Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia

Abstract

BackgroundAlthough chronic adrenocorticotropic hormone (ACTH) and androgen hyperstimulation are assumed to be involved in the pathogenesis of adrenal myelolipomas associated with poor-compliance patients with congenital adrenal hyperplasia (CAH), the expression of their receptors has not yet been demonstrated in these tumors so far.MethodsWe analyzed Melanocortin 2 receptor (MC2R), Androgen Receptor (AR), Leptin (LEP), and Steroidogenic factor 1 (SF1) expression using real-time qRT-PCR in two giant bilateral adrenal myelolipomas from two untreated simple virilizing CAH cases and in two sporadic adrenal myelolipomas. In addition, the X-chromosome inactivation pattern and CAG repeat numbers in AR exon 1 gene were evaluated in the 4 cases.ResultsThe MC2R gene was overexpressed in myelolipomas from 3 out of 4 patients. AR overexpression was detected in 2 tumors: a giant bilateral myelolipoma in a CAH patient and a sporadic case. Simultaneous overexpression of AR and MC2R genes was found in two of the cases. Interestingly, the bilateral giant myelolipoma associated with CAH that had high androgen and ACTH levels but lacked MC2R and AR overexpression presented a significantly shorter AR allele compared with other tumors. In addition, X-chromosome inactivation pattern analysis showed a polyclonal origin in all tumors, suggesting a stimulatory effect as the trigger for tumor development.ConclusionThese findings are the first evidence for MC2R or AR overexpression in giant bilateral myelolipomas from poor-compliance CAH patients.

Adrenocortical carcinoma associated with giant bilateral myelolipomas in classic congenital adrenal hyperplasia

“…However, fewer than 20 cases of giant bilateral myelolipomas in CAH patients have been reported to date, and the role of ACTH or other hormones in their development is still uncertain. 3 The presented case highlights the need for proper and careful management of patients with CAH. However, it also shows that the risk of malignancy exists even in tumors considered as benign.…”

Adrenal myelolipoma(s) as presenting manifestation of subclinical Cushing’s disease (eutopic ACTH-dependent Cushing’s syndrome)

“…In these conditions, circulating ACTH is normal, minimally elevated or suppressed but still demonstrates significant driving force for tumour formation. Increased tissue expression of ACTH (melanocortin 2 receptor) receptors within the tumour perhaps perpetuates the effect of ACTH in these conditions 6. Excess circulatory androgen is a ‘sine qua non’ in individuals with inadequately treated CAH.…”

“…Adrenal androgens, synthesised in zona reticularis of adrenal cortex are ACTH dependent and ACTH dependent CS syndrome patients often have hyperandrogenemia. Over expression of androgen receptors (AR) has also been observed in such tumours and thus may play a stimulatory role in these patients 6. However, earlier study looking at increased tissue expression of these receptors in giant adrenal myelolipoma by a semiquantitative approach to analyse mRNA expression did not demonstrate similar findings and this particular mechanism of tumour formation is not sacrosanct 7…”

Giant adrenal myelolipoma - clinical spectrum and management: a single centre experience

“…Though rare, bilateral myelolipomas have been described in literature. [7][8][9][10][11][12][13] Myelolipomas are usually of small size often less than 4 cm diameter. Majority of the patients are asymptomatic but it can attain very large size and cause symptoms.…”