Use of ketoconazole in the treatment of a virilizing adrenocortical carcinoma
Johan A. Verhelst, Patrick Druwé, Peter van Erps’, Louis J. Denis1 and Charles Mahler
Departments of Endocrinology and Urology1, Middelheim Hospital, Antwerp, Belgium
Abstract. Ketoconazole, an oral antimycotic agent, is known to have a potent inhibitory effect on adrenal ste- roid production. It was given at a dose of 1200 mg/day to a 52-year-old female patient with a virilizing adrenocor- tical carcinoma in order to achieve better metabolic con- trol 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), androstene- dione (>35 nmol/l) and DHEA-sulphate (>28 nmol/l) fell to normal levels in 6 days. By contrast, levels of 17-OH- progesterone (30 nmol/l) and progesterone (2.45 nmol/1) increased slightly, indicating inhibition af adrenal 17,20- lyase. Cortisol (620 nmol/l at 08.00 h) fell to very low le- vels (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 hypoadre- nalism which seems to occur earlier in tumoural than in normal adrenal metabolism.
Ketoconazole is an orally active antifungal agent which has been shown to inhibit in vivo and in vitro adrenal and gonadal steroid synthesis (1, 2). This effect results from inhibition of cytochrome P-450-dependent enzymes: 17,20-lyase and to lesser extent 11-ß-hydroxylase, 17-hydroxylase, 18- hydroxylase and cholesterol side-chain cleavage enzymes of the adrenal gluco- and mineralcorti- coid biosynthesis (3). This effect of ketoconazole proved to be valuable in treating patients with hor- mone-dependent disorders such as metastatic prostatic carcinoma (4,5) and pituitary-dependent Cushing’s disease (6-10). However, the hormonal effects as well as the usefulness of ketoconazole in
the treatment of endocrinologically active adrenal gland neoplasms are less well known. In a few pa- tients with Cushing’s syndrome secondary to adre- nal adenoma or carcinoma effective inhibition of tumoural steroidgenesis was obtained by ketoco- nazole (11-14). It was suggested that ketoconazole could have its role in the therapy of endocrinologi- cally active adrenocortical carcinoma when other therapeutic measures are not available or had failed (13). We present the first description of the hormonal effects of ketoconazole on a virilizing adrenocortical carcinoma, and discuss its clinical applications.
Subjects and Methods
Case report
A 52-year-old woman was admitted to our hospital in July 1988 for hirsutism of two-years standing. She had suffered from recurrent depression during 10 years. Two years before admission, regular menstruation stopped and excessive coarse hair growth gradually appeared on her chin, chest, midline abdomen and thighs. In the fol- lowing months temporal balding developed and daily shaving became necessary. A medical examination shortly before admission revealed arterial hypertension, hyperglycemia and a weight loss of 3 kg.
On physical examination, the salient features included severe hirsutism, temporal balding, deepening of the voice, breast atrophy, and clitorimegaly. No muscle weak- ness, buffalo hump, truncal obesity, striae or facial ple- thora were noted. Blood pressure was 170/110 mmHg.
Her hematocrit was 0.432, hemoglobin 144 g/l, and leukocyte count 10.7 109/1 with a normal differential for-
mula. Fasting blood glucose was 18.8 mmol/l (normal 3.9-6.1). Urinary C-peptide levels were 57 nmol/24 h (normal 7-11). There were no electrolyte abnormalities. Lactate dehydrogenase was 554 U/l (normal 120-240) and alkaline phosfatase 223 U/1 (normal 60 -170). Other liver function tests were normal. Chest X-ray and ECG re- vealed no abnormalities.
The results of hormonal examination in serum and urine are shown in Table 1. Very high levels were found of total serum testosterone, free testosterone, dihydrotes- tosterone, DHEA-sulphate, androstenedione, and uri- nary 17-ketosteroids. Estradiol was high as a result of pe- ripheral conversion of testosterone and probably tumou- ral aromatase activity. LH and FSH are suppressed. 17- OH-progesterone and 11-deoxycortisol are also elevated, but progesterone and aldosterone are within normal limits. This indicates excessive steroid production start- ing predominantly at the 17-hydroxylase step. Cortisol secretion is disturbed to a lesser extent with elevated cor- tisol levels at 20.00 h, disappearence of the circadian rhythm, and slightly elevated urinary 17-OH corticoste- roids levels. Unfortunately no dexamethasone suppress- ion test nor measurements of free urinary cortisol were performed before treatment.
An ultrasonogram and CT scan of the abdomen showed a solid inhomogeneous mass with a diameter of 12 cm at the top of the left kidney. There were no liver metastases. Doubt existed about possible hilar adeno- pathy at the left kidney. Bone scintigraphy was normal. A tentative diagnosis was made of virilizing adrenal tu- mour, probably malignant.
After informed consent, ketoconazole was started in this patient, the aim being to ameliorate her metabolic condition and to lower surgical risk before operation.
Methods
Ketoconazole was donated by Janssen Pharmaceutica (Beerse, Belgium). We administered 400 mg ketocona- zole orally every 8 h, a dose currently used in the treat- ment of metastatic prostatic carcinoma (5). All serum hormone levels were measured by commercially avail- able RIA kits: Medgenics (Fleurus, Belgium) for LH, FSH, free and total testosterone DPC (Los Angeles, USA) for aldosterone, 17-OH progesterone, DHEA-sulphate and cortisol; DSL (Texas, USA) for androstenedione; Amer- sham (United Kingdom) for dihydrotestosterone; Tech- land, (Sart-Tilleman, Belgium) for sex binding globulin, and Urodiagnostics (Apeldoorn, the Netherlands) for ACTH. Urinary 17-ketosteroids were measured as Porter- Silber chromogens. Urinary 17-OH corticosteroids were measured by the Zimmerman method (15).
Results
Clinical changes
The patient experienced rapid improvement in her metabolic condition during ketoconazole
Total Testosterone ( nmol/l )
20
15
10
5
0
2
0
2
4
6
8
10
12
30
DHEAS ( nmol/l )
20
10
0
2
0
2
4
6
8
10
12
2000
Estradiol ( pmol/l )
1500
1000
500
0
-2
0
2
4
6
8
10
12
17-OH Progesterone ( nmol/l)
35
D
30
25
20
15
-2
0
2
4
6
8
10
12
Days of treatment
treatment. Blood pressure dropped from a mean level of 170/110 to 140/80 mmHg by day 4 of the trial. Hyperglycemia disappeared after 5 days: glu- cose 6.0 mmol/l (normal 3.9-6.1). The medication was subjectively well tolerated. Hepatic and renal function remained unchanged. After 8 days, sub- stitution therapy with hydrocortisone 30 mg/day was given for correcting hypoadrenalism.
700
Cortisol ( nmol/l)
600
500
400
300
200
100
0
-2
0
2
4
6
8
10
12
20
ACTH ( pmol/l)
16
12
8
4
2
0
17-OH-corticosteroids ( umol/d ]
2
4
6
8
10
12
50
40
30
20
10
0
2
0
2
4
6
8
10
12
17-Ketosteroids ( pmol/d )
140
120
100
80
60
40
20
0
-2
0
2
4
6
8
10
12
Days of treatment
Sex steroids
In Figs. 1 and 2 the dramatic response of some ste- roids during ketoconazole treatment is shown.
Levels of total and free testosterone (Fig. 1, top), androstenedione and DHES-sulphate (Fig. 1, sec- ond) dropped markedly beginning 24 h after start of treatment, and reaching normal levels in 6 days after which a steady state was reached.
Dihydrotestosteone and estradiol levels (Fig. 1, third) fell likewise.
In contrast, progesterone and 17-OH-proges- terone (Fig. 1, bottom) slightly increased above basal values. Aldosterone levels remained un- changed.
Levels of cortisol dropped to very low values at day 6, and rose again with substitution therapy after day 8 (Fig. 2, top). ACTH levels rose slightly above mean pretreatment value (Fig. 2, second).
Urinary levels of 17-OH corticosteroids) Fig. 2, third) and 17-ketosteroids (Fig. 2, bottom) grad- ually decreased.
