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Acromegaly caused by growth hormone releasing hormone (GHRH) secreting tumor in multiple endocrine neoplasia (MEN-1).

Introduction

Multiple endocrine neoplasia type 1 (MEN-1) is defined as presence of any two tumors out of the following; parathyroid, neuroendocrine tumor (NECT) and pituitary neoplasia. (1) Hypersecretion of growth hormone releasing hormone (GHRH) is rare manifestation of NECT; however half of such cases are found with MEN-1. (2) Incidence rate of acromegaly with GH over secretion is up to 15% in MEN-1 pituitary tumors similar to non-MEN-1 pituitary tumors. (3)

[FIGURE 1 OMITTED]

There are two different etiologic mechanisms of acromegaly caused by excess GH in MEN-1 with different treatment implications. Mostly it is due to pituitary adenomas, which arise clonally from inactivation of both alleles of the MEN-1 gene in a tumor precursor cell. (4) The second mechanism is overproduction of GHRH by NECT including pancreatic islet (2) or carcinoid tumor leading to polyclonal and hyperplastic pituitary gland with over production of GH.

In this report, we describe a case of acromegaly, in a patient with MEN-1 with emphasis on screening for GHRH secreting tumors in MEN-1 patients with acromegaly, confirmation of the diagnosis, treatment options and importance of life long surveillance.

Case Report

A 36 year old man presented with increase in hand and shoe size, excessive sweating, tingling and numbness in his hands. He had been recently diagnosed with carpel tunnel syndrome. He belongs to known MEN-1 kindred. He was diagnosed with MEN-1 ten years ago.

He had hyperprolactinemia (initial prolactin level of 2470 ng/ml (2.517 ng/ml) and a 2.5 x 2.5 x 2.0 cm pituitary mass) which responded well to cabergoline with near normalization of prolactin (50 ng/ml) and significant shrinkage of pituitary mass. He also had hypercalcemia due to primary hyperparathyroidism.

A screening CT scan of pancreas five years ago had revealed 7.8 x 6.2 x 6.2 cm mass in the head of pancreas (Fig-1). Endocrine testing showed normal gastrin, VIP, pancreatic polypeptide and 24 hour urine 5-HIAA levels. The mass was being conservatively monitored.

Physical examination showed coarse facial features, loss of nasolabial fold, acral enlargement, swollen inter-digital spaces and multiple skin tags.

Laboratory data showed IGF-1 1500 ng/ml (114-449 ng/ml), GH 93 ng/ml (2-5 ng/ml), calcium 11.3, intact PTH 84 pg/ml (11-54).

Repeat MRI of head showed 2.2 x 1.8 x 1.8 cm pituitary tumor which had increased in size compared to previous study. GHRH level 6969 pg/ml (<50 pg/ ml) was found to be very high.

GHRH arteriovenous gradient across the pancreatic tumor was measured. Left radial vein GHRH level was 4800 pg/ml while splenic vein GHRH level was 289000 pg/ ml. He underwent pancreatic tumor resection. Hormonal profile showed significant drop in IGF-1 761 ng/ml, GH 7.9 ng/ml and GHRH 42 pg/ ml after surgery. A170 mg of tumor extracted for m-RNA which revealed 235000 pg/mg of GHRH. (Table 1)

Since then he has normal GH and GHRH levels and normal IGF-1 values.

Discussion

In acromegaly, the overproduction of GH is mostly caused by pituitary adenoma; the frequency of GHRH hyper secretion causing acromegaly is estimated to be less than 1%. (5,6) Ectopic GHRH secretion usually originates from NECT, commonly from a bronchial carcinoid or enteropancreatic NECT. (7) Rarely ectopic GHRH from thymic tumors, small cell lung cancer, adrenal adenoma and pheochromocytoma have been reported. (8)

Clinical (Table 2) and biochemical features of acromegaly, including high IGF-1, GH levels and nonsuppressible GH response to oral glucose load, are often indistinguishable between GH-producing pituitary adenoma and ectopic GHRH producing tumors. Serum GHRH concentration is a reliable method to differentiate between GHRH induced acromegaly and acromegaly from a pituitary adenoma (classic acromegaly). (5,6)

Plasma GHRH levels are strikingly high (above 300 pg/ml) in ectopic GHRH induced acromegaly whereas in classic acromegaly; GHRH levels are usually undetectable but occasionally mildly elevated (less than 300 pg/ml). (5,9) GHRH induced acromegaly exhibits mild hyperprolactinemia due to hyperstimulation of pituitary lactotroph cells by GHRH, as seen in human GHRH transgenic mice. (10)

Specific dynamic tests (TRH stimulation, GHRH stimulation and oral glucose suppression) do not differentiate the above two types of acromegaly with certainty, and have produced variable results. (11)

The criteria for definitive diagnosis of ectopic GHRH production has been described as high levels of circulating GHRH, an arteriovenous concentration gradient of GHRH in the region of the tumor, presence of GHRH or mRNA of GHRH in the tumor or significant decline of GHRH, GH and IGF-I levels after removal of the tumor to near normal. (11,12) Our case met almost all these criteria.

