| **GENDER DIFFERENCESAND INTERACTION OF HORMONESON AUTOIMMUNE DISEASES**

**Jill P. Buyon, MDAssociate Professor of MedicineNew York University School of Medicine**

Throughout a woman’s life, from menarche to menopause,sex hormones play an important role. The changes in hormone levels are impressive. Forexample, 17-�-estradiol, the most potent naturally occurring estrogen in humans, variesby 10-fold during the normal menstrual cycle, reaches the highest circulating levelsduring the third trimester of pregnancy (exceeding peak menstrual levels by almost100-fold), and falls to about a tenth of the lowest menstrual cycle level at menopause.

It should be no surprise that diseases that target womencan be induced, exacerbated or even ameliorated by hormonal fluctuations accompanying themenstrual cycle, pregnancy and the climacteric. On the other hand, certain diseases and/or the medications used in their treatment can alter normal hormonal levels. It is nowwell recognized that the immune and endocrine systems interdigitate.

Women are particularly prone to autoimmune diseases, manyof which involve the musculoskeletal system, such as rheumatoid arthritis, systemic lupuserythematosus, Sjogren’s syndrome, and scleroderma. Curiously, these diseases strikedifferent age groups and therefore impact on women’s wellness in different ways. Inboth health and disease there are important decisions unique to women, such as safe andeffective birth control, planning a pregnancy, and taking exogenous estrogens aftermenopause. These issues take on increasing importance as reduction in the morbidity andmortality of autoimmune diseases continues.

Rheumatoid arthritis (RA) has a frequency of about 1percent in the general adult population, a 3-to-1 female-to-male ratio and peak incidencebetween ages 45-54. Since the early observations of Hench in 1938, it has been wellappreciated that pregnancy is associated with improvement in the clinical signs andsymptoms of RA in more than 70% of patients. Unfortunately, most women have a significantrecurrence of disease in the first 8 weeks postpartum, and nearly all have a return totheir pre-pregnancy disease state by the end of 6-8 months.

Sex hormones, particularly estrogen, were considered likelyto be responsible for pregnancy-induced remission. Disappointingly, studies aimed atimproving RA by means of exogenous estrogens have not shown benefit. Because antibodies topaternally inherited fetal HLA (genes that influence immune responses) occur during normalpregnancy, it has been recently hypothesized that maternal-fetal disparity in HLAalloantigens might be associated with remission. In a study by Nelson and her colleagues,maternal fetal disparity in alleles of HLA, DRB1, DQA, and DQB occurred in pregnanciescharacterized by remission or improvement as compared with pregnancies characterized byactive arthritis. This is an exciting area of research that may have a major impact ondisease therapy. Apart from the favorable effect of pregnancy on existing RA, there isalso evidence suggesting that pregnancy may decrease the risk of developing RA, or atleast postpone the onset. Available data support an approximately 2-fold risk of RA innulliparous women. Analysis of newly diagnosed women with RA and age-matched controlssuggests that either nulliparity is a risk factor for RA, or that women destined todevelop RA have reduced fertility which antedates the onset of arthritis. There has beenno evidence for an increase in the adverse pregnancy outcomes of either spontaneousabortion or still-births in women who subsequently develop RA. The use of oralcontraceptives does not pose any apparent problems to the woman with RA, and someinvestigators believe it may forestall the onset of disease.

Systemic lupus erythematosus (SLE) exhibits the mostprofound female predilection, approaching a female-to-male ratio of 15-to-1 during thereproductive years, but is lower during childhood and menopause. The frequency is about 1per 300 in African-American women, and 1 per 1000 in Caucasians. The peak incidence isaround age 30. In addition to the overwhelming sex preponderance in SLE, further supportfor the inference that female hormones are associated with SLE is provided by Lahita andhis colleagues, who reported that females and males with SLE have skewed estronemetabolism in which more feminizing 16-hydroxylated metabolites are favored. Additionally,females with SLE can oxidize testosterone to androstenedione at a greater rate than males,implying that the high levels of estrogens go unopposed by androgens. Murine models oflupus also support the hormone hypothesis in that estrogens accelerate the disease.

