Available online 14 February 2024, 101877

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Ectopic acromegaly is a rare condition caused by extrapituitary central or peripheral neuroendocrine tumours (NET) that hypersecrete GH or, more commonly, GHRH. It affects less than 1% of acromegaly patients and a misdiagnosis of classic acromegaly can lead to an inappropriate pituitary surgery. Four types of ectopic acromegaly have been described: 1) Central ectopic GH-secretion: Careful cross-sectional imaging is required to exclude ectopic pituitary adenomas. 2) Peripheral GH secretion: Extremely rare. 3) Central ectopic GHRH secretion: Sellar gangliocytomas immunohistochemically positive for GHRH are found after pituitary surgery. 4) Peripheral GHRH secretion: The most common type of ectopic acromegaly is due to peripheral GHRH-secreting NETs. Tumours are large and usually located in the lungs or pancreas. Pituitary hyperplasia resulting from chronic GHRH stimulation is difficult to detect or can be misinterpreted as pituitary adenoma in the MRI. Measurement of serum GHRH levels is a specific and useful diagnostic tool. Surgery of GHRH-secreting NETs is often curative.

Section snippetsEctopic Secretion of GH

Between 1982 and 2022, 21 cases of ectopic GH secretion were published, 15 of which involved central GH secretion from GH-secreting ectopic pituitary adenomas. *[7], [8] Six additional cases were reported of peripheral secretion of GH by a pancreatic [9] or bronchial [10], [11], [12] NET, a case of ovarian teratoma [13] and a case of non-Hodgkin's lymphoma. [14]

Ectopic Secretion of GHRH

GHRH is a hypothalamic hormone that specifically stimulates the transcription of the GH gene, and the synthesis and secretion of GH, as well as the proliferation of somatotroph cells. [16], [17] The majority of patients with ectopic acromegaly produced by hypersecretion of GHRH have peripheral NET. Fewer patients have been reported with tumors of hypothalamic origin. [2], [3], *[4], *[5], [6]

Central Ectopic GHRH Secretion

Gangliocytomas are benign tumors of the nervous system, usually found in the sellar and hypothalamic regions. They comprise neurons embedded in a fibrillary background expressing not only neuronal histological markers but also hormone-releasing factors like CRH (corticotropin releasing hormone) and GHRH. In mixed gangliocytoma-pituitary adenomas, a rare tumor variant, there is an adenomatous component of the pituitary gland, which often secretes GH. [18] Sylvia Asa et al. (1984) studied six

Peripheral GHRH Secretion

The association of acromegaly with carcinoid tumors has been recognized since the mid-20th century. [23], [24], [25] Frohman et al. were the first to partially isolate a peptide with GH-releasing activity from extracts of lung and pancreatic carcinoid tumors. [26] In 1982, two teams simultaneously isolated GH-releasing peptides from pancreatic tumors of two acromegalic patients. *[27], [28] The sequences of two of the three isolated peptides (1-40 and 1-44) were found to be similar to that of

Case Report

A 37-year-old man consulted for enlarged feet and hand edema, which prevented him from wearing a wedding ring. Physical examination showed slight edema of the face, feet and hands. Visual fields by confrontation were normal. Routine laboratory tests were normal, but an elevated serum IGF-1 level of 746 µg/mL (normal age-adjusted range, 64-284 µg/L) prompted a 75 g-glucose challenge test which revealed a lack of GH suppression, with a nadir level of 6.0 µg/L. Serum prolactin, testosterone and free

Conclusions

We have reviewed the spectrum of ectopic acromegaly and presented some new findings. Not much has changed in the field of ectopic pituitary adenomas since the last review by Ramirez et al. in 2013.[7] Peripheral GH secretion remains unusual in what is itself a rare disease The theory of neuronal transdifferentiation has challenged the original postulates of hypothalamic acromegaly. However, ectopic acromegaly due to p-GHRH-NET remains the most important clinical issue. If we exclude the

Uncited references

[56]; [58]; [59]; [60]; [61]; [63]; [64]; [66]

Acknowledgements

We are grateful to Dr Lawrence Frohman for generously providing the GHRH antibody and to Dr Martin Bidlingmaier for kindly assisting with the determination of plasma GHRH.

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