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.

Investigation of Cushing's syndrome by inferior petrosal sinus sampling.

Bilateral simultaneous inferior petrosal sinus sampling, in combination with CRH stimulation, is now able to confirm the diagnosis of pituitary-dependent Cushing's disease with near certainty. In expert hands, the procedure is straightforward and safe. As well as confirming the differential diagnosis, the test may aid surgical success, especially if no adenoma is apparent at transsphenoidal exploration. In this article, we review the technique and its interpretation and consider which patients should undergo the procedure.

Bombesin-like peptides in human endocrine tumors: quantitation, biochemical characterization, and secretion.

Bombesin-like immunoreactivity (BLI) in 20 human endocrine tumors was studied using an antiserum directed toward the C-terminal region of bombesin. Additionally, plasma BLI was assayed in normal subjects and patients with known BLI-containing tumors. In 7 tumors (medullary carcinoma of the thyroid, n = 2; carcinoid of the lung, n = 3; hepatic carcinoid, n = 1; pheochromocytoma, n = 1), the BLI content ranged from 6-2000 pg/mg wet wt of tissue. Sephadex G-50 gel chromatography of tumor extracts under acid-dissociating conditions revealed 2 peaks of BLI: 1 coeluting with porcine gastrin-releasing peptide (GRP) and 1 with bombesin. Reverse phase ODS silica HPLC analysis of the G-50 peaks using a methanol-trifluoroacetic acid gradient showed that human tumor BLI more closely resembled porcine GRP and its C-terminal fragment GRP-(14-27) than bombesin itself. Partial tryptic digestion of the tumor GRP-like peptide generated a product which, on HPLC, was similar to GRP-(14-27). Elevated plasma BLI was detected in the peripheral circulation of three subjects and in the vessels draining the tumor metastases of one of these patients. BLI was undetectable in normal subjects. These results indicate 1) that BLI is present in and may be secreted by various human endocrine tumors, and 2) that human tumor BLI closely resembles porcine GRP and its C-terminal fragment GRP-(14-27).

Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy.

Blood samples were obtained, at the time of organ donation, from 31 consecutive brain-stem-dead (BSD) donors referred to one transplant coordinator during a 9-month period. Twenty-four cases (77%) had clinical diabetes insipidus (DI), which was poorly controlled with marked dehydration in a majority of cases (serum osmolality range 268-357; median 302 mOSM/kg). Serum triiodothyronine (T3) was subnormal in 25 (81%); all had normal or high serum reverse T3; and the serum free thyroxine (T4) index was subnormal in 9 (29%), and TSH was subnormal in 7 (23%). In no case were T4 and TSH both subnormal and results were typical of the sick euthyroid syndrome rather than TSH deficiency. Of 21 cases not receiving corticosteroids, 5 (24%) had a serum cortisol above 550 nmol/L (20 micrograms/dl), excluding ACTH deficiency, and only 1 had undetectable cortisol levels. Those with severe hypotension did not have significantly lower serum cortisol (mean 354 vs. 416; P greater than 0.5). Levels of prolactin, growth hormone, gonadotrophins, and gonadal steroids were variable, but only a minority were frankly deficient in these hormones. BSD donors frequently have DI, which is often managed poorly by nonspecialists and requires appropriate replacement therapy. In contrast most patients are not totally deficient in anterior pituitary hormones. Routine hormonal therapy with cortisol and T3 cannot, therefore, be justified on endocrinological grounds. Widespread introduction of such treatment should only follow controlled trials that clearly demonstrate clinically significant improvement in the transplanted organ function, without detriment to the donor.

Pituitary incidentalomas.

