the innate immune response . It is a multiprotein complex that acts as a sensor and response mechanism to pathogens primed by nuclear factor kappa B ( NF-κB ), one of the main regulators of inflammation . A key component of the inflammasome is the effector protein caspase-1 . Usually inactive , caspase-1 becomes activated upon the assembly of the inflammasome and gets to work cleaving pro-inflammatory cytokines into their active forms . 2 Levels of these inflammatory factors have been shown to be much higher in menopausal women . 10 Part of the reason for this is the interaction of oestrogen receptors and NF-κB signalling pathways , which usually reduces the activation of NFκB . This cross-talk between estrogen receptors and NF-κB modulates NFκB ’ s ability to initiate inflammasome activation . 1 However , the reduced levels of oestrogen in menopausal women and subsequent increase in the NF-κBinflammasome axis activity worsens existing autoimmune conditions , especially Multiple Sclerosis ( MS ), and may instigate others , such as Rheumatoid Arthritis . 11
Other exogenous factors add to the inflammatory state seen at the intersection of autoimmunity and the MT . It has been postulated that the modern western lifestyle is a major contributor . 4 Changing reproductive patterns such as delays in first pregnancy , fewer pregnancies , fewer immune challenges due to improved sanitation and public health measures , and a positive energy balance have contributed to a longer lifetime exposure to ovarian hormones and the associated cycle of immune modulation . Additionally , by-products of industrialisation and environmental xenoestrogens , such as Bisphenol A ( BPA ), influence oestrogen receptor signalling and activate the NF-κB-inflammasome axis . Researchers suggest that exposure to these exogenous chemicals impairs ovarian function and can instigate early menopause in addition to oxidative stress and further inflammation . 4
Adding to this inflammatory state is the impact of BPA on increasing levels of leptin . 12 Aside from regulating appetite , leptin can negatively affect the proliferation of T-Regulatory ( Treg ) cells which will affect immune tolerance . Leptin levels are twice as high in women as in men , predisposing women to leptin resistance and increasing adiposity . Oestrogen deficiency in the MT further reduces the sensitivity of leptin receptors , increasing appetite and enhancing the impact on immune response . 4
Key symptoms and overlapping challenges
While there are some women who have few symptoms , the oestrogen fluctuations of the MT may be accompanied by what some researchers refer to as the climacteric syndrome . 6 This can include , but is not limited to , symptoms such as brain fog and dizziness , headaches , mood changes and cognitive disturbances , vasomotor symptoms such as hot flushes and night sweats , sleep disturbances , joint pains and epithelial tissue changes that result in dryness and itchiness . 5 Women with autoimmune disorders can experience similar symptoms , making menopause-associated autoimmune dysregulation difficult to differentiate from the autoimmune process itself . Autoimmune disorders that intersect with menopause include Rheumatoid Arthritis ( RA ), Sjogren ' s syndrome , Multiple Sclerosis ( MS ), Systemic Lupus Erythematosus ( SLE ), and Hashimoto ' s thyroiditis . Though there are other autoimmune disorders that predispose women to early menopause and disease flares during the MT , these conditions will be briefly reviewed in the context of the MT .
Fatigue , bone loss , joint pain , sleep disturbances and gastrointestinal issues are common in both the MT and RA , a disorder characterised by chronic synovial inflammation leading to progressive and permanent joint damage . Bone loss is accelerated in the early stages of RA , and in the MT the loss of oestrogen further aggravates the increased risk of osteoporosis , especially if glucocorticoid medications are being used to manage the inflammation and pain of RA . 13 Oestrogen is believed to act as a protective mechanism against rheumatoid arthritis and Sjogren ’ s syndrome . However , as oestrogen levels decline throughout the MT , protective , regulatory cytokines such as interleukin-10 ( IL-10 ) and transforming growth factor-β ( TGFB ) also diminish . 3
The onset of Sjögren ’ s Syndrome ( SS ) is ten times more likely to present in women than men , and its onset is typically later in life , frequently in the post-menopausal years . Primary SS is characterised by lymphocytic infiltration of exocrine glands contributing to dryness of the eyes and mouth and has systemic effects that cause fatigue , vaginal dryness and dyspareunia . 13 There is a particular aspect of the hormonal changes in the MT that may make SS worse during this phase of life . Normally , dehydroepiandrosteronesulphate ( DHEAS ) is produced in the adrenal glands of women who lack oestrogen . DHEAS is converted into dehydroepiandrosterone ( DHEA ) in exocrine glands and other peripheral tissues and can be converted to androgens and oestrogens . DHEA also suppresses TNF-α and IL-6 , which are elevated in SS . Thus , the potential role of DHEA in smoothing the MT falters in sufferers of SS due to the pathology in these glands . 13
MS is an immune-mediated disorder of the central nervous system characterised by demyelination and progressive neurodegeneration . Oestrogen binds to oestrogen receptors ( ERα and ERβ ) in the central nervous system , promoting transcription of antiinflammatory genes and suppressing pro-inflammatory pathways . 11 Low concentrations of oestrogen can enhance neuroinflammatory signals and has been associated with neurodegeneration via decreased brainderived neurotrophic factor ( BDNF ) and conversion of microglia to a more inflammatory phenotype . This suggests that women with MS may experience
202 | vol30 | no4 | JATMS