients (38%), and IGF-I fell to normal in 8 patients (33%). All 27 tumors shrank during sc Oct; for microadenomas the median tumor volume reduction was 49% (range, 12-73), and for macroadenomas it was 43% (range, 6-92). After 24 wk of Oct-LAR (end of phase 2), the GH level was less than 5 mU/liter in 11 of 14 patients (79%), and IGF-I was normal in 8 of 15 patients (53%). In the 15 patients given Oct-LAR (10 macroadenomas), wk 48 scans showed a further overall median tumor volume reduction of 24%. At the end of the study 79% of patients had mean serum GH levels below 5 mU/liter, 53% had normal IGF-I levels, and 73% showed greater than 30% tumor shrinkage. Twenty-nine percent of patients achieved all 3 targets, but no patient with pretreatment GH levels above 50 mU/liter did so at any stage of the study. Primary medical therapy with Oct offers the prospect of normalization of GH/IGF-I levels together with substantial tumor shrinkage in a significant subset of acromegalic patients. This is most likely to occur in patients with pretreatment GH levels less than 50 mU/liter (20 microg/liter).

Misinterpretation of prolactin levels leading to management errors in patients with sellar enlargement.

Serum prolactin concentrations and clinical features were correlated with the histopathologic diagnosis in 128 patients, without acromegaly or Cushing's syndrome, referred for surgical treatment of a presumed pituitary adenoma. A serum prolactin concentration of more than 8,000 mU/liter was always due to a prolactin-secreting adenoma. Prolactin levels of less than 8,000 mU/liter occurred with a variety of pathologic diagnoses. Fifteen patients had lesions other than pituitary adenomas, most commonly intrasellar craniopharyngioma; 10 of these had modest hyperprolactinaemia (maximum, 5,260 mU/liter) and four had received inappropriate bromocriptine therapy. Adenomas that were not prolactinomas frequently caused mild hyperprolactinaemia, although this was usually less than 3,000 mU/liter; three of these patients, however, had serum prolactin concentrations greater than this (maximum, 8,000 mU/liter). If the serum prolactin concentration is less than 3,000 mU/liter in the presence of significant pituitary enlargement, surgical removal is essential for both diagnosis and treatment since only prolactin-secreting adenomas are likely to shrink with dopamine agonist therapy. A serum prolactin concentration between 3,000 and 8,000 mU/liter is consistent with any diagnosis, whether the fossa is greatly enlarged or not, and great care must be taken with dopamine agonist therapy in such patients.

The efficacy and safety of lanreotide Autogel in patients with acromegaly previously treated with octreotide LAR.

OBJECTIVE: Lanreotide Autogel is a sustained-release aqueous gel formulation supplied in a prefilled syringe, with injection volume <0.5 ml. The aim of this study was to establish the efficacy and safety of Autogel in patients with acromegaly previously treated with octreotide LAR. DESIGN: A 28-week, open, multicentre study. PATIENTS: Twelve patients with acromegaly, treated with 20 mg octreotide LAR for >4 months, with serum GH levels <10.0 mU/l. METHODS: Autogel (90 mg) was given every 28 days during weeks 0-12. At week 16 the dose was titrated based on GH levels at weeks 8 and 12. If GH levels were <2.0, 2.0-5.0, or >5.0 mU/l, Autogel was reduced to 60 mg, maintained at 90 mg, or increased to 120 mg respectively, for the next three injections. GH and IGF-I levels were reassessed at weeks 24 and 28. RESULTS: Ten patients completed the study. Five remained on 90 mg Autogel throughout the study; in two patients the dose was reduced to 60 mg from week 16; in three patients it was increased to 120 mg. Mean GH levels were: baseline, 3.0+/-1.7 mU/l; week 12, 3.5+/-1.8 mU/l; week 28, 3.3+/-1.6 mU/l (NS). Mean IGF-I levels were: baseline, 212+/-70 microg/l; week 12, 185+/-91 microg/l; week 28: 154+/-61 microg/l (P=0.027). Six patients at baseline and eight at week 28 had normalised GH and IGF-I levels. Three patients reported adverse events: musculoskeletal pain (n=2) and injection-site symptoms (n=1). CONCLUSIONS: Lanreotide Autogel is effective and well tolerated in patients with acromegaly. This study in a small group of patients with well-controlled acromegaly suggests that the majority of patients switched from 20 mg LAR to 90 mg Autogel will have equivalent or better disease control.

