HIGHLIGHTED TOPICS
Genome and Hormones: Gender Differences in Physiology
Invited Review: Sex ratio and rheumatic disease^*

Barbara Volcker Center, Hospital for Special Surgery, Joan and Sanford I. Weill Medical College, Cornell University, New York, New York 10021

	ABSTRACT

TOP ABSTRACT INTRODUCTION THE BASIC DATA IMMUNIZATION AND INFECTION AS... POTENTIAL CAUSES OF SEX... LESSONS FROM ANIMAL MODELS CONCLUSION REFERENCES

Human illnesses affect men and women differently. In some cases (diseases of sex organs, diseases resulting from X or Y chromosome mutations), reasons for sex discrepancy are obvious, but in other cases no reason is apparent. Explanations for sex discrepancy of illness occur at different biological levels: molecular (e.g., imprinting, X-inactivation), cellular (sex-specific receptor activity), organ (endocrine influences), whole organism (size, age), and environmental-behavioral, including intrauterine influences. Autoimmunity represents a prototypical class of illness that has high female-to-male (F/M) ratios. Although the F/M ratios in autoimmune diseases are usually attributed to the influence of estrogenic hormones, evidence demonstrates that the attributed ratios are imprecise and that definitions and classifications of autoimmune diseases vary, rendering at least part of the counting imprecise. In addition, many studies on sex discrepancy of human disease fail to distinguish between disease incidence and disease severity. In April 2001, the Institute of Medicine of the National Academy of Sciences published Exploring the Biological Contributions to Human Health: Does Sex Matter? (Wizemann T and Pardue M-L, editors). This minireview summarizes the section of that report that concerns autoimmune and infectious disease. Some thyroid, rheumatic, and hepatic autoimmune diseases have high F/M ratios, whereas others have low. Those that have high ratios occur primarily in young adulthood. Gonadal hormones, if they play a role, likely do so through a threshold or permissive mechanism. Examples of sex differences that could be caused by environmental exposure, X inactivation, imprinting, X or Y chromosome genetic modulators, and intrauterine influences are presented as alternate, theoretical, and largely unexplored explanations for sex differences of incidence. The epidemiology of autoimmune diseases (young, female) suggests that an explanation for sex discrepancy of these illnesses lies in differential exposure, vulnerable periods, or thresholds. Biologists have an opportunity to inform medical scientists about sex differences that explain different attack rates in specific diseases, and physicians offer biologists experiments of nature to test theories of sex.

autoimmunity; hormones; X chromosome; imprinting; environmental exposure

	INTRODUCTION

TOP ABSTRACT INTRODUCTION THE BASIC DATA IMMUNIZATION AND INFECTION AS... POTENTIAL CAUSES OF SEX... LESSONS FROM ANIMAL MODELS CONCLUSION REFERENCES

HUMAN ILLNESSES AFFECT men and women differently. In some cases (that is, for diseases of sex organs and for diseases resulting from X or Y chromosome mutations), reasons for sex discrepancy are obvious, but in others no reason is apparent. Possible explanations for sex discrepancy of illness can be found at different biological levels: molecular (e.g., imprinting, X inactivation), cellular (sex-specific receptor activity), organ (endocrine influences), whole organism (size, age), and environmental, including intrauterine influences.

Autoimmunity represents a prototypical class of illness that has high female-to-male (F/M) ratios. Although the F/M ratios are usually attributed to the influence of estrogenic hormones, critical review of the supporting evidence demonstrates that attributed ratios are imprecise and that definitions and classifications of autoimmune diseases differ substantially, rendering at least part of the enumeration imprecise. In addition, many papers on the topic of sex discrepancy of human disease fail to distinguish between disease incidence and disease severity, confusing the discussion.

In April 2001, the Institute of Medicine of the National Academy of Sciences published Exploring the Biological Contributions to Human Health: Does Sex Matter? (60-65). This minireview summarizes the section of the Institute of Medicine report that concerns autoimmune and infectious disease.

	THE BASIC DATA

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In general terms, autoimmune diseases are those diseases in which the adaptive (or memory) immune system initiates an injurious attack on one's own normal tissues. The many diseases called autoimmune are either systemic (involving many body organs) or organ specific. Symptoms of systemic diseases include arthritis, fevers, rashes, and glomerulonephritis; organ-specific illnesses usually cause insidious painless failure of the target organ, such as the thyroid gland. The immune system may initiate an attack on self because the normal controlling mechanisms of the immune system are impaired, because a host response to an extrinsic immunogen, such as a virus, fails to distinguish between normal tissue and the object of the attack (cross-reactivity), or because immunogenic tissues, normally hidden from the immune system, are made visible to the immune system (loss of tolerance). Any or all of these mechanisms may occur in human autoimmune disease; specific mechanisms have not been clearly identified for most of these illnesses. Autoimmunity is defined by the demonstration of a specific immune response, regardless of the mechanism.

