The study of the immune system in the menopause is a relatively new field of research, and only few data are available on some key components of the immune system and hormonal ovarian deficiency in the menopause. In fact, only recently has this subject captured relevant attention in literature reviews.

The immune system is a function of the body affected profoundly by aging, and since the immune system interacts with every organ and tissue in the body, and the neuroendocrine system is affected by the menopause, numerous studies suggest that hormonal gonadal deficiency could also affect immune function. Thus, hormones can affect immune cells and, consequently, immune system activities.

None the less, it is difficult to determine whether immunological differences observed in the menopause result from hormonal deficiency of ovarian steroids or instead are the results of age-related changes in immune function (Table Age-related changes in the immune system).

Table Age-related changes in the immune system.

  • Thymic gland involution
  • Reduced T-helper and T-suppressor cells
  • Decreased cell-mediated cytotoxicity
  • Increased circulating autoantibodies
  • Increase in circulating immune complexes
  • Decreased levels of specific antibody response
  • Diminished delayed hypersensitivity
  • Diminished production of interleukin-2
  • Increased production of interleukin-6

In addition, it is well documented that immunocompetence declines with age, and the immune system begins to lose some of its functions and cannot respond as quickly or as efficiently to stimuli. Age-related changes of the immune system have been observed at all levels, ranging from chemical changes within cells to differences in the kinds of proteins found on the cell surface, and even to alterations of entire organs.

One major change that occurs as the body ages is a process termed, ‘thymic involution. The thymus is the organ where T cells mature. T cells constitute an extremely important, highly specialized population of lymphocytes that have many functions, ranging from killing bacteria to assisting other cell types of the immune system.

This review covers a summary of the immune system, links between the neuroendocrine system, sex hormones and the immune system, autoimmune diseases related to alterations in sex hormones, mainly with reference to estrogen deficiency in the menopause, and hormone replacement therapy (hormone replacement therapy) and immune functions.

Overview Of The Immune System

The immune system is an interactive network of lymphoid organs, cells, humoral factors and cytokines. The essential function of the immune system in host defense is best illustrated when it goes wrong: underactivity resulting in the severe infections and tumors of immunodeficiency, overactivity in allergic and autoimmune disease.

Immunity is divided into two parts determined by the speed and specificity of reactions. The immune system eliminates foreign material in two ways: natural/innate immunity and adaptive/specific immunity.

Natural immunity produces a relatively unsophisticated response that prevents access of pathogens to the body and provides immediate host defense. This is a primitive evolutionary response that occurs without the need of prior exposure to similar pathogens. For example, macrophages and granulocytes engulf invading micro-organisms at the site of entry. These macrophages are estrogen-sensitive.

Adaptive immunity is the hallmark of the immune system of higher animals. This response consists of antigen-specific reactions through T lymphocytes and B lymphocytes. Specific immunity comprises two types of immune response: humoral immunity, in which antibodies are produced, and cellular immunity, which involves cell lysis by specialized lymphocytes (cytolytic T cells). Adaptive immunity is characterized by an anamnestic response that enables immune cells to, ‘remember’ the foreign antigenic encounter, and by the use of cytokines for communication and regulation of the innate immune response.

Immune cells mediate their effects by releasing cytokines and thus establishing particular microenvironments. T-helper (Th) lymphocytes originating from the thymus play a major role in creating a specific microenvironment for a particular organ or tissue. T-helper cells are subdivided functionally by the pattern of cytokines they produce. On stimulation, precursor Th0 lymphocytes become either T-helper 1 or T-helper 2 cells. The difference between these cells is only in the cytokines secreted; they are morphologically indistinguishable. However the responses they generate are very different. Thl cytokines induce mainly a cell-mediated inflammatory response and inhibit Th2 differentiation. Thl cells secrete interleukin-2 (IL-2) and interferon-y (IFN-y), setting the basis for a proinflammatory environment. A Thl response, is essential to the host to control the replication of intracellular pathogens, but possibly contributes to the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Conversely, Th2 cells produce IL-4, -5, -6 and -10, which are predominantly involved in antibody production. Thus, the Th2 response is associated with allergic disease. The actions of the two types of lymphocyte are closely intertwined, both acting in concert and responding to counterregulatory effects of their cytokines.

