Use of ketoconazole in the treatment of a virilizing adrenocortical carcinoma

Abstract

Ketoconazole, an oral antimycotic agent, is known to have a potent inhibitory effect on adrenal steroid production. It was given at a dose of 1200 mg/day to a 52-year-old female patient with a virilizing adrenocortical carcinoma in order to achieve better metabolic control pre-operatively. Together with a rapid normalisation of hypertension and hyperglycemia, a dramatic fall was noticed in serum and urinary adrenal steroids after a few days. Levels of total testosterone (20 nmol/l), androstenedione (>35 nmol/l) and DHEA-sulphate (>28 nmol/l) fell to normal levels in 6 days. By contrast, levels of 17-OH\x=req-\ progesterone (30 nmol/l) and progesterone (2.45 nmol/l) increased slightly, indicating inhibition af adrenal 17, 20\ x=req-\ lyase. Cortisol (620 nmol/l at 08.00 h) fell to very low levels (50 nmol/l) on day 6 of the trial. We conclude that ketoconazole is very effective in suppression of adrenal tumoural steroidogenesis and merits consideration in pre-operative use. We warn against dangerous hypoadrenalism which seems to occur earlier in tumoural than in normal adrenal metabolism.

Favourable response of a virilizing adrenocortical carcinoma to preoperative treatment with ketoconazole and postoperative chemotherapy

“…The efficacy of ketoconazole to inhibit cortisol production led to its trial as an inhibitor of steroidogenesis in cases of cortisol overproduction (15)(16)(17). Very recently its efficacy was also demonstrated in patients with virilizing and feminizing adrenal carcinoma with or without hypercortisolism (6,7,18,19). In our patient, ketoconazole at a dose of 200 mg, later 400 mg, thrice daily, dramatically lowered plasma A4 and T levels in the presence of still high 17 OHP levels.…”

“…An increase in P450 reducíase over P450C17 in the tumour and thereby increased electron availability may be an important factor determining whether a steroid will undergo 17,20-bond scission after 17a-hydroxylation rather than 21-hydroxylation (14). Al¬ ternatively, relative deficiency of P4äoC2i, as evi¬ denced by the increased 17 OHP/11-deoxycortisol ratio, and even more relative deficiency of P45oCn, as evidenced by the high 11-deoxycortisol/cortisol ratio, may account for the hypercortisolism being only mild in this patient (7,8).…”

“…Ketoconazole is a broad spectrum antimycotic agent which is a potent inhibitor of en¬ zymes of the cytochrome P450 system in gonadal but also in adrenal steroid synthesis (4,5). It has been used preoperatively in Cushing's syndrome with virilization due to adrenocortical carcinoma to reduce the increased operation risk of a higher bleeding tendency, poor wound healing and thromboembolism associated with hypercortisolism, and to achieve a better metabolic control (6)(7)(8).…”

Somatostatin analogs and radiopeptides in cancer therapy

“…An overall tumor response rate of 43% was observed in the cotreatment group compared to 49% in the “tamoxifen‐alone” treatment group, indicating that there is no application yet for octreotide in the treatment of these tumors. Clinical trials with octreotide or lanreotide in patients with hormone‐refractory prostate cancer have been reported with variable results 112–116. However, the promising response rate obtained in some of them116 indicates that octapeptide analogs of sst may represent an alternative approach, possibly in association with conventional hormonal manipulation such as castration or antiandrogen drugs.…”