Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis: possible clinical implications

Clinical observations suggest that the rate of metastatic development and l ong-term mortality following surgery in breast cancer patients is influence d by the menstrual phase during which surgery is conducted. The menstrual c ycle is known to modulate various physiological responses and medical condi tions that involve adrenergic mechanisms (e.g., asthma). Natural killer act ivity (NKA), an immune function controlling metastasis, is suppressed follo wing surgery, and in vitro by adrenaline. We therefore hypothesize that the clinical observation may be partly attributable to surgery-induced adrener gic suppression of NK-dependent resistance to metastasis, a suppression tha t depends on menstrual phase during surgery. To test this hypothesis in rat s: 140 F344 females at different phases of their oestrous cycle were inject ed with a beta -adrenergic agonist, metaproterenol (MP) (0.4 or 0.8 mg kg(- 1), s.c.), or with vehicle, before i.v. inoculation with MADB106 tumour cel ls. This syngeneic mammary adenocarcinoma line metastasizes only to the lun gs, and is highly sensitive to NKA. In a second experiment, the suppression of NKA by MP was studied in vitro in blood drawn at different phases of th e oestrous cycle (n = 36). Finally, the effects of stress on the number and activity of NK cells were assessed along the oestrous cycle (n = 71). The findings indicate that the suppressive effects of MP on resistance to metas tasis and on NKA, are significantly greater during the oestrous phase chara cterized by high oestradiol levels (D3/proestrus/oestrus). Similarly, NKA p er cell was suppressed by stress only during this phase. In untreated anima ls, in which inadvertent stress was minimized, no effects of the oestrous c ycle on NKA or on resistance to metastasis were evident. These findings ind icate that the oestrous cycle modulates adrenergic suppression of NKA and o f resistance to metastasis. The relevance of these findings to the above cl inical observation, as well as that of our related findings in women from a parallel study, is discussed. (C) 2000 Cancer Research Campaign.