Thus, T lymphocytes play a major role in the immune response. They have been found to be susceptible to dysregulated function with aging, and these alterations affect both antibody- and cell-mediated responses.

In addition, the concept of the immune system has advanced from merely response to infectious agents to include a variety of complex situations and interactions with most, if not all, of the body’s systems. For the purpose of understanding, Mor assumes a division of these inter-actions into classical immune regulation and non-immune regulation by leukocytes. Each of the components of non-immune regulation is sensitive to the reproductive milieu and therefore to gonadal function. The elements of non-immune regulation include stimuli, effector cells, signals and target cells. Chiefly among these are the circulating monocytes that arise in the bone marrow and are the precursors to the tissue macrophages. In many organs, estrogen regulates the number of tissue macrophages. Thus, gonadal steroids represent primary signals for non-immune regulation. Acting via steroid receptors they can regulate monocyte number, cytokine production by monocytes and differentiation of monocytes into macrophages in the tissues. Monocytes contain estrogen receptors, but macrophages contain both aromatase and estrogen receptors. They respond to estradiol by secretion of cytokines, which can act in an autocrine or paracrine manner to regulate cell number and cell function.

Also, considerable evidence has accumulated suggesting that the interaction between estrogens and cells of the immune system can have non-immune regulatory effects. Thus, the role of estrogens in the prevention of bone loss is mediated by mechanisms involving the inhibition of proinflammatory cytokines by bone marrow cells. Moreover, disorders frequently affecting women after the menopause, such as cardiovascular disease, osteoporosis and neurodegenerative disorders, can be ascribed to the loss of sex hormone-dependent regulation of physiological functions, as well as to a modification of the non-immune regulatory functions of resident immune cells.

Neuroendocrine And Immune Systems

Until recently, the immune system was considered to constitute a largely autonomous self-regulating system. However, it is now clear that the immune system interacts with the neuroendocrine system and with virtually all tissues and organs, and that the central nervous system is the highest immunoregulatory organ, controlling immune and inflammatory reactions with the aid of classical hormones, neuroptides and neurotransmitters. A failure of this central neuroimmunoregulatory network invariably leads to disease, which may be a consequence of hyperactivity (for example, autoimmune diseases, allergy, chronic inflammatory conditions) or hypoactivity (immunodeficiency, susceptibility to infectious disease, cancer, etc.) of the immune system. The evidence that suggests interactions between the immune system and the neuroendocrine system comes from several observations. First, immune and neuroendocrine cells share common signal molecules and receptors; second, hormones and neuropeptides can alter the functional activities of immune cells; and third, the immune system is innervated by noradrenergic sympathetic and peptidergic nerve fibers. These nerve fibers are in direct contact with lympho cytes and macrophages, performing neuroeffector functions and releasing neurotransmitters that exert direct effects on the immune function. Finally, the immune system and its products, such as cytokines, can modulate the function of neural and endocrine systems. Communications between the immune and neuroendocrine systems utilize both hormonal and neural mechanisms. The hypothalamicpituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis function as a neuroendocrine circuit, incorporating complex feedback mechanisms that preserve homeostasis. Cytokine effects on neural and endocrine systems include activation of the HPA and HPG axes. The cytokines IL-1 and IL-6, in particular, are crucial factors in the activation of the neuroendocrine system.

Sex Hormones And The Immune System

It has long been suspected that there is a strong interaction between sex hormones and the immune system. Numerous in vitro and in vivo experiments have demonstrated that sex hormones affect and modify the action of cells of the immune system.

