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Primary Hypogonadism Associated with O,P’ DDD (mitotane) Therapy
Mario Sparagana
To cite this article: Mario Sparagana (1987) Primary Hypogonadism Associated with O,P’ DDD (mitotane) Therapy, Journal of Toxicology: Clinical Toxicology, 25:6, 463-472, DOI: 10.3109/15563658708992649
To link to this article: http://dx.doi.org/10.3109/15563658708992649
Published online: 25 Sep 2008.
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PRIMARY HYPOGONADISM ASSOCIATED WITH o,p’ DDD (MITOTANE) THERAPY
Mario Sparagana, M.D. Medical and Research Services Veterans Administration Hospital Hines, Illinois 60141 and Department of Medicine Loyola University Stritch School of Medicine Maywood, Illinois 60153
ABSTRACT
Mitotane is a drug which is concentrated largely in adipose tissue and the adrenal glands. It has a remarkable specificity for the adrenal cortex and can produce necrosis of that organ; consequently, it has been used as a therapeutic agent for adre- nocortical carcinoma. Because of the similarity between adreno- cortical and testicular tissue, mitotane could be expected to cause testicular damage; however, there is sparse support for this in the literature. We recently studied a patient who developed impotency due to primary testicular failure at the time that he was treated with mitotane. A testicular biopsy, performed about four months after the drug was discontinued, showed normal appearing Leydig cells and atrophy of the semini- ferous tubules with the picture of a maturation arrest. In the four and one half years since he last received mitotane, the patient’s libido has slowly improved and his plasma testoster- one, gonadotropins and LH response to gonadotropin-releasing hormone have become essentially normal. We propose that mito- tane can be cytotoxic to the testis as it is to the adrenal cortex.
INTRODUCTION
In the course of toxicity studies with the insecticide DDD (2,2-bis (parachlorophenyl)-1- dichloroethane), Nelson and
Woodward (1) observed a striking propensity for this drug to produce adrenocortical damage. Later, it was found that an isomer, o,p’ DDD (1, 1-dichloro-2-2’ (o-chlorophenyl)-2-parachlo- rophenyl) ethane), was less toxic and more active (2). Because of its relatively specific cytotoxic effect on the adrenal cor- tex, o,p’ DDD (mitotane) was used subsequently to treat patients with adrenocortical carcinoma (3-9). It has also been used in the therapy of Cushing’s syndrome due to bilateral adrenal hy- perplasia (10,11). Since the adrenal cortex and testis have certain similarities in their biosynthetic functions and enzyme content, it would not be surprising to find that mitotane also produced some degree of testicular damage, but little has appeared in the literature to support this. The pharmaceutical company marketing the drug had no evidence from preclinical toxicology or subsequent studies that mitotane was toxic to the testis. We also did a computer search which failed to reveal such evidence. There is a report that impotency and gynecomas- tia appeared in 6 out of 16 patients treated with mitotane (9), but no further details were given. Gynecomastia has also been reported by others (10,11).
Recently we used mitotane to treat a patient with Cushing’s syndrome and he developed primary testicular failure during the drug therapy.
CASE REPORT
Our patient was a black male, 41-years old in July 1982, when he presented with the ectopic ACTH syndrome. He manifested hypertension, muscle weakness, and abnormal mental symptoms. Blood biochemical studies showed hypokalemia and hyperglycemia. The plasma cortisol and ACTH, and urinary free cortisol and Porter-Silber chromagens were very elevated, and they all failed to suppress with 8 mg of dexamethasone per day. An extensive search for a tumorous source of ectopic ACTH production was
unsuccessful. The computed tomography scan of the pituitary was normal.
Because of the severe nature of his illness, he was placed on 500 mg of aminoglutethimide and 6 grams of mitotane every 12 hours starting on 9/30/82 for a period of three months, when the drugs were stopped on 1/3/83 because of gastrointestinal and central nervous system toxicity. He had to be placed on corti- sone and fludrocortisone shortly after starting the mitotane and these had to be continued.
His adrenocortical hyperfunction had been controlled by the mitotane and his clinical status improved. However, he comp- lained of impotency which failed to improve after the mitotane was discontinued. He had no problem with potency until his illness developed, and was the father of two children. The patient appeared well virilized without gynecomastia. His testes were of normal consistency but reduced in size (3.0 cm in the longest dimension) and he was not able to provide a semen specimen.
