Influence on the immune system activity by sex hormones has been widely reported. Fertile women are proner to the onset of autoimmune diseases than men, but this increased susceptibility disappears after menopause. The hormonal changes are very likely to be responsible for this event, but precise correlations between sex hormone levels and immune functions have not been defined. For this reason we have analyzed phenotype and natural cytotoxicity of peripheral blood lymphocytes (PBL) from 35 women in menopause, comparing them with the same parameters of 28 fertile and 8 postmenopausal women and correlating them with the hormonal pattern of each group. We have also considered 8 women with premature menopause. Hormonal levels have been detected by radioimmune assays, while PBL phenotype has been studied by immunofluorescence and FACS analysis. The natural killer (NK) cell activity has been calculated on the basis of a chromium release assay. Postmenopausal women showed a reduction of the number of total lymphocytes (1650 +/- 215 cells/mmc) in comparison to fertile women (2081 +/- 200 cells/mmc, P < 0.01). The decrease mainly involved B and CD4+ T lymphocyte subpopulations (P < 0.05 and P < 0.01, respectively). Women with premature menopause had lower percentage of CD4 lymphocytes (34% vs 47%, P < 0.01) and higher percentage of CD8 (30% vs 22%, P < 0.02) and NK cells (32% vs 14%, P < 0.009) than fertile women of the same age. The percentage of circulating lymphocytes expressing HLA class II antigens also resulted as being increased (22% vs 9%, P < 0.01). The number of total, CD2, CD4 T lymphocytes, B and NK cells correlated positively with LH and negatively with FSH serum levels (P < 0.05 and P < 0.002, respectively). PRL positively influenced CD2, CD4 and B lymphocyte numbers (P < 0.001). FSH and 17 beta-estradiol inversely affected CD8 and B lymphocyte numbers (P < 0.005 and P < 0.02, respectively). In conclusion, the increase of FSH and the decrease of PRL levels appear to be involved in the reduction of B and CD4 T lymphocytes thus lowering the risk for the onset of autoimmune diseases during and after menopause. Generalized activation of the immune system (raised expression of HLA class II antigens) with elevated numbers of cytotoxic subpopulations (CD8 and NK lymphocytes) is present in women affected by premature menopause suggesting the involvement of autoimmune dysregulation in the pathogenesis of this syndrome.