Circulating growth hormone releasing factor concentrations in normal subjects and patients with acromegaly.

A highly specific and sensitive radioimmunoassay was developed for measuring circulating growth hormone releasing factor (GRF) in human plasma. Before measuring immunoreactive GRF plasma samples were extracted on to Vycor glass. Immunoreactive GRF concentrations in plasma samples from 37 fasting normal subjects ranged from less than 10 to 60 ng/l (mean 21 ng/l). Fasting concentrations in 76 out of 80 acromegalic subjects were within the normal range, but the remaining four patients had values of 92 to 25 000 ng/l. Of these, only the patient with the highest concentration had evidence of ectopic GRF secretion from a disseminated carcinoid tumour. Two of the others had longstanding pituitary tumours, and the fourth patient had a pituitary growth hormone (GH) secreting tumour proved by its removal and subsequent remission of acromegaly. There was no correlation between serum GH and plasma immunoreactive GRF concentrations, irrespective of whether the patients were untreated or had been given radiotherapy or dopamine agonists. The assay should help elucidate the physiological role(s) of GRF and may also prove useful in differentiating between pituitary and hypothalamic defects in patients with acromegaly.     

Ectopic corticotrophin-releasing-factor and growth hormone releasing factor secretion: diagnosis using human pituitary cell culture

Cell culture of human pituitary tissue has been used to diagnose a patient with Cushing's syndrome due to ectopic secretion of corticotrophin-releasing factor (CRF; case 1) and a case of acromegaly associated with ectopic secretion of a growth-hormone releasing factor (GRF; case 2). In both patients a pituitary tumour was not detected. Case 1 had a small cell carcinoma and symptoms of the ectopic ACTH syndrome, but in culture the carcinoma failed to secrete detectable ACTH. However, the culture medium used to maintain this carcinoma in vitro was found to contain a substance which stimulated ACTH secretion by human pituitary corticotrophs in cell culture. Radioimmunoassays and HPLC indicated that this substance had similar elution characteristics to human CRF and cross-reacted with antiserum to ovine CRF. Case 2 was found to have a lung tumour, the removal of which led to regression of her acromegalic symptoms. In culture, this tumour did not secrete GH, but did secrete a GRF. We conclude that the Cushing's syndrome and acromegaly, in cases 1 and 2, respectively, were due to ectopic secretion of CRF and GRF leading to hyperstimulation of the pituitary gland.     

Remission of Acromegaly After Pituitary Apoplexy: Case Report and Review of Literature

ObjectiveTo identify and present cases of acromegaly in which pituitary apoplexy resulted in remission of acromegaly, with normalization of insulinlike growth factor-I and growth hormone levels.MethodsWe present a case history of a personal patient and review the related literature in PubMed and Ovid MEDLINE.ResultsA 34-year-old man with classic acromegaly had spontaneous pituitary apoplexy, resulting in remission of his acromegaly and diabetes. Moreover, we identified 21 other similar cases in the literature and analyze the clinical presentations, possible apoplexy triggers, and hormonal sequelae. All these patients were “cured” of acromegaly, and 68% of them experienced other pituitary hormone insufficiencies after pituitary apoplexy, including 2 cases of panhypopituitarism.ConclusionPituitary apoplexy can result in remission of acromegaly and in partial or complete anterior or posterior (or both) pituitary insufficiency. Thus, after suspected or confirmed pituitary apoplexy, pituitary hormone secretion must be reevaluated. This assessment may result in initiation of appropriate substitution therapy, a change in management of growth hormone overproduction, or both interventions. (Endocr Pract. 2009;15:725-731)     

Cavernous sinus haemangioma with intrasellar extension mimicking non-functioning pituitary adenoma – A case report and review of literature

Fifty-three-year-old male suffering from a presumptive non-functioning pituitary adenoma was qualified for stereotactic radiosurgery in our institution. Two attempts of surgical treatment were taken three months before radiotherapy. Excessive bleeding did not allow to remove the tumour or to take samples for histopathological examination. Diagnosis was put on the basis of radiological assessment and lack of hypersecretion of pituitary hormones. However, radiological reevaluation in our Institute revealed the presence of a well-bounded tumour invading the cavernous sinus with high contrast enhancement in FLAIR and T2-sequence. Moreover, a constriction of the normal pituitary gland with tumour mass was seen. The imaging features of the lesion finally led to diagnosis of cavernous sinus haemangioma with intrasellar expansion. The patient received radiosurgical treatment with the use of linear accelerator (LINAC). A dose of 7 Gy in one fraction was administered to achieve satisfactory local control, prevent potential further bleeding and reduce the risk of progressive neurological deficits. Stable size of the tumour and absence of any complications are confirmed in six years of follow-up.     

