Female Reproductive Hormones and Immunity
Sexual dimorphism influences many aspects of health including immune function, responsivity and disease susceptibility[1,2]. Such sex-based differences are mediated by a complex interplay between genetic and hormonal factors particularly involving the X chromosome (which carries innate and adaptive immune genes) and steroid hormones. Steroid hormones regulate immune system development, homeostasis, gene expression, signalling and immune cell functionality[2,3]. Consequently, hormonal fluctuations during the menstrual cycle and different life stages significantly influences immune function. This article reviews how the interplay between female steroid hormones and the immune system affects reproductive health.
Oestrogens induce their biological activity through alpha and beta oestrogen receptors (ERalpha and ERbeta)[4-6]. Sex steroid hormones oestrogen (primarily 17beta oestradiol [E2]) and progesterone regulate the menstrual cycle, fertilisation, implantation and early embryonic development[7,8]. In premenopausal women, oestrogen synthesis from the developing ovarian follicles during the follicular phase increases until ovulation. Following ovulation, during the luteal phase, progesterone derived from the corpus luteum increases until the onset of menstruation. During perimenopause, both oestrogen and progesterone levels progressively decline, with significant fluctuations in these hormones occurring in the transition to menopause. Conversely, in pregnancy, oestrogen and progesterone levels increase throughout gestation. Steroid hormones regulate immunity via a range of mechanisms (see Table 1) and, reciprocally, the immune system is closely involved in many reproductive processes in pregnant, pre- and post-menopausal women under the influence of the characteristic steroidal hormonal patterns that occur during these life stages.
This involves complex interactions between cervical epithelial cells; female reproductive tract and gastrointestinal microbiota; and immune cells concentrated in the female reproductive tract (T cells, macrophages, neutrophils and mast cells, dendritic and natural killer cells)[10,11].
Menstrual cycle changes in immune system components
During the follicular phase, there is an increase in angiogenesis, tissue regeneration and AMP secretions; also, local immune cell concentrations are reduced and proinflammatory cytokine secretion from uterine epithelial cells are inhibited by elevated oestrogen levels[10,11]. High oestrogen also supports vaginal microbiome proliferation, with higher Lactobacilli concentrations through until ovulation[15,21].
At the onset of ovulation, angiogenesis, AMPs and epithelial barrier proteins are at their highest. Uterine endometrial cells, mediated by sex steroid hormones, also produce cytokines and chemokines which induce the recruitment of local immune cells (NK cells, neutrophils macrophages). Cervical and vaginal IgA, IgG, IL-6 and IL-8 concentrations are reduced to promote sperm cell survival[10,11,22].
During the luteal phase, when sex steroid hormones decline as menses approaches, these immune cell concentrations continue to increase as an inflammatory response is initiated. Local AMP synthesis increases, while local cytotoxic cell activity and neutrophil bactericidal activity decreases, to enhance the capacity for implantation. If a pregnancy does not occur, a local inflammatory response involving immune cells and cytokines causes subsequent tissue disintegration, resulting in the onset of menstruation when lower vaginal microbiota diversity is occurs[10,15,22,23].
If conception takes place, a complex communication ensues between many endometrial, foetal and placental tissue immune factors throughout the pregnancy. This enables blastocyst implantation and placental and foetal growth; it also promotes immune tolerance of the foetus’ hemiallogeneic tissue and protects it from infection, promoting an environment that supports pregnancy maintenance[2,17,18]. The increased systemic inflammatory environment and higher prevalence and risk of infections in peri- and post-menopausal women is associated with the impact of reduced oestrogen and progesterone levels on immune system functionality[2,10,13]. This includes reductions in immune cell concentrations and activity and immune factors (AMP, cervical mucous)[1,10,13]. Significant alterations in the vaginal microbiome occurs including decreased Lactobacilli diversity and abundance and reduced NK cell activity, mucosal, cell-mediated and humoral immunity[17,21].
This complex interplay between steroid hormones and many aspects of the immune system can become dysregulated, adversely affecting reproductive health in pre- and post-menopausal women and during pregnancy, including those listed in Table 2.
Overall, this review highlights that effective management of female reproductive health requires assessment of the bidirectional relationship between steroid hormones and immune system factors on the development, progression and severity of many conditions experienced by pregnant, pre- and post-menopausal women.