Acromegaly caused by ectopic growth hormone-releasing hormone production from a bronchial carcinoid tumor

Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma. In rare cases, however, it is caused by the ectopic production of growth hormone-releasing hormone (GHRH). We report a case of acromegaly due to ectopic production of GHRH from a bronchial carcinoid in a 42-year-old female. The carcinoid tumor was successfully treated with bilobectomy.     

Ectopic growth hormone-releasing hormone secretion by thymic carcinoid tumour

The case of a 33-year-old-woman with Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome and acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion by a thymic carcinoid tumour is reported. Immunohistochemistry revealed positive immunoreactivity for GHRH, vasoactive intestinal polypeptide, somatostatin and alpha-subunit in the tumour cells. A previously undescribed new germ line mutation of the MEN1 protein gene was revealed.     

Acromegaly due to ectopic secretion of GHRH by bronchial carcinoid in a patient with empty sella

GH hyperproduction due to ectopic secretion of GHRH is a rare cause of acromegaly. Since 1959, approximately 50 cases of ectopic GHRH production from extrapituitary tumors have been described. Here we report the clinical and biochemical features of a 47-yr-old Caucasian woman with ectopic GHRH syndrome sustained by a bronchial carcinoid. The criteria for the diagnosis of acromegaly due to ectopic GHRH secretion were satisfied in our patient (i.e. confirmation of active GH hypersecretion, unequivocal demonstration of GHRH production and secretion from an extrapituitary tumor and cure of acromegaly after neoplasm removal). The tumor was an atypical carcinoid and there was a familial history of lung and colorectal cancer. Acromegaly was slightly active (mean GH value: 7.4 ng/ml, IGF-I: 436 ng/ml) and after tumor removal there was a progressive decline of GH levels, consistent with remission of pituitary somatotroph hyperplasia. Pituitary radiology showed an empty sella demonstrating for the first time its association with ectopic GHRH syndrome.     

Acromegaly associated with a bronchial carcinoid tumor: evidence for ectopic production of growth hormone-releasing activity.

A patient with acromegaly, pituitary enlargement, and elevated plasma GH levels also had a bronchial carcinoid tumor. Signs and symptoms of active acromegaly along with elevated GH levels persisted for 11 yr after hypophysectomy and pituitary stalk section. Resection of the bronchial carcinoid reduced plasma GH to barely detectable levels. Extracts of the frozen carcinoid tumor were devoid of significant GH, but when added to isolated pituitary cells of estrogen-primed male rats in 4-day primary culture exhibited specific GH-releasing activity in vitro. These findings strongly suggest that the patient's acromegaly resulted from continual stimulation of pituitary somatotrophs by a GH-releasing factor secreted by the bronchial carcinoid.     

Medical management of acromegaly due to ectopic production of growth hormone-releasing hormone by a carcinoid tumor

A 59-yr-old woman with a disseminated carcinoid tumor was evaluated for acromegaly. She had previously undergone a hypophysectomy for acromegaly and an enlarged pituitary, with a reduction in her serum GH levels from 100 to 4 micrograms/L. Recurrence of acromegalic symptoms 2 yr later was accompanied by elevated serum GH (16 micrograms/L) and insulin-like growth factor I (IGF-I; 528 micrograms/L) and plasma GHRH levels (12 micrograms/L; normal, less than 30 ng/L). Computed tomographic scan did not reveal pituitary enlargement. Metastatic carcinoid tissue in bone removed at biopsy contained GHRH (100 pg/mg tissue). High performance liquid chromatography of plasma GHRH revealed predominantly GHRH-(3-40)-OH, a biologically inactive GHRH metabolite, along with mature GHRH forms, while carcinoid tissue contained both GHRH-(1-40)-OH and GHRH-(1-44)-NH2. Treatment with pergolide initially resulted in reduction in serum GH and IGF-I levels and amelioration of symptoms of acromegaly. However, after 14 months of pergolide therapy, serum GH levels increased despite administration of up to 1000 micrograms pergolide/day. Plasma GHRH levels remained elevated throughout the treatment period. Subsequent treatment with SMS 201-995, a long-acting somatostatin analog, for over 1 yr resulted in sustained reductions of ectopic GHRH secretion, GH hypersecretion, and IGF-I levels. Plasma GHRH levels correlated with simultaneously measured serum GH levels in response to acute SMS 201-995 administration. SMS 201-995 was an effective medical treatment for acromegaly caused by ectopic GHRH production in this patient.     

