**2. Cytotoxic agents**

Cytotoxic chemotherapy seems to alter endocrine functions in a relatively small proportion of patients and is infrequently associated with thyroid abnormalities in the absence of irradiation. Cytotoxics may sensitize the thyroid gland to the effects of concomitant radiation therapy, increasing the risk of radiation-induced primary hypothyroidism [9].

In a small published series, some agents such as 5-fluorouracil, glucocorticoids, estrogens, tamoxifen, podophyllin and L-asparaginase alter levels of thyroid hormone–binding proteins without any clinical consequence [10-15]. L-asparaginase can also be responsible for transient hypothalamic or pituitary hypothyroidism [16]. Other agents such as lomustine, vincristine, and cisplatin have *in vitro* effects on thyroid cells, but clinically relevant consequences have not been reported [17]. Mitotane is the only active agent against advanced adrenocortical cancer (ACC) and is under evaluation in patients who underwent radical resection of this rare disease. Mitotane showed a complex interference on the endocrine system that may require multiple hormone replacement therapy. In a prospective trial [18] on 17 patients who underwent radical resection for ACC, a marked reduction in free-T4 (FT4) levels was found, without any significant changes in serum thyroid stimulating hormone (TSH) and free-T3 (FT3) concentration. FT4 reduction was inversely correlated with mitotane concentrations and dropped in the hypothyroid range in most evaluable patients. These findings mimic central hypothyroidism and are consistent with data from clinical experiments which showed that mitotane directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells [19]. Alternatively, it has been suggested that mitotane may affect deiodase activity, thus changing the FT4 to FT3 ratio. However, despite limited information on free thyroid hormone concentrations during mitotane treatment has been reported, for some patients thyroxine replacement may be necessary [20].

An increased incidence of primary hypothyroidism has been documented in patients treated with multiple drug regimens, with or without radiotherapy [2]. In patients with testicular cancer who received combinations of cisplatin, bleomycin, vinblastine, etoposide, and dactinomycin, 4 out of 27 individuals (15%) developed primary hypothyroidism. In particular, the cumulative doses of cisplatin and vincristine seem to exacerbate these symptoms [21]. In another trial evaluating the combination of mechlorethamine, vinblastine, procarbazine and prednisolone (MOPP regimen) as treatment of Hodgkin's disease, 44% of patients developed elevated serum TSH concentrations, even though a causative role of iodine load during lymphangiograpy cannot be excluded [22]. Children with brain tumors (not involving the hypothalamic-pituitary axis) who receive vincristine, carmustine or lomustine, and procarbazine in combination and brain irradiation have a 35% incidence of hypothyroidism, compared with a 10% incidence in the group with brain irradiation alone [23]. Young age and use of chemotherapy have been associated with a higher incidence of hypothyroidism in patients receiving radiotherapy for medulloblastoma [24]. Again, the highest incidence occurred when the thyroid gland was included in the radiation field. Finally, there is no evidence that cytotoxic agents by itself may represent a risk factor for developing thyroid tumors, compared to radiotherapy [2].
