The hypogonadotropic hypogonadism that is characteristic of male Cushing's disease is a reversible phenomenon. In fact, cure of hypercortisolism restores the decreased plasma testosterone and FSH and LH levels to normal and improves sexual and gonadal disturbances (58,72,73).

Selective trans-sphenoidal adenomectomy after accurate preoperative localization of the corticotroph adenoma represents the treatment of choice for Cushing's disease. In experienced hands, a cure rate of 80-90% may be expected in microadenomas. However, the cure rate decreases to 50% with macroadenomas (63,67). A trans-sphenoidal approach was also successfully used in ACTH-producing adenomas located in the pituitary stalk (74).

Patients who are unresponsive to surgical treatment or those in whom surgery is deemed inappropriate (large invasive tumors or high surgical risk) are referred for pituitary irradiation with adjunctive medical therapy, and/or bilateral adrenalectomy. Conventional radiotherapy is given in 25 fractional doses throughout 35 d, for a total dose of 4500 cGy (rad) using a three-field technique. This strategy may cure up to 15% of patients after several years, but it can lead to hypopituitarism and worsening hypogo-nadism (14,68).

Medical therapy is adjunctive in Cushing's disease. It is suitable for patients who are undergoing surgery, in those treated with radiotherapy to achieve early biochemical remission, and whenever definitive treatment must be delayed (75). Current medical therapies include drugs to decrease ACTH secretion, inhibit corticosteroid synthesis, or block their peripheral actions. The first class of drugs (serotonin antagonists, dopamine agonists, y-aminobutyric acid [GABA]-agonists and somatostatin analogs) inhibit ACTH release. However, few cases so treated have achieved permanent remission (75). The second group of drugs includes inhibitors of steroidogenesis (mitotane, metyrapone, aminoglutethimide, and ketoconazole). These drugs have the advantage of being rapidly effective in most cases. However, the mechanism(s) of action has little selectivity, and extra-adrenal effects are likely to occur. Ketoconazole inhibits various cytochrome P450 enzymes, including C17-20 lyase involved in the synthesis of sex steroids. Thus, the drug not only lowers cortisol levels but also decreases testosterone levels such that gynecomastia, impotence, loss of libido, and oligospermia could occur (71). The third class of drugs is represented by the glucocorticoid antagonist (mifepris-tone). Although a potentially important therapy, mifepristone has been used to treat only a few patients, and further clinical studies are needed to assess its long-term effectiveness and safety (75). A few studies reported the efficacy of cabergoline treatment in patients with Cushing's disease and Nelson's syndrome. However, only a limited number of case reports have been published (76,77).

Finally, bilateral adrenalectomy is reserved for cases in which other treatment modalities have failed. However, the risk for Nelson's syndrome is high with this approach (14).

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