Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia

INTRODUCTION — Among the causes of Cushing's syndrome are three rare types of nodular adrenocortical diseases that are usually bilateral (table 1):

●Corticotropin (ACTH)-dependent bilateral macronodular adrenal hyperplasia, secondary to long-term adrenal stimulation in patients with Cushing's disease or ectopic ACTH syndrome. However, the adrenals rarely reach the massive size that can be seen with primary bilateral macronodular adrenal hyperplasia, and plasma ACTH may still be detectable.

●ACTH-independent micronodular adrenal hyperplasia and its most frequent variant, primary pigmented nodular adrenocortical disease (PPNAD), which may be sporadic or familial (as part of the Carney complex).

●Primary bilateral macronodular adrenal hyperplasia (PBMAH), a disorder previously referred to as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH).

PBMAH will be reviewed here. Other causes of Cushing's syndrome and PPNAD are discussed separately. (See "Causes and pathophysiology of Cushing syndrome" and "Cushing syndrome due to primary pigmented nodular adrenocortical disease".)

OVERVIEW — Primary bilateral macronodular adrenal hyperplasia (PBMAH) has been described by various terms, including corticotropin (ACTH)-independent macronodular adrenal hyperplasia (AIMAH), primary macronodular adrenal hyperplasia (PMAH), massive macronodular adrenocortical disease (MMAD), autonomous macronodular adrenal hyperplasia (AMAH), ACTH-independent massive bilateral adrenal disease (AIMBAD), and "giant" or "huge" macronodular adrenal disease. However, we prefer and use primary bilateral macronodular adrenal hyperplasia (PBMAH) here.

PBMAH is an uncommon cause (<2 percent) of endogenous Cushing's syndrome, characterized by enlarged adrenal glands containing multiple nonpigmented nodules that are greater than 10 mm in diameter but can be as large as 30 to 40 mm in diameter [1]. It can be diagnosed in patients with Cushing's syndrome but more often in those with incidentally found bilateral macronodular adrenals and modest secretion of cortisol who are between the ages of 40 and 60 years; as 10 to 15 percent of adrenal incidentalomas are bilateral, PBMAH is one of the causes of bilateral adrenal incidentalomas, but its precise prevalence has not been determined in population studies [2].

Aside from PBMAH, the differential diagnosis of bilateral adrenal incidentalomas includes disorders that are not associated with cortisol excess: bilateral adrenal adenomas, pheochromocytomas, metastasis, congenital adrenal hyperplasia (CAH), hemorrhage, lymphoma, and infiltrative and infectious diseases (table 1) [2]. (See "Evaluation and management of the adrenal incidentaloma".)

In PBMAH, plasma ACTH levels become progressively suppressed when cortisol secretion is sufficiently elevated (increased urinary free cortisol [UFC] levels).

Treatment of PBMAH with overt Cushing's syndrome is usually surgical; bilateral adrenalectomy was previously utilized in most patients with PBMAH and severe Cushing's syndrome (UFC >3 times upper limit of normal), but more recently, unilateral adrenalectomy was found to normalize UFC in a high proportion of patients with less severe Cushing's syndrome [3]. (See 'Treatment' below.)

In patients in whom aberrant hormone receptors have been identified, specific pharmacologic therapies have been utilized in selected cases as alternatives to adrenalectomy. (See 'Pharmacologic therapy' below.)

PATHOGENESIS — Aberrant hormone receptors, local production of corticotropin (ACTH) in adrenal tissues, and genetic mutations have been identified in the pathogenesis of PBMAH.

Aberrant hormone receptors — The most prevalent abnormality in patients with PBMAH results from the aberrant adrenal expression of ectopic receptors or increased activity of eutopic peptide hormone receptors (table 2) [4,5]. Cortisol secretion becomes driven by a hormone that escapes cortisol-mediated feedback. In a series of patients with PBMAH (and mild or overt Cushing's syndrome) who were screened for aberrant receptors, more than 85 percent had at least one and usually several aberrant responses (most commonly to vasopressin and serotonin 5-hydroxytryptamine 4 [5-HT4] agonists) [6-10]. Examples of aberrant receptors include the following:

●Vasopressin – Vasopressin-responsive Cushing's syndrome is the most frequent aberrant stimulator of cortisol secretion in patients with PBMAH. In these patients, cortisol secretion increases with upright posture or other physiological stimuli of endogenous vasopressin, such as hypertonic saline infusion [4,5,8,11-18]. In most, cortisol secretion was regulated by the V1-vasopressin receptor (no stimulation by desmopressin, a preferential V2 receptor agonist), expressed at either normal or high levels.

The V1-vasopressin receptor is normally expressed in the adrenal cortex but is not a major regulator of steroidogenesis. In patients with PBMAH, the exaggerated steroidogenic responses to vasopressin are secondary to the increased activity and/or expression of a "eutopic" receptor-effector system.

●Beta-adrenergic – PBMAH and Cushing's syndrome have been reported in patients with aberrant adrenal expression of beta-adrenergic receptors. Plasma cortisol and aldosterone levels increase in response to elevations in endogenous catecholamines that occur with upright posture, insulin-induced hypoglycemia, and exercise [19]. Isoproterenol infusion stimulates cortisol and aldosterone secretion, and propranolol blocks this effect and reduces basal cortisol secretion with long-term control of hypercortisolism [20]. These effects were not seen in normal subjects. Similar findings have been reported in other patients with PBMAH [8,16,21]. High-affinity binding sites compatible with beta-1- or beta-2-adrenergic receptors were efficiently coupled to steroidogenesis in the adrenal tissues in these patients, but not in controls, indicating the ectopic nature of this receptor [16,19,21].