The importance of presurgical somatostatin analogue therapy in acromegaly

Different types of treatment, including surgery, medical therapy and radiotherapy, are possible in achieving control of acromegaly. Of the medical therapies available, somatostatin analogues are effective in the majority of patients and can induce pituitary tumour shrinkage. The rationale and outcome of somatostatin analogue treatment before surgery in patients with acromegaly is briefly presented. In summary, the benefits of somatostatin analogues given preoperatively should be considered carefully as optimisation of cardiovascular, respiratory and metabolic functions is clinically relevant for perioperative morbidity. Somatostatin analogues also induce significant shrinkage of GH-secreting pituitary tumours, although this does not seem to be helpful in terms of improved surgical outcome.     

Immunohistochemical examination of pituitary adenomas. Comparison to clinical and endocrinological findings

A comparison was made with the data of 62 cases of pituitary adenoma, evaluated pre- and postoperatively, including as well the results of immunohistochemical hormone examination (also for calcitonin). Prolactin was found in 18 of the 21 adenomas carrying the preoperative diagnosis of prolactinoma, whereas cells containing other hormones (growth hormone, LH, FSH, TSH, ACTH, beta-endorphin), were only occasionally present. The growth hormone was strongly positive in the adenoma tissue in 16 of the 17 cases of acromegaly. 5 of these adenomas were accompanied by a marked hyperprolactinemia and also contained many prolactin cells. 6 of the 19 adenomas diagnosed as being 'inactive' contained hormone-positive cells, but only a very small number of cells. ACTH was found in 3 of the 4 pituitary adenomas of patients with Cushing's disease. 2 of these were also positive for beta-endorphin. The tissue of 1 gonadotrophic adenoma (with elevated FSH in serum) gave positive results with an anti-LH antiserum. Calcitonin was not found in any adenoma. The preoperative serum prolactin levels did not quantitatively correlate with the percentage of prolactin-positive cells.     

Diagnostic Value of Thyrotropin-Releasing-Hormone Stimulation in Patients With Pituitary Tumor

Plasma prolactin response to thyrotropin-releasing-hormone (TRH) stimulation was diminished in 30 patients with prolactinomas and 9 patients with acromegaly who had normal serum prolactin levels. There was no overlap of prolactin responses when compared with 32 control patients. Responses of ten patients with adrenocorticotropin (ACTH)-secreting pituitary tumors were similar to those of controls. Plasma growth hormone concentrations after TRH stimulation changed significantly in 28% of normal control and 20%, 25% and 50% of patients with prolactin-, growth hormone- and ACTH-secreting pituitary tumors, respectively. Our data suggest that the blunted TRH-induced rise in plasma prolactin levels in patients with prolactinomas and those with acromegaly may be related to humoral factor(s) affecting TRH receptor or postreceptor function. Growth hormone responses to TRH are nonspecific and should not be considered a marker for active acromegaly.     

Sebum Excretion in Acromegaly

The sebum excretion rate (S.E.R.) was measured in 20 patients with acromegaly. Eleven were untreated at the time of the measurement and nine had previously undergone surgical hypophysectomy or had received pituitary irradiation by yttrium-90 or radiotherapy. In five patients the S.E.R. was measured before and after such treatment. The mean S.E.R. in the untreated acromegalics was much greater than in a normal population and decreased significantly after successful pituitary ablation. No significant decrease in mean S.E.R. occurred in the group of patients with a poor clinical response to ablation. The correlations between S.E.R. and log serum growth hormone, plasma 11-hydroxycorticosteroid levels, and heel-pad thickness were significant, but there was no significant correlation between S.E.R. and serum protein-bound iodine levels. This suggests that the changes in S.E.R. were due to pituitary ablation but could not necessarily be attributed solely to changes in growth hormone, thyroid-stimulating hormone, or adrenocorticotrophic hormone. The association between the clinical state of the acromegaly and the S.E.R. was better than the association between acromegaly and serum growth hormone. We conclude that the S.E.R. is a useful addition to the clinical and endocrinological data used in assessing acromegaly.     