Studies of his hypothalamic-pituitary-gonadal axis on 8/12/83 showed a low testosterone and elevated gonadotropins in the plasma, and an exaggerated response to gonadotropin- releasing hormone (GnRH) (Table 1).
This combination of data is compatible with primary testi- cular failure. Repeat testing on 11/28/83 revealed little change in the defect.
On 12/12/83, his ectopic ACTH syndrome recurred. The steroid therapy was stopped, and a 12 day course of mitotane, 2 gm per day, was given. Another thorough investigation failed to reveal a tumor. On 4/20/84, about four months after stopping mitotane, the patient underwent a bilateral adrenalectomy and a testicular biopsy. The testes were atrophic with no signs of inflammation or fibrosis. The Leydig cells appeared normal, but the seminiferous tubules showed a maturation arrest; no sperm were present.
| Date | T* | Minutes | ||||||
|---|---|---|---|---|---|---|---|---|
| GnRH | 0 | 30 | 45 | 60 | 90 | 120 | ||
| ng/dl | mIU/ml Mitotane (12 gm) per day (9/30/82-1/3/83) | |||||||
| 8/12/83 | 220 | LH | 31 | 365 | 340 | 300 | 230 | 200 |
| FSH | 60 | 180 | 195 | 200 | 200 | 200 | ||
| 11/28/83 | 200 | LH | 26 | 210 | 200 | 190 | 150 | 140 |
| FSH | 44 | 90 | 96 | 84 | 92 | 91 | ||
| Mitotane (2 gm) per day (12/22/83 - 1/3/84) | ||||||||
| 4/20/84 | Bilateral adrenalectomy & testicular biopsy | |||||||
| 2/21/86 | 310 | LH | 16.4 | 255 | 236 | 170 | 140 | 139 |
| FSH | 24 | 66 | 75 | 65.8 | 59.2 | 62.9 | ||
| 12/23/86 | 410 | LH | 18.6 | 175.5 | 165.4 | 143.3 | 119.5 | 109.7 |
| FSH | 16.2 | 35.2 | 34.3 | 38 | 39.2 | 39.9 | ||
| 5/6/87 | LH | 14.0 | 131 | 111 | 93.9 | 75.4 | 77.3 | |
| FSH | 15.6 | 28.6 | 28.4 | 27.9 | 27.8 | 25.2 | ||
| Normal | LH | 5-20 | 20-110 | 18-87 | 11-54 | |||
| FSH | 5-20 | Responses < 50% of those for LH | ||||||
T* (testosterone) 400-1100
The impotency had persisted so the patient was given intra- muscular testosterone enanthate which produced improvement in libido. On January 3, 1986, the testosterone was stopped and the patient was reevaluated. He continued to show findings compatible with primary testicular failure, but the GnRH test on 2/12/86 showed improvement (Table 1). Subsequently, the basal gonadotropins declined to the normal range and there was only a slightly exaggerated response of LH and FSH to GnRH and some delay in the return towards the baseline (Table 1). His basal
plasma testosterone has increased from an initial value of 220 to 450 ng/dl (normal 400-1100 ng/dl). Recently, administration of 1500 units of human chorionic gonadotropin produced a rise of his plasma testosterone to 1000 ng/dl, indicating responsive Leydig cells.
He has remained off testosterone, and his libido has improved gradually. His testes remain atrophic, but now he is able to produce a semen specimen. We feel that his ectopic ACTH syndrome may have been caused by a benign pulmonary lesion. Bronchoscopy and yearly CT scans of the lungs have failed to reveal a significant lesion such as a bronchial carcinoid.
DISCUSSION
The early toxicity studies of the insecticide DDD, carried out in ten dogs, consistently revealed atrophy of the adrenal cortex and fatty degeneration of the liver at postmortem exam (1). The other organs, including the testes, appeared grossly and microscopically normal, except for incidental lesions such as focal myocarditis or focal gastric hemorrhage.
Because of its high selectivity and toxicity for the adrenal cell, mitotane (o,p’ DDD) was selected for use in the treatment of adrenocortical carcinoma. Daily administration of the drug in excess of 3 gm per day can produce adrenal atrophy and necrosis.
Reports of patients with adrenal carcinoma who were treated with mitotane do not mention abnormalities in the plasma testos- terone and gonadotropins or damage to the gonads at postmortem exam (3-9). Moy (12) measured the postmortem levels of mitotane in the tissues of an adrenal cancer patient, who had been treated with the drug, and found a relatively low concentration of mitotane in the testes. On the other hand, it has been shown that rabbits accumulate mitotane in their livers and testes as well as in their fat tissue and adrenal glands (13) so that testicular damage could be produced.