The combined presence of adrenal beta-adrenergic receptor and V1-vasopressin receptor has been observed in other patients with PBMAH [8,16,19,21]. The combined overexpression of beta-2-adrenoreceptor, serotonin 5-HT4 receptor, and V1-vasopressin receptor also was demonstrated [20,22].

●LH/hCG – Hypercortisolism due to aberrant luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptors was first identified in a woman with history of transient Cushing's syndrome during sequential pregnancies; however, persistent Cushing's syndrome and PBMAH developed only after the postmenopausal sustained increase of LH secretion [23]. Administration of the long-acting gonadotropin-releasing hormone (GnRH) agonist, leuprolide acetate, resulted in suppression of endogenous LH and normalization of cortisol production [23]. In a 22-year-old woman who presented with transient bilateral adrenal hyperplasia and severe Cushing's syndrome during two pregnancies, in vivo and in vitro studies in resected adrenals demonstrated that hCG could stimulate the transformation of progenitor subcapsular adrenal LH/hCG receptor-expressing cells into hyperplastic adrenocortical cells, increasing their steroidogenesis under hCG stimulation [24]. In a 59-year-old woman with androgen-secreting PBMAH resulting in virilization, aberrant LH/hCG receptors were identified in one resected adrenal. Suppression of endogenous LH with leuprolide acetate normalized androgen secretion from the contralateral adrenal, thereby avoiding bilateral adrenalectomy [25]. A 64-year-old woman with PBMAH expressing LH/hCG receptor and aromatase presented with mastodynia, which regressed by long-term therapy with leuprolide acetate [26].

In nonpregnant women, most cases of Cushing's syndrome in nonpregnant women are due to an ACTH-secreting pituitary adenoma (Cushing's disease). In contrast, the frequency of ACTH-independent cases is considerably higher in pregnant women with Cushing's syndrome. It seems likely that LH/hCG receptors on the adrenal are at least in part responsible for this phenomenon. (See "Diagnosis and management of Cushing syndrome during pregnancy", section on 'Causes'.)

●Serotonin – Other cases of aberrant receptors for LH/hCG or serotonin, either alone or in combination, have been reported [11,12,27]. In one of the patients described above [23], serotonin 5-HT4 receptor agonists, cisapride and metoclopramide, also stimulated plasma cortisol.

Following the initial description of combined aberrant LH and serotonin 5-HT4 receptors in PBMAH, several other patients were found to have increased secretion of cortisol following stimulation with cisapride, metoclopramide, or tegaserod [11,12,18,27-30]. In most cases, a large overexpression of 5-HT4 receptor was found in the adrenals [31-33]. The ectopic expression and function of serotonin 5-hydroxytryptamine 7 (5-HT7) receptor was identified in a patient with serotonin-responsive PBMAH and Cushing's syndrome [30].

●GIP – The ectopic expression of glucose-dependent insulinotropic peptide (also known as gastric inhibitory polypeptide [GIP]) receptor in zona fasciculata cells causes "food-dependent" cortisol production. Plasma cortisol levels may be relatively low during fasting and increase transiently following meals [34-36]. GIP-dependent Cushing's syndrome has been reported in approximately 20 patients with PBMAH [34-41]. GIP receptors are not expressed in the normal adult or fetal zona fasciculata [36-39,42]. GIP receptor overexpression in PBMAH occurs from a single allele of the GIPR gene (ch 19q) and, in some cases of unilateral adenoma or PBMAH, resulted from chromosome 19q region gene duplication and rearrangement [43].

The adrenal nodules in some patients with GIP-dependent PBMAH can progress asynchronously, first in one adrenal, later in the other [39]; in one report, the adrenal adjacent to the macronodules was not atrophic but showed diffuse adrenal hyperplasia with ectopic GIP receptor expression [39], suggesting that larger nodules were the result of secondary clonal proliferation events [44]. In one case, GIP-dependent PBMAH zones were mixed with bilateral myelolipomas [41].

Other reported cases include patients with combined aberrant expression of GIP receptor and LH/hCG receptor [12,45].

●Angiotensin – In a patient with PBMAH and a large increase in plasma aldosterone and cortisol levels during upright posture, short-term oral administration of the angiotensin II receptor antagonist candesartan completely inhibited the elevation in cortisol and aldosterone [46]. In vitro stimulation of cortisol secretion by angiotensin II was also found in patients with PBMAH and Cushing's syndrome who had increases in cortisol levels with upright posture [12].

●Other receptors – In a study that looked to identify novel abnormally expressed G-protein-coupled receptors (GPCRs) in patients with PBMAH, several new aberrant receptor genes were identified, one of which (the alpha-2A-adrenergic receptor [ADRA2A], highly expressed in 13 of 18 BMAHs) may be a potential target for pharmacologic treatment of Cushing's syndrome due to PBMAH [47]. Clonidine (an ADRA2A agonist) administration resulted in an increase in cortisol production; the increase could be blocked by an ADRA2A antagonist, yohimbine. In other patients, the administration of glucagon increased plasma cortisol, while octreotide inhibited plasma cortisol in patients with PBMAH and mild Cushing's syndrome [6]. (See 'Screening for aberrant receptors' below.)

Paracrine secretion of ACTH — The hypercortisolism associated with primary PBMAH was previously considered to be corticotropin (ACTH) independent. However, it appears that cortisol secretion in PBMAH is at least partially regulated by intra-adrenal ACTH, which is produced by steroidogenic cells in the hyperplastic adrenals [48,49].

In a report of 30 patients with PBMAH, proopiomelanocortin (POMC) mRNA was detected in all 26 PBMAH adrenal gland samples analyzed; moderate/intense immunostaining for ACTH was detectable in clusters of steroidogenic cells in most samples [49]. Conversely, no ACTH staining was present in normal adrenal cortex or cortisol-secreting adenomas [49]. ACTH secretion was also confirmed by the demonstration of an ACTH gradient in adrenal vein sampling in two PBMAH patients, but ACTH plasma levels remained low.

In vitro, adrenal ACTH secretion was not regulated by corticotropin-releasing hormone (CRH), dexamethasone, or mifepristone. In contrast, tissues that expressed aberrant GPCRs released ACTH and cortisol during perifusion with GIP, serotonin, or hCG. ACTH receptor antagonists inhibited cortisol secretion by 40 percent in these tissues. Thus, in vitro studies show that cortisol production is apparently controlled both by aberrant GPCR and ACTH produced within the adrenocortical tissue, amplifying the effect of the aberrant receptors' ligands. The ectopic expression of POMC and synthesis of ACTH has been confirmed in PBMAH tissues in primary cultures; ACTH synthesis and aberrant GPCR were maintained in primary cultures of cells with or without ARMC5 (armadillo repeat-containing 5 gene) mutations [50]. The confirmation that paracrine adrenal production of ACTH and other peptides is central in cortisol regulation of PBMAH will necessitate confirmation by other groups and in vivo demonstration that inhibition of adrenal ACTH and other receptors reverses hypercortisolism in affected patients [48].

Genetic causes — Several molecular causes have been identified in the pathogenesis of primary PBMAH, indicating that it is a heterogeneous disease [7]. Most cases of PBMAH were thought to be sporadic [51-54]. However, there are now several reports of familial cases of PBMAH whose presentation suggests autosomal dominant transmission [16-18,55-60].

In familial cases of PBMAH, a number of aberrant hormone receptors, but no genetic abnormality, had been identified in individual families investigated initially, including V1-V2- and V3-vasopressin [17], beta-adrenergic [58], combined V1-vasopressin and beta-adrenergic [16,20], and combined 5-HT4 and V1-V2-vasopressin [18] (see 'Aberrant hormone receptors' above). Several genetic abnormalities have now been identified in PBMAH kindreds.

●Germline mutations of ARMC5 are found in approximately 25 percent of apparently sporadic PBMAH patients [61-65]. ARMC5 behaves as a tumor suppressor gene, and different somatic ARMC5 mutations or deletions were found in each adrenal nodule examined and appeared to accelerate the proliferation of affected cells [61,66,67]. In two studies, a high percentage of first-degree relatives of the probands carried a germline ARMC5 mutation and unsuspected PBMAH [61,63].

In one large family, which included 22 mutation carriers, two had Cushing's syndrome, 17 had only mild cortisol excess, while three patients aged 25, 29, or 76 years were silent carriers; in 6 of 22, only one adrenal was enlarged, suggesting variable penetrance of the ARMC5 mutation [63]. A high prevalence of biallelic ARMC mutations were identified in other families with PBMAH [20,68-71]. The relationship between ARMC5 mutations and aberrant receptors or ACTH expression has not been studied in detail yet; no ARMC5 mutation carriers had GIP-dependent Cushing's syndrome, but some had aberrant regulation by vasopressin, beta-adrenergic, and serotonin agonists [20,64,69]. Somatic mutation of ARMC5 was also found in meningiomas, which can occur in familial PBMAH, suggesting that other tumors could result from mutations of the ARMC5 tumor suppressor gene (which is expressed in several human tissues) [17,40,63,69]. Two models of ARMC5 gene knockout in mice should allow better understanding of the mechanisms of its mutations in adrenal proliferation and function [72,73].

However, in patients with bilateral adrenal incidentalomas, germline ARMC5 mutations are rarely found [74,75].

●Cushing's syndrome associated with McCune-Albright syndrome (MAS) is a rare variant of PBMAH that presents in infancy or childhood. MAS is a sporadic disease characterized by polyostotic fibrous dysplasia with café au lait spots, sexual precocity, and other endocrine and nonendocrine disorders [31,76]. An activating somatic of the alpha-subunit stimulatory guanine nucleotide-binding protein, Gs, occurs in some adrenal cells in a mosaic pattern, which leads to the formation of adrenal nodules [77,78]. Activating mutations of Gs alpha have been occasionally found in the PBMAH nodules of pediatric or adult patients without any other features of MAS [78,79]. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

●Bilateral adrenal nodules also have been described as part of multiple endocrine neoplasia syndrome type 1 (MEN1). A retrospective analysis of 715 MEN1 patients found the presence of adrenal lesions in 20 percent, and of those with lesions >1 cm, 12.9 percent had bilateral lesions without further evaluation of how many were PBMAH; most unilateral or bilateral tumors were nonfunctional, but primary aldosteronism was more frequent than in a control group of adrenal incidentalomas without MEN1 [80]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

●PBMAH or adrenal nodules have been reported in patients with familial adenomatous polyposis and a mutation in the adenomatous polyposis coli (APC) gene [7,81] and with hereditary leiomyomatosis and renal cell cancer disorders due to mutations in the fumarate hydratase (FH) gene [82]. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome'.)

●Missense germline mutations in phosphodiesterase 11A isoform 4 gene (PDE11A) have been identified initially in kindreds with nonpigmented micronodular hyperplasia but have now been found at higher frequency in patients with various adrenocortical tumors, including PBMAH [83]. As noted above, PBMAH is thus probably genetically heterogeneous, with occasional cases that occur in association with other syndromes [7,32,81,82,84,85], and this has been reviewed in further detail [86-88]. (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease".)

