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Departments of Internal Medicine,
1 Surgery, and
2 Nuclear Medicine Division, University of Messina School of Medicine, Policlinico Universitario, Messina, Italy
3 Section of Endocrinology, Clinical-Experimental Department of Medicine and Pharmacology, Program of Clinical and Molecular Endocrinology, Azienda Ospedaliera Gaetano Martino—Messina, University of Messina School of Medicine, Policlinico Universitario, Messina, Italy
(Requests for offprints should be addressed to A Lasco, Via Faustina e Tertullo, 19 98100 Messina, Italy; Email: alasco{at}unime.it)
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Abstract |
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Introduction |
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TopAbstractIntroductionCase reportResultsDiscussionReferences |
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Case report |
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At admission, height was 160 cm, weight 60 kg, blood pressure 135/80 mmHg, and hirsutism severe (Ferriman–Gallway score = 30); hirsutism was accompanied by fronto-temporal balding, masculine body build and clitoromegaly (80 mm2, sagittal x transverse diameters) and oily skin (Fig. 1
). Cushingoid features, such as moon face, buffalo hump, striae rubrae, were absent. No abdominal or pelvic masses were palpated.
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Results |
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. Morning serum cortisol was normal and fell normally to < 5 µg/dl after the 1 mg dexamethasone overnight test. Serum free testosterone, serum total testosterone, serum androstenedione, serum 17-hydroxyprogesterone and serum dehydroepiandrosterone sulfate (DHEAS) were elevated by 950, 575, 90, 80 and 50% respectively, than the corresponding upper normal limits. All these steroids were suppressed insignificantly by dexamethasone. Serum estradiol was slightly above normal, while serum gonadotropin concentrations were inappropriately low for a postmenopausal woman.
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). Adrenal scintigraphy showed, in the scans taken 2 and 7 days after injection of 131I-labeled cholesterol, a focal area of tracer accumulation below the liver and above the kidney, a position consistent with the right adrenal gland (Fig. 1).
As the above results clearly supported the diagnosis of a VAT and because the tumor could have been a virilizing carcinoma, based on its overwhelming preference for the right gland and occurrence at a median age (53 years) comparable to our patient’s age (Derksen et al. 1994), we recommended prompt surgical excision of the mass. However, the patient repeatedly postponed admission to the Department of Surgery. Eventually she refused explicitly the intervention, preferring to be treated medically for the hirsutism. Thus, in April 2000, we started treating her with CPA (Androcur) at a dose of 50 mg daily. This treatment was followed by the reversal of the clinical symptoms (Fig. 1, top) and normalization of the steroid hormone levels (Fig. 2). This normalization, in turn, was secondary to the CT-documented disappearance of the adrenal mass (Fig. 1, middle). At the end of July 2000, CPA was withdrawn.
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). No recurrence in the clinical (Fig. 1, top) or hormone (Fig. 2) abnormalities had occurred as of February 2004, the latest control visit. Adrenal scintigraphy performed in February 2004 demonstrated no focal activity in the right adrenal gland (Fig. 1, bottom). Her husband confirmed that libido had returned normal, and the whole family confirmed that she was no longer aggressive. |
Discussion |
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-dihydrotestosterone (DHT) through activation of the 5 reductase activity (Boudou et al. 1990). Appearance of tumors has been reported in association with cyclosporine therapy (Ptachinski et al. 1985), but we are aware of only one case of adrenal adenoma (Fahmi et al. 1998). This was a left adrenal adenoma oversecreting aldosterone which appeared in a 58-yr-old man who had received a cadaveric renal transplant and had been treated with cyclosporine as an immunosuppressant (Fahmi et al. 1998). Concerning our patient, considering that cyclosporine was not the only drug taken and that it had been discontinued 3 years before the appearance of the hyperandrogenic symptoms, we tend to exclude its role in the formation of the VAT.
Careful pharmacological history is an essential part of the diagnostic work-up of hirsutism/virilization. Since history of our patient had disclosed prolonged therapies with three of the drugs mentioned above, we could have stopped any further investigation. However, the progression of the symptoms 5 months after withdrawal of nandrolone and the absence of Cushingoid features, prompted us to search for an ovarian tumor or a purely virilizing adrenal tumor. Indeed, a 2.3-cm nodule in the right adrenal gland was demonstrated, which agrees with the right-sided preference of VAT (Derksen et al. 1994).
The disappearance of our patient’s tumor was the result not of surgical excision, but medical therapy with a short-term CPA course. However, based on the patient described below (Laszlo et al. 2000), not all antiandrogens seem as effective as CPA. This patient (Laszlo et al. 2000) matches our patient for gender, side and size of the purely VAT, same duration of the antiandrogen therapy (although with a different drug) and same duration of previous treatment with three drugs (although different from the three taken by our patient). This 55-year-old woman, who for the past 7 years had been treated with ß-blockers, ACE inhibitors and diuretics for hypertension, was operated for a 3.0 x 2.6 cm purely VAT of the right gland. Unlike our patient, only serum testosterone was increased. Prior to surgical excision and for 4 months, the patient was treated with 50 mg daily flutamide. Steroid hormones either remained unchanged or even increased, indicating that no shrinkage of the mass had occurred.
