Macimorelin as a Diagnostic Test for Adult GH Deficiency.

Purpose: The diagnosis of adult GH deficiency (AGHD) is challenging and often requires confirmation with a GH stimulation test (GHST). The insulin tolerance test (ITT) is considered the reference standard GHST but is labor intensive, can cause severe hypoglycemia, and is contraindicated for certain patients. Macimorelin, an orally active GH secretagogue, could be used to diagnose AGHD by measuring stimulated GH levels after an oral dose. Materials and Methods: The present multicenter, open-label, randomized, two-way crossover trial was designed to validate the efficacy and safety of single-dose oral macimorelin for AGHD diagnosis compared with the ITT. Subjects with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for AGHD and healthy, matched controls (n = 25) were included in the efficacy analysis. Results: After the first test, 99% of macimorelin tests and 82% of ITTs were evaluable. Using GH cutoff levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for ITTs, the negative agreement was 95.38% (95% CI, 87% to 99%), the positive agreement was 74.32% (95% CI, 63% to 84%), sensitivity was 87%, and specificity was 96%. On retesting, the reproducibility was 97% for macimorelin (n = 33). In post hoc analyses, a GH cutoff of 5.1 ng/mL for both tests resulted in 94% (95% CI, 85% to 98%) negative agreement, 82% (95% CI, 72% to 90%) positive agreement, 92% sensitivity, and 96% specificity. No serious adverse events were reported for macimorelin. Conclusions: Oral macimorelin is a simple, well-tolerated, reproducible, and safe diagnostic test for AGHD with accuracy comparable to that of the ITT. A GH cutoff of 5.1 ng/mL for the macimorelin test provides an excellent balance between sensitivity and specificity.

Selective use of the insulin tolerance test to diagnose hypopituitarism.

The insulin tolerance test is considered the gold standard for assessing the hypothalamic-pituitary-adrenal and growth hormone (GH) axes, but its use varies considerably among different endocrine units. We recommend using the insulin tolerance test to assess the hypothalamic-pituitary-adrenal axis within 3 months of pituitary surgery, where adrenocorticotropic hormone 1-24 testing is equivocal, and to assess for GH deficiency where the patient is being considered for GH replacement therapy. We also discuss safety issues, how to ensure adequate hypoglycaemia and possible alternative tests, such as the overnight metyrapone test and glucagon test.

Development of pituitary apoplexy during TRH/GnRH test in a patient with pituitary macroadenoma.

Pituitary apoplexy occurs as a very rare complication following pituitary function tests. Signs and symptoms are due to the rapid expansion of an infarcted and/or haemorrhagic pituitary adenoma. We report a case of macroadenoma, in which pituitary apoplexy developed 30 minutes after administration of thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH) injections. Magnetic resonance (MR) imaging had earlier revealed several haemorrhagic zones. After the TRH and GnRH injections, the patient complained of visual defect. MR imaging demonstrated an increase in the size of the pituitary adenoma and several haemorrhagic zones that formed a fluid-fluid level at the centre of the lesion. The pituitary mass was removed using the transsphenoidal approach. On immunostaining, follicle-stimulating and luteinising hormones were strongly positive, while prolactin was weakly positive. Pituitary functions were evaluated by dynamic function tests at six weeks post operation. The patient's pituitary functions and visual acuity were found to be normal.

Evaluation of the pituitary function with insulin tolerance (hypoglycaemia) testing: are there any differences using insulin lispro compared to regular insulin?

BACKGROUND/AIM: The insulin tolerance test (ITT) remains the gold standard for evaluating the pituitary function, but has potential risks when hypoglycaemia is induced. There are scarce data using short-acting insulin analogs for ITTs. This pilot study compares the effects of insulin lispro (LPI) with regular insulin (RGI) during an ITT. METHODS: Patients with suspected hypopituitarism (n = 103) randomly received either LPI (n = 51) or RGI (n = 52). RESULTS: All patients reported signs and symptoms when hypoglycaemia was induced. In the LPI group, hypoglycaemia occurred sooner (23.6 +/- 1.6 vs. 28.3 +/- 1.4 min, p < 0.05), and duration of hypoglycaemia (25.0 +/- 1.7 vs. 31.9 +/- 1.9 min, p < 0.05) and time for blood glucose levels to return to a 'safe' level (>3.3 mmol/l; 56.5 +/- 2.3 vs. 76.0 +/- 2.1 min, p < 0.001) were shorter as compared with the RGI group. No differences in peak growth hormone and cortisol levels were observed between the two groups. CONCLUSIONS: Our data suggest that despite inducing similar symptomatology, LPI exerted a quicker onset and a shorter duration of hypoglycaemia as compared with RGI. Thus, using LPI might reduce the potential risks associated with an ITT by shortening the hypoglycaemic phase of the test.