CLINICAL FEATURES

●Later age at onset – Patients with PBMAH and Cushing's syndrome typically present in the fifth and sixth decades [51-54], a later age of onset compared with unilateral adrenal cortisol-producing adenomas, primary pigmented nodular adrenocortical disease (PPNAD), or pituitary corticotroph adenomas (Cushing's disease).

●Bilateral adrenal incidentalomas, mild cortisol production – The majority of patients with PBMAH have only mild cortisol production and present with bilateral adrenal incidentalomas [1]. In these patients, no symptoms of Cushing's syndrome may be present, and the nodular adrenals are identified when abdominal imaging (ultrasound, computed tomography [CT] scan, or magnetic resonance imaging [MRI]) are performed for unrelated reasons.

In patients in whom cortisol secretion is sufficient to produce mild or overt Cushing's syndrome, the symptoms and signs are similar to other etiologies of primary adrenal Cushing's syndrome. (See "Epidemiology and clinical manifestations of Cushing syndrome".)

●Enlarged adrenals – Primary PBMAH is associated with adrenal glands weighing from 25 to 500 g (normal range 4 to 6 g per adrenal) that contain multiple nonpigmented nodules greater than 10 mm in diameter [51-53]. The enlargement of the adrenal glands is not associated with pain. The nodules appear to be typical benign adrenal nodules, but the internodular cortex may be either hyperplastic (in most cases) or atrophic. PBMAH may present with asynchronous nodular hyperplasia in one gland and later in the contralateral gland [1,39,63].

●PBMAH with overt Cushing's syndrome – Laboratory findings are similar to those seen in corticotropin (ACTH)-independent Cushing's syndrome with unilateral tumors and include the following (see "Establishing the cause of Cushing syndrome"):

•Increased serum and 24-hour urinary free cortisol (UFC) and low to undetectable plasma ACTH (<10 pg/mL [<2 pmol/L]) in the basal state and after administration of corticotropin-releasing hormone (CRH) [51-54]. (Cut-offs vary depending on normal range of ACTH assays.)

•Increased late-night salivary cortisol levels.

•Serum dehydroepiandrosterone sulfate (DHEAS) levels are usually suppressed as ACTH levels become suppressed.

•Cortisol production is not suppressed by low- or high-dose dexamethasone tests.

•An exception to this general pattern occurs in patients with gastric inhibitory polypeptide (GIP)-dependent Cushing's syndrome in whom cortisol hypersecretion occurs in response to meals and serum cortisol may be low in the fasting state [34,35]. (See 'Aberrant hormone receptors' above.)

•Steroid hormone synthesis is relatively inefficient in PBMAH, as a consequence of decreased steroidogenic enzymatic activity resulting frequently in elevated 17-hydroxyprogesterone levels basally or after stimulation with ACTH [6,11].

•Co-secretion of serum aldosterone, 18-hydroxycorticosterone, corticosterone, and estrone may cause hypertension, primary aldosteronism, or feminization in the rare patients in whom they are increased [26,89,90].

INITIAL EVALUATION

Bilateral incidentalomas

Hormonal hypersecretion — Most patients with PBMAH present with bilateral incidentalomas and mild cortisol excess (see 'Clinical features' above). Their initial evaluation is similar to that for a unilateral incidentaloma and includes tests to look for hormonal hypersecretion, most importantly, the degree of cortisol excess (Cushing's syndrome), but also catecholamine and aldosterone excess (eg, pheochromocytomas and aldosteronomas) (see "Evaluation and management of the adrenal incidentaloma", section on 'Evaluation for hormonal secretion' and "Evaluation and management of the adrenal incidentaloma", section on 'Subclinical Cushing syndrome'):

●1 mg overnight dexamethasone suppression test

●24-hour urinary metanephrine or plasma free metanephrine levels

●Aldosterone/renin ratio (only if the patient has hypertension)

In contrast with unilateral incidentalomas, the following additional testing is also indicated in patients with bilateral macronodules, including:

●Early-morning cortisol and corticotropin (ACTH) levels to rule out primary adrenal insufficiency from bilateral infiltrative/infectious/metastatic diseases.

●A serum 17-hydroxyprogesterone level is measured to rule out nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency, which may sometimes present as silent bilateral adrenal incidentalomas. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on '17-hydroxyprogesterone'.)

As noted, the majority of patients with primary PBMAH have no or mild clinical features of Cushing's syndrome. They have normal urinary free cortisol (UFC), detectable ACTH levels still responsive to corticotropin-releasing hormone (CRH), but with subnormal suppression of plasma cortisol following dexamethasone [4,5,11]. In these patients, low- or high-dose dexamethasone will produce partial suppression of cortisol but not to <1.8 mcg/dL (50 nmol/L) in the morning following nighttime 1 mg dexamethasone administration [4,9,11].

After a nighttime dose of dexamethasone (1 mg), a range of morning cortisol levels from 1.8 mcg/dL (50 nmol/L) to an intermediate level of 5 mcg/dL (140 nmol/L) to >10 mcg/dL (280 nmol/L) can be seen.

●Patients with serum cortisol concentrations >10 mcg/dL typically have elevated UFC, suppressed ACTH, and progressive clinical signs of Cushing's syndrome.

●Those between 1.8 and 10 mcg/dL may have minimal clinical manifestations, but this is probably also affected by various factors, including duration of disease and glucocorticoid receptor sensitivity.

One case of massive PBMAH in a male patient was found to produce large amounts of adrenal androgens (dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS]) without any cortisol excess (ACTH not suppressed) or clinical symptoms and was detected only as bilateral incidentaloma [91].