Bromocriptine in management of large pituitary tumours.

Bromocriptine has an accepted place in the management of small pituitary tumours that secrete either prolactin or growth hormone. The treatment of large tumours with extrasellar extensions is more difficult, however: though surgery is the standard treatment, it is often unsuccessful in returning excessive hormone secretion to normal and may cause hypopituitarism. A prospective trial was undertaken to assess the frequency with which changes in pituitary function and size of large tumours occurs. Nineteen patients were studied before and during treatment with bromocriptine (7.5 to 60 ml/day) for three to 22 months, using contrast radiology and a detailed assessment of pituitary function. Eighteen patients had hyperprolactinaemia and two of these also had raised concentrations of growth hormones; one patient had an apparently non-functioning tumour. In 12 patients (63%) tumour size decreased with bromocriptine and no tumour enlarged. Nine patients had visual-field defects, which improved in seven, becoming normal in five. Pituitary function improved in nine patients (47%) becoming entirely normal in three. Bromocriptine should be the treatment of choice in patients with large pituitary tumours with extrasellar extensions, provided close supervision is maintained.     

New medical approaches in pituitary adenomas

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5-1.0 microg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D(2) receptors using specific radiotracers such as (123)I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing's disease or Nelson's syndrome.     

Acromegaly as An Endocrine Form of Myopathy: Case Report and Review of Literature

ObjectiveTo describe a case of muscle weakness in a patient with acromegaly and to review the pathophysiologic features of this disorder.MethodsWe present the clinical, laboratory, electromyographic, and muscle biopsy findings in our patient and review related reports in the literature.ResultsA 58-year-old woman with acromegaly presented with complaints of bilateral hip pain, weakness, and instability 8 months after transsphenoidal resection of a growth hormone (GH)-secreting pituitary macroadenoma. She had biochemically normal thyroid and adrenal function and no evidence of any neuropathy, inflammatory myopathy, or rheumatologic disorder to explain her symptoms. Investigations revealed increased levels of GH, insulin-like growth factor-I, serum creatine kinase (CK), and the MB fraction of CK, normal results of nerve conduction studies, and nonspecific findings on electromyography and muscle biopsy. A review of the literature revealed that although muscle weakness is a well-recognized feature of acromegaly, only a few cases similar to ours have been reported since acromegaly was first described in the late 1800s. Little is known about the natural history, best diagnostic approach, and optimal therapy for this debilitating complication.ConclusionMuscle weakness in acromegaly is common and may result from a combination of the direct effect of GH excess on muscle and other metabolic derangements (hypothyroidism, hypoadrenalism, or diabetes). Mechanical factors may also contribute, such as joint laxity in conjunction with hypermobility. Affected patients may benefit from a reduction in GH levels and physiotherapy for adaptive training. Persistently increased serum CK levels in a patient with diabetes, for whom no other cause is found, should prompt an investigation for acromegaly. More research into this aspect of acromegaly is needed for enhancement of our understanding of, and therapy for, this debilitating condition. (Endocr Pract. 2005;11:18-22)     

Spontaneous endocrine cure of gigantism due to pituitary apoplexy.

An 11 year old, tall boy presented with symptoms typical of pituitary apoplexy. A large necrotic and haemorrhagic tumour was removed, which was shown to be an adenoma secreting growth hormone and prolactin. Subsequent treatment comprised cranial irradiation and hormone replacement. Eighteen months after operation growth was static and plasma growth hormone and prolactin concentrations were undetectable. Treatment of pituitary apoplexy should comprise excision of the tumour and postoperative irradiation; such treatment after early recognition of the condition offers the best chance of preserving normal pituitary function in children with gigantism.     