Acromegaly caused by a growth hormone-releasing hormone secreting carcinoid tumour of the lung: the effect of octreotide treatment

In acromegaly, the overproduction of growth hormone is usually caused by a pituitary adenoma. We report a 74-year-old woman with acromegaly caused by ectopic overproduction of growth hormone-releasing hormone (GHRH), a rare diagnosis. The GHRH appeared to be produced by a carcinoid tumour of the lung. Treatment with monthly long-acting octreotide resulted in a reduction in the symptoms and normalisation of the insulin-like growth factor-I, which has been maintained for more than two years now. A review of literature concerning causes and treatment of ectopic GHRH-producing tumours is presented.     

Acromegaly secondary to an incidentally discovered growth-hormone-releasing hormone secreting bronchial carcinoid tumour associated to a pituitary incidentaloma

In this report we emphasize the opportunity of considering the uncommon causes of chronic GH-excess in the initial diagnostic process, such as GHRH hypersecretion, especially in the presence of ambiguous pituitary neuroimaging. This topic may have an important clinical significance in order to plan the most cost-effective diagnostic procedures and management and to avoid unnecessary pituitary neurosurgery.     

Acromegaly due to a growth hormone-releasing hormone-secreting intracranial gangliocytoma

In more than 95% of cases acromegaly is due to GH hypersecretion by a pituitary adenoma. GHRH hypersecretion accounts for about 0.5% of cases of acromegaly. Intracranial GHRH-secreting tumors are extremely rare and only a few well-documented cases have been reported. The clinical features of acromegaly due to intracranial GHRH-secreting tumor are indistinguishable from those of other patients with "classical acromegaly". In cases of intrasellar gangliocytomas, not even radiological findings help to make the correct diagnosis, which can only be made with the hystological study. We present the case of a woman with acromegaly; the magnetic resonance demonstrated a 2x1.8x1.2 cm mass in the jugum sphenoidalis region, associated with a partial empty sella. There was a partial response to high-dose lanreotide therapy, so surgical treatment was decided, although only part of the tumor could be removed. Histopathological diagnosis was consistent with gangliocytoma, and immunostaining in the ganglionic cells was positive for GHRH. After surgery, hormone hypersecretion persisted, so medical treatment was reintroduced. In summary, we report a well-documented case of an intracranial GHRH-secreting gangliocytoma, an exceedingly rare cause of acromegaly. Clinical and biochemical data did not allow to make the correct diagnosis, which was only made on the pathological study. This case underscores that acromegaly can be due to causes other than a GH-secreting adenoma, and underlines that finding an image not typical of a pituitary adenoma should raise the suspicion that an unusual cause subsides the acromegaly.     

Acromegaly and Cushing's syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6