Differing definitions of autoimmunity cause conflicting answers to the question: Which diseases are autoimmune? Most definitions require demonstration of autoantibody, the most easily measurable component of the immune response, and of autoantigen. One popular definition accepts cell-mediated autoreactivity as a defining characteristic, another includes immunization and passive transfer in animal models, and still another includes participation of the major histocompatibility complex (MHC) (20, 30, 48). Differences among authors in their definitions of autoimmunity cause published lists of autoimmune diseases to differ.

Similarly, classifications of autoimmunity differ. The most widely accepted classification distinguishes organ-specific autoimmune diseases from systemic (48), another differentiates between primary (autoimmunity to normal tissue) and secondary (autoimmunity to "damaged" tissue) autoimmune diseases (20), and a third classifies by mechanism, e.g., cellular vs. humoral (antibody) responses (30).

Despite the inconsistencies, most contemporary medical texts agree that several thyroid (Hashimoto, Graves), rheumatic (systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjögren), and hepatic (autoimmune hepatitis, primary biliary cirrhosis) diseases are autoimmune. These diseases mostly affect women. However, some authors also consider ankylosing spondylitis, vasculitis, Goodpasture's disease, multiple sclerosis, juvenile onset diabetes, and inflammatory bowel disease to be autoimmune. These latter diseases are not highly female predominant; some are male predominant.

Because most published F/M ratios derive from the epidemiologically weak sources of individual clinics, physician's practices, and voluntary agencies (1), published F/M ratios vary considerably (Table 1). Ratios also differ by age. Among rheumatic diseases, lupus, Sjögren, and scleroderma consistently have F/M ratios 3; the rheumatoid arthritis ratio is between 2 and 3; dermatomyositis and vasculitis have a ratio close to 1; and B27 spondyloarthropathy is male predominant. Published F/M ratios vary 4-fold for scleroderma, 3-fold for lupus, 10-fold for Hashimoto thyroiditis, 7-fold for multiple sclerosis, and 5-fold for Goodpasture's disease (Table 1) (7, 45).

View this table: [in this window] [in a new window]   Table 1.   Female-to-male ratios of autoimmune diseases cited by various authors and AARDA

In human autoimmune illness, the term "female predominance" refers to sex differences of incidence, not severity. Severity differences are slight or nonexistent (59). Investigators who work with animal models of these diseases, however, use the term female predominance to mean differences of both incidence and severity, i.e., disease appears at a younger age and in a more severe form in females. This error, the failure to distinguish between incidence and severity in animal models, may invalidate the implied lessons for human illness.

	IMMUNIZATION AND INFECTION AS TESTS OF IMMUNE RESPONSE

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Immune attack on infecting organisms is a normal, health-maintaining response. Response to infection uses the same components of both the innate (inflammatory, constitutive) and adaptive (memory, inducible) immune systems, as does immune attack on self (autoimmunity). Immunization of healthy people or animals engages the adaptive immune response to prevent invasion by the chosen organism; infection engages both the innate and the adaptive immune apparatuses to eradicate an invader. Thus examinations of sex-specific responses to immunization and infection test the hypothesis that intrinsic sex differences of immune response account for differences in autoimmune disease frequencies.

Vaccination studies inconsistently show higher antibody titers in women but few important clinical differences between genders (Table 2) (full text with detailed references may be found at http://www.nap.edu/catalog/10028.html). Intriguingly, arthritic adverse reactions to immunization may be more common in women, implying that the quality rather than the quantity of response may differ between the genders. With regard to infection, viruses generally affect men and women equally. However, Coxsackie virus myocarditis is male predominant, possibly because male hearts have more virus receptors than do female. Bacterial infections also affect the sexes equally. In acute and chronic Lyme disease (a type of arthritis caused by the spirochete Borrelia burgdorferi and a possible infectious model for rheumatoid arthritis), male and female incidence and severity are similar. Sex-specific attack rates of mycobacterial, fungal, and parasitic diseases are also equal; differences that do exist are mostly explained by societally caused differences in exposure to the infecting agent. Cytokines that constitute part of the adaptive immune response are used to treat cancers. They sometimes induce symptoms of both male- and female-predominant autoimmune rheumatic disease (29). Thus neither immunizations nor infections strongly support the idea that intrinsic male-female differences in the immune response account for the high F/M ratios of rheumatic disease.

View this table: [in this window] [in a new window]   Table 2.   Sex differences in response to immunization

	POTENTIAL CAUSES OF SEX DISCREPANCY

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Environment. The possibility that environmental factors are responsible for sex discrepancy of autoimmune disease is supported by the examples of drug-induced lupus (66) and toxin-induced scleroderma-like disease. More men than women take drugs that induce lupus (male predominant), more men are exposed to silica inducers of scleroderma-like disease (male predominant), and more women have been exposed to the contaminated cooking oil that caused a scleroderma-like illness in Spain (female predominant) (2). More women than men took contaminated L-tryptophan, a putatively "natural" antidepressant; the resulting epidemic of eosinophilia-myalgia syndrome was female predominant (50).