Sex hormones have been shown to modulate a great variety of mechanisms involved in the immune response, including thymocyte maturation and selection, cell trafficking, and cytokine and monokine production; lymphocyte proliferation; and expression of adhesion molecules and human leukocyte antigen (HLA)-class receptors.

Estrogens have stimulating effects on B-cell function, which seem dependent on inhibition of suppressor T cells; estrogens increase B-cell response and antibody production. On the other hand, progesterone and androgens depress antibody production. The above observations suggest that estrogens enhance B cell-mediated diseases but suppress T cell-dependent conditions. Androgens appear to suppress both B-cell and T-cell immune responses, and virtually always suppress disease expression.

In addition, sex hormones may affect the immune system not only by direct effects on immune-competent cells but indirectly through changes in the HPA axis.

The HPA axis inhibits the reproductive axis at many levels; thus, corticotropin-releasing hormone (CRH) inhibits the gonadotropin-releasing hormone (GnRH) neuron of the hypothalamic arcuate nucleus directly, and via (3-endorphins. As the GnRH neuron has no estradiol receptors, estradiol may act through hypothalamic CRH to inhibit GnRH secretion, and hence exert negative feedback through this mechanism. Gluco-corticoids inhibit GnRH secretion as well as gonadotropin and gonadal steroid hormone production. Conversely, estradiol appears to exert positive effects on CRH production both in the hypothalamus and peripheral tissues.

Estradiol stimulates the expression of adhesion molecules by immune cells while inhibiting the production of IL-6, an inflammatory cytokine, which plays a major role in the control and termination of inflammation directly via inhibition of tumor necrosis factor-α (TNF-α) and IL-1 production, and indirectly via stimulation of glucocorticoid secretion and activation of the acute phase of reaction. Hence, we can conclude that gonadal axis hormones, directly and indirectly through the HPA axis, alter the tone of the immune system and the quantity and quality of the inflammatory responses. These complex interactions between the HPA axis and immune and gonadal systems may prove to be fundamental in the genesis and perpetuation of autoimmune disease.

Sex Differences In The Immune Response

The immune system is clearly sexually dimorphic. Physiological, experimental and clinical data confirm differences in immune responses between the sexes. Therefore, gender emerges as one of the most important epidemiological risk factors for the development of autoimmune diseases. For instance, data on the incidence of a great variety of autoimmune diseases show that females represent the majority of patients affected in most of the conditions: 85% in Hashimoto’s thyroiditis and Grave’s disease, over 90% in systemic lupus erythematosus and Sjogren’s syndrome, and 65-75% in Addison’s disease, myasthenia gravis and rheumatoid arthritis. Females have higher immunoglobulin levels and stronger humoral and cell-mediated immune responses.

During the reproductive years, females tend to have more a vigorous immune response, stronger antibody response to immunization and infection, increased production of autoreactive autoimmune antibodies, increased resistance to the induction of immunological tolerance and a greater ability to reject tumors and homografts, compared with males.

Changes In Immune System During The Menopause

The menopause represents a low-estrogen state, and possibly a Thl (type 1) immune environment. During the menopause, deficiency of estrogen results in a failure of estrogen’s regulation of the immune system. It is now generally agreed that the immune responses may polarize into cytokine environments characteristic of Thl and Th2 cells. In general, the normal reproductive woman has a strong tendency to respond to foreign antigens by developing a Thl (type 1) immune response (cell-mediated) and by expressing high levels of proinflammatory cytokines.

In menopausal women, the number of peripheral blood monocytes is increased and the percentage of estrogen receptor-positive monocytes is relatively decreased. Furthermore, estrogen replacement therapy for a period of 3 months led to a decline in the numbers of monocytes to the values observed in young women and an increase in percentage of estrogen receptor-positive monocytes. Declining estrogen levels may facilitate the development of cell-mediated autoimmune diseases such as rheumatoid arthritis, whereas high estrogen levels may promote autoimmune diseases associated with humoral immunity such as systemic lupus erythematosus.

Autoimmune Diseases And The Menopause

For years scientists and physicians have suspected that estrogens and other steroid hormones play a role in autoimmune diseases. A shifting balance between cellular (Thl) and humoral (Th2) immunity is theorized to underlie the etiology of many autoimmune conditions. Rheumatoid arthritis (RA) strikes women chiefly during the peri- and postmenopausal periods. Mounting evidence suggests that RA may develop in response to the sudden drop in adrenal and gonadal steroid hormones induced by the menopause, which creates a shift towards the Thl immune response. Thus, the predominance of this disease among women suggests that sex hormones may modulate immune susceptibility. The reasons for the sex bias in autoimmune diseases are unclear, but may include factors such as sex-related differences in immune responsiveness and response to infection, sex steroid effects and other sex-linked parameters. Women may have greater susceptibility to autoimmune diseases, in part because of more robust immune responses, yet have a better prognosis, perhaps as a result of heightened recovery mechanisms. Estrogen has a biphasic effect on the normal immune response, and in autoimmune diseases estrogens suppress T cell-dependent immune function but stimulate T cell-independent, B cell-dependent humoral immunity.

Notably, RA in postmenopausal women is associated with accelerated bone reabsorption, compared with RA in premenopausal women. However, RA is uncommon in men under the age of 45, but the risk increases markedly in older age groups. These observations suggest that factors regulating the gender differences are linked to aging and reproductive functions. Although an understanding of the mechanisms is clearly incomplete, sufficient data are available to suggest that one of the mechanisms through which adrenal and gonadal hormones act is via their regulatory effects on TNF-a, IL-12 and IL-10 production by activated macrophages.

Research into neuroendocrine-immune interactions over the past few years indicates that hormones are important contributory factors in RA, and may be involved in both the altered responses to inflammatory insults with the development of chronic inflammatory disease and the microvascular dynamics.

There is evidence that deficient levels of gonadal androgens (testosterone and dehydrotestosterone) and adrenal androgens (dehydroepiandrosterone sulfate, dehydroepiandrosterone sulfate) are present and even pre-exist in both male and female subjects affected with RA. Females have significantly reduced levels of dehydroepiandrosterone sulfate, while in males the consistent finding is low testosterone levels. dehydroepiandrosterone sulfate can counteract the immunosuppressive effects of corticosteroids by enhancing IL-2 and IFN production, and thus enhance Thl cellular responses. On the other hand, gonadal androgens inhibit macrophage activation by abolishing IL-6, TNF-a and IL-1 production. Thus, from currently available data reviewed above, it can be concluded that patients with RA have a predominantly proinflammatory hormonal milieu which promotes the development of chronic inflammatory disease.

In vivo and in vitro studies have demonstrated that sex hormones interfere with a number of putative processes involved in the pathogenesis of RA, including immunoregulation, interaction with inflammatory mediators and the cytokine system, and a direct effect on the cartilage itself. All these observations point towards the importance of gonadal hormones. However, trials on the potential therapeutic use of sex hormones in RA are limitred. Further work is necessary to determine whether the role of sex hormones is as central protagonist or supporting cast in the complex arena of rheumatoid arthritis.

Hormone Replacement Therapy And The Immune System

Hormone replacement therapy (hormone replacement therapy) confers many health benefits to postmenopausal women. Despite links between estrogens and immune function prior to the menopause, the immune status of women receiving hormone replacement therapy has not been rigorously investigated.

Mor has found that, during the climacteric, the function of the immune system becomes more similar to that in men. This alteration is in both function and cellular composition. The number of circulating macrophage precursors (monocytes) increases during the menopause. This estrogen-regulated function could be due to an increase of bone marrow precursors or a decrease of cell migration into tissues. hormone replacement therapy decreases the monocyte number to levels found in premenopausal women. Moreover, in animal studies, ovariectomy up-regulates myeloid cell differentiation into the monocyte-macrophage lineage and increases thymic weight, while estrogen replacement therapy decreases the number of thymocytes and the size of the thymus.

