SEX HORMONES AND SYSTEMIC LUPUS ERYTHEMATOSUS

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Systemic lupus erythematosus (SLE) is a disease like most of the connective tissue diseases, where the prevalence is greatest in young women of childbearing age.8 This is one of the most obvious clinical observations in both the human form of the disease and that of certain animal models. Because of this, gender and age are most likely linked to both cause andpathogenesis. Despite these facts, an explanation of this sexual predilection is elusive, although there are many theories. Factors like sex hormones60 and genetics85 are suspected reasons for the large number of young women with the disease. The sex steroid hypothesis is particularly attractive. Sex steroids are important to the health of most vertebrates because they play an important role in the maturation of organ systems that affect animals throughout life.6 Although the most obvious effects of sex steroids occur at puberty as the development of secondary sexual characteristics, major developmental changes occur long before that, even before parturition. Various genetic theories centered about the X chromosome are popular explanations for the female predominance of autoimmune disease in human beings74 and animals.77, 81

Basic research on the sexual dimorphism of the immune system is likely to validate either argument. There are good clues from the clinic and laboratory that are revealing. One clue is the close link between organ-specific cytokine production during the normal menses, pregnancy, and immune function. Changes occur at the cellular level in animals and cell culture in response to sex steroids. Clinical changes occur in men and women who experience an excess or depletion of sex hormones. Sex hormones are important modulators of activity for many systems of the body like the brain, gonadal tissue, and skin. The immune system is also an organ system in which sex steroids play a major role in both normal maturation and disease.

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SEXUAL DIMORPHISM AND LUPUS

Estrogen is shown to augment CD8 levels101 and CD4-mediated cytolysis80 in human beings. Estrogen also enhances production of interferon-γ and interleukin (IL)-10 by T-helper (Th)1 and Th2 cells. Early studies show that T-cell helper activity priming B cells to differentiate was also affected by estrogens, whereas androgens generally had the opposite effect.98 Cytokine regulation of the immune system is well accepted, and the production by the ovary of immunopotent cytokines that regulate local

MOLECULAR AND CELLULAR MECHANISMS OF SEX HORMONE ACTION AS IT APPLIES TO SYSTEMIC LUPUS ERYTHEMATOSUS

Sex hormones could affect the immune system by modifying T-cell receptor signaling and regulating the expression of T-surface cell signals or autoantigens, the transcription or translation of cytokine genes, or lymphocyte homing. Research shows that the regulation of cytokine genes is dependent on sex hormone levels in experimental systems.78, 107 The other mechanisms, although attractive, have not been proven.

Recent evidence indicates that calcineurin mRNA levels in T cells from a group of

MURINE MODELS OF AUTOIMMUNITY AND THE SEX HORMONES

It is appropriate to mention the manner by which gender affects lupus in the experimental mouse. There are several strains of mice that are used as models of autoimmune disease (Table 1).9 The disease in some murine models predominates in female mice; examples are the New Zealand White/Black (NZW/NZB) Fl hybrid and the MRL lpr strains, in which female mice die at a younger age than male mice.44, 45 The NZB/NZW strains were the first mouse strains in which the effects of gonadal hormones were

GENERAL REMARKS ABOUT MURINE LUPUS AND SEX STEROIDS

Evidence cited previously indicates that gender plays a major role in the modulation of autoimmune diseases of certain mouse strains; in one case, it is hormonally predisposed, although in the other, there is a clear relation to the Y chromosome. There are certainly many other aspects to consider in the morbidity of murine SLE. Undoubtedly, factors like genetics and a possible transmissible agent could play a major role. Unlike the case in mice, it is apparent that sex steroids act on the

Androgens

Androgens have many effects on immune function. They are immunosuppressive because of in vitro observations in normal lymphocytes and because of their effects on the disease manifestations of inbred autoimmune mice.2 Testosterone has also been shown to suppress anti-DNA antibody production in peripheral blood mononuclear cells from patients with SLE.55 This was shown to occur through the downregulation of IL-6 and the inhibition of B-cell activity. Graft rejection in rodents is delayed by

SEX STEROIDS AND HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS

In human SLE, there is little consistency of disease manifestation from patient to patient even within the same family. A patient or sibling from one family may present with autoimmune hemolytic anemia, whereas another may present with encephalopathy. Siblings from the same family who are of different genders might be equally affected.

Although gender plays a major role in the expression of SLE, it is not likely to be the cause but rather a modifier of expression. Most patients who present with

PROLACTIN

There is great interest in the effects of prolactin on immune function in mice and human beings.52 There are diverse effects of hyperprolactinemia in male and female mice. In the male NZW/NZB mouse, autoimmune disease is accelerated and mortality is worsened by prolactin.112, 114

High prolactin concentrations are particularly associated with worsened renal disease in inbred lupus mice. The use of prolactin inhibitors like bromocriptine has beneficial effects in these mice, namely, renal disease

MEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS

The age at onset of the disease is more evenly distributed in men, because one fourth are diagnosed after the age of 50 years.97 The hormonal metabolic data suggest that an increase in feminizing 16-hydroxylated estrogenic metabolites is found in men with SLE, although no clinical findings of hyperestrogenism are found.61, 63, 65, 68, 69 Studies of a murine strain like the BXSB associate the onset of SLE-like diseases with the presence of the Y chromosome and are not hormonally dependent. A

PATIENTS WITH KLINEFELTER'S SYNDROME

Some patients with Klinefelter's syndrome also have a variety of rheumatic diseases like SLE and scleroderma.12, 29, 32, 39, 57, 58 Such men commonly have gynecomastia, infertility, a female fat pattern, and the usual sequela of hypogonadism. These Klinefelter's syndrome patients have met the American College of Rheumatology criteria for SLE serologically and clinically. The incidence of SLE or any other autoimmune disease is not increased in patients with Klinefelter's syndrome. The patient

EXOGENOUS HORMONES AND LUPUS

A major controversy among investigators is whether androgen therapy should become part of the lupus treatment protocol and whether the use of exogenous estrogen can be used in the pre- and postmenopausal SLE patient. The estrogen issue is under study by several groups worldwide. A large multicenter study to examine both pre- and postmenopausal estrogen use is underway in the United States. This study is called the Safety of Estrogens in Lupus Erythematosus–National Assessment. Early data17

SUMMARY

Lupus is one disease in which sex hormones and gender are quite important. Studies of autoimmune diseases like lupus have made the hormone connection more important and increased our overall understanding of the sexual dimorphism of the immune system. It is clear that some fundamental biologic mechanism is at work here and that only knowledge of the molecular mechanisms behind the action of the hormones can help us to understand the gender preference in this illness.54 Hormones may be potent

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    Department of Medicine, The New York Medical College, and the Department of Rheumatology, Saint Vincent's Hospital and Medical Center, New York, New York

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