Pituitary apoplexy after thyrotropin-releasing hormone stimulation test in a patient with pituitary macroadenoma.

Pituitary apoplexy is a rare complication of pituitary tumors. We report a case of a 41-year-old female with acromegaly due to a pituitary macroadenoma, who developed pituitary apoplexy after a thyrotropin-releasing hormone (TRH) 200 microgram intravenous injection stimulation test. Neither emergency computed tomography (CT) scans nor magnetic resonance imaging (MRI), performed 6 hours and 12 hours, respectively, after the active episode, disclosed the evidence of acute hemorrhage or infarction. Two days later, the pituitary mass, removed by transsphenoidal approach, showed ischemic necrosis and acute hemorrhage. The TRH test is generally safe for evaluating pituitary function, but pituitary apoplexy may occur after the procedure. CT and MRI may miss the diagnosis of pituitary apoplexy, especially if performed immediately after the acute episode.

Oral hydration during growth hormone stimulation with clonidine.

The arginine-clonidine growth hormone (GH) stimulation test causes hypotension, requiring intravenous fluids to stabilize blood pressure (BP) and delaying departure from clinic. We hypothesized that oral hydration during the stimulation test would decrease need for intravenous fluids and shorten clinic stay. Children drank a diet electrolyte drink (10 ml/kg) on arrival to the test, which was repeated after clonidine. Fifteen children (7 girls) were tested without oral hydration, and 23 (6 girls) were tested with oral hydration (age range, 2-15 years). Compared with no oral hydration, intake of >13 ml/kg rarely required intravenous fluids, improved diastolic BP, and permitted discharge at the end of the GH test, with a higher BP.

Apoplexy accompanying pituitary adenoma as a complication of preoperative anterior pituitary function tests.

Pituitary apoplexy occurs as a very rare complication of the pituitary function test. We have experienced two cases of pituitary apoplexy following anterior pituitary function tests for preoperative assessment: a triple bolus test and a TRH test. To elucidate such a rare complication, we outline our two cases and review 28 cases from the literature. The clinical characteristics, etiology, pathophysiology, and diagnostic and therapeutic implications are also discussed. The combined data suggest that pituitary function tests have the potential to precipitate pituitary apoplexy, and its manifestations range from a clinically benign event to a catastrophic presentation with permanent neurological deficits or even death, although most patients may fortunately have a good outcome. We suggest that the pituitary function test should not be done as a routine test, and when such a test is planned, the patient should be observed with caution for any symptomatic changes for at least 2 hours following the test for appropriate treatment. Further, MRI, especially enhanced studies, may provide an earlier diagnosis of the pituitary apoplexy since CT scan images often fail to demonstrate either density changes or obvious enlargement of the pituitary adenoma at the acute stage.

[Tolerance of the oral clonidine test in 180 patients: efficacy of the volemic expantion in controlling arterial hypotension]. / Tolerância ao teste da clonidina em 180 pacientes: estudo da eficácia da expansão volêmica para o controle de hipotensão arterial.