The optimal strategy for hormonal screening of a patient with any incidentally discovered pituitary mass is unknown. The authors' review of the endocrinologic literature supports the view that such patients are at slightly increased risk for morbidity and mortality. This risk implies a benefit of early diagnosis for at least for some of the disorders, suggesting the importance of case finding. Nevertheless, the data in Table 1 illustrate that clinically diagnosed hormone-secreting pituitary tumors are far less common than incidentalomas. Clinically, one cannot accurately determine the approximately 0.5% of patients with incidentaloma who are at increased risk among the vast majority who are not. Given the limitations of diagnostic tests, effective hormonal screening requires a sufficiently high pretest probability to limit the number of false-positive results. This condition is met to varying degrees in the patient with a small incidentally discovered pituitary mass but no signs or symptoms of hormone excess. Even the more common lesions, such as prolactinoma, are relatively rare. [table: see text] Subjecting patients to unnecessary testing and treatment is associated with risk. In addition to its initial cost, testing may result in further expense and harm as false-positive results are pursued, producing the "cascade effect" described by Mold and Stein as a "chain of events (which) tends to proceed with increasing momentum, so that the further it progresses the more difficult it is to stop." The extensive evaluations performed for some patients with incidentally discovered masses may reflect the unwillingness of many physicians to accept uncertainty, even in the case of an extremely unlikely diagnosis. This unwillingness may be driven, in part, by fear of potential malpractice liability, the failure to appreciate the influence of prevalence data on the interpretation of diagnostic testing, or other factors. The major justification for further evaluation of these patients is not so much to avoid morbidity and mortality for the rare patient who truly is at increased risk but to reassure patients in whom further testing is negative and the physician. Physicians must take care not to create inappropriate anxiety in patients by overemphasizing the importance of an incidental finding unless it is associated with a realistic clinical risk. The authors' recommendations are based on currently available information to minimize the untoward effects of the cascade. As evidence accumulates, these recommendations may need to be revised. The benefit of the diagnosis of an adrenal or pituitary disorder must be considered in the context of the patient's overall condition. Additional studies are needed to analyze the clinical utility of hormonal screening for these common radiologic findings. Data from these studies can be used to identify critical gaps in knowledge and to adopt the epidemiologic methods of evaluation of evidence that have been applied to preventive measures. One must be careful to recognize lead-time bias, in which survival can appear to be lengthened when screening simply advances the time of diagnosis, lengthening the period of time between diagnosis and death without any true prolongation of life; and length bias, which refers to the tendency of screening to detect a disproportionate number of cases of slowly progressive disease and to miss aggressive cases that, by virtue of rapid progression, are present in the population only briefly. Physicians must avoid the pitfalls of overestimation of disease prevalence and of the benefits of therapy resulting from advances in diagnostic imaging. Clinical judgment based on the best available evidence should be complemented and not replaced by laboratory data.

Management of pituitary incidentalomas. A survey of British and American endocrinologists.

The results of a survey of endocrinologists concerning their approaches to the evaluation of a patient with an incidentally discovered pituitary mass are presented in this article. The practices of British and American endocrinologists are compared. The wide variation in diagnostic approaches to the practice of ordering tests in the United Kingdom and the United States highlights the need for research and debate regarding the most appropriate management of patients with such findings.

Characterization of immunoreactive dynorphin in human phaeochromocytomas.

The prodynorphin-derived opioids, dynorphin (DYN) and alpha-neoendorphin (alpha NE) were studied in 24 human phaeochromocytomas and related tumours. Nineteen tumours, extracted in HCl (0.1 mol/l), contained concentrations of immunoreactive DYN (ir-DYN) ranging from less than 0.5 to 794 pmol/g wet weight. None of the extracts in HCl contained ir-alpha NE (all less than 2.4 pmol/g). Sephadex G-50 gel filtration chromatography of ir-DYN in HCl (0.1 mol/l) extracts of six tumours revealed three small peaks of ir-DYN of higher molecular size (approximately 12,000, 6000 and 3000 daltons), a minor peak of ir-DYN eluting just after DYN(1-17), and a broad major peak, consisting of at least three components, which was significantly retarded and eluted after the salt volume of the column. High-pressure liquid chromatography (HPLC) of these extracts revealed multiple peaks of ir-DYN, most of which did not coelute with any synthetic DYN peptides. On both gel filtration chromatography and HPLC, one of the minor peaks coeluted with DYN(1-32). None of the peaks of ir-DYN coeluted with DYN(1-17) which had been acetylated using acetic anhydride. Extracts of the same tumours in acetic acid (0.1 mol/l) yielded similar values for ir-DYN content, but parallelism in the assay was improved. Sephadex G-50 chromatography revealed a different pattern of ir-DYN with a major peak coeluting with DYN(1-17) and, in two tumours, a minor peak coeluting with DYN(1-8). Studies with HPLC revealed, however, that substantial degradation of synthetic DYN occurred during extraction in acetic acid (0.1 mol/l) in spite of the precautions taken. Phaeochromocytomas frequently contain ir-DYN in concentrations which may approach that of the mammalian pituitary. These tumours did not, however, contain ir-alpha NE and, with the possible exception of a small amount of DYN(1-32), the ir-DYN present did not correspond with any known sequences. Thus, whilst prodynorphin is expressed in phaeochromocytomas, it does not seem to be processed to the usual end-products, and post-translational modifications therefore seem likely. Enzymatic degradation of DYN may occur during extraction in acetic acid (0.1 mol/l), and this medium should, therefore, be avoided in studies of such labile peptides.

Immunocytochemical study of 18 tumours causing ectopic Cushing's syndrome.