Sexual disorders, such as amenorrhea and decreased libido, can be seen in patients with untreated Cushing’s syndrome (14). Testicular changes similar to those seen in our patient have been reported in these patients (15). However, if patients with Cushing’s syndrome are treated with low doses of mitotane, it can actually improve the sexual disorder. The hypogonadism of Cushing’s syndrome appears to be secondary to suppressed gona- dotropins due to the elevated cortisol. In contrast with the findings in our patient, Luton, et al (14), found a significant decrease in plasma testosterone, LH, and FSH, and a blunted response of the gonadotropins to GnRH in eight patients with Cushing’s disease. After successful treatment with mitotane, the plasma testosterone and gonadotropins reverted to normal, suggesting that the elevated steroids of the Cushing’s syndrome had caused the hypogonadotropic hypogonadism. In contrast, our patient with Cushing’s syndrome developed primary testicular failure following therapy with a large dose of mitotane. Although no studies of testosterone, LH and FSH were done prior to the treatment with mitotane, his libido had been normal several months before the therapy, Since there was no other obvious cause for his primary testicular failure, we suggest that the testicular failure arose because of damage to his testes from the mitotane therapy. Pesticides, similar to mitotane, have been reported to lower the sperm count and raise the plasma LH and FSH of pesticide factory workers (16,17). Aminogluthetimide has been reported to cause cytotoxic damage to the adrenal cortex (18) but has not been shown to do so in the testis (19).
Studies of the effect of o,p’ DDD on the adrenal cortex indicate that it can interact with adrenal cytochrome P-450 and this may be required for adrenal necrosis and inhibition of steroid formation (20). Spironolactone, which depletes micro-
somal cytochrome P-450, prevents the adrenal necrosis (21). Since the administration of spironolactone is known to decrease the cytochrome P-450-dependent enzymes in the adrenal gland, it may be that oxidation or hydroxylation of o,p’ DDD by these enzymes is a prerequisite for adrenal necrosis to occur (22). Mitotane is oxidized to its ethene and acetate derivatives o,p’ DDE and o,p’ DDA (23). Perhaps these or similar metabolites of o,p’ DDD produce the toxic damage (24).
The testis is a steroid-forming organ similar to the adrenal; it also has cytochrome P-450-dependent enzymes (25), which may change the o,p’ DDD to a toxic metabolite capable of causing testicular damage. A patient with an interstitial-cell tumor of the testis was successfully treated with o,p’ DDD (26). Such observations lend credence to the proposal that mitotane therapy may have caused the testicular damage in our patient. If we had obtained a testicular biopsy while our patient was receiving mitotane treatment, we might have found an infiltra- tion with inflammatory cells and fibrosis. We don’t know why our patient’s testes were particularly susceptible to cytotoxic damage by mitotane. It is possible that he was especially predisposed to form toxic metabolites in conjunction with his testicular cytochrome P-450-dependent enzymes.
Our patient’s libido and Leydig cell function (Table 1) has gradually improved over the four years since he last received mitotane. It is possible that some other factor produced his reversible testicular damage, but no obvious cause, such as an orchitis or heavy intake of alcohol, was apparent. We propose that mitotane was the causative agent.
Gonadal dysfunction and histological abnormalities have not been explored systematically in humans treated with mitotane. If gonadal function is more vigorously investigated in such patients, testicular dysfunction may be more frequently diagnosed.
REFERENCES
1. Nelson AA, Woodard G, Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2, 2-bis (parachlorophenyl)-1, 1-dichloroethane (DDD or TDE). Arch Path 48, 387-394 (1949).
2. Cueto C, Brown JHV, Biological studies on an adrenocorti- colytic agent and the isolation of the active components. Endocrinology 62, 334-339 (1958).
3. Bergenstal DM, Hertz R, Lipsett MB, Moy RH, Chemotherapy of adrenocortical cancer with o,p’ DDD. Ann Int Med 53, 672-682 (1960).
4. Hutter Am, Kayhoe DE, Adrenal cortical carcinoma: Results of treatment with o,p’ DDD in 138 patients, AM J Med 41, 581-592 (1966).
