Apparent activities of 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase are impaired in adrenal incidentalomas

Abstract

Objective: An increased response of 17-hydroxyprogesterone to ACTH stimulation has been observed in adrenal incidentaloma and linked to an impairment of either 21-hydroxylase or of 11b-hydroxylase activity. To analyse this question further, we investigated the steroidogenic pathways in a series of 17 adrenal incidentalomas. Design and Patients: 17 patients (7 women, 10 men; mean age, 62 Ϯ 12 years) with non-histologically analyzed adrenal incidentalomas were prospectively evaluated. Methods:The following variables were investigated: 24-h urinary methanephrines and free cortisol excretion; plasma levels of ACTH and dehydroepiandrosterone; overnight dexamethasone suppression test; 1-24 ACTH stimulation test with measurement of: cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, aldosterone, 11-deoxycorticosterone, progesterone, 17-hydroxypregnenolone, D4-androstenedione, dehydroepiandrosterone and 21-deoxycortisol. Results: Discordant features of subclinical hypercorticism were noted in one case. No patient had dehydroepiandrosterone sulfate levels in the normal range for his or her age. Peak 17-hydroxyprogesterone and peak 21-deoxycortisol disclosed impairment of 21-hydroxylase in 11 and 10 cases respectively. An increased 11-deoxycortisol/cortisol ratio identified reduced activity of 11b-hydroxylase in 11 patients. Eight patients displayed features of mild 17,20-lyase impairment, which was related to 21-hydroxylase dysfunction. Whereas only 2 patients showed no enzyme modification, 9 displayed alterations of at least two pathways. Conclusion: In our hands, a combination of enzyme dysfunction was frequently observed. Shared biochemical mechanisms could explain combined 17,20-lyase and 21-hydroxylase alterations, whereas coexistence of 21-hydroxylase (particularly when based on peak 21-deoxycortisol) and 11b-hydroxylase is more puzzling.

Coexistence of 21-Hydroxylase and 11β-Hydroxylase Deficiency in Adrenal Incidentalomas and in Subclinical Cushing’s Syndrome

“…On the whole, a hyperresponsiveness of 17-OHP and S levels after stimulation has been frequently found in adrenal incidentalomas, and this seems to be correlated with the size of these lesions, as demonstrated in our series and by others [9, 10]. These findings, however, do not clarify whether the abnormal responses may be consequent to an alteration of intratumoral steroidogenesis, as suggested by the normalization of 17-OHP and S peaks in 7 of 8 operated patients; alternatively, a congenital enzymatic deficiency may be present, as presumable in rare instances of unmodified responsiveness after surgery.…”

“…While no evidence of 11β-hydroxylase deficiency was observed in preliminary reports [11, 12], Sadoul et al [9]obtained a greater frequency of 11β-hydroxylase alterations in a smaller group of patients; however, in the latter study the upper limits of normal S peak and of stimulated S/F ratio – as determined from literature data – were lower than those obtained in our normal controls. Interestingly, these authors supported the concept of complex enzymatic alterations in adrenal incidentalomas by identifying also an apparent decreased activity of 17,20-lyase in 47% of the patients [9]. …”

“…The present observation of high 17-OHP/S and 17-OHP/F ratios after ACTH in many hyperresponsive patients supports the impaired activity of 21-hydroxylase; in contrast, the finding of a normal 17-OHP/S ratio in 6 cases may suggest the coexistence of a partial deficiency of 11β-hydroxylase, as confirmed by the concomitant high S/F ratio in the same patients. Accordingly, Sadoul et al [9]reported an elevated 17-OHP/S ratio in 2 of their 11 cases with a high 17-OHP peak after ACTH as a consequence of a concomitant increase of S levels.…”

“…Particularly, low dehydroepiandrosterone sulfate (DHEA-S) levels, mild forms of 21-hydroxylase deficiency, high or upper-normal urinary free cortisol (UFC) excretion, and lack of cortisol suppressibility by low-dose dexamethasone have been reported [3, 4, 5, 6, 7]. Exaggerated responses of 17-hydroxyprogesterone (17-OHP) after adrenocorticotropic hormone (ACTH) stimulation, probably due to a low 21-hydroxylase activity, have been observed in about 30–65% of the patients by many authors [3, 4, 6, 8, 9, 10]. Although it has been suggested that the exaggerated response of 17-OHP could result from other defects, such as 11β-hydroxylase deficiency, or from a combined impairment of enzymatic activities [5], the frequency of enhanced 11-deoxycortisol (S) rises after ACTH has been less extensively investigated [5, 9].…”

A unique case of a benign adrenocortical tumor with triple secretion of cortisol, androgens, and aldosterone. Development of multiple sclerosis after surgical removal of the tumor

“…[9][10][11][12][13] In our case reduced activity of 21-hydroxylase within the tumor (normal 17OHP levels after tumor excision) could account for the exaggerated response of 17OHP to ACTH, and the increased testosterone, and Ä 4Á levels. Similar overresponse of 17OHP to ACTH has been described before in ten patients with sub-clinical Cushings syndrome, 14 showing that alterations in enzymatic pathways can coexist with the presence of cortisol autonomy.…”