Degree of cortisol excess — So, if the initial screening with 1 mg overnight dexamethasone does not suppress cortisol to <1.8 mcg/dL (50 nmol/L), we perform the following additional tests to evaluate the degree of cortisol oversecretion:

●24-hour UFC (twice). (See "Establishing the diagnosis of Cushing syndrome", section on '24-hour urinary cortisol excretion'.)

●Salivary late-night cortisol (twice). This is a screening test for Cushing's syndrome and is described in detail separately. (See "Establishing the diagnosis of Cushing syndrome", section on 'Bedtime salivary cortisol'.)

●Fasting ACTH (if not done previously). (See "Establishing the cause of Cushing syndrome".)

●Aldosterone-to-renin ratio is performed to detect mild aldosterone excess, even in the absence of hypertension, when UFC is elevated and ACTH suppressed. Co-secretion of aldosterone can be seen in PBMAH. (See 'Aberrant hormone receptors' above.)

●Additional blood tests such as DHEAS levels, total testosterone, sex hormone-binding globulin (SHBG), and estradiol may be measured depending upon the clinical findings (eg, virilization in women, hypogonadism or gynecomastia in men, and patients with elevated UFC and suppressed ACTH).

Imaging findings — The results of adrenal computed tomography (CT) and magnetic resonance imaging (MRI) are variable, ranging from apparently unilateral nodules to massive bilateral enlargement [39,51-54,92]. Multiple nodules may be seen that are greater than 10 mm in diameter, but can be as large as 30 to 40 mm in diameter [1] (55 mm in one study [92]). However, in some cases, diffuse enlargement of both adrenals can be present without distinct nodules. In one series of 12 patients, 11 had enlarged multinodular glands; 9 patients underwent pituitary CT or MRI, and all were normal [92].

Adrenal scintigraphy with iodine-131 (131-I)-labeled cholesterol showed bilateral uptake in four of five patients in one report [92]. Although not widely available, this imaging technique could help identify which gland to remove if one chooses unilateral adrenalectomy. A preliminary study indicated increased fluorodeoxyglucose-positron emission tomography (FDG-PET) signal in PBMAH tissues despite absence of malignancy; the frequency of such increased FDG-signal uptake remains to be confirmed in larger cohorts [93,94].

DIAGNOSIS — The diagnosis of PBMAH is made in patients with:

●Overt Cushing's syndrome and suppressed corticotropin (ACTH) levels in whom bilaterally enlarged nodular adrenals are found at abdominal computed tomography (CT) scan (a minority of cases).

●Incidentally found bilateral adrenal hyperplasia with several macronodules in whom a subnormal suppression of cortisol is found (>1.8 mcg/dL or >50 nmol/L) following 1 mg overnight dexamethasone suppression test (the majority of cases).

However, in individuals with single nodules in each adrenal and subclinical cortisol secretion, the diagnosis could be bilateral adenomas or an early phase of PBMAH.

Differential diagnosis — Primary PBMAH, a pituitary ACTH-independent form of Cushing's syndrome, must be distinguished from (table 1):

●Unilateral cortisol-producing adrenal adenomas

●Primary pigmented nodular adrenocortical disease (PPNAD)

●Secondary ACTH-dependent macronodular adrenal hyperplasia (Cushing's disease or ectopic ACTH secretion)

Features that can help distinguish between these disorders include the following:

●Primary PBMAH versus secondary ACTH-dependent macronodular hyperplasias – Measure plasma ACTH:

•Plasma ACTH is suppressed by excess cortisol in PBMAH (<10 pg/mL [<2 pmol/L]). In contrast, ACTH is inappropriately normal or slightly high in ACTH-dependent macronodular hyperplasia (≥15 pg/mL [3.3 pmol/L]). (See "Establishing the cause of Cushing syndrome".)

•Rare patients with ACTH-dependent hyperplasia have low but consistently detectable plasma ACTH concentrations (≤10 pg/mL [2 pmol/L]), presumably due to its suppression by some of their adrenal nodules, which have acquired the capacity to secrete cortisol constitutively by unidentified mechanisms [95,96]. (See "Establishing the cause of Cushing syndrome".)

●Among the different primary adrenal sources of Cushing's syndrome, there are several features that are suggestive of PBMAH:

•Most patients with overt Cushing's syndrome due to PBMAH present in the fifth and sixth decades [51-54], a later age of onset compared with unilateral cortisol-producing adenomas or PPNAD.

•Size of adrenal gland nodules usually clearly distinguish PPNAD (micronodular) from PBMAH (macronodular).

•While the typical laboratory findings of PBMAH with overt Cushing's syndrome include high fasting serum and urinary cortisol and suppressed plasma ACTH and dehydroepiandrosterone sulfate (DHEAS) concentrations [51-54], an exception to this general pattern occurs in patients with PBMAH and gastric inhibitory polypeptide (GIP)-dependent Cushing's syndrome, in whom cortisol hypersecretion occurs in response to meals [34,35].

•Metastatic or infiltrative adrenal diseases – In PBMAH, the increase in cortisol following administration of exogenous ACTH is greater than in normal adrenals and reflects the large adrenal cell mass [6,8]. This biochemical finding can be useful in distinguishing PBMAH from other causes of bilaterally enlarged adrenals such as metastatic or infiltrative diseases, where steroidogenic response to ACTH administration is decreased. In PPNAD, cortisol response is usually limited following exogenous ACTH stimulation.

FURTHER EVALUATION AFTER DIAGNOSIS — Further evaluation is needed in patients diagnosed with PBMAH and overt or mild Cushing's syndrome.

Metabolic consequences of hypercortisolism — Once the diagnosis of PBMAH is established, further evaluation is necessary to look for potential metabolic consequences of cortisol excess. Patients should undergo evaluation for glucose intolerance and type 2 diabetes (fasting glucose, glycated hemoglobin [A1C] levels, or oral glucose tolerance test [OGTT]), hypertension (including 24-hour monitoring if necessary), coronary heart disease, and bone health (bone mineral density and vertebral fracture assessment).