Coexisting acromegaly and primary empty sella syndrome

The normal functions of the pituitary gland may be suppressed when the gland is compressed onto the sella floor by arachnoid tissue extending through an impaired sella diaphragm. Interestingly, pituitary hormone hypo- and hypersecretion, including acromegaly, have been observed in patients with an 'empty sella'(1-4). This 'empty sella syndrome' has been classified into a primary form, in which no inciting factor (pituitary irradiation or surgery for a pituitary tumor) is present, and a secondary form, in which the empty sella occurs after pituitary procedures. In this report we describe a patient who presented with clinical and biochemical features of acromegaly and who had an empty sella on pituitary magnetic resonance imaging (MRI).     

The use of the corticotropin-releasing hormone test to monitor the recovery of patients with Cushing's disease or Cushing's syndrome due to an adrenal adenoma after adenomectomy

Six patients with Cushing's disease and three with Cushing's syndrome due to an adrenal adenoma were monitored after their adenomectomy with the corticotropin-releasing hormone test to evaluate the progress of recovery of their pituitary adrenal function. Before surgery the patients with Cushing's disease showed either high, normal or low responses of plasma ACTH and cortisol to 100 micrograms synthetic ovine corticotropin-releasing hormone (CRH) administered intravenously, whereas all three patients with Cushing's syndrome due to an adrenal adenoma showed no response of plasma ACTH or cortisol to CRH. One or two months after surgery, the patients who had Cushing's disease had low levels of basal plasma ACTH and cortisol and their responses to CRH were extremely low. However, the same patients were tested later, it was found that their responses to CRH gradually increased and reached normal ranges approximately within one year after tumor removal, which coincided with the overall improvement in their clinical signs and symptoms due to adrenal insufficiency. In contrast, the recovery of the pituitary adrenal function in patients who had Cushing's syndrome due to an adrenal adenoma was not complete even one year after surgery. Thus the corticotropin-releasing factor test is a useful criteria to evaluate the recovery of the pituitary adrenal function in these patients after surgery, since the responses of plasma ACTH and cortisol to the administered CRH are parallel with the improvements in clinical signs and symptoms due to adrenal insufficiency in patients with Cushing's disease.     

Unusual Case of Metastatic Neuroendocrine Tumor

ObjectiveTo report a rare case of metastatic growth hormone (GH)-secreting pituitary carcinoma causing acromegaly.MethodsWe present a case report and review the available literature on this topic.ResultsA 68-year-old woman presented with persistent acromegaly after treatment for a GH-secreting pituitary adenoma. Evaluation of long-standing cervical adenopathy revealed findings consistent with a metastatic neuroendocrine tumor. Further work-up revealed additional thyroid, parathyroid, and cervical masses. After operative treatment including total thyroidectomy, subtotal parathyroidectomy, partial thymectomy, and right modified radical neck dissection, the patient’s symptoms diminished, and her GH levels approached the normal range. Surgical pathology findings were consistent with a GH-secreting pituitary carcinoma metastatic to the cervical lymph nodes, multinodular thyroid hyperplasia with a focus of papillary microcarcinoma, and parathyroid hyperplasia.ConclusionOverall, pituitary carcinomas are extremely rare. To date, about 100 cases have been reported in the world’s literature, and of these, only 19 cases originated from GH-secreting cells. Our examination of the symptoms, signs, diagnosis, and treatment of our patient, in comparison with the previously reported cases, should enhance awareness of this unusual disease process. (Endocr Pract. 2007;13:72-76)     

A case of acromegaly improved by pituitary apoplexy.

This report deals with a detailed course of one patient with acromegaly who had a pituitary apoplexy. The pituitary apoplexy occurred suddenly 5 days after administration of a oral hypoglycemic agent, buformin, during hospitalization. Immediately after the attack changes of the concentrations of several hormones such as serum growth-hormone, serum thyroid hormone and urinary 17-hydroxycorticosteroids were followed until the development to hypopituitary state. Simultaneously with the decrease of the concentrations of the above-mentioned hormones, a regression of the physical manifestations of acromegaly and a complete amelioration of diabetes mellitus were observed.     