Clonidine stimulation test is widely used to evaluate growth hormone secretion. Side effects are somnolence (35%) and arterial hypotension (AH) (5%). The aims of this paper were to evaluate the tolerance to this test regarding blood pressure (BP) decrease, sedation and the efficacy of saline resuscitation to prevent AH. BP was measured at basal, 60 and 120 min. Sedation was determined by the Ramsay scale. Patients were divided into two groups: Group 1 (n = 80) received saline resuscitation only upon severe AH (drop of mean BP [MBP] > 20% from initial MBP) and/or postural hypotension; Group 2 (n = 100) received saline resuscitation from the beginning of the test. Both groups presented a significant MBP fall and 75% presented somnolence at 60 min. MBP drop did not correlate with either sedation or the clonidine dose. Group 1 presented more hypotension (59% x 28%) and greater MBP drop at 60 min. Only one patient had an asthma attack. We conclude that the hypotension effects caused by oral clonidine diminish with saline resuscitation since the beginning of the test. This test must have specialized medical support with strict BP evaluation and precocious intervention when needed.

Tolerância ao teste da clonidina em 180 pacientes: estudo da eficácia da expansão volêmica para o controle de hipotensão arterial / Tolerance of the oral clonidine test in 180 patients: efficacy of saline resuscitation in controlling arterial hypotension

O teste da clonidina é amplamente usado para avaliar a secreção do hormônio do crescimento. Os efeitos colaterais são sonolência (35 por cento) e hipotensão arterial (HA) (5 por cento). Nossos objetivos foram avaliar a tolerância ao teste quanto à queda da pressão arterial (PA), grau de sedação e eficácia da expansão volêmica para controle da HA. A PA foi medida nos tempos basal, 60 e 120 min. A sedação foi baseada na escala Ramsay. Os pacientes foram divididos em dois grupos: o Grupo 1 (n= 80) recebeu expansão volêmica apenas com HA grave (queda da PA média [PAM] > 20 por cento da PAM inicial) e/ou hipotensão postural; o Grupo 2 (n=100) recebeu expansão volêmica desde o início do teste. Nos dois grupos, a PAM caiu significativamente e 75 por cento apresentaram sonolência aos 60 min. Não houve correlação da queda da PAM com grau de sedação e dose administrada. O Grupo 1 apresentou mais hipotensão (59 por cento x 28 por cento) e maior queda da PAM aos 60 min. Apenas um paciente apresentou broncoespasmo. Concluímos que o efeito hipotensor da clonidina diminui com expansão volêmica desde o início no teste. Este teste deve ser sempre feito com acompanhamento médico especializado para observação estrita da PA e intervenção precoce, se necessária.

Pituitary apoplexy induced by corticotrophin-releasing hormone in a patient with Cushing's disease.

Pituitary apoplexy can occur spontaneously or following anterior pituitary stimulation tests. Apoplexy is a rare complication of Cushing's disease. We report a 19-year-old woman who was admitted to the National Institutes of Health for evaluation of possible Cushing's syndrome. Her symptoms and initial laboratory work were suggestive of Cushing's disease. Magnetic resonance imaging (MRI) revealed a macroadenoma of the pituitary gland. As part of her evaluation she received corticotrophin-releasing hormone (CRH). Two days later she developed severe headache, accompanied by nausea and vomiting, followed by meningismus, ptosis and diplopia. A diagnosis of pituitary apoplexy was made and she was treated conservatively with dexamethasone. Her neurological symptoms resolved shortly afterwards. By the time of discharge her anterior pituitary function was suppressed. All symptoms and signs of Cushing's syndrome resolved thereafter. This is the first case to demonstrate that CRH administration can induce pituitary apoplexy in a patient with Cushing's disease. Therapy with glucocorticoids was effective in our case, suggesting that conservative treatment can be successfully and safely applied in certain cases with pituitary apoplexy.

Safety of the insulin tolerance test.

Concerns have been raised about the hazards of the insulin tolerance test (ITT), used to measure growth hormone secretion. In Glasgow, we continue to use this test, adhering to a strict protocol. A review of outcome over a 10 year period (1989-99), during which 550 ITTs were performed, was undertaken. No serious adverse events occurred; in particular, no child fitted or required intravenous glucose. Fewer tests were done during the latter five years, with a higher yield of growth hormone (GH) deficiency, reflecting our increasingly conservative approach to paediatric GH therapy during this period. We conclude that the ITT is safe and reliable in a paediatric setting provided that a strict procedure is followed.

Apoplexy of pituitary macroadenoma after combined test of anterior pituitary function.