Futhermore, in a prospective study Kamada and colleagues have shown the effect of hormone replacement therapy on postmenopausal changes of lymphocytes and T cell subsets. Since endocrinosenescence occurs simultaneously with immunosenescence, they aimed to determine whether or not lymphocytes and T cell subsets were altered in postmenopausal women. hormone replacement therapy induced a significant increase in the percentage of lymphocytes, but showed no effect on aberrations of naive cells and memory/ activated cells. Therefore, hormone replacement therapy prevents the decline in lymphocytes observed in postmenopausal women, but appears not to influence the observed alteration in T cell subsets.

Porter and colleagues studied the immune effects of hormone replacement therapy in postmenopausal women, and their findings showed a reversal of immune alterations associated with normal aging, suggesting that preservation or improvement of immune function may be associated with the use of hormone replacement therapy.

Fahlman and associates examined the effects of long-term hormone replacement therapy on selected indices of resting immune function in postmenopausal women. From this study, they concluded that women taking hormone replacement therapy had increased lymphocyte blastogenesis and decreased natural cellmediated cytotoxicity, compared with controls.

Research focused on immunology and the menopause is yet scarce; more investigations will be necessary to further our understanding of the aging process of the ovaries in general.

Summary

The immune system is a function of the body profoundly affected by aging.

The essential function of the immune system in host defense is best illustrated when it goes wrong; underactivity resulting in the severe infections and tumors of immunodeficiency, overactivity in autoimmune and allergic diseases.

During the menopause, a deficiency of estrogen results in a failure of estrogen’s regulation of the immune system. Estrogen can modify immune cell function and, consequently, immune activities. For instance, the role of estrogen in the prevention of bone loss is mediated by immune mechanisms involving the inhibition of proinflammatory cytokines by bone marrow cells. Moreover, disorders frequently affecting women after the menopause, such as cardiovascular disease, osteoporosis and neurodegenerative disorders, can be ascribed to the loss of sex hormone-dependent regulation of physiological functions, as well as to a modification of the non-immune functions of resident immune cells.

In addition, gender and sex hormones exert powerful effects on the susceptibility to, and progression of, numerous human and experimental autoimmune diseases. This has been attributed to direct immunological effects of sex hormones that exert a clear gender dimorphism on the immune system. Globally, estrogens depress T cell-dependent immune function and diseases. The menopause repre sents a low-estrogen state and possibly a type 1 immune environment. Androgens suppress both T cell and B cell immune responses, and virtually always result in the suppression of disease expression. Declining estrogen levels may facilitate the development of T-cell mediated diseases such as rheumatoid arthritis. As well defects in the hypothalamic-pituitaryadrenal axis have been proposed to play an important role in the pathogenesis of auto immune diseases. Adrenal and gonadal deficiency facilitates excessive macrophage production of TNF and IL-12 that characterizes rheumatoid arthritis.

Current evidence indicates that the neuroendocrine system is the highest regulator of immune inflammatory reactions. The hypothalamus-pituitary-adrenal axis constitutes the most powerful circuit regulating the immune system. Abnormalities of neuroimmunoregulation contribute to the etiology of autoimmune disease, chronic inflammatory disease, immunodeficiency and allergic disorders.

Hormone replacement therapy confers many health benefits to postmenopausal women. Despite links between estrogen and immune function prior to the menopause, the immune status has not been rigorously investigated. The number of circulating macrophage precursors (monocytes) increases during the menopause. hormone replacement therapy decreases the monocyte number to levels found in premenopausal women, and some of the impairment observed in the menopause can be restored after hormone replacement therapy. Although much is currently known about the menopausal process, much is yet to be explained. Currently, there are more questions than answers related to links between sex hormones, the menopause and the immune system. However, with the current advances in molecular biology, answers to most of these questions may be found in the near future.

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