Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity

Abstract

Physiological responses that involve adrenergic mechanisms, such as stress-induced changes in cardiovascular indices, were reported to fluctuate along the menstrual cycle. Metastatic development following surgery was also reported to vary according to the menstrual phase during which a primary breast tumour was removed. Natural killer (NK) cells are believed to play an important role in controlling metastases. Our recent studies in rats demonstrated that adrenergic suppression of NK activity and of resistance to metastasis is more profound during oestrous phases characterized by high levels of oestradiol. In the current study in humans, we examined the in vitro impact of a β-adrenergic agonist, metaproterenol (MP), on NK activity, comparing blood drawn from (a) women tested at 3–4 different phases of their menstrual cycle ( n = 10), (b) women using oral contraceptives (OC) ( n = 10), and (c) men ( n = 7). NK activity in each blood sample was assessed in the presence of 5 different concentrations of MP (10 –8 M to 10 –6 M), and in its absence (baseline). The results indicated marked group differences in the magnitude of NK suppression by MP: EC 50 was 2.6-fold lower in the luteal phase compared to the follicular phase, and 1.8-fold lower in OC users compared to men, who were least susceptible to the effects of MP. No significant group differences or menstrual effects in baseline levels of NK activity were evident. These findings provide the first empirical evidence for menstrual regulation of adrenergic impact on cellular immune competence. Relevance of these findings to the relation between the timing of breast cancer excision within the menstrual cycle and survival rates is discussed. © 2000 Cancer Research Campaign http://www.bjcancer.com

Effect of Gender and Menstrual Cycle on Immune System Response to Acute Mental Stress: Apoptosis as a Mediator

“…Our analysis showed that experimental stress applied during the luteal phase deteriorated the immune system more since the CD4+/CD8+ cell ratio and NK cell number were lower in this group compared to the follicular phase. This finding points out that women behave differently during the different phases of the menstrual cycle and they may be more vulnerable to immune system-related diseases during the luteal phase, as was also suggested by Shakhar et al [46] and Mo et al [47] . The lowest CD4+/ CD8+ T lymphocyte ratio was found in posttest samples obtained from men; together with the decrease in NK cell number this finding suggests a shift of the immune response to probably humoral immunity as we have shown previously [2] , but the change in NK cells was not due to increased apoptosis in the present study but most likely due to recompartmentalization as suggested by Dhabhar [29] .…”

In vivo suppression of NK cell cytotoxicity by stress and surgery: Glucocorticoids have a minor role compared to catecholamines and prostaglandins

“…These effects are mediated through activation of leukocyte membrane receptors for these ligands, and intracellular initiation of the cAMP-PKA cascade common to both receptor systems [59, 60]. Potentially underlying the aforementioned sex differences in the impact of catecholamines on NKCC are the (i) menstrual cycle and female gonadal hormones that were shown to affect human and rat NK cell susceptibility to adrenergic stimulation [24, 61], presumably through modulating expression levels of adrenergic receptors on leukocytes [62], and (ii) testosterone that was shown to increase rat susceptibility to adrenergic suppression of in vivo levels of NKCC [55]. …”

Exploiting the critical perioperative period to improve long-term cancer outcomes

“…This assertion is supported by several characteristics of the RCT and other studies indicating the perioperative effects of sex hormones on cancer outcomes, specifically, that they were observed in women with positive but not negative lymph nodes, were due to distal malignant recurrence, were not evident before 3 years post-surgery, and were independent of tumour hormone receptor status. 11,128 These observations suggest that surgery potentiated an ongoing metastatic process, not through direct effects of sex hormones on the malignant tissue (as it was independent of receptor status), but through an indirect mechanism, such as immunosuppression 131,132 or other processes that facilitate progression of an early stage of a metastatic process. 11,127 …”