Pituitary apoplexy has been reported as a very rare complication of combined tests of anterior pituitary function and of TRH or gonadotropin-releasing hormone (GnRH) administration in pituitary tumor. A 34-year-old man with a GH-secreting pituitary macroadenoma and diabetes mellitus received an injection of 400 microg TRH, 100 microg GnRH, and 0.15 U/Kg regular insulin. Twenty minutes later, he complained of a severe headache and vomited. Visual acuity and visual field did not change and his headache was persistent during the next 24 hours of conservative management. Magnetic resonance imaging (MRI) of the sella turcica done the day after the event showed definitive elevation of the optic chiasm and slight enlargement of tumor and focal areas of mixed high signal and low signal intensities in the macroadenoma on noncontrast T1-weighted images. Headache subsided markedly within a day of octreotide therapy. Transsphenoidal removal of the pituitary tumor was performed 9 days after the hormone study. Ischemic necrosis and hemorrhage were confirmed in the acidophilic adenoma with positive immunostaining for GH. Postoperative course was uneventful and his serum insulin-like growth factor-1 (IGF-1) level and blood glucose levels were normalized. Three months after the surgery the dynamic test was repeated without adverse effects. To our knowledge, this is a very rare case of apoplexy of GH-secreting pituitary adenoma after a combined stimulation test of anterior pituitary function.

Gonadotropin-releasing hormone-induced partial empty sella clinically mimicking pituitary apoplexy in a woman with a suspected non-secreting macroadenoma.

Pituitary apoplexy has been reported as a rare complication of dynamic testing used for the study of pituitary functional reserve. In 1993, a diagnosis of non-secreting macroadenoma with moderate functional hyperprolactinaemia was made in a 43-year-old woman. Soon after the start of therapy with bromocriptine up to 5 mg/die, the patient complained of nausea and postural hypotension. As the symptoms persisted even when the dose was reduced to 2.5 mg/die, the patient was transferred to therapy with quinagolide at the dosage of 37.5 microg/die. PRL levels quickly normalized (range 1.4-5.7 ng/ml) as well as menstrual cycles, and no side-effect was reported. In 1995 a sellar magnetic resonance imaging (MRI) showed no shrinkage of the known macroadenoma. In 1996, few hours after a gonadotropin-releasing-hormone (GnRH) test, which showed normal LH and FSH response and with baseline PRL levels in the normal range, the patient started complaining of severe frontal headache, nausea and vomiting. No gross visual defects were present. An emergency computed tomography (CT) showed no evident hemorrhagic infarction in the macroadenoma. The symptoms completely resolved in few days with steroidal and antiemetic therapy. A new MRI performed in 1998 showed a partial empty sella and PRL levels were in the normal range under dopaminergic treatment. The pituitary functional reserve proved normal on dynamic testing. The temporal association between the onset of symptoms and the GnRH test strongly suggests an association between the two events. No evident signs of pituitary apoplexy (either on emergency CT or hormonal evaluation) were detected. The authors suggest that GnRH can cause severe side-effects that mimic pituitary apoplexy without related morphological evidence and that, in our particular case, it can have caused the gradual disappearance of the non-secreting macroadenoma. Moreover, a causal role of the chronic dopaminergic treatment cannot be completely ruled out.

Pituitary apoplexy induced by a combined anterior pituitary test: case report and literature review.

We report the case of a 31-year-old woman with a pituitary adenoma who suffered symptomatic pituitary apoplexy. The patient developed a severe headache 2 min after undergoing a combined anterior pituitary function (CAP) test. Emergent computed tomography revealed a hemorrhagic pituitary tumor with evidence of a small subarachnoid hemorrhage. The headache improved spontaneously within half a day. Transsphenoidal surgery was performed 4 days later. Histologic examination demonstrated that the tumor was an eosinophilic adenoma with areas of diffuse hemorrhage. Although pituitary apoplexy caused by endocrinological testing has been reported in only 28 patients, apoplexy caused by a CAP test has been reported in only 1 patient. All of the previous cases had pituitary macroadenomas, 69% of which were involved in suprasellar extension. Non-functioning adenomas (24%) and prolactinomas (24%) were the most often affected by endocrine stimulation tests. With respect to the stimulants of pituitary adenomas, gonadotropin-releasing hormone (76%), TSH-releasing hormone (69%), and insulin (34%) were primarily responsible for the apoplexy. This case report with the literature review suggests that routine testing on pituitary function should be ordered cautiously given the risk of possible apoplexy.