When an arthritogenic organism (B. burgdorferi, parvovirus B19) infects both sexes equally, its "autoimmune" sequel, i.e., arthritis, is not sex discrepant (12). Sex discrepancies that occur in infectious disease are attributable to different exposures, differences in processing infecting organisms, vulnerable periods, or threshold immune responses. The high attack rate of malaria in the postpartum period is an example of a vulnerable period (18). Prolonged incubation periods make determination of different exposures difficult to exclude. For instance, lupus blood tests are positive decades before clinical illness appears (4, 44). If lupus has an infectious cause, exposure to a causative agent may have been remote, and sex discrepancy of that exposure would be correspondingly difficult to discern.

Hormones. Medical case reports of amelioration of autoimmune disease after castration or worsening after hormone treatment suggest that gonadal hormones modulate disease severity in individuals (31). Such reports do not, however, constitute evidence for differences of sex incidence in populations. Indeed, most population studies of the relationship of hormone therapy to autoimmune disease show little effect on either incidence or severity. Estrogen replacement therapy, oral contraceptives, and ovulation induction as treatment for infertility probably do not worsen lupus (26). Although synoviocyte estrogen receptors may be target organs in rheumatoid arthritis (13), a possible explanation for female predominance in this illness, these receptors would also be present in synovium of patients with chronic Lyme disease and ankylosing spondylitis, neither of which is female predominant. In ankylosing spondylitis, androgens have no apparent role (23).

Rheumatoid arthritis remits during pregnancy, as does multiple sclerosis. Although studies often attribute pregnancy-associated remission or flare of the disease to the effects of pregnancy-associated hormones, the rheumatoid remission may instead be due to human leukocyte antigen (HLA) mismatch between mother and fetus (40). Lupus does not or only slightly worsens during pregnancy (35). Thus pregnancy data do not in themselves establish a role for hormones in modulating autoimmune disease.

A threshold mechanism, i.e., a specific level of estrogen at a vulnerable time, could explain a hormone-caused increase in disease incidence but not severity. Estrogen may play a permissive role, allowing survival of forbidden autoimmune clones (10).

Sex hormones might influence F/M ratios in nonimmunologic ways. Vascular pathology is prominent in the systemic autoimmune diseases. Hypothetically, hormone (or other sex) effects on endothelium, rather than on immunocytes, might be critical for nonimmunologic disease initiation. An unknown sex difference related to ovulation or menstruation cytokines, to apoptosis, or to vascular rheology might be responsible for the different disease experiences of the two sexes.

Genes. Abundant evidence confirms genetic control of autoimmunity. Family and twin studies, HLA associations with specific illnesses, disease susceptibility or resistance genes, and transgene experiments (47, 55) demonstrate that susceptibility to autoimmune disease is familial. Specific marker genes are often identified. Evidence of this type is particularly strong for spondyloarthropathy, rheumatoid arthritis, and lupus. HLA types by themselves do not explain sex dimorphism, but sex-discrepant HLA-associated effects are possible (33).

Ankylosing spondylitis, the only sex-discrepant rheumatic disease studied for X-chromosome markers to date, has no X-chromosome susceptibility locus (28). Except for the CD40 ligand, few putative immunologic markers are on the X or Y chromosome. No conclusive evidence for imprinting or differential X inactivation differences exists for autoimmune diseases. However, sex-different chromosomal markers, imprinting, and inactivation have been rarely sought in autoimmunity (53, 56). Skewed X inactivation in the thymus may lead to inadequate thymic deletion and hence loss of T-cell tolerance (16).

Non-MHC genes may be relevant to sex discrepancy. In a mouse model of diabetes, mutation of a tissue- or developmental stage-specific proteasome product is sex discrepant. Sex dimorphism of T-cell trafficking may be due to sex-determined cell surface markers (66). Other chromosomal effects may be operative.

Whole body, life stages, and life events. Most female-predominant diseases cluster in the young-adult years, whereas autoimmune diseases that affect younger or older patients are more evenly divided between the sexes. Characteristics of young adulthood that may explain female predominance (other than sexual intercourse or pregnancy) include chronobiological, nonhormonal effects of menstrual cycles, gonadal hormones, thresholds, vascular responses, immune responses, and other variables that are as yet unknown. The large quantity and long duration of circulating fetal cells in scleroderma patients (19) suggest a profound new biological difference between men and women, the implications of which are unknown.

	LESSONS FROM ANIMAL MODELS

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Experimental animal models of autoimmune disease that test causes of sex discrepancy include immunization, inbreeding, transgenic, and gene knockout models. These models give mixed messages (Table 3).

