With the increasing use of ultrasonography and computed tomography, incidentally discovered adrenal tumors are common, with a prevalence of at least 3% among the general population over the age of 50 years [1]. Although most of these tumors are nonfunctioning adrenocortical adenomas [2], 5% to 30% of patients with adrenal incidentaloma show some degree of hypercortisolism without typical signs or symptoms of overt Cushing syndrome (OC) [34]; this is called ‘subclinical Cushing syndrome (SC).' Although SC and OC have been considered different diseases with different genetic alterations [5], in SC, it is assumed that cortisol production is insufficient to cause a clinically recognizable syndrome and to suppress the release of corticotropin releasing hormone and adrenocorticotropic hormone (ACTH). Temporary adrenal insufficiency lasting several months ensues from surgical resection of an autonomously functioning adrenal tumor in OC due to suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis, during which glucocorticoid replacement is mandatory. However, it is still unclear whether all adrenalectomized patients with SC also exhibit the HPA axis impairment observed in OC.

The aims of this study were to evaluate the different degrees of cortisol excess and the HPA axis recovery time after adrenalectomy in patients with SC and OC. Moreover, we wanted to determine the relationship between the degree of cortisol excess and the HPA axis recovery time after surgery.

According to our results, patients with SC showed a lower degree of cortisol excess than did those with OC. The recovery time was shorter in patients with SC than that of OC. The degree of cortisol excess was accompanied by a difference in the recovery time of the HPA axis after surgery in all subjects.

SC is a status of cortisol excess defined by dynamic hormonal tests in patients with adrenal incidentalomas who have no overt symptoms of Cushing syndrome [89]. SC was initially defined as preclinical Cushing syndrome [10]; however, it has been considered a different disease category than OC. Different molecular pathogenetic mechanisms have been reported in SC compared with OC [5], and about two-third of SC remain subclinical during long-term clinical follow-up of SC [11]. Comparison of cortisol levels showed clear differences in clinical characteristics: patients with OC had more severe biochemical activity parameters than did those with SC [5]. These findings are similar to those of our study.

To date, the definition of SC is still controversial, and there is no gold standard diagnostic test because of the low reliability of the available hormonal assays (24-hour UFC, ACTH levels, and DST) [12]. DST is the most important diagnostic method to evaluate cortisol excess, but there has been no consensus on the cut-off level to use for diagnosis of SC. We used a low cut-off value (1.8 µg/dL) for excellent sensitivity of the test, despite the decline in specificity, and 2-day LDSTs (2 mg) and HDSTs (16 mg) were performed as confirmative tests, also with a low cutoff value (1.8 µg/dL) [12].

Untreated Cushing syndrome has an increased mortality rate due to cardiovascular, thromboembolic, and infectious complications [1314]. Although patients with SC show subtle cortisol excess, they usually exhibit one or more symptoms from cortisol excess, including hypertension, diabetes, dyslipidemia, and osteoporosis [151617]. In our results, there were no differences in the frequencies of hypertension, diabetes, and obesity between patients with SC and OC. Although the most appropriate treatment for SC remains controversial, surgical resection of adrenal tumors has shown beneficial effects on cardiovascular risk factors in most studies, with low surgical morbidity rates [1819].

Cortisol oversecretion from autonomously hyperfunctioning adenomas of the adrenal gland leads to suppression of the HPA axis, resulting in hypofunctioning of the contralateral adrenal gland. The recovery of the HPA axis may be delayed; therefore, the patient often requires glucocorticoid replacement therapy for several months to a year and sometimes even longer after adrenalectomy. However, adrenal insufficiency did not occur in 27% of the patients with SC, whereas all OC patients showed adrenal insufficiency in our study. HPA axis recovery time was shorter in patients with SC than those with OC (4.0 months vs. 17.0 months, P<0.001), and it correlated well with preoperative cortisol levels. Few studies have compared the recovery time between patients with OC and SC. Di Dalmazi et al. [20] reported that only 65% of SC patients had postsurgical adrenal insufficiency, compared with 99.7% of OC patients. They also reported that the mean recovery time was 6.5 months (range, 1 to 50) in SC patients and 11.2 months (range, 1 to 60) in those with OC, and they observed a tight relationship between the degree of hypercortisolism and the time to recovery, similar to our data. Some studies reported that old age at surgery is a critical factor influencing recovery time in patients with adrenal CS [2122], but the clinical features were only explained as a factor influencing recovery time in patients with adrenal CS independently of age in our study by multivariate analysis. These results support that SC patients have a lower degree of cortisol excess that is not sufficient to fully suppress the HPA axis. However, Berr et al. [22] reported that ectopic CS, which had the highest cortisol excess, showed the shortest recovery time, compared with CS due to adrenal or pituitary etiologies. In general, ectopic CS shows rapid progression of the disease compared with adrenal CS; therefore, the recovery time might be influenced not only by the degree of cortisol excess but also by the period of exposure to cortisol excess. This is explained by findings of adrenal insufficiency after exposure to exogenous steroids. Adrenal insufficiency is frequently seen in patients treated with long-term glucocorticoids and is related to the duration and the cumulative dose of steroids [23].

There were several limitations in this study. First, the clinical features defining OC may vary among patients treated by different physicians. The clinical symptoms and signs of CS overlap those of many other common diseases, but CS displays more specific signs, such as muscle weakness, ecchymoses, and central obesity. In our study, three experienced endocrinologists confirmed whether the patient had OC or SC. Seconds, the correlation between the recovery time and preoperative cortisol levels showed statistically significant in all subjects, but the significance disappeared in the subgroup analyses of each patient with OC or SC. This finding is limited by the small sample size. Last, the dosage of steroid replacement and the time to evaluate the patient using a postoperative cortisol stimulation test (rapid ACTH stimulation test) were not controlled, because this study was retrospective. The intervals between tests were variable, ranging from 1 to 6 months, but this should not have been a significant issue, since we decided the timing of the test while decreasing the steroid dosages, levels of morning cortisol and watching the signs and symptoms of patients during follow-up at 1-month intervals.

In conclusion, the degree of cortisol excess differs between the two disease categories, and the time to adrenal function recovery was associated with the degree of cortisol excess. Some of the patients with SC showed no suppression of the HPA axis, and the majority of patients with SC recovered rapidly from HPA suppression within several months. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients.