Endocrinol Metab.  2011 Mar;26(1):1-11. 10.3803/EnM.2011.26.1.1.

ACTH-Independent Macronodular Adrenal Hyperplasia

• Mermejo LM
• Mazzuco TL
• Grunenwald S
• Fragoso MC
• Bourdeau I
• Lacroix A

• KMID: 2169118
• DOI: http://doi.org/10.3803/EnM.2011.26.1.1

Abstract

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an uncommon cause of Cushing's syndrome (CS). The pathophysiology of this disorder is heterogeneous in its molecular origin and also in its clinical presentation. AIMAH can present mainly as an incidental radiological finding with sub-clinical CS or rarely with overt CS. In a few familial cases reported with AIMAH, specific aberrant G-protein coupled receptors were expressed in the adrenals of all affected members, but sporadic cases are more common. The aberrant adrenal function of G-protein coupled receptors can lead to cell proliferation and abnormal regulation of steroidogenesis. Unilateral or bilateral adrenalectomy has been the most frequently used treatment for this adrenal disorder; alternatively, the identification of aberrant receptors using in vivo protocol of investigation can offer specific pharmacological approach to control abnormal steroidogenesis and possibly prevent AIMAH progression.

Keyword

ACTH-independent macronodular adrenal hyperplasia (AIMAH); Aberrant adrenal G-protein coupled receptors; Cushing's syndrome; Familial forms

MeSH Terms

Adrenalectomy
Cell Proliferation
Cushing Syndrome
GTP-Binding Proteins
Hyperplasia
Cushing Syndrome
GTP-Binding Proteins

Figure

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  Fig. 1. CT scan from 3 patients with AIMAH and Cushing's syndrome. The left and right upper panels are from the same patient and illustrate the variable nature of nodular hyperplasia of both adrenals on sequential slices of CT scan. The white arrows are pointed towards the adrenal glands.

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  Fig. 2. Regulation of steroidogenesis by aberrant hormone receptors in adrenal cortex. In this model, the ectopic or eutopic receptors regulate steroidogenesis by mimicking the cellular events triggered by ACTH receptors activation. Reproduced with permission from Lacroix et al. Trends Endocrinol Metab 15:375–382, 2004 [47].

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  Fig. 3. Further in vivo characterization of aberrant adrenal hormone receptors following the initial screening protocol. Adapted from Lacroix et al. The Endocrinologist 9:9–15, 1999 [52].

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  Fig. 4. Hypothesis of sequential genetic events leading to AIMAH. The initial event is the aberrant expression of the LH/hCG receptor in the adrenal cortex during early embryonic life. Upon stimulation of this receptor, as during pregnancy (activation by hCG), diffuse adrenal hyperplasia (polyclonal) and transient CS occurs, but this is still reversible when hCG and LH levels are reduced following delivery. After menopause, the constant elevation of LH causes diffuse hyperplasia and CS. Other (second, third) somatic events occur progressively with time in a small number of cells; the monoclonal proliferation of these cells leads to appearance of several nodules which have maintained the expression of aberrant LH/hCGR. The inhibition of LH levels is able to control the excess production of steroids; this may be able to induce regression of adrenal growth at the stage of hyperplasia, but it may become insufficient to cause tumor regression when other oncogenic events have provided additional growth advantage to these cells. Reproduced with permission from Lacroix et al. Trends Endocrinol Metab 15:375–382, 2004 [47].

Reference

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