These data provided the rationale for human trials withmale hormones. Initial studies fell short of expectations. Administration of19-nortestosterone, 100 mg/ml per week, had limited use in the treatment of SLE in women.No significant improvement in serologies was noted. However, in two recent studies (openlabel and prospective) patients with mild to moderate SLE receiving dehydroepiandosterone(DHEA) had decreased disease activity, as measured by patient’s and physician’soverall assessment, and were able to reduce their dosages of prednisone. A largerprospective multicenter placebo-controlled trial, involving approximately 200 patients, toevaluate the effectiveness of DHEA in lowering the dosage of prednisone is currentlyunderway.

Health issues facing the woman with SLE are quite differentthan for the woman afflicted with RA. Unlike the rule of "remission" applied topregnancies in women with RA, the influence of pregnancy on disease activity in women withSLE is variable. While earlier literature emphasized a high risk of disease exacerbationsduring pregnancy, and women were frankly discouraged from having children, recentinvestigations have not reached similar conclusions. The assumption that pregnancy inducesa disease flare is tainted, since SLE is a chronic disease punctuated by episodes of acuteillness and spontaneous remission. Whether flare rates increase during or after pregnancyis still unsettled, since different studies have defined flare differently and haveemployed varying criteria for patient inclusion. Important case-controlled investigationsby Lockshin and his colleagues have concluded that pregnancy is not associated with anincreased flare rate compared to nonpregnant women with SLE. It is likely that much largerstudies from a coordinated group of cooperating centers will be required to settle whetherpregnancy does or does not induce lupus flares. However, investigations to date havereached one consensus: pregnancy outcome is optimal when disease is in complete clinicalremission for 6-12 months. A successful pregnancy requires a good outcome for both motherand baby.

Fetal well-being continues to be a major concern in themanagement of lupus pregnancies, with preterm birth occurring in approximately half of thelive births. Fetal monitoring is an important advance in management. In rare cases,mothers with SLE have antibodies to proteins SSA/Ro and SSB/La that are associated withpermanent heart disease and transient rashes in the child.

Sterility and fertility rates for women with SLE arecomparable to control groups without disease. Fertility may be depressed during severedisease activity. As expected, amenorrhea can occur at such times. Moreover, menstrualirregularities have been noted in patients receiving glucocorticoids, and age-dependentpremature ovarian failure occurs in patients receiving cyclophosphamide. If we simplyaccept the dogma that estrogens and lupus do not mix, women with lupus are often advisedto avoid exogenous estrogens. 

What are the options for the sexually active lupus patientwho finds barrier methods unacceptable? Estrogen-containing oral contraceptives have beenreported to exacerbate SLE in several case reports and in a single retrospectiveinvestigation focusing on patients with renal disease. By contrast, in a more recentretrospective investigation from Finland, patients taking oral contraceptives experienceda low incidence of flare that did not differ from a control group.

We have recently completed a retrospective multicentersurvey on the past and present usage of oral contraceptives in 404 women with SLE andfound that only a few patients reported flares while taking oral contraceptives.

Happily, patients with SLE are living longer and healthissues related to menopause must be considered. Specific indications for hormonereplacement include control of vasomotor hot flushes, atrophic vaginitis and urethritis,and prevention of retardation of postmenopausal and steroid-induced osteoporosis. Inaddition, there is now compelling evidence to suggest that postmenopausal estrogens canreduce the incidence of coronary artery disease. These latter salutary effects ofpostmenopausal estrogens assume particular importance because of the increased risks ofosteoporosis and myocardial infarction in women with SLE. Two retrospective studies, onedone in England and another by our group in collaboration with four other centers, havenot demonstrated an increased rate of flare in postmenopausal women taking hormonereplacement. Appreciating the importance if these issues and their impact on healthydelivery, a large prospective double-blind placebo-controlled study is currently underwayin five major medical centers to evaluate the safety of oral contraceptives and hormonalreplacement therapy in women with SLE. We are optimistic that this project will providethe basis for more definitive recommendations.

Primary Sjogren’s syndrome (SS) occurs inapproximately 1 in 1,250 females. Although the peak incidence is in middle age, women ofchildbearing years are also afflicted. This is particularly important because theoverwhelming majority of women with Sjogren’s syndrome have anti-SSA/Ro and SSB/Laantibodies and therefore may be at even higher risk than women with SLE for having a childwith heart problems or rashes.

Sjogren’s syndrome in association with otherautoimmune diseases is not as uncommon; it occurs in up to