Surgical and pathological findings
Twelve days after institution of ketoconazole ther- apy, the patient underwent surgery. The right adrenal and both ovaries were atrophic. The left adrenal appeared grossly enlarged (diameter 12 cm) and inhomogenous. It was fixed at the top of the left kidney. A left adrenalectomy and nephrec- tomy was performed. No signs of macroscopical metastasis were noted. Microscopical examination revealed an adrenocortical carcinoma with inva- sion of the left kidney. Surrounding lymph nodes were not invaded.
Postoperative course
The postoperative period was uncomplicated. The patient did very well. Blood pressure stayed within normal values as did blood glucose values. Hirsut- ism gradually disappeared over the following months. Antidepressive medication could be sub- stantially lowered.
Because of suspected insufficiency of the right adrenal gland, substitution therapy was continued immediately after operation with high doses of so- luble cortisol (200 mg/day) and was gradually dim- inished to hydrocortisone 30 mg/day after 10 days. Hormonal evaluation after 2 weeks (Table 1) showed subnormal values for all adrenal hor- mones. Low values of serum cortisol can be ex- plained by discontinuation of the drug on the day of blood sampling. Further reduction of substitu- tion therapy failed to rise levels of all hormones substantially after 2 months (results not shown).
Discussion
Virilising adrenocortical carcinoma is a rare tu- mour (16). To our knowledge this is the first de- scription of the effects of ketoconazole in this type of tumour. In contrast to the well known effects of
| Parameters | |||
|---|---|---|---|
| Pre-operative | Postoperative | Normal values | |
| Serum | |||
| LH (U/I) | 6.4 | 14 | 14-74* |
| FSH (U/1) | 6.7 | 58 | 38-161* |
| PRL (ug/1) | 14 | 34 | 2-18* |
| Estradiol (pmol/l) | 1850 | 73 | 0-184* |
| Progesterone (nmol/1) | 2.45 | 0.32 | <6* |
| Aldosterone (nmol/l) | 0.72 | 0.07 | 0.14-0.76 |
| 17-OH-progesterone (nmol/l) | 30 | 0.5 | 1-5 |
| 11-deoxycortisol (nmol/l) | >720 | 20 | 0-60 |
| DHEA-sulphate (umol/l) | >30 | 0.1 | 0.3-1.7 |
| Androstenedione (nmol/l) | >35 | 0.3 | 3.0-10.5 |
| Dihydrotestosterone (nmol/l) | 2.0 | 0.4 | 0.2-0.9 |
| Sex binding globulin (pmol/ml) | 15 | 34 | 41-79 |
| Free testosterone (fmol/l) | 149 | 5 | 6.9-26 |
| Total testosterone (nmol/l) | 20 | 0.9 | 0-2.0 |
| ACTH (pmol/l) | 10 | 6.8 | 4-22 |
| Cortisol (nmol/1) 8.00 h | 620 | 50 | 110-690 |
| 20.00 h | 530 | 30 | 0-410 |
| Urine | |||
| 17-OH corticosteroids (umol/day) | 29 | 6 | 5-25 |
| 17-ketosteroids (umol/day) | 125 | 9 | 20-60 |
* Postmenopausal values
ketoconazole on normal adrenal steroidogenesis (3), reports on the effects of ketoconazole on func- tional adrenal gland neoplasms are scarce. We are aware of only six reports where ketoconazole was used to inhibit adrenal tumoural steroidogenesis, all of them in patients with Cushing’s syndrome secondary to adrenal carcinoma or adenoma (12-14, 17, 18). Our patient seems unique owing to the fact that there were no clinical signs of Cush- ing’s disease and that cortisol levels were relatively low compared with testosterone levels. This could be explained by a pre-existing partial 11-ß-hydrox- ylase block in the tumour, inhibiting transition from 11-deoxycortisol to cortisol. Although no dexamethasone suppression test was performed, we think that cortisol production was predomi- nantly of tumoural origin regarding disappear- ance of diurnal cortisol rhythm and postoperative insufficiency of the contralateral gland.
We used a dose of three times 400 mg/day be- cause of own experience with this dose of ketoco-
nazole in orchiectomised patients with metastatic prostatic carcinoma (5, 19).