Eighteen cases of Cushing's syndrome caused by ectopic production of peptide hormones were investigated by histological and immunocytochemical methods and the findings correlated with clinical and biochemical observations. Immunocytochemistry showed immunoreactive adrenocorticotrophic hormone (ACTH) or peptides derived from the ACTH precursor (pro-opiomelanocortin (POMC], or both, in a total of 10 cases: five of these also contained immunoreactive-alpha-melanocyte stimulating hormone, indicating more extensive translational processing of POMC than normally occurs in healthy corticotrophs of the anterior pituitary; in two further cases peptides capable of stimulating ACTH release from the anterior pituitary were present. In the remaining six cases immunocytochemistry failed to show the presence of ACTH, other POMC derived peptides, or peptides with ACTH releasing properties. These findings correlate well with the histological and clinical observations, in that the six tumours had been clinically overt, caused rapid death, and histologically seemed to be highly malignant. In contrast, the 12 other tumours were occult to radiological examination, patients had a much improved survival rate, and histologically the tumours seemed to be less aggressive. All but one of the tumours in this series showed a degree of neuroendocrine differentiation, indicated by the presence of neuron specific enolase. These results suggest that one feature of highly malignant tumours, which cause an ectopic endocrine syndrome, is a high secretion of peptide hormones, leaving amounts that are too small to be shown by immunocytochemistry.

Dunnigan-Kobberling syndrome: an autosomal dominant form of partial lipodystrophy.

Dunnigan-Kobberling syndrome is a form of partial lipodystrophy characterized by sparing of the face. Despite descriptions of six families since 1974, details of total body adipose tissue distribution and studies of carbohydrate and fat metabolism are lacking. The mode of inheritance also remains unclear, with most authors favouring an X-linked dominant transmission lethal in the hemizygous male. We examined 23 members of a family, of whom at least eight had partial lipodystrophy. Auxological evaluation and cross-sectional imaging showed absence of subcutaneous fat, presence of adipose tissue inside the body cavities, and skeletal muscle hypertrophy. Biochemical evaluation identified insulin resistance but revealed inadequate suppression of non-esterified fatty acids. In this family, male-to-male transmission supports an autosomal dominant mode of inheritance for Dunnigan-Kobberling syndrome.

'Dynorphin' in plasma: enzymatic artifact and authentic immunoreactivity.

The potent opioid peptide dynorphin (DYN) is found in posterior pituitary vasopressinergic neurones and in adrenal medullary cells suggesting that secretion into plasma is likely. We have developed a sensitive radioimmunoassay in order to study plasma DYN in man. It transpired that extraction prior to assay was essential since unextracted plasma caused gross and non-parallel inhibition of binding of tracer. Plasma extracted using leached silica glass ( Vycor ) caused inhibition of tracer binding which diluted in parallel to synthetic DYN suggesting the presence of substantial amounts of DYN-like immunoreactivity ( irDYN ) in plasma. Further investigation however demonstrated that this irDYN was artifactual and caused by enzymatic degradation of tracer. Although use of Seppak C18 cartridges resulted in reliable extraction of synthetic porcine DYN from acidified plasma, we have not detected irDYN in any plasma so far studied using this technique. However, extraction of non-acidified plasma using our antibody coupled to Sepharose CNBr-activated 4B followed by gel filtration chromatography demonstrated a single peak of irDYN of molecular size similar to DYN. These data suggested that a small amount of a DYN-like peptide does circulate in human plasma although this is not identical to porcine DYN(1-17). The implication of our results for the measurement of other similar peptides in plasma is discussed.

RIA/chromatographic evidence for novel opioid peptide(s) in Squilla mantis ganglia.

Proteins extracted from suboesophageal ganglia of Squilla mantis, an arthropod shown to be sensitive in vivo to opiates and to contain native opioid like peptide(s), were fractionated by gel filtration into three pools according to their molecular weight: A (Mr greater than 65,000), B (10,000 less than Mr less than 65,000) and C (Mr less than 10,000). None of these pools showed any immunoreactivity when radioimmunoassayed using antisera raised against Met-enkephalin either before or after sequential trypsin/carboxypeptidase B proteolysis. Further purification of pool C by HPLC followed by RIA using antibodies directed to Met-O-enkephalin,Leu-enkephalin,Dynorphin 1-13 and human beta-endorphin, showed only a trace amount of Met-enkephalin cross-reactivity (about 10 fmoles/mg of protein extract). No detectable amount of Leu- or Met-enkephalin was found after HPLC fractionation of proteolyzed pool B. Radioreceptor assay of HPLC fractions derived from trypsin/carboxypeptidase B treated pools B and C showed major areas of activity common to both pools, but nevertheless with differing retention times compared to the standard opioid peptides used.

The use of the short tetracosactrin test for the investigation of suspected pituitary hypofunction.

