Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: Dynamic endocrine studies and treatment with the somatostatin analogue octreotide

Abstract

Acromegaly and hyperprolactinemia have been described in association with polyostotic fibrous dysplasia; the pathogenetic mechanisms involved in the development of the endocrinopathies is unknown. We report a 26-year-old man with polyostotic fibrous dysplasia and hypersecretion of GH and PRL. Plasma GH, PRL, and insulin-like growth factor-I (IGF-I) were elevated. Glucose-non-suppressible plasma GH concentrations, GH responsiveness to TRH and GHRH, and GH suppression after a test-dose of somatostatin, octreotide, and bromocriptine were found. Plasma GHRH levels were within the normal range (< 25 ng/l). Computed tomography of the sella turcica and visual fields were normal. [111In-DTPA-D-Phe1]-octreotide scintigraphy were used to localize a possible tumor; no radioactivity was visualized at the site of the hypothalamus, the pituitary or elsewhere in the body but a considerable accumulation of radioactivity was found in the os frontalis. Therapy with octreotide by continuous sc infusion partially suppressed GH and IGF-I (and normalized PRL). The results suggest that hypersecretion of GH in our patient is not due to a GH-secreting pituitary tumor, eutopic or ectopic hypersecretion of GHRH or autonomous somatotroph function. The origin of the disease in this patient might be an abnormal hypothalamic regulation of somatotrophs and/or an alteration in the transmembrane signalling systems.

Pituitary Pathology in Carney Complex Patients

“…These findings are in agreement with the hypothesis that pituitary tumors develop from clonal expansion of transformed somatic cells [28,29]. They are also consistent with observations in patients with MAS [14][15][16] and some patients with MEN 1 [30]. CNC and MAS are genetic conditions that share skin pigmentation abnormalities, adrenocortical hyperplasia, thyroid tumors and even myxomas.…”

“…Mammosomatotroph hyperplasia may be the only lesion that is in fact common in CNC and MAS [33]. Clinically, too, both share a "pro-acromegalic" state [34], which only rarely leads to the detection of an adenoma [10,[14][15][16]34]. Similar, longstanding somatotroph hyperplasia, which only occasionally leads to pituitary adenoma has been seen in several other patients, albeit GHRH-induced [35,36].…”

“…Although growth hormone (GH) and prolactin (PRL) secretion are frequently abnormal in affected patients [9,10], clinical acromegaly or significant hyperprolactinemia and GH-or PRL-producing tumors, respectively, have been detected in less than one fifth of them [11,12]. The pattern of biochemical abnormalities of GH and PRL secretion without pituitary tumors that are detectable by common imaging modalities, and infrequent development of clinically significant acromegaly is reminiscent of the situation in McCune-Albright syndrome (MAS) [13][14][15][16]. Studies of tumors excised from patients with CNC had indicated that their molecular abnormality may be in the molecular pathway that involves the stimulatory α-subunit of the guanine nucleotide-binding protein (Gsα) [17,18], GNAS-the gene responsible for MAS [13].…”

Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities

“…There were no such abnormalities detected in the normal and the hyperplastic tissue surrounding the tumor [16]. This observation is consistent with the concept that clonal expansion of genetically transformed somatic cells [19] underlies pituitary tumor development in CNC patients, which appears to also be the case in MAS [20][21][22][23] but not in MEN 1, unless associated with elevated GHRH levels [24].…”

“…Carney complex (CNC), a rare condition, has been described in about 500 people to date and is caused in more than 60% of the cases that meet diagnostic criteria by an inactivating mutation in the gene encoding protein kinase A (PKA) type 1A regulatory (R1α) subunit (PRKAR1A) at 17q22-24; a second, as yet uncharacterized, locus at 2p16 has also been implicated in some families [6,7]. The pituitary gland is frequently affected in CNC and the clinical features are reminiscent of McCune-Albright syndrome (MAS) [8][9][10][11]: despite frequent abnormalities of growth hormone (GH), insulinlike growth factor 1 (IGF-1), and prolactin (PRL) secretion, clinical acromegaly or significant hyperprolactinaemia and growing GH-or PRL-producing tumors are rare [12][13][14][15]. Mouse models of R1α deficiency have been created but they failed to reproduce a specific or a significant pituitary phenotype, although mild abnormalities were seen.…”