[Acute pituitary necrosis after multiple pituitary stimulation test]. / Nécrose hypophysaire aiguë après test de multistimulation hypophysaire.

Iatrogenic necrosis of the pituitary gland is well-known but rarely caused by stimulation tests used to investigate pituitary adenomas; 26 cases have been reported in the literature. We report 2 new cases where the chronology of the events suggests the sudden necrosis resulted from stimulation tests. Several mechanisms have been proposed. It is not possible to define increased risk as a function of the adenoma histology. In most cases, voluminous tumors are revealed by visual dysfunction. These accidents should not overshadow the role of function tests in neurosurgical situations. Outcome is usually favorable after acute necrosis.

[Fatal hemorrhagic necrosis of pituitary macro-adenoma after a stimulation test]. / Nécrose hémorragique mortelle d'un macro-adénome hypophysaire après test de stimulation.

Pituitary stimulation tests are widely used to explore hypophyseal adenomas. There are few disadvantages, although a few cases of pituitary necrosis have been published. We report a new case with a dramatic outcome. A 30-year-old man with clinical signs of acromegalia and major visual disorders was found to have a voluminous macro-adenoma of the pituitary gland. Thirty minutes after beginning the stimulation test, the patient complained of major headache and experienced persistant vomiting for several hours. Brain magnetic resonance imaging the next day did not reveal evidence of pituitary necrosis. Sudden onset coma occurred one hour later. The CT scan demonstrated hemorrhagic necrosis of the adenoma. The patient died despite emergency surgery. Due to the risk of hemorrhagic necrosis of a pituitary adenoma, baseline assays may be sufficient for diagnosis in patients with clinical signs highly suggestive of pituitary oversecretion, especially when a voluminous tumor is involved. Rigorous clinical surveillance is required after stimulation tests.

Pituitary apoplexy after pituitary function test: a report of two cases and review of the literature.

BACKGROUND: Although most of pituitary apoplexy occur spontaneously, some precipitating factors have been reported. We experienced two cases of pituitary apoplexy after a pituitary function test. METHODS: In order to clarify the causal relation between the pituitary function test and apoplexy, we presented our two cases and reviewed 20 cases in the literature. RESULTS: (Case 1) A 48-year-old man with a pituitary macroadenoma received an injection of 500 micrograms thyrotropin-releasing hormone (TRH), 100 micrograms gonadotropin-releasing hormone (GnRH), and 0.1U/kg insulin as a preoperative test of pituitary function. Fifteen minutes later, he complained of diminished vision and headache. (Case 2) A 54-year-old man with a large cystic adenoma had an administration of 500 micrograms TRH and 100 micrograms GnRH. Ten minutes later, he complained of blurring of his left eye and headache. Although, in both cases, CT scans showed neither intratumoral hemorrhage nor infarction, the surgical specimen showed necrotic and hemorrhagic adenoma. The patients made excellent clinical recoveries after surgical decompression. Twenty-two reports including our two cases were reviewed. In 15 cases (68%), TRH was associated with apoplectic events and seemed to be the agent most likely to have an etiologic role because of its vasoactive properties. Eighteen patients (82%) had pituitary macroadenomas with suprasellar extension. In 72% of 18 surgical cases, some recovery of visual function was obtained. CONCLUSIONS: An apparent relationship between the test and the apoplectic events raises the possibility of the development of pituitary apoplexy after a pituitary function test. Unless there is a specific indication, pituitary function test should be avoided especially in patients with a large pituitary tumor.

Pituitary apoplexy after stimulation tests.

Pituitary apoplexy occurs after infarction of a non-neoplastic pituitary or sudden expansion of an adenoma following haemorrhage or infarction. It usually occurs spontaneously but can follow a number of causes including pituitary stimulation tests. Since this complication is potentially life-threatening, the benefits of subjecting patients who might have pituitary tumours to such tests should be considered.