In our patient, the fact that DHEA-sulphate, an- drostenedione, and testosterone, but not 17-OH- progesterone or progesterone were normalised in 6 days, indicates an almost total inhibition of adre- nal 17,20-lyase.
This is in agreement with the effects on normal adrenal metabolism (2), and suggests that the same enzymatic pathways are blocked by ketoconazole in normal and tumoural adrenal tissue. Similarly, Contreras et al. showed normalisation of androgen excess by inhibition of 17,20-lyase in two patients with Cushing’s syndrome, one with a functional adrenal rest tumour (12) and one with metastatic adrenal carcinoma (13), after, respectively, 2 and 3 weeks. Difference in response time between their and our results might be due to another dose scheme used in their patients: gradual increase from 400 or 600 mg/day to 1000 or 1200 mg/day over 2 to 3 weeks.
Likewise, an inhibitory effect on oversecretion of estradiol was seen in our patient, but postmeno- pausal values were not reached (400 nmol/l, post- menopausal 0-184). This effect could be ex- plained by less availability of androgen precursors although additional aromatase inhibition by keto- conazole cannot be excluded (20).
Cortisol levels in our patient dropped dramati- cally, reaching a state of hypoadrenalism after 6 days. This could be attributed to an almost total in- hibition of 11-ß-hydroxylase since levels of 17-OH- progesterone were increased. ACTH levels rose only slightly but insufficiently to compensate. Al- though partial inhibition of 11-ß-hydroxylase by high dose ketoconazole (up to 1200 mg/day) in normal adrenals is well known (3,21), basal cortisol levels hardly change in the vast majority of pa- tients even after long-term treatment (4) and signs of adrenal insufficiency are uncommon (5).
In agreement with our results, Contreras et al. described hypoadrenalism occuring respectively 1 and 21/2 months after starting therapy in 2 patients with Cushing’s syndrome (12, 13). Pronounced lowering effects of ketoconazole on cortisol levels were also reported in a patient with an adrenal adenoma (22) and a patient with adrenocortical micronodular adenomatosis (19). This could be ex- plained by insufficient compensatory ACTH elev- ation (6-8) or inability of tumour cells to respond (22). We think that in our patient three additional reasons could account for this effect: the use of a high dose of ketoconazole which could severely af- fect 11-ß-hydroxylase (3), a pre-existing partial 11- ß-hydroxylase block in the tumour, and insuffi- ciency of the contralateral adrenal gland.
Basal mineralocorticoid metabolism was unaf- fected, which is in agreement with results in nor- mal and tumoural adrenal glands (3).
From a clinical perspective, ketoconazole has been used with success in patients with Cushing’s syndrome secondary to metastatic adrenal carci- noma when chemotherapy (o,p’-DDD) was not available (13, 14, 18).
In two reports, ketoconazole was given to pa- tients with Cushing’s syndrome secondary to adre- nal gland neoplasms in order to achieve better metabolic control before operation (13, 19). Our experience confirms this finding and shows that normalisation of steroid excess can be reached in a short period without serious adverse reactions and without delaying surgery. In agreement with
others we suggest early corticoid substitution ther- apy (13) or lower doses of ketoconazole (19) to avoid Addisonian crises.
References
1. Loose D, Kan P, Hirst M, Marcus R, Feldman D. Keto- conazole blocks adrenal steroidogenesis by inhibit- ing cytochrome P-450-dependent enzymes. J Clin In- vest 1983; 71: 1495-9.
2. Pont A, Graybill J, Craven P et al. High-dose ketoco- nazole theraphy and adrenal and testicular function in humans. Arch Intern Med 1984; 144: 2150-3.
3. Sonnino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987; 317; 812-8.
4. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet 1984; 2: 433-5.
5. Denis L, Chaban M, Mahler C. Clinical applications of ketoconazole in prostatic cancer. Progr Clin Biochem Res 1985; 185A: 319-26.