Screening for aberrant receptors — In our center and several other academic centers [1,4-9,11,13-19,21-23,25,27-30,34-40,45], we suggest that patients with PBMAH and clinical or mild Cushing's syndrome undergo screening for aberrant receptors as this may change the therapeutic strategy (table 2). Protocols have been developed to systematically evaluate for these aberrant receptors (table 2) [4-9,12].

The strategy is to examine whether cortisol or other steroids change in response to physiological (upright posture, mixed meals) and pharmacologic (gonadotropin-releasing hormone [GnRH], vasopressin, glucagon, metoclopramide) tests that modulate the levels of ligands for the potential aberrant receptors. Of note, thyrotropin-releasing hormone (TRH) testing has rarely yielded aberrant responses, and TRH is not widely available. We therefore do not consider TRH testing to be necessary when screening for aberrant receptors.

Another group has suggested restricting tests to those for which a therapy is possible, ie, mixed meal, posture test, and luteinizing hormone-releasing hormone (LHRH) test [97]. As this disease is relatively rare, we recommend that patients be referred to expert centers that can offer detailed investigation capacity.

Screening family members — First-degree relatives (>25 years of age) of patients with PBMAH who do not carry armadillo repeat-containing 5 (ARMC5) gene mutations should be screened for PBMAH by first looking for evidence of hypercortisolism. This can be done with an overnight 1 mg dexamethasone test; those who do not suppress their plasma cortisol on the following morning below 1.8 mcg/dL (50 nmol/L) should undergo adrenal computed tomography (CT) scan to look for possible features of PBMAH (adrenal nodules, bilateral enlargement). (See "Dexamethasone suppression tests", section on 'Overnight screening test' and 'Imaging findings' above.)

●Family members who are found to have PBMAH should undergo detailed biochemical and clinical investigation described above and targeted evaluation for the aberrant hormone receptors that were found in the initial case if it can lead to specific targeted medical therapy.

●Patients with PBMAH associated with other genetic causes such as multiple endocrine neoplasia syndrome type 1 (MEN1) or familial adenomatous polyposis should undergo the recommended evaluation/screening for those disorders. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors' and "Familial adenomatous polyposis: Screening and management of patients and families".)

●The search for germline ARMC5 mutations (and possibly other genes as more are identified) now allows familial screening through a simple blood test and identify who should undergo further evaluations [48,61]. (See 'Genetic causes' above.)

TREATMENT — The initial patients identified with PBMAH were evaluated because of severe Cushing's syndrome and underwent bilateral adrenalectomy. However, considering the wide range of clinical presentations from asymptomatic bilateral incidentaloma cases to overt Cushing's syndrome, we currently recommend the following approaches based on severity of cortisol excess:

Patients without aberrant receptors

Overt Cushing's syndrome

Bilateral adrenalectomy — We suggest bilateral surgical adrenalectomy for patients with PBMAH, equally enlarged macronodular adrenals, and clinically severe Cushing's syndrome (elevated urinary free cortisol [UFC] >3 times above upper limit of normal in repeated samples) who have no evidence of aberrant receptors that would be amenable to specific medical therapy. Surgical bilateral adrenalectomy is uniformly effective in these patients. Unilateral adrenalectomy is sometimes performed if one adrenal is much larger than the other as this could also result in normalization of UFC without permanent adrenal insufficiency [3,98].

We agree with the Endocrine Society guidelines and suggest thromboprophylaxis in patients with overt Cushing's syndrome going to surgery because of their high risk of thromboembolism [99] (see "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Thromboembolic events'). Post-adrenalectomy, these patients will require lifetime glucocorticoid and mineralocorticoid replacement but are not at risk for Nelson syndrome (corticotroph tumor progression), because the pituitary is intrinsically normal. Therefore, pituitary radiation to prevent Nelson syndrome is unnecessary. (See "Persistent or recurrent Cushing disease: Surgical adrenalectomy", section on 'Nelson syndrome'.)

Adrenal enzyme inhibitors are sometimes given to patients with overt Cushing's syndrome to control cortisol secretion before surgery, particularly if surgery needs to be delayed for some underlying condition such as infection, recent cerebrovascular or coronary event, or pulmonary emboli [100,101]. (See "Medical therapy of hypercortisolism (Cushing's syndrome)", section on 'Initial therapy'.)

Surgical adrenalectomy, including surgical approach and postoperative hormone replacement, is discussed in greater detail separately. (See "Persistent or recurrent Cushing disease: Surgical adrenalectomy" and "Adrenalectomy techniques".)

Modest cortisol excess

Unilateral adrenalectomy — In patients with moderately increased cortisol production (the majority of PBMAH patients with Cushing's syndrome have less than threefold increase in UFC levels) but with clinical evidence of cortisol excess, we suggest unilateral adrenalectomy as it can restore UFC levels to normal [3,102-105]. However, as the cell mass subsequently increases in the contralateral adrenal, medical therapy with steroidogenesis inhibitors or a second adrenalectomy may become necessary [98,102-104,106].

In a review of 117 PBMAH cases from 23 publications treated with unilateral adrenalectomy, initial remission was achieved in 109 patients (93 percent). A total of 18 patients (15 percent) experienced a recurrence of hypercortisolism, and 16 patients (14 percent) required a completion contralateral adrenalectomy within a median time of 72 months. Transient hypocortisolism occurred in 32 percent and require careful monitoring and replacement with glucocorticoids [3].