Neuroimaging studies of the hypothalamic pituitary gland in ectopic GHRH induced acromegaly have provided variable results, from no tumor to slight enlargement or well defined pituitary mass. (9) Histopathology specimens of Pituitary glands from GHRH induced acromegaly have shown a continuum of hyperplasia to adenoma and adenomatous transformation can be found on a background of hyperplasia. (9)

As MEN-1 patients can have both pituitary tumors and NECT, it seems reasonable to screen all MEN-1 patients with acromegaly for ectopic GHRH induced acromegaly (Table 3). Serum GHRH levels can be used as an initial screening test.

Previously reported GHRH secreting NECT were usually large enough to be seen on CT scan of abdomen and chest respectively. Octreotide scintigraphy can be useful in detecting the tumors that have rich somatostatin receptors (9,13,14) but the test is not definitive.

Surgical removal of the GHRH producing tumor is the therapy of choice for ectopic GHRH induced acromegaly. (9) In case of an inoperable tumor, high surgical risk or unsuccessful surgery, GH hypersecretion can be controlled either by pituitary surgery or pituitary radiation. Another alternative is medical treatment. Dopamine agonist therapy has variable effect on GH and IGF1 levels but doesn't affect GHRH levels or tumor size. (9) Long acting somatostatin analog octreotide can inhibit GHRH secretion from NECT as well as GH secretion from anterior pituitary gland directly. It can reduce GH and IGF1 levels at relatively lower doses, but higher doses are required for suppression of GHRH levels, shrinkage of the primary tumor and reduction of secondary pituitary enlargement. (9, 13,14)

Although commercially not available, GHRH antagonists have shown to effectively decrease GH secretion in ectopic GHRH induced acromegaly on experimental basis. (15) When potent GHRH antagonists will become commercially available, it might be the most suitable therapeutic option for this rare disease.

CONCLUSION

Patients with acromegaly and MEN-1 should be screened for ectopic GHRH secretion.

Measurement of GHRH arteriovenous gradient across NECT, measurement of GHRH or mRNA for GHRH in resected tumor and post operative decline in GHRH level can confirm the ectopic source. Surgical removal of the GHRH secreting tumor is the treatment of choice. Medical therapy with Somatostatin analog is an alternative for surgically unsuitable patients.

Lifelong surveillance for recurrence of tumor and acromegaly should be continued with GHRH and IGF-1 levels.

Abbreviations

MEN-1: Multiple endocrine neoplasia type 1, NECT: Neuroendocrine tumor, GHRH: Growth hormone releasing hormone, GH: Growth hormone, IGF-1: Insulin like growth factor.

REFERENCES

(1.) Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001; 86:5658-5671.

(2.) Liu SW, van de Velde CJ, Heslinga JM, Kievit J, Roelfsema F. Acromegaly caused by growth hormone-relating hormone in a patient with multiple endocrine neoplasia type I. Jpn J Clin Oncol. 1996 Feb; 26(1):49-52.

(3.) Marx S, Spiegel AM, Skarulis MC, Doppman JL, Collins FS, Liotta LA. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med. 1998 Sep 15; 129(6):484-94.

(4.) Weil RJ, Vortmeyer AO, Huang S, et al. 11q13 allelic loss in pituitary tumors in patients with multiple endocrine neoplasia syndrome type 1. Clin Cancer Res. 1998 Jul; 4(7):1673-8.

(5.) Throner MO, Frohman LA, Leong DA. Extrahypothalmic growth-hormone-releasing factor (GFR) secretion is a rare cause of acromegaly: plasma GRF levels in 177 acromegalic patients.J Clin Endocrinol Metab 1984; 59:846-9.

(6.) Penny ES, Penman E, Price J, et al. Circulating growth hormone releasing factor concentrations in normal subjects and patients with acromegaly. Br Med J (Clin Res Ed). 1984 Aug 25; 289(6443):453-5.

(7.) Gola M, Doga M, Bonadonna S, Mazziotti G, VVescovi PP, Giustina A. Neuroendocrine tumors secreting growth hormone-releasing hormone:pathophysiological and clinical aspects. Pituitary 2006; 9 (3):221-9

(8.) Faglia G, Arosio M, Bazzoni N. Ectopic acromegaly. Endocrinol Metab Clin North Am. 1992 Sep; 21(3):575-95.

(9.) Scheithauer BW, Carpenter PC, Bloch B, Brazeau P. Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor. Am J Med. 1984 Apr; 76(4):605-16.

(10.) Stefaneanu L, Kovacs K, Horvath E, et al. Adenohypophysial changes in mice transgenic for human growth hormone-releasing factor: a histological, immunocytochemical, and electron microscopic investigation. Endocrinology. 1989 Nov; 125(5):2710-8.

