Cyclosporine A-induced mammary hyperplasia and hyperprolactinemia in New Zealand White rabbits

Purpose: To investigate the potential activity of cyclosporin A (CsA) to induce mammary hyperplasia in New Zealand White (NZW) rabbits. Methods: Female NZW rabbits were used throughout experiments. To simulate the conditions of immunosuppression, CsA (10 mg/kg of body weight/d) was administered intravenously on a daily basis for 14 days and methylprednisolone (5 mg/kg/d) was administered on the first two days. The CsA (10 mg/kg/d) also was administered without methylprednisolone for 14 days to another cohort of rabbits. Mammary tissue of each rabbit was palpated and serially measured during this treatment period. The CsA was discontinued, and rabbits were monitored for 14 more days during the washout period. Sequential plasma concentrations of prolactin, 17 betap-estradiol, and progesterone in each blood sample were determined by use of radioimmunoassay. Results: All NZW rabbits treated with CsA and methylprednisolone for immunosuppression consistently developed striking mammary tissue hyperplasia. At the end of treatment with CsA and methylprednisolone, mammary glands had extensive changes consistent with actively lactating glands. Similar but less extensive hyperplasia developed in response to CsA alone. Plasma concentration of prolactin increased during treatment and decreased during the washout period. Plasma concentration of 17 betap-estradiol increased during treatment and continued to increase during the washout period. Plasma progesterone concentration decreased at the end of treatment. On discontinuation of CsA, mammary hyperplasia regressed. Conclusions: Cyclosporine A, with or without methylprednisolone, induces mammary hyperplasia and hyperprolactinemia in NZW rabbits. This rabbit model may be a reliable in vivo system by which to study immunosuppressant-induced structural and functional changes of mammary glands similar to those observed in humans.