Guía de práctica clínica para el diagnóstico y tratamiento de la apoplejía hipofisaria

Classic pituitary apoplexy (PA) is an acute, life-threatening clinical syndrome caused by acute hemorrhage and/or infarction of the pituitary gland. PA is considered a neuroendocrinological emergency. However, there is no consensus about the best options for PA diagnosis and management.ObjectiveTo develop a clinical practice guideline with a number of recommendations for diagnosis and treatment of patients with PA based on the medical evidence available, in order to help clinicians involved in their care.MethodsThe clinical guideline for diagnosis and treatment of pituitary apoplexy issued in 2006 by the Neuroendocrinology Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN) and the British Clinical Practice Guideline published in 2011 were taken as the basis. The text has been adapted to the format used in most international medical journals. For this, after updated medical literature, the quality of evidence and the strength of the recommendations were evaluated using the system proposed by the Agency for Health Care Policy and Research (AHCPR).ConclusionsDiagnosis of pituitary apoplexy should be considered in all patients with acute severe headache with or without neuro-ophthalmic signs. Patients with PA must undergo a complete history and physical examination. All patients with suspected pituitary apoplexy should have urgent blood samples drawn to test electrolytes, renal function, liver function, coagulation screen, complete blood count, and basal levels of pituitary and peripheral hormones, and to rule out adrenocorticotropic hormone (ACTH) deficiency. Formal visual field assessment should be performed when the patient is clinically stable. Magnetic resonance imaging (MRI) is the imaging test of choice to confirm diagnosis. Indications for empirical urgent corticosteroid therapy in patients with PA include hemodynamic instability, impaired consciousness, reduced visual acuity, and severe visual field defects. In patients with these severe neuro-ophthalmic signs, surgery should be considered. Surgery should preferably be performed within seven days of the onset of symptoms. Patients with mild and stable signs may be managed conservatively with careful monitoring. Treatment and long-term follow-up of patients with PA should be conducted by a multidisciplinary team consisting, amongst others, of an experienced pituitary neurosurgeon, an ophthalmologist, and an endocrinologist.     

Treatment of acromegaly

Mortality is increased in individuals with acromegaly unless serum growth hormone (GH) levels are below 2 microg/l and serum insulin-like growth factor (IGF)-I levels are normal following treatment. These combined criteria have been used to define remission of the disorder in this review. Transsphenoidal surgery achieves remission targets in an average of 55% of patients. For those not in remission following surgery, options include repeat surgery or use of adjuvant therapy. Fractionated external beam pituitary radiotherapy achieves 10-year remission rates of 47% but leaves patients exposed to excess GH until remission occurs. Stereotactic radiotherapy and gamma knife radiosurgery achieve remission rates of 40% over 3 years, and dopamine agonists produce remission in about 20% of patients. Somatostatin analogues induce remission in 59% of patients within the first year of treatment. The GH receptor antagonist pegvisomant leads to remission in 90% of patients, using IGF-I levels for assessment. Optimal treatment for a patient with acromegaly thus depends on the likely efficacy of treatment, cost, surgical skill, severity of side effects, tolerability, control of tumour growth, and improvement in complications related to tumour mass. A primary surgical approach, followed by medical therapy for those not in remission, remains the preferred option in most centres.     

Provocation of a paradoxical growth hormone response to corticotropin-releasing hormone by pretreatment with metoclopramide in patients with acromegaly and normal subjects

Two of 7 patients with acromegaly and one of 7 normal subjects exhibited a paradoxical rise in growth hormone (GH) to human corticotropin-releasing hormone (CRH) when pretreated with metoclopramide, although CRH alone did not induce an increase in GH. In one of these two patients with acromegaly, the GH increase to metoclopramide alone also reached the criteria of a paradoxical response. These two acromegalic patients showed a GH increase to metoclopramide pretreatment before and up to two months after surgery. In another acromegalic patient, whose GH level remained high 5 months after surgery, metoclopramide induced an increase in GH level, while in a patient who had an above-normal GH level 18 months after surgery, the resumption of physiological GH secretion after surgery was evidenced by a postoperative absence of a GH response to metoclopramide. It is suggested from these results that the GH response to metoclopramide and the metoclopramide-provoked GH response to CRH in patients with acromegaly result from the secretion of GH from nonadenomatous cells of the pituitary.