View this table: [in this window] [in a new window]   Table 3.   Animal models of human autoimmune diseases, according to potential genetic, hormone, life stage, and environmental influences

Genetic strains of mice and rats are differently susceptible to an immunization model of thyroiditis. Despite the female predominance of human thyroiditis, in rodents, estrogen increases anti-thyroid antibody titer but not histological thyroid inflammation. In contrast, the severity of induced mouse thyroiditis does vary with iodide content of the diet and with types of chow. Genetic and extrinsic environmental factors, therefore, influence experimental thyroiditis incidence more than do hormones.

The (NZB × NZW)F₁ mouse model of lupus shows high female incidence and severity (earlier onset, more severe disease); however, the MRL lpr/lpr model is sex neutral, and the BXSB model is male predominant (32). Castration and replacement experiments, primarily in (NZB × NZW)F₁, demonstrate estrogen enhancement and testosterone suppression of spontaneous disease severity and incidence. Genetic susceptibility is linked to MHC and other immune-relevant genes, such as those controlling complement and apoptosis. Like its human counterpart, lupus in mice develops in young adulthood, implying that incubation, maturation, or cumulative damage is required for disease expression. At maturation, but not before, susceptible mouse strains have more numerous and more avid estrogen receptors on lymphoid and uterine tissue than do nonsusceptible strains, a possible explanation for strain susceptibility differences but not necessarily for sex differences (17).

Male and female mice in germ-free environments are equally affected by lupus, but germ-free females develop higher autoantibody levels. Germ-free, antigen-free animals have less frequent disease than do germ-free or conventionally raised animals, indicating environmental contribution to illness and leaving open the possibility that differential exposure causes sex discrepancy in humans (36). Both the p21 knockout and the DNase 1 knockout mouse lupus models show slightly higher autoantibody levels in females. Inexplicably, glomerulonephritis is much worse in female p21 knockouts but equals that of males in DNase 1 knockouts (6, 38).

The human HLA B27 gene transgenically expressed in rats induces a phenotype with features of both psoriasis and ankylosing spondylitis. In a germ-free environment, the spondylitis does not occur. Introduction of specific gastrointestinal pathogens to the germ-free B27 transgenic animal induces spondylitis (55). Male predominance is true of this model, as it is of the human disease, but the reasons are unknown.

In these animal models of autoimmune disease, genetic, hormone, life stage, and environmental factors are all relevant to disease causation. No consistent cause for sex discrepancy appears.

	CONCLUSION

TOP ABSTRACT INTRODUCTION THE BASIC DATA IMMUNIZATION AND INFECTION AS... POTENTIAL CAUSES OF SEX... LESSONS FROM ANIMAL MODELS CONCLUSION REFERENCES

Table 4 shows a sample of mechanisms that account for sex differences in nonautoimmune human illnesses. The most striking differences of incidence occur when exposures to infectious agents or toxins differ between the sexes. Explanations for sex discrepancy occur at all biological levels, from molecular to societal.

View this table: [in this window] [in a new window]   Table 4.   Nonimmunological mechanisms by which men and women differ in nonautoimmune disease incidence

If (unidentified) infections or toxins induce autoimmune disease, exposure differences remain as plausible explanations for the sex differences. Gonadal hormones, if they play a role, likely do so through a threshold or permissive mechanism rather than through the quantitative immunomodulation that in vitro hormone manipulation models imply. Differences related to X inactivation, imprinting, X or Y chromosome genetic modulators, and intrauterine influences remain as alternate explanations for sex differences of incidence. The epidemiology of the sex-discrepant autoimmune diseases (young, female) suggests that an explanation for sex discrepancy lies in differential exposure, vulnerable periods, or thresholds. All of these topics remain to be explored. Discerning mechanisms for sex discrepancy will not only provide insight into human disease but also will inform biology about basic processes related to sex.

	FOOTNOTES

^*  This paper derives largely from material published in the Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter? (copyright 2001 by the National Academy of Sciences). The full report can be viewed at http://www.nap.edu/catalog/10028.html.

  * This paper derives largely from material published in the Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter? (copyright 2001 by the National Academy of Sciences). The full report can be viewed at http://www.nap.edu/catalog/10028.html.   Address for reprint requests and other correspondence: M. D. Lockshin, Barbara Volcker Center, Hospital for Special Surgery, Joan and Sanford I, Weill Medical College, Cornell Univ., 535 East 70th St., New York, NY 10021 (E-mail: lockshinm{at}hss.edu).

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TOP ABSTRACT INTRODUCTION THE BASIC DATA IMMUNIZATION AND INFECTION AS... POTENTIAL CAUSES OF SEX... LESSONS FROM ANIMAL MODELS CONCLUSION REFERENCES

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