In 15 patients with PBMAH treated by unilateral adrenalectomy, resection of the larger gland led to remission of hypercortisolism after three months in all 15 patients and a low risk of recurrence. In a second study of 25 PBMAH cases undergoing unilateral adrenalectomy, biochemical remission was initially achieved in 21 (84 percent) [106]. After a median of 50 months of follow-up, only eight patients (32 percent) were still biochemically controlled. Adrenalectomy of the contralateral side had to be performed in three (12 percent).

We do not suggest adrenal venous sampling to select which adrenal to remove, as standardization for data interpretation are lacking. In the largest study of 10 patients, an adrenal/peripheral vein ratio of ≥6.5 was considered consistent with a cortisol hypersecretion, and a cortisol lateralization ratio of ≤2.0 was in favor of bilateral source of cortisol [107]. The largest adrenal gland on computed tomography (CT) scan is selected for unilateral adrenalectomy [3].

Some experts have proposed alternative conservative surgical procedures in PBMAH patients with unilateral adrenalectomy on one side and subtotal contralateral adrenal resection [108,109]. In 17 patients, including 10 patients with modest cortisol excess, 95 percent achieved complete hypercortisolism control postoperatively, while 71 percent experienced recovery of their hypothalamic-pituitary-adrenal (HPA) axis at a median follow-up of 41 months. Only one patient developed relapse of hypercortisolism after 30 months requiring a completion surgery [109]. However, as many patients had only modest cortisol excess, the risk-benefit ratio of performing a bilateral procedure over unilateral adrenalectomy alone is not clear. It may be further evaluated prospectively in more severe cases rather than bilateral adrenalectomy [3].

Minimal cortisol excess

Monitoring without surgery — In patients with very mild cortisol excess (normal UFC, normal corticotropin [ACTH], cortisol suppression following 1 mg overnight dexamethasone <5 mcg/dL) who are being monitored without adrenal surgery, clinical evaluation and biochemical assessment (1 mg overnight dexamethasone test, UFC, basal ACTH, fasting glucose) every 6 to 12 months and yearly CT scan are sufficient as PBMAH is a benign process that has not been shown to become malignant.

We suggest unilateral adrenalectomy if there is disease progression with increased UFC, complete suppression of ACTH, and clinical effects of hypercortisolism such as osteoporosis, diabetes, hypertension, or neuropsychological manifestations (see 'Unilateral adrenalectomy' above). As studies in unilateral adrenal incidentaloma have reported progressive adverse cardiovascular outcomes in patients with plasma cortisol >5.1 mcg/dL (140 nmol/L) after a 1 mg dexamethasone test [110,111], we are more commonly referring patients to unilateral adrenalectomy when signs of cortisol excess develop.

Patients with PBMAH and aberrant receptors

Pharmacologic therapy — In some patients in whom aberrant hormone receptors have been identified, specific pharmacologic therapies blocking the aberrant receptors can be effective as alternatives to adrenalectomy. Despite normalization of cortisol secretion with specific aberrant receptor-targeted therapy, no tumor regression has been observed; this may be secondary to incomplete receptor blockade or to the possibility that proliferation is regulated by armadillo repeat-containing 5 gene (ARMC5) mutations or other secondary genetic events [5,44,61,112].

●We suggest beta blocker therapy for PBMAH patients with Cushing's syndrome and aberrant beta-adrenergic receptors. In catecholamine-dependent Cushing's syndrome and PBMAH, beta-adrenergic receptor antagonists (propranolol) are effective in the long-term control of hypercortisolism [10,19,22]. Propranolol can be started at 60 mg/day, increasing every two weeks up to 320 mg/day in two to three divided doses in order to achieve mid-normal levels of UFC. We suggest monitoring patients weekly initially for the first month (UFC, blood pressure, pulse), monthly for three months and every three months if stable afterwards.

In patients who experience side effects such as nightmares or who have compliance problems with split doses of propranolol, we have used nadolol, another nonselective antagonist that is administered as a single daily dose (40 to 320 mg).

Symptomatic bradycardia without reaching normalized UFC may limit the use of beta-adrenergic receptor antagonists so that bilateral adrenalectomy is required. If beta-adrenergic receptor antagonists do not normalize UFC, we suggest adrenalectomy. (See 'Bilateral adrenalectomy' above.)

●We suggest gonadotropin-releasing hormone (GnRH) agonist therapy for patients with luteinizing hormone (LH) or human chorionic gonadotropin (hCG) receptors. In LH/hCG-dependent PBMAH and Cushing's syndrome, suppression of endogenous LH levels with long-acting leuprolide acetate controlled steroid secretion and avoided bilateral adrenalectomy [23,25]. We typically use a monthly dose of depot leuprolide acetate (3.75 mg intramuscular).

Levels of 24-hour UFC, morning plasma cortisol, and LH levels are monitored two and four weeks after the first injection. Treatment is continued if UFC normalizes or improves at least by 50 percent within the first three months based upon two UFC samples each month. If UFC levels are not normalized within three months, unilateral or bilateral adrenalectomy is recommended, depending on levels of cortisol excess as described previously.

For patients who are well controlled on GnRH agonist therapy, we suggest follow-up every three to four months for the first year (with UFC, morning plasma cortisol, and serum LH). Of note, we have followed patients every six months thereafter; some have remained controlled for more than 10 years. In premenopausal women or males, we suggest adding gonadal steroids to the GnRH agonist to avoid the consequences of hypogonadism (estrogen-progestin therapy in women and testosterone in men). We also suggest monitoring bone mineral density. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'GnRH with add-back therapy'.)

●In patients with gastric inhibitory polypeptide (GIP)-dependent Cushing's syndrome, we suggest surgical adrenalectomy rather than pharmacologic therapy (see 'Aberrant hormone receptors' above). Pharmacologic blockade of postprandial release of GIP with octreotide or pasireotide leads to clinical and biochemical improvement of Cushing's syndrome, but the beneficial effect does not persist in the long term, probably because of eventual desensitization of somatostatin receptors in GIP-secreting duodenal K cells [35,36,40]. Thus, we suggest surgical adrenalectomy in these patients.

●When specific receptor antagonists for ACTH, vasopressin, serotonin, GIP, or other aberrant receptors become available, a broader range of pharmacologic therapies could become useful [48,49]. Until these become available, surgical adrenalectomy is recommended.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome".)

SUMMARY AND RECOMMENDATIONS

●Primary bilateral macronodular adrenal hyperplasia (PBMAH) has been described by various terms, including corticotropin (ACTH)-independent macronodular adrenal hyperplasia (AIMAH), primary macronodular adrenal hyperplasia (PMAH), massive macronodular adrenocortical disease (MMAD), autonomous macronodular adrenal hyperplasia (AMAH), ACTH-independent massive bilateral adrenal disease (AIMBAD), and "giant" or "huge" macronodular adrenal disease. (See 'Pathogenesis' above.)

●PBMAH is more frequently familial than previously believed (autosomal dominant transmission), and approximately 25 percent of apparent sporadic cases carry a germline mutation of armadillo repeat-containing 5 gene (ARMC5). The disease appears heterogeneous as several other genetic abnormalities can be rarely associated. (See 'Genetic causes' above.)

●PBMAH results in hypercortisolism through a number of mechanisms that are described above (see 'Pathogenesis' above). In the majority of patients with PBMAH, cortisol appears to be regulated by a number of aberrant G-protein-coupled receptors (GPCRs) and by locally produced ACTH. Aberrant receptors include vasopressin, serotonin 5-hydroxytryptamine 4 (5-HT4), gastric inhibitory polypeptide (GIP), beta-adrenergic, luteinizing hormone (LH)/human chorionic gonadotropin (hCG), and others. (See 'Aberrant hormone receptors' above.)

●The clinical presentation and biochemical findings of Cushing's syndrome in PBMAH are similar to those seen in other types of ACTH-independent Cushing's syndrome. However, patients with PBMAH typically have a later age of onset (fifth and sixth decades), and patients with GIP-dependent Cushing's syndrome have a unique pattern of cortisol hypersecretion ("food dependent") (table 1). (See 'Aberrant hormone receptors' above.)

●The diagnosis of PBMAH is made in patients with overt Cushing's syndrome and suppressed ACTH and dehydroepiandrosterone sulfate (DHEAS) levels with bilaterally enlarged nodular adrenals. The diagnosis is also made in patients with incidentally found bilateral diffusely enlarged adrenals or with multinodular adrenals and mild hypercortisolism in whom a subnormal suppression of cortisol is found (>1.8 mcg/dL or >50 nmol/L) following 1 mg overnight dexamethasone suppression test. (See 'Diagnosis' above.)

●Patients with PBMAH can be distinguished from those with chronic ACTH-dependent Cushing's syndrome (Cushing's disease or ectopic ACTH) with bilateral nodular adrenal hyperplasia who have elevated ACTH levels. (See 'Differential diagnosis' above.)

●Patients with PBMAH and clinical or mild Cushing's syndrome should undergo testing for aberrant receptors as this may change the therapeutic strategy. (See 'Aberrant hormone receptors' above and 'Screening for aberrant receptors' above.)

●In addition, we recommend screening of first-degree relatives of index cases without known genetic mutation using 1 mg overnight dexamethasone suppression test for the presence of familial PBMAH. Genetic screening for ARMC5 (or eventually other genes responsible for PBMAH) has become available to screen first-degree relatives of index cases. (See 'Screening family members' above.)

●In patients with PBMAH in whom aberrant hormone receptors are not present or for which no specific pharmacologic blockade is available or effective:

•We perform bilateral adrenalectomy for very severe Cushing's syndrome with urinary free cortisol (UFC) >3 times the upper limit of normal and equally enlarged adrenals. (See "Persistent or recurrent Cushing disease: Surgical adrenalectomy".)

In similar patients but with very asymmetric adrenal size, unilateral resection of the largest adrenal can be performed. (See 'Unilateral adrenalectomy' above.)

•In patients with moderately increased cortisol production (less than threefold increase in UFC levels) and clinical evidence of cortisol excess, we suggest unilateral adrenalectomy as it can restore UFC levels to normal (Grade 2C) (see 'Unilateral adrenalectomy' above). Such patients can present transient secondary adrenal insufficiency and require glucocorticoid replacement postoperatively.

•In patients with PBMAH and normal levels of urinary cortisol, the decision between observation and surgery should be based on biochemical (suppressed ACTH, elevated late-night salivary cortisol, and cortisol >5 mg/dL following 1 mg dexamethasone overnight test) and clinical evidence of cortisol excess (hypertension, diabetes, osteoporosis, or neuropsychological manifestations). (See 'Minimal cortisol excess' above.)

●For patients with PBMAH and overt Cushing's syndrome regulated by aberrant receptors (see 'Patients with PBMAH and aberrant receptors' above):

•We suggest treatment with beta-blockers for patients with PBMAH and aberrant beta-adrenergic receptors (Grade 2C). (See 'Pharmacologic therapy' above.)

•We suggest treatment with gonadotropin-releasing hormone (GnRH) agonists (and sex steroid replacement) for patients with PBMAH and LH/hCG receptors (Grade 2C). (See 'Pharmacologic therapy' above.)

DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.