6. Angelli A, Frairia R. Ketoconazole therapy in Cush- ing’s disease. Lancet 1985; 1:821.
7. Sonino N, Boscaro M, Merola G, Mantero F. Pro- longed treatment of Cushing’s disease by ketocona- zole. J Clin Endocrinol Metab 1985; 61: 718-22.
8. Loli P, Berselli ME, Tagliaferri M. Use of ketocona- zole in the treatment of Cushing’s syndrome. J Clin Endocrinol Metab 1986; 63: 1365-71.
9. McCance D, Hadden D, Kennedy L, Sheridan B, At- kinson A. Clinical experience with ketoconazole as a therapy for patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 1987; 27: 593-9.
10. Boscaro M, Sonino N, Rampazzo A, Mantero F. Re- sponse of pituitary-adrenal axis to corticotrophin re- leasing hormone in patients with Cushing’s disease before and after ketoconazole treatment. Clin Endo- crinol (Oxf) 1987; 27: 461-7.
11. Engelhardt D, Mann K, Horemann R, Braun S, Karl H. Ketoconazole inhibits cortisol secretion of an adrenal adenoma in vivo and in vitro. Klin Wo- chenschr 1983; 61: 373-5.
12. Contreras P, Altieri E, Liberman C, et al. Adrenal rest tumor of the liver causing Cushing’s syndrome: treatment with ketoconazole preceding an apparent surgical cure. J Clin Endocrinol Metabol 1985; 60: 21-8.
13. Contreras P, Rojas A, Biagini L, Gonzalez T. Regres- sion of metastatic adrenal carcinoma during pallia- tive ketoconazole treatment. Lancet 1985; 2: 151-2.
14. Contreras P, Rojas A, Constamallieri I., Michelsen H, Pumarino H, Arteaga E. Endocrine effects of ketoco- nazole in 10 patients with Cushing’s syndrome. 67th Annu Meet Endocr Soc, Baltimore, 1985. Abstract 138.
15. Drexter IJ, Heisler A, Scism GR, Stern S, Pearson S, McGavack TH. The determination of urinary ste- roids. I. The preparation of pigment-free extracts and a simple procedure for estimation of total 17-ketosteroids. J Clin Endocrinol Metab 1952; 12: 55-9.
16. Mattox JH, Phelan S. The evaluation of adult females with testosterone producing neoplasms of the adre- nal cortex. Surg Gyn Obstet 1987; 164: 98-101.
17. Engelhardt D, Knorr D. The influence of ketocona- zole on serum levels of cortisol, 11-deoxycortisol, corticosterone and 11-deoxycorticosterone in nor- mals and in patients with Cushing’s syndrome. Acta Endocrinol (Copenh) 1984; 105 (Suppl 264): 115-6.
18. Lore F, Di Cairano G, Nobli F, Marchetti G, Romei M. Effects of ketoconazole on hormone secretion in metastatic adrenal carcinoma. Eur J Cancer Clin Oncol 1986; 22: 738. Abstract.
19. De Coster R, Mahler C, Denis L, et al. Effects of high- dose ketoconazole and dexamethasone on ACTH- stimulated adrenal steroidogenesis in orchiec- tomized prostatic cancer patients. Acta Endocrinol (Copenh) 1987; 115: 265-71.
20. Ayub M, Stitch SR. Effect of ketoconazole on placen- tal aromatase, 3-ß-hydroxysteroid dehydrogenase- isomerase and 17-ß-hydroxysteroid dehydrogenase. J Steroid Biochem 1986; 25: 981-4.
21. Engelhardt D, Dorr G, Jaspers C, Knorr D. Ketocona- zole blocks cortisol secretion in man by inhibition of adrenal 11-ß-hydroxylase. Klin Wochenschr 1985;63: 607-12.
22. Oelkers W, Bahr V, Hensen J, Pickartz H. Primary adrenocortical micronodular adenomatosis causing Cushing’s syndrome: effects of ketoconazole on ste- roid production and in vitro performance of adrenal cells. Acta Endocrinol (Copenh) 1986; 113: 370-7.
Received February 2nd, 1989. Accepted April 19th, 1989.
Dr C. Mahler, Department of Endocrinology, Middelheim Hospital, Lindendreef 1, B-2020 Antwerp, Belgium.