Pituicytoma (pilocytic astrocytoma). Case report.

Tumors of the posterior pituitary are rare and the previous nomenclature has been confusing. A 40-year-old man presented with visual failure and disconnection hyperprolactinemia (830 mU/liter) due to a large invasive pituitary tumor shown to be a pituicytoma (pilocytic astrocytoma). Its astrocytic nature was confirmed by positive immunostaining for glial fibrillary acidic protein and the finding of cytoplasmic filaments on electron microscopy. This case report contains the pathological description of a pituicytoma and illustrates that a non-adenomatous pituitary lesion may masquerade as a pituitary adenoma. Large pituitary lesions associated with serum prolactin concentrations of less than 3000 mU/liter require early surgical biopsy.

Sensitive and specific bromocriptine radioimmunoassay with iodine label: measurement of bromocriptine in human plasma.

Plasma bromocriptine assays must have high sensitivity because plasma concentrations are low, and high specificity because bromocriptine is extensively metabolised. This paper describes the simple preparation of a radioiodine-labelled derivative of dihydroergocriptine and its use in a radioimmunoassay employing an antiserum directed against the intact bromocriptine molecule. The method could measure plasma bromocriptine at concentrations of 0.05 nmol/L, had between-assay coefficients of variation of less than 10% and was more convenient than previous assays using tritium radiolabels.

Antithyroid drug regimen for treating Graves' hyperthyroidism.

BACKGROUND: Antithyroid drugs are widely used in the therapy of hyperthyroidism. There are wide variations in the dose, regimen or duration of treatment used by health professionals. OBJECTIVES: To assess the effects of dose, regimen and duration of antithyroid drug therapy for Graves' hyperthyroidism. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Central), MEDLINE, EMBASE, BIOSIS, CINAHL, HEALTHSTAR, Current Controlled Trials and reference lists. We contacted investigators and hand searched conference abstracts. Most recent search: June 2002. SELECTION CRITERIA: Randomised and quasi-randomised trials of antithyroid medication for Graves' hyperthyroidism were used. DATA COLLECTION AND ANALYSIS: Trial allocation to included, excluded and awaiting assessment categories was made by consensus. Two reviewers independently extracted data and assessed trial quality. Pooling of data for primary outcomes, and select exploratory analyses were undertaken. MAIN RESULTS: Nineteen randomised trials involving 2233 participants were included. Overall the quality of trials as reported was poor; specifically in terms of allocation concealment, assessor blinding and loss to follow-up. Four trials examined the effect of duration of therapy on relapse rates of Graves' hyperthyroidism. In one trial using the Titration regimen, longer duration therapy (18 months) had significantly fewer relapses (37% vs 58%) than six month therapy (Odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.18 to 0.96). In one quasi-randomised trial using the Block-Replace regimen, there was no significant difference between the six and 12 month (relapses rates 41% versus 35%) arms of the study. Extending the duration of therapy to over 18 months was not associated with improved relapse rates (Peto OR = 0.75, 95% CI 0.39 to 1.43). Ten trials examined the effect of Block-Replace versus Titration regime. Relapse rates were similar in both groups at 54% in the Block-Replace group and 58% in the Titration group (Peto OR = 0.83, 95% CI 0.63 to 1.10). Participants reporting rashes (11% versus 5%) and withdrawing due to side effects (16% versus 9%) were significantly higher in the Block-Replace group compared to the Titration group respectively. Three studies considered the addition of thyroxine after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups were not significant (Odds ratio = 0.58, 95% CI 0.05 to 6.21). REVIEWER'S CONCLUSIONS: The evidence (based on three studies) suggests that the optimal duration of antithyroid drug therapy for the Titration regimen is 12 to 18 months. The six month Block-Replace regimen was found to be as effective as the 12 month treatment in one quasi-randomised study. The Titration (low dose) regimen had fewer adverse effects than the Block-Replace (high dose) regimen and was no less effective in trials (based on 10 trials) of equal duration. The incidence of hypothyroidism was not reported and there were no deaths in the study populations.

Antithyroid drug regimen for treating Graves' hyperthyroidism.