(11.) Biermasz NR, Smit JW, Pereira AM, et al. Acromegaly caused by growth hormonereleasing hormone-producing tumors: long-term observational studies in three patients. Pituitary. 2007; 10(3):237-49

(12.) Losa M, von Werder K. Pathophysiology and clinical aspects of the ectopic GH-releasing hormone syndrome. Clin Endocrinol (Oxf). 1997 Aug; 47(2):123-35.

(13.) de Jager CM, de Heide LJ, van den Berg G, et al. Acromegaly caused by a growth hormonereleasing hormone secreting carcinoid tumor of the lung: the effect of octreotide treatment. Neth J Med. 2007 Jul-Aug; 65(7):263-6.

(14.) Drange MR, Melmed S., Long-acting lanreotide induces clinical and biochemical remission of acromegaly caused by disseminated growth hormone-releasing hormone-secreting carcinoid. J Clin Endocrinol Metab. 1998 Sep; 83(9):3104-9.

(15.) Jaffe CA, DeMott-Friberg R, Frohman LA, et al. Suppression of growth hormone (GH) hypersecretion due to ectopic GH-releasing hormone (GHRH) by a selective GHRH antagonist. J Clin Endocrinol Metab. 1997 Feb; 82(2):634-7.

Tipu Faiz M. Saleem, MD

Associate Professor, Division of Endocrinology,

JCESOM, Marshall University, Huntington

Prasanna Santhanam, MD

Assistant Professor, Division of Endocrinology,

JCESOM, Marshall University, Huntington

Eyad Hamoudeh, MD

Fellow, Division of Endocrinology, JCESOM,

Marshall University, Huntington

Tamer Hassan, MD

Resident, Division of Internal Medicine,

JCESOM, Marshall University, Huntington

Saba Faiz MD

Fellow, Division of Endocrinology, JCESOM,

Marshall University, Huntington
Table-1 Confirmation of GHRH hypersecretion by tumor causing
acromegaly

Biochemical Features Normal Range Pre-Operative Post-Operative

IGF-1 (114-449) ng/ml 1500 ng/ml 761 ng/ml
GH (2-5) ng/ml 93 ng/ml 7.9 ng/ml
Peripheral vein GHRH (<50) pg/ml 4800 pg/ml 42 pg/ml
Splenic vein GHRH NA 289000 pg/ml --
m-RNA for GHRH in
resected tumor NA 235000 pg/mg

Table 2. Clinical Effects of Acromegaly

 Endocrine and Metabolic
Local Tumor Effects Somatic Effects Effects

Cranial nerve palsy Acral Enlargement- Carbohydrate--
Headache thickness of hands and Diabetes Mellitus,
Pituitary enlargement soft tissue Impaired Glucose
Visual field defects Tolerance, Insulin
 Cardiovascular-
 Asymmetric septal Resistance and
 hypertrophy, Left Hyperinsulinemia
 Ventricular
 Hypertrophy, HTN, CHF, Electrolytes--
 Cardiomyopathy Increased Aldosterone,
 Low Renin
 Gastrointestinal-
 Colonic Polyps Lipids--
 Hypertriglyceridemia
 Musculoskeletal--
 Acroparasthesias, Minerals--
 proximal Myopathy, Hypercalciuria,
 prognathism, Increased 1,25 (OH)2
 gigantism, carpal D3,Urine
 tunnel syndrome, Hydroxyproline
 frontal bone
 prominence, Neoplasms--MEN-1,
 arthralgia, jaw Hyperparathyroidism,
 malocclusion Islet Cell Tumors

 Pulmonary-- Reproduction--
 Narcolepsy, Sleep Galactorrhea,
 Apnea-Central and menstrual
 Obstructive abnormalities,
 decreased libido,
 Skin--Hyperhydrosis, impotence, low Sex
 Skin tags Hormone Binding
 Globulin
 Visceromegaly--
 Kidney, liver, Thyroid--low Thyroxine
 prostate, thyroid, Binding Globulin,
 tongue, salivary Goiter
 gland, spleen

Modified from Bonert V, Melmed S. Acromegaly. In Bar RS, ed. Early
Diagnosis and Treatment of Endocrine Disorders (Contemporary
Endocrinology). Totowa, NJ: Humana Press, 2002:201-228.

 Table 3. When to suspect GHRH dependent acromegaly? I Indications
 for measurement of GHRH levels in acromegaly

 1. Known case of multiple endocrine neoplasia (MEN-1)

 2. Family history of multiple endocrine neoplasia (MEN-1)

 3. Presence of known neuroendocrine tumor (NECT)

 4. Co-existence of hyperprolactinemia and acromegaly

 5. Absence of classic pituitary adenoma in MRI (either normal or
 hyperplastic pituitary gland)
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Title Annotation:Scientific Article
Author:Saleem, Tipu Faiz M.; Santhanam, Prasanna; Hamoudeh, Eyad; Hassan, Tamer; Faiz, Saba
Publication:West Virginia Medical Journal
Article Type:Case study
Date:Mar 1, 2012
Words:1979
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