Multiple factors which are thought to influence the expression of autoimmune diseases include a genetic predisposition to autoimmunity and one or more triggering factors. A relationship between hormones and autoimmunity has been inferred since the expression of many autoimmune diseases, and the severity of symptoms, seem to be related to changes in hormone levels. This has prompted several questions, including "can hormones be used to treat autoimmune diseases? Although there is information on the relationship of hormones and autoimmune diseases, there are many aspects of this relationship that are not completely understood.
Hormones are products of the endocrine glands. They are substances produced in comparatively large quantities by a specific gland, and are secreted into the blood stream to act at distant sites in the body. For example, estradiol (an estrogen) is produced by the ovaries and influences nerve cells, bone, muscle, and other endocrine glands, and metabolism in general. Hormones often provide communication between different systems. For example, estrogen can modify immune sell function, and influence the production of regulatory factors produced by immune cells and tissues.
There are different types of hormones, grouped by chemical class. Sex steroid hormones include estrogens, progestins, and androgens (such as testosterone) and are produced in the ovary or testes. Steroid hormones, such as cortisol or DHEA (dehydroepiandrosterone, and androgen) are produced by the adrenal. Other hormones, such as thyroxine are produced by the thyroid gland, and protein hormones such as prolactin, thyroid stimulating hormone (TSH), adrenocorticotropin (ACTH) and others are produced by the pituitary gland.
Sex steroid hormones, including estrogen, progesterone and testosterone.
The available information supports the concept that sex steroid hormones influence the expression (symptoms and severity) of some autoimmune diseases. However, the mechanism by which hormones influence autoimmunity is not completely understood. There are several observations which suggest a relationship between sex steroid hormones and autoimmune diseases:
It is well known that there is a greater incidence of many autoimmune diseases in women. Therefore it has been inferred that sex steroid hormones, particularly estrogens, are a factor in the susceptibility to autoimmune disorders. However, the action of hormones is linked to genetics, HLA (histocompatibility antigens), age and sex. There is no clear evidence that hormones are solely responsible for the difference in incidence of autoimmunity between men and women.
Hormones affect immune cell functions and consequently immune system activities. In general, androgens (such as testosterone) and progesterone are thought to have suppressive effects (and perhaps have a protective role), prolactin is stimulatory and estrogen can be either stimulatory or inhibitory for immune function. However, studies of isolated immune cells in culture show that sex steroids have a variety of effects. For example, estrogen decreases cell mediated immunity and T lymphocyte suppressor cells which permits enhanced B lymphocyte activity (and antibody production). In animal models, hormone effects have been shown to be complex with different effects depending on the strain and the specific disease.
The symptoms associated with some autoimmune diseases change with natural changes in estrogen and progesterone such as those that occur during the menstrual cycle, pregnancy and at menopause. The onset of some autoimmune diseases may coincide with pregnancy or menopause. For example, autoimmune thyroiditis (Hashimoto's and Graves) and rheumatoid arthritis generally improve during pregnancy (pregnancy is associated primarily with elevated progesterone and to a lesser extent estrogen), but tend to return post partum. In contrast to RA, SLE tends to flare during pregnancy. Thus there may be different hormone milieus that protect against different autoimmune diseases.
In addition, the typical age of onset varies among autoimmune diseases. For example, SLE onset commonly occurs after puberty and during the reproductive years, while RA onset tends occur later with a peak around the age of menopause and declining estrogen levels. However, the incidence rates for men and women become similar around the age of menopause, suggesting that aging is a more critical factor than hormone changes.
Overall, these observations represent "guilty-by-association". During pregnancy other hormones, such as prolactin and cortisol, also increase significantly. In addition, there may be less obvious alternations in sex steroid metabolism associated with autoimmunity but the cause and effects relationship has not yet been determined.
Estrogen in the form of birth control pills and hormone replacement at menopause have been reported to exacerbate Sle activity, but there is not complete agreement on this effect of estrogen on SLE (see below). Similarly, there is a lack of clarity regarding the effects of estrogen on RA. There is no significant information on the effects of estrogen on other autoimmune diseases.
Adrenal hormones, the HPA axis and DHEA
A newer area of research concerns the relationship of the adrenal axis and adrenal hormones to autoimmunity. The hypothalamic-pituitary-adrenal axis (HPA) is closely linked to the gonadal axis and is sexually dimorphic (is different form men and women).
The most striking evidence for a role of HPA axis in autoimmunity is seen in studies of animal models. Lewis and Fisher rats differ in their susceptibility to induction of autoimmune diseases. In addition, Lewis rats which are more susceptible, have depressed HPA activity, accompanied by lower levels of corticosterone (cortisol) and DHEA. Thus they have a poorer ability to regulate inflammation and immunity.