BACKGROUND: Antithyroid drugs are widely used in the therapy of hyperthyroidism. There are wide variations in the dose, regimen or duration of treatment used by health professionals. OBJECTIVES: To assess the effects of dose, regimen and duration of antithyroid drug therapy for Graves' hyperthyroidism. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Central), MEDLINE, EMBASE, BIOSIS, CINAHL, HEALTHSTAR, Current Controlled Trials and reference lists. We contacted investigators and hand searched conference abstracts. Most recent search: June 2002. SELECTION CRITERIA: Randomised and quasi-randomised trials of antithyroid medication for Graves' hyperthyroidism were used. DATA COLLECTION AND ANALYSIS: Trial allocation to included, excluded and awaiting assessment categories was made by consensus. Two reviewers independently extracted data and assessed trial quality. Pooling of data for primary outcomes, and select exploratory analyses were undertaken. MAIN RESULTS: Nineteen randomised trials involving 2233 participants were included. Overall the quality of trials as reported was poor; specifically in terms of allocation concealment, assessor blinding and loss to follow-up. Four trials examined the effect of duration of therapy on relapse rates of Graves' hyperthyroidism. In one trial using the Titration regimen, longer duration therapy (18 months) had significantly fewer relapses (37% vs 58%) than six month therapy (Odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.18 to 0.96). In one quasi-randomised trial using the Block-Replace regimen, there was no significant difference between the six and 12 month (relapses rates 41% versus 35%) arms of the study. Extending the duration of therapy to over 18 months was not associated with improved relapse rates (Peto OR = 0.75, 95% CI 0.39 to 1.43). Ten trials examined the effect of Block-Replace versus Titration regime. Relapse rates were similar in both groups at 54% in the Block-Replace group and 58% in the Titration group (Peto OR = 0.83, 95% CI 0.63 to 1.10). Participants reporting rashes (11% versus 5%) and withdrawing due to side effects (16% versus 9%) were significantly higher in the Block-Replace group compared to the Titration group respectively. Three studies considered the addition of thyroxine after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups were not significant (Odds ratio = 0.58, 95% CI 0.05 to 6.21). REVIEWERS' CONCLUSIONS: The evidence (based on three studies) suggests that the optimal duration of antithyroid drug therapy for the Titration regimen is 12 to 18 months. The six month Block-Replace regimen was found to be as effective as the 12 month treatment in one quasi-randomised study. The Titration (low dose) regimen had fewer adverse effects than the Block-Replace (high dose) regimen and was no less effective in trials (based on 10 trials) of equal duration. The incidence of hypothyroidism was not reported and there were no deaths in the study populations.

Pituitary metastasis from malignant bronchial carcinoid.

Metastases from a carcinoid tumor to the pituitary gland have, to our knowledge, not been described. We present a 49-year-old woman diagnosed as having a primary carcinoid tumor arising in the submucosa of a large bronchus who 8 years later presented with multiple metastases including one to the pituitary gland, which was in partial failure of pituitary function. This case illustrates than when confronted with a pituitary tumor resembling an adenoma but negative for pituitary hormones, the possibility of a metastasis from a carcinoid tumor should be considered.

The Australian Study of HIV and Injecting Drug Use. Part I: prevalence for HIV, hepatitis B and hepatitis C among injecting drug users in four Australian cities.

The objective of this study was to assess differences in HIV, hepatitis B and hepatitis C seroprevalence among injecting drug users (IDU) in four Australian cities. Eight hundred and seventh-two current IDU were recruited in approximately equal numbers from each of Adelaide, Melbourne, Perth and Sydney, and interviewed individually using a structured questionnaire. Fingerprick blood samples were taken from the majority of respondents, and tested for past exposure to the three viruses. HIV and hepatitis B and C raw seroprevalences were compared across cities, and comparisons were made of age-standardized seroprevalences for hepatitis B and C. Three percent of all respondents were HIV seropositive; 19% (23% age-standardized) were hepatitis B seropositive and 55% (60% age-standarized) were hepatitis C seropositive. There were general city differences and gender, sexual preference and treatment status group differences between the cities. Sydney respondents had the highest risk of infection for all three viruses in all comparisons. This was particularly striking for HIV among non-heterosexual men. Various explanations for the findings were considered, including city differences in demographic and drug use variables, underlying patterns of risk behaviour, and period/cohort effects. It was concluded that none of these explanations appeared to fit the pattern of findings, and that these probably represented true underlying differences in size of pools of infection. The reasons for this, however, cannot be ascertained from this study.