Abstract and Introduction
Despite the fact that women living in industrialized countries are likely to spend a third of their lives in menopause, the influence of the estrogen withdrawal associated with menopause on many body systems is not fully understood. This is particularly true of the immune system. Autoimmune diseases show a clear predominance in women, implying a central role for estrogen in their development. A thorough elucidation of that role, however, has been challenged by the observation of undeniable contributions to autoimmune disease by genetics, immunosenescence and environmental triggers as well. The global incidence of autoimmune disease has risen steadily in recent years, worldwide and in all ages, in parallel with steadily increasing global lifespans. Given the prevalence of autoimmunity in women, and the significant increase in the number of women in their postmenopausal years, the effect of menopause on autoimmunity is an area well deserving of further research effort.
Life expectancy in human beings has increased dramatically in the last century and is expected to continue to increase, reaching 100 years in the USA and other industrialized countries by approximately 2040. In the USA, life expectancy has increased 10% since 1970 from an average of 70.8 years to an average of 78.3 years. Women, on average, currently live nearly 3 years longer than men.
The dramatic gains in life expectancy achieved have allowed for concomitant gains in an understanding of immune system aging, termed immunosenescence. Recent analyses of immune system aging have revealed that individual longevity is closely tied to the preservation of healthy immune function.
The immunosenescence that occurs as humans age is therefore of increasing interest in medicine and deserving of research effort as life expectancy, particularly in developed countries, is increasing at a more rapid rate than concomitant improvements in meeting the medical needs of the elderly. This is particularly true in women, who at current life expectancies will spend more than a third of their lifetimes in menopause.
Menopause, a period of time defined by the cessation of menstruation, is an experience common to all aging females. Cessation of menses results from a gradual deterioration in ovarian function, with declining production of follicles and falling levels of numerous endogenous hormones. Estrogen produced in postmenopausal females, furthermore, is of a different form than the one that is predominant during the reproductive years. Levels of the ovarian-derived 17b estradiol (E2), as ovarian follicles cease production, plunge as menopause nears, and estrogen in the form of estrone (E1) becomes the predominant form. E1 is produced by secretion of androstenedione by the ovarian stroma and the adrenal gland and is aromatized to E1 in the peripheral circulation. Conversion to E1 occurs primarily in adipose tissue, but also in muscle, liver, bone, bone marrow, fibroblasts and hair roots. Postmenopausal deficits in estrogen and progesterone, and the replacement of E2, the primary estrogen of the reproductive years, to E1 carry impact far beyond the immune system.
Estrogen, with receptors in nearly every tissue of the body, is a principal regulator of homeostasis in the female body, with the hormonal tides characteristic of a woman's reproductive years having demonstrable effects on nearly every body system. The sudden and dramatic removal of estrogen from the female body, particularly in the form of estradiol, is a veritable tsunami with significant and largely negative effects on many body tissues, including a loss of skin integrity and tone, poorer muscle tone (affecting heart, vasculature, eye and bladder function; declining brain function; and deterioration in bone strength). Estrogen levels, and particularly the estrogen withdrawal of menopause, undeniably impact autoimmunity in women as well.
Autoimmune disease as a category affects an estimated 50 million Americans and is the top cause of morbidity in women in the USA. The annual cost of only seven of the 100+ known autoimmune diseases (Crohn's disease, ulcerative colitis, systemic lupus erythematosus [SLE], multiple sclerosis [MS], rheumatoid arthritis [RA], psoriasis and scleroderma) are estimated, through epidemiological studies, to total as much as US$70 billion annually.
The development of autoimmunity clearly involves genetic and environmental contributions to existing levels of endogenous estrogen and the precise contributions of each are not fully understood. Additional research, to focus on how autoimmune disease is impacted by the plummeting estrogen levels associated with menopause, is needed.
Expert Rev of Obstet Gynecol. 2012;7(6):557-571. © 2012 Expert Reviews Ltd.