A 50-year-old male presented with diabetes mellitus and Cushing's syndrome associated with a large mediastinal mass. The levels of serum cortisol were high (1500–1800 nmol/l) without diurnal variation. Plasma ACTH levels (200–250 ng/l) and urinary excretion of cortisol were also increased. The levels of these hormones did not change in response to stimulation with corticotrophin releasing hormone (CRH) or suppression with high doses of dexamethasone. The patient had an elevated baseline GH level (7.3 mU/l), and the levels of immunoreactive GH-releasing hormone (GHRH) in eight plasma samples were markedly increased (600–1500 ng/l). Circulating levels of IGF-1, chromogranin A and neuropeptide Y (NPY) were also increased. Computer-assisted tomography and octreotide scintigraphy revealed a large mediastinal tumour and metastases in the left supraclavicular fossa. During treatment with octreotide, the baseline GH level was decreased (to 4.4 mU/l), while the GH pulse height was unchanged. Surgical removal of most of the tumour tissue resulted in a further decrease in the baseline serum GH level to a value (1.6 mU/l) about 20% of that before treatment, while the pulse height and mean GH were affected to a lesser extent. Postoperatively, circulating levels of cortisol and IGF-1 decreased, and the patient exhibited clinical improvement. Histological examination showed a neuroendocrine tumour with characteristics consistent with a foregut carcinoid of thymic origin. Immunoreactive GHRH, ACTH and NPY, but not immunoreactive GH, were detected in 80–90% of the tumour cells and the three peptides appeared to be co-localized. In primary culture, cells from this tumour displayed calcium influx in response to GHRH or GH releasing peptide-6 (GHRP-6), while there were not such responses by cells from another carcinoid not producing GHRH, ACTH or NPY. These results demonstrate a rare case of ectopic production of GHRH, ACTH and NPY, and indicate that the tumour cells were responsive to GHRH and GHRP-6 as well as octreotide.     

Ectopic growth hormone-releasing hormone secretion by a bronchial carcinoid tumor: clinical experience following tumor resection and long-acting octreotide therapy

Pituitary - Acromegaly resulting from the ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. We present a case of acromegaly secondary to proven GHRH-secretion by a bronchial...     

Acromegaly due to ectopic growth hormone (GH)-releasing hormone (GHRH) production: dynamic studies of GH and ectopic GHRH secretion

Dynamic studies of GH and GH-releasing hormone (GHRH) secretion were performed in a man with a GHRH-producing carcinoid tumor and acromegaly. Insulin hypoglycemia stimulated and metoclopramide inhibited both GH and GHRH acutely. Bromocriptine suppressed GH both acutely and chronically without altering circulating GHRH levels and also blunted the GH response to exogenous GHRH. TRH acutely stimulated GH, but not GHRH, secretion, and iv bolus doses of synthetic GHRH-(1-40) stimulated GH release acutely. Somatostatin infusion decreased both GH and GHRH concentrations and blunted the GH responses to TRH and GHRH-(1-40). We conclude that prolonged exposure of the pituitary gland to high concentrations of GHRH is associated with chronic GH hypersecretion and may be accompanied by a preserved acute GH response to exogenous GHRH; a paradoxical response of GH to TRH may be mediated at the pituitary level, consequent to prolonged pituitary exposure to GHRH; bromocriptine suppression of GH in acromegaly is due to a direct pituitary effect of the drug; and somatostatin inhibits both ectopic GHRH secretion as well as GH responsiveness to GHRH in vivo. Since GH secretory responses in patients with somatotroph adenomas are similar to those in this patient, augmented GHRH secretion may play a role in development of the "classic" form of acromegaly.     

Acromegaly due to GHRH-secreting large bronchial carcinoid. Complete recovery following tumor surgery.

A case of acromegaly, secondary to GHRH secretion by a large bronchial carcinoid is reported. A 61-year-old woman presented with typical symptoms and signs of acromegaly for at least 10 years. She suffered from recurrent pneumonias, but repeated chest X-ray examinations failed to demonstrate the bronchial tumor. The diagnosis was confirmed by elevated GH, IGF-1 and GHRH secretion. We have shown an enlarged pituitary gland without focal lesions together with a cerebral meningioma on MRI and the presence of a bronchial carcinoid tumor. The latter was confirmed by histology carried out after bronchoscopy and tumor excision. We observed partial suppression of GH secretion following short-term oral bromocriptine administration in this patient. Surgical removal of the carcinoid tumor resulted in a complete clinical, hormonal and radiological cure of acromegaly. This case of acromegaly due to ectopic GHRH secretion by bronchial carcinoid differs from others described in the literature by an atypical large tumor size, the suppression of elevated GH secretion by oral bromocriptine and a concomitant meningioma.     