The short Synacthen (tetracosactrin) test (SST) is an established method of assessing adrenocortical reserve, and is increasingly replacing the insulin tolerance test (ITT) for the assessment of the hypothalamic-pituitary-adrenal (HPA) axis. However, there is no consensus on how the test is performed, and various time points and routes of administration are used. The present study was done, first, to determine whether there was any difference in cortisol responses when Synacthen was administered intramuscularly compared with intravenously and, secondly, to compare cortisol responses at 30 and 60 min. We found no significant difference between the two routes of administration. However, cortisol responses at 60 min were significantly higher than at 30 min (P < 0.05). Previous validations for the use of the SST in place of the ITT have used cortisol responses 30 min after Synacthen. We conclude that where the SST is used to assess the HPA axis, cortisol response at 30 min after intravenous Synacthen should be used.

A survey of the current methods used in the UK to assess pituitary function.

A national survey of the current methods used by specialists to evaluate pituitary function in the UK was performed by postal questionnaire. Seventy-three respondents, of whom 89% were consultants and 80% clinical endocrinologists, returned the questionnaire. Fifty per cent routinely used the insulin stress test (IST) to evaluate the hypothalamo-pituitary-adrenal (HPA) axis, while 50% routinely used tetracosactrin stimulation, there being little overlap between the two groups. This represents a significant change in clinical practice since the last survey in 1988. In those who used ACTH stimulation there was almost an equal split into those who administered the tetracosactrin intramuscularly (45%) or intravenously (47%). Furthermore, either the peak or 60 min cortisol value was used by 71% when interpreting the result of the test, despite the fact that in previous studies only the 30 min cortisol value has been shown to correlate with the IST result. The IST remains the most frequently used method to assess growth hormone reserve in adult subjects. The thyrotrophin-releasing-hormone and gonadotrophin-releasing-hormone tests are still used routinely by approximately a quarter of clinicians. These results provide data that could be used to develop guide-lines for the use of tests to investigate pituitary function.

Two macroprolactinomas presenting with neurological signs.

Macroprolactinomas commonly cause pressure effects on immediate parasellar structures, in particular on the optic chiasm to cause visual field defects. Pressure on more distant brain structures is rarely reported. We describe two massive prolactinomas presenting with neurological signs, including signs of hemiparesis which, to our knowledge, has not been reported previously.

A cross-sectional study of the prevalence of cardiac valvular abnormalities in hyperprolactinemic patients treated with ergot-derived dopamine agonists.

CONTEXT: Concern exists in the literature that the long-term use of ergot-derived dopamine agonist drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease. OBJECTIVE: The aim of the study was to determine the prevalence of valvular heart abnormalities in patients taking dopamine agonists as treatment for lactotrope pituitary tumors and to explore any associations with the cumulative dose of drug used. DESIGN: A cross-sectional echocardiographic study was performed in a large group of patients who were receiving dopamine agonist therapy for hyperprolactinemia. Studies were performed in accordance with the British Society of Echocardiography minimum dataset for a standard adult transthoracic echocardiogram. Poisson regression was used to calculate relative risks according to quartiles of dopamine agonist cumulative dose using the lowest cumulative dose quartile as the reference group. SETTING: Twenty-eight centers of secondary/tertiary endocrine care across the United Kingdom participated in the study. RESULTS: Data from 747 patients (251 males; median age, 42 y; interquartile range [IQR], 34-52 y) were collected. A total of 601 patients had taken cabergoline alone; 36 had been treated with bromocriptine alone; and 110 had received both drugs at some stage. The median cumulative dose for cabergoline was 152 mg (IQR, 50-348 mg), and for bromocriptine it was 7815 mg (IQR, 1764-20 477 mg). A total of 28 cases of moderate valvular stenosis or regurgitation were observed in 24 (3.2%) patients. No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION: This large UK cross-sectional study does not support a clinically concerning association between the use of dopamine agonists for the treatment of hyperprolactinemia and cardiac valvulopathy.

Cluster headache secondary to macroprolactinoma with ipsilateral cavernous sinus invasion.

We present a 25 year-old man with episodic cluster headache that was refractory to all standard pharmacological prophylactic and abortive treatments. Because of the lack of response, an MRI brain was performed which showed a large pituitary tumour with ipsilateral cavernous sinus invasion. The serum prolactin was significantly elevated at 54,700 miU/L (50-400) confirming a macro-prolactinoma. Within a few days of cabergoline therapy the headache resolved. He continues to be headache free several years after starting the dopamine agonist. This case highlights the importance of imaging the pituitary fossa in patients with refractory cluster headache, It also raises the potential anatomical importance of the cavernous sinus in pituitary-associated headache.