5. Lubitz JA, Freeman L, Okun R, Mitotane use in inoperable adrenal cortical carcinoma. JAMA 223, 1109-1112 (1973).
6. Hajjar RA, Hickey RC, Samaan NA, Adrenal cortical carci- noma. A study of 32 patients. Cancer 35, 549-554 (1975).
7. Hogan TF, Citrin DL, Johnson BM, Nakamura S, Davis TE, Borden EC, o,p’-DDD (Mitotane) therapy of adrenal cortical carcinoma. Observations on drug dosage, toxicity and steroid replacement. Cancer 42, 2177-2181 (1978).
8. Schteingart DE, Motazedi A, Noonan RA, Thompson NW, Treatment of adrenal carcinomas. Arch Surg 117, 1142-1146 (1982).
9. Van Slooten H, Moolenaar AJ, Van Seters AP, Smeenk D, The treatment of adrenocortical carcinoma with o,p’ DDD: Prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol 29, 47-53, (1984).
10. Luton JP, Mahoudeau JA, Bouchord P, Thieblot P, Hautconverture M, Simon D, Laudat MH, Touitou Y, Bricaire H, Treatment of Cushing’s syndrome by o,p’ DDD. Survey of 62 cases. N Engl J Med 300, 459-464 (1979).
11. Schteingart DE, Tsao HS, Taylor CI, Mckenzie A, Victoria R, Therrien BA, Sustained remission of Cushing’s disease with mitotane and pituitary irradiation. Ann Int Med 92, 613-619 (1980).
12. Moy RH, Studies of the pharmacology of o,p’ DDD in man. J Lab Clin Med 58, 296-304 (1961).
13. Shevchenko AV, Korpachev VV, Distribution characteristics of the adrenocortical function inhibitor chloditon (o,p’ DDD) in the body. Fiziol Biokhim Patol Endokr Sist 5, 25-7 (1975).
14. . Luton JP, Thieblot P, Valcke JC, Mahouideau JA, Bricaire H, Reversible gonadotropin deficiency in male Cushing’s disease. J Clin Endocrol Metab 45, 488-495 (1977).
15. Gabrilove JL, Nicolis GL, Sohval AR, The testis in Cushing’s syndrome. J Urol 112, 95-99 (1974).
16. Whorton D, Krauss RM, Marshall S, Milby TH, Infertility in male pesticide workers. Lancet 2, 1259-1261 (1977).
17. Lipshultz LI, Ross CE, Whorton D, Melby T, Smith R, Joyner RE, Dibromochloropropane and its effect on testicular function in man. J Urol 124, 464-468 (1980).
18. Marek J, Motlik K, Ultrastructure of acute adrencortical damage due to aminoglutethimide (Elipiten” Ciba) in rats. Virchows Archiv B Cell Path 27, 173-187 (1978).
19. Starka L, Motlik K, Marek J, Failure of aminoglutethimide to produce changes in morphology and steroid biosynthesis of rat testicles. Endocrinologia Experimentalis 6, 165-170 (1972).
20. Young RB, Bryson MJ, Sweat ML, Street JC, Complexing of DDT and o,p’ DDD with adrenal cytochrome P-450 hydroxy- lating systems. J Steroid Biochem 4, 585-591 (1973).
21. Andrews LS, Menard RH, Maling HM, Gillette JR, The effect of o,p’ DDD (Mitotane) administration on mitochondrial and microsomal cytochrome P-450 in adrenal of male dogs. Fed Proc Fed Am Soc Exp Biol 37, 644 (1978).
22. Menard RH, Inhibition of o,p’ DDD (Mitotane) induced adrenal atrophy and necrosis by spironolactone adminis- tration. Proc Am Assoc Cancer Res 19, 148 (1978).
23. Benson WR, The chemistry of pesticides. Ann NY Acad Sci 160, 7 (1969).
24. Touitou Y, Bogdan A, Legrand JC, Desgrez P, Metabolism of o,p’ DDD (Mitotane) in humans and animals. Current notions and practical deductions. Ann Endocrinol 38, 13-25 (1977).
25. Payne AH, Quinn PG, Sheela Rani CS, Regulation of micro- somal cytochrome P-450 enzymes and testosterone production in Leydig cells. Recent Prog Horm Res 41, 153-197 (1985).
26. Abelson D, Bulaschenko H, Trommer PR, Valdes-Dakena A, Malignant interstitial-cell tumor of the testis treated with o,p’ DDD. Metabolism 15, 242-256 (1966) .