Intractable hypercalcaemia due to parathyroid hormone-related peptide secretion by a carcinoid tumour

Hypercalcaemia, a common complication of malignancy, may result from either the lytic effect of multiple osseous metastases or the effect of tumour-derived humoral factors. Excessive secretion of parathyroid hormone-related peptide (PTHrP), a major cause of humoral hypercalcaemia of malignancy, has been incriminated as the cause of hypercalcaemia in patients with lung, breast, renal, head and neck and, occasionally, haematological malignancies. Carcinoid tumours, while frequently the source of ectopic hormone secretion, are infrequently associated with hypercalcaemia. We report the case of a 59-year-old woman with fulminant hypercalcaemia due to excessive PTHrP secretion from a hepatic carcinoid and we present the change in her serum PTHrP concentrations during infusion of a somatostatin analogue.     

Growth hormone secretion dynamics in a patient with ectopic growth hormone-releasing factor production

A female patient with acromegaly, hypercalcemia, and Zollinger-Ellison syndrome was found to have a very high plasma concentration (average 2,300 pmol/liter; normal less than 50 pmol/liter) of growth hormone-releasing factor as measured by a radioimmunoassay to human pituitary growth hormone-releasing factor-1-44. The plasma concentration of growth hormone averaged 25 mIU/liter (normal less than 5 mIU/liter) and there was no rise following an intravenous 100 micrograms bolus of human pituitary growth hormone-releasing factor-1-44. Plasma growth hormone and growth hormone-releasing factor levels were unaffected by bromocriptine, insulin-induced hypoglycemia, and sleep. A long-acting somatostatin analogue lowered both the growth hormone-releasing factor and the growth hormone levels. Thyrotropin-releasing hormone stimulation and oral glucose tolerance tests produced significant increases in plasma growth hormone levels whereas the growth hormone-releasing factor level remained unchanged, suggesting that when normal somatotrophs are exposed to maximal growth hormone-releasing factor stimulation, thyrotropin-releasing hormone becomes a secretagogue of growth hormone from the pituitary. It is proposed that in the absence of a radioimmunoassay for growth hormone-releasing factor, a lack of growth hormone response to growth hormone-releasing factor in a patient with acromegaly is compatible with a source of ectopic growth hormone-releasing factor production.     

Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor

Rarely, acromegaly is produced by neuroendocrine neoplasms elaborating a substance similar to or identical with growth hormone-releasing factor. This report reviews the cases described to date and presents the clinicopathologic features of a patient with acromegaly, mild sellar enlargement, and elevated growth hormone levels associated with a large bronchial carcinoid tumor. Normalization of serum growth hormone levels and regression of acromegaly followed resection of the bronchial tumor, which was shown, by bioassay and immunocytochemistry, to contain a growth hormone-releasing factor.     

Acromegaly due to a growth hormone-releasing hormone-secreting bronchial carcinoid tumor: further information on the abnormal responsiveness of the somatotroph cells and their recovery after successful treatment

We studied GH secretion in a patient with acromegaly and a bronchial carcinoid tumor before and again after surgical removal of this tumor. Before removal of the carcinoid tumor, plasma GH increased slightly after glucose loading (OGTT) and markedly after TRH (650%) and insulin (440%) treatment. Plasma GH did not change after GH-releasing hormone (GHRH), LHRH, or L-dopa administration. Somatostatin (SRIH) infusion lowered plasma GH. No change in plasma immunoreactive GHRH (IR-GHRH) occurred after TRH, glucose, insulin, or SRIH administration. Two weeks after removal of the carcinoid tumor, TRH induced GH secretion (250%) when the IR-GHRH level was undetectable and somatomedin-C was within normal limits. Fifteen weeks after surgery, the patient had normal GH secretion. In conclusion: no pattern of GH secretion is diagnostic of acromegaly due to ectopic GHRH secretion, but the lack of GH response to exogenous GHRH and a large response during hypoglycemia may be features of this condition. When acromegaly and abnormal GH responsiveness are induced by a GHRH-secreting tumor, the increases in plasma GH after TRH, glucose, and insulin administration are not mediated by GHRH. After removal of the GHRH-secreting tumor, persistent paradoxical GH response to TRH does not require abnormally high IR-GHRH levels and does not preclude complete recovery.     

Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment

Ectopic acromegaly represents less than 1% of the reported cases of acromegaly. Although clinical improvement is common after treatment with somatostatin (SMS) analogs, the biochemical response and tumor size of the growth hormone-releasing hormone (GHRH)-producing tumor and its metastases are less predictable. Subject A 36-year-old male was referred because of a 3-year history of acromegaly related symptoms. He had undergone lung surgery in 1987 for a “benign” carcinoid tumor. Endocrine evaluation confirmed acromegaly Plasma IGF-1: 984 ng/ml (63–380), GH: 49.8 ng/ml (<5). MRI showed a large mass in the left cerebellopontine angle and diffuse pituitary hyperplasia. Pulmonary, liver and bone metastases were shown by chest and abdominal CT scans. Ectopic GHRH secretion was suspected. Methods Measurement of circulating GHRH levels by fluorescence immunoassay levels and immunohistochemical study of the primary lung tumor and metastatic tissue with anti-GHRH and anti-somatostatin receptor type 2 (sst2A) antibodies. Results Basal plasma GHRH: 4654 pg/ml (<100). Pathological study of liver and bone biopsy material and lung tissue removed 19 years earlier was consistent with an atypical carcinoid producing GHRH and exhibiting sst2A receptor expression. Treatment with octreotide LAR 20–40 mg q. month resulted in normalization of plasma IGF-1 levels. Circulating GHRH levels decreased dramatically. The size of the left prepontine cistern mass, with SMS receptors shown by a radiolabeled pentetreotide scan, decreased by 80% after 18 months of therapy. Total regression of pituitary enlargement was also observed. No changes were observed in lung and liver metastases. After 24 months of therapy the patient is asymptomatic and living a full and active life.     

Acromegaly and bronchial carcinoid tumor. Apropos of a case]

Acromegaly due to ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. A 29-year-old woman with acromegaly secondary to ectopic GHRH secretion by a bronchial carcinoid tumor is presented. Normalization of GHRH levels, reversal of pituitary hyperplasia and regression of acromegaly followed resection of the bronchial tumor. The authors stressed the interest of GHRH dosage in patients with acromegaly and pituitary hyperplasia.     

Somatostatin analogs in vitro effects in a growth hormone-releasing hormone-secreting bronchial carcinoid

A 29-yr-old woman presented with acromegaly, pituitary gland enlargement, and an isolated pulmonary mass of 3.3 cm in diameter, which displayed a very high tracer uptake after OctreoScan. Plasma GHRH levels were markedly elevated. The patient underwent left lung upper lobectomy, and histopathology disclosed a bronchial atypical carcinoid. The tissue was examined for somatostatin (SRIH) receptor subtypes (SSTRs) 1-5 expression by RT-PCR. Cultured tumor cells were treated with SRIH, lanreotide (BIM-23014), or SRIH analogs selective for SSTR2 (BIM-23120), SSTR5 (BIM-23206), or SSTR1 (BIM-23926). GHRH was measured in the medium after 6 h, and cell viability was assessed after 48 h. RT-PCR analysis showed expression of SSTR1, -2, and -5. GHRH secretion was significantly reduced by SRIH (-50%), Lan (-35%), as well as by the SSTR2, SSTR5, and SSTR1 selective agonists (-55, -75, and -20%, respectively), whereas cell viability was not affected. Our data show SSTR expression in a GHRH-secreting bronchial carcinoid and provide evidence that, in vitro, selective SSTR activation differently inhibit ectopic GHRH secretion. These findings suggest that SSTR-specific SRIH analogs may be useful in the medical therapy of GHRH-secreting bronchial carcinoids.