Effects of lithium on the pituitary-gonadal axis in the rat: evidence for dose-dependent changes in plasma gonadotropin and testosterone levels.

The purpose of the present study was to examine the effects of lithium, a drug which is now used rather widely in the treatment of acute mania and the prophylaxis of manic-depressive bipolar disorders, on the pituitary-gonadal function in the laboratory rat. Sexually adult male rats, maintained under standardized laboratory conditions (LD 14: 10; lights on at 06:00 h, CST), were injected (ip) with lithium chloride both acutely for 1 day and chronically for 5 days, and by utilizing a low and high dose. For the low dose, lithium was injected twice daily (at 10:00 and 15:00 h) at 2.5 meg/Kg for 1 and 5 days, whereas in the high dose groups, also receiving lithium twice daily and at the same hours, the dosages were 5 meq/Kg for 1 day and 3.5 meq/Kg for 5 days. Animals were sacrificed 4 hours after the last lithium (or saline) injections. Plasma and pituitary levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and plasma levels of testosterone (T) were measured by radioimmunoassay (RIA). The administration of the low dose led to a significantly higher (P less than 0.001) plasma FSH, but unaltered plasma LH, levels after 5 days. In contrast, the high dose lithium led to significant suppressions of plasma LH (P less than 0.02; on day 5) and FSH (P less than 0.001; on both day 1 and 5) levels. The levels of plasma T also showed a significant reduction following the low dose (P less than 0.02; on day 5), as well as the high dose lithium treatment, as evident after both 1 (P less than 0.02) and 5 (P less than 0.02) days. Regardless of the dosage, or the duration of treatment, pituitary gonadotropin levels remained unaltered following lithium. The results of our present experiments suggest that lithium administration, either acutely or on a chronic basis, might be associated with significant adverse effects on the pituitary-testicular axis. Furthermore, since some of the hormonal changes were evident when plasma lithium concentration was within the therapeutic range, our data may have potential clinical implications.