Both flutamide and CPA inhibit the binding of DHT to the androgen receptor, but the former is a nonsteroidal drug while the latter is a potent progestative agent (Speroff et al. 1999). We have screened extensively the literature for possible antiproliferative effects of CPA. Other than the well-known effect, shared with the other antiandrogens, on androgen-dependent cancers (Griffin & Wilson 1998), an antiproliferative action has been reported only in meningiomas (Adams et al. 1990). In contrast, both flutamide and CPA (flutamide > CPA) inhibited the DHT-induced inhibition of proliferation on the adrenocortical carcinoma cell line NCI-H295 (Rossi et al. 1998). The effect of CPA was mimicked by another progestative agent, 11--hydroxyprogesterone, and by the dopamine agonist bromocriptine. Thus, these three drugs were proposed for the medical treatment of meningiomas (Adams et al. 1990).
The case reported here is the second patient with a purely VAT we have seen. Previously, one of us observed a 20-year-old woman with a 15-cm VAT of the right gland (Benvenga 1995). Citation of this case is pertinent because VATs overexpress cell-surface receptors LDL (Nakagawa et al. 1995), namely the receptors used by the LDL to provide 80% of the cholesterol needed for adrenal steroidogenesis (Orth & Kovacs 1998). Due to this overexpression, LDL are internalized at high rates, and circulating both LDL cholesterol and total cholesterol decrease; however, cholesterol concentration in blood increases once the tumor has been removed. In our patient, serum total cholesterol was relatively low, namely close to the fifth percentile for gender- and age-matched controls, prior to CPA therapy but it increased progressively during therapy. After disappearance of the tumor, cholesterol has remained stable but at levels that were approximately 35 mg/dl greater than prior to CPA therapy, reinforcing the concept that the step-wise increase in circulating cholesterol was not random, but due to the drug.
If the shrinkage of virilizing adrenal tumor caused by CPA will be confirmed (hopefully also in large tumors), then we have already available a drug to prepare patients for surgery and, when tumors are relatively small, even to avoid surgery.
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References |
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Baker J 1999 A report on alterations to the speaking and singing voices of four women following hormonal therapy with virilizing agents. Journal of Voice 13 496–507.[CrossRef][Medline]
Benvenga S 1995 Another case of hypocholesterolemia associated with virilizing adrenal adenoma. Journal of Clinical Endocrinology and Metabolism 80 3391–3392.[Medline]
Boudou P, Fiet J, Vexiau P, Villette JM, Hardy N & Dreux C 1990 Greater conversion of testosterone to 5 alphadiidrotestosterone, reflecting increased peripheral 5 alpha-reductase activity, in mice treated with high dose cyclosporine. Journal of Steroid Biochemistry 36 597–601.[Medline]
Carr BR1998 Disorders of the ovaries and female reproductive tract. In Williams’ textbook of Endocrinology, pp 751–817. Eds JD Wilson, JW Foster, HM Kronenberg & PR Larsen. Philadelphia: WB Saunders.
Derksen J, Nagesser S, Meinders E, Haak HR & van de Velde C 1994 Identification of virilizing adrenal tumor in hirsute women. New England Journal of Medicine 331 968–973.
Fahmy HI, Melby JC, Mesler DE, Beazley RM, Cho SI & Idelson BA 1998 Primary hyperaldosteronism causing post-transplantation hypertension: localization by adrenal vein sampling. American Journal of Kidney Diseases 31 853–885.
Griffin JE & Wilson JD 1998 Disorders of the testes and the male reproductive tract. In Williams’ textbook of Endocrinology, pp 819–875. Eds JD Wilson, JW Foster, HM Kronenberg & PR Larsen. Philadelphia: WB Saunders.
Karpas AE1987 Iatrogenic hirsutism. In The cause and management of hirsutism. A pratical approach to the control of unwanted hair, pp 61–69. Eds RB Greenblatt, VB Mahesh & RD Gambrell. Lancaster: Parthenon Publishing.
Laszlo FA, Toth S, Kocsis J, Pavo I & Szecsi M 2000 Testosterone-secreting gonadotropin-responsive adrenal adenoma and its treatment with the antiandrogen flutamide. Journal of Endocrinological Investigation 24 622–627.
Nakagawa T, Ueyama Y, Nozaki S, Yamashita S, Menju M, Funahashi T, Kameda-Takemura K, Kubo M, Tokunaga K & Tanaka T 1995 Marked hypocholesterolemia in a case with adrenal adenoma: Enhanced catabolism of low-density lipoproteins (LDL) via the LDL receptors of tumor cells. Journal of Clinical Endocrinology and Metabolism 79 1532–1539.
Orth DN & Kovacs WJ 1998 The adrenal cortex. In Williams’ textbook of Endocrinology, pp 517–564. Eds JD Wilson, JW Foster, HM Kronenberg & PR Larsen. Philadelphia: WB Saunders.
Ptachinski RJ, Buckart GJ & Venkataraman R 1985 Cyclosporine. Drug Intelligence & Clinical Pharmacy 19 90–100.
Rossi R, Zatelli MC, Valentini A, Cavazzini P, Fallo F, Del Senno L & Degli Uberti EC 1998 Evidence for androgen receptor gene expression and growth inhibitory effect of dihydrotestosterone on human adrenocortical cells. Journal of Endocrinology 159 373–380.[Abstract]
Speroff L, Glass RH & Case NG 1999 Hirsutism. In Clinical Gynecologic Endocrinology and Infertility, edn 6, pp 523–556. Eds L Speroff, RH Glass & NG Case. Baltimore: Lippincott Williams & Williams.
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