The prevalence of PBMHA in patients with AIs and with bilateral AIs and subtle hypercortisolism in our series was of 4.2% and 31.6%, respectively. The prevalence of PBMHA has not been determined in popular studies despite the fact that 15% of AIs are bilateral [6] and up to 40% of bilateral lesions are associated with ACS [9]. Song et al. reported a cohort of 1049 patients with AIs [14] and showed that only 1 patient (0.1%) had PBMHA. Lomte et al. [5] retrospectively analysed a cohort of 70 patients with bilateral adrenal masses and they found that only 3 patients (4.3%) harboured PBMHA. The prevalence of PBMHA in our cohort is higher than in those two other studies. This may be explained by the fact that in the cohort of Song et al. [14] the diagnosis of PBMHA was established by histology (the number of biopsied masses was low, only 12) and not on the basis of the secretory profile and radiological features. The differences with Lomte et al.´s study [5] can be attributed to the higher prevalence of familial pheochromocytoma (40%) and tuberculosis (27.1%) which is more prevalent in India than in our country.
Patients with PBMHA presented a prevalence four times greater of ACS than non-PBMHA, but these differences were related to a higher tumour size and total adenomatous mass of patients with PBMHA. The ACS prevalence in AIs is widely variable in the previous reported studies [12][15][16]. In two observational studies performed in Italian population, the prevalence of ACS varied from 9,2% in a multicentre cohort with more than a thousand patients with AIs [15] to 29% in a small group of 41 patients with AIs and typical adrenal adenoma image [16]. However, no previous study compared the prevalence of ACS in PBMHA vs. other bilateral AIs without PBMHA definition criteria. Therefore, we believe that larger prospective and multicentre studies should be carried out to confirm our findings.
Regarding tumour size and ACS risk, there is some discrepancy in previous studies about the prevalence of ACS and the size of AIs. In accordance with our findings, Vassiliadi et al. [9] found a significantly higher size and levels of cortisol after DST in bilateral AIs when compared with unilateral lesions. Besides, the ACS was diagnosed in more patients with bilateral than in unilateral AIs (41.5% vs 12.2%, respectively), even when various criteria were used to define the ACS. In another small retrospective study with 33 bilateral AIs (5 of them PBMAH), those subjects with positive responses to the aberrant receptor study had bigger adenomas, higher cortisol levels after DST, higher night cortisol levels and a tendency to lower levels of ACTH [17]. According to these results, it seems that the significant higher size of the bilateral lesions could justify the more frequency of ACS in this group. Perhaps, the larger tumour size in bilateral than in unilateral AIs could be related to a longer duration of the disease in bilateral tumours, which may also explain the higher risk of ACS. On the other hand, Morelli et al [18] performed a prospective study with 175 patients with unilateral AIs and 38 with bilateral AIs (30 of them corresponding to PBMAH), and although the maximum diameter of the adrenal lesions was significantly higher in bilateral than unilateral forms, the magnitude of hypercortisolism was similar in both unilateral and bilateral AIs.
Despite the higher prevalence of ACS in patients with PBMHA than in non-PBMHA, no differences in the cardiometabolic risk were observed between them. To our knowledge, no previous study has analysed this issue. Previous AIs incidentalomas series focused in the differential phenotype of unilateral and bilateral AIs have described similar results [19][18][20]. Actually, the lack of association of bilateral AIs with ACS-related comorbidities was observed in some studies reporting an association between the prevalence of ACS and bilaterality of AIs [19][18]. This finding could be related to the presence of different sensitivity to hypercortisolism, in patients with bilateral AIs [21]. In this sense, Majnik et al [21] found that the prevalence of T2DM in patients with bilateral AIs (40.9%) was significantly higher compared with unilateral adrenal tumours (23.2%). This could be related with the higher prevalence of N363S variant in bilateral AIs suggesting a role in the pathogenesis in bilateral AIs. Even though, the studies that focused on the role of single-nucleotide polymorphisms (SNP) of the glucocorticoid (GC) receptor gene analysis in the risk of ACS in AIs found controversial results [21][22]. Some authors showed an association between GC receptor SNP and ACS risk [23] [24], other authors [22][21][25] found that the presence of SNP of GC receptor did not influence the development of Cushing’s disease, or adrenal dependent Cushing´s syndrome. So, scanty data are available in patients with AIs to confirm the hypothesis that single polymorphic variant could influence cortisol secretion and risk of comorbidities, and even less about the differences in GC receptor SNP prevalence in bilateral and unilateral AIs.
Aberrant receptors study was positive in 60% of patients with PBMHA, being metoclopramide test the most frequently altered. Previous studies also described that aberrant receptors are highly prevalent in PBMHA [26][27][28]. Hsiao et al. [26] showed that the most frequent response to aberrant receptor expression tests in 14 patients with PBMHA was vasopressin (45.5%); Mircescu et al. [27], described AVP administration and upright posture test (in 3 of 6 patients with PBMHA) as the most affected one; Libé et al. [28] showed in a prospective study of 32 patients with PBMAH, that the most frequently observed responses were to upright posture (67%) and metoclopramide (56%) tests. Therefore, most studies, including ours, supported that vasopressin and serotonin receptors are probably the more prevalent functional receptors in PBMAH, which is in accordance with previous reports [29][30].
The presence of abnormal receptors can lead to innovative pharmacological therapies as alternatives to adrenalectomy, including suppression of the ligands or the use of specific receptor antagonists [27]. However, it should be noted that in none of the 2 patients of our study the medical treatment was effective. Libé et al. [28] found an inhibition of cortisol secretion by octreotide in the three Cushing’s syndrome patients who positively responded to the mixed meal, in all the glucagon responsive patients, and in 12 of 13 (92%) patients with ACS. In accordance with this, previous studies demonstrated a correction of hypercortisolism with chronic subcutaneous octreotide administration in patients with food-dependent Cushing’s syndrome [31][32], and endogenous GIP levels inhibition is thought to be the possible underlying mechanism [17]. Moreover, long-term control of hypercortisolism has also been obtained by blockade of ectopic ᵦ-adrenergic receptor with propranolol [27][33] and by inhibition of LH secretion with leuprolide acetate [27][34]. In contrast, Albiger et al. [35] reported, on the follow-up of 16 patients with PBMAH and Cushing’s syndrome, one case with food-dependent CS treated with octreotide LAR and two patients with a positive postural test treated with propranolol, with a limited clinical response despite marked improvement in biochemical values. Thus, surgery is the current recommended therapy for PBMAH [36]. However, adrenal steroidogenesis inhibitors remain a valid option for nonsurgical candidates.
One of the major strengths of our study is that it includes a large number of subjects who were consecutively evaluated in our centre between 2013 and 2019, and the long-term follow-up. Moreover, this is the first study focusing on the differential phenotype of PBMHA compared to other bilateral AIs with associated MACE. The limitations are mainly related to the retrospective nature of the study, and the possible bias induced by individual decisions for adrenalectomy or medical treatment of comorbidities. Moreover, information in the last visit was not available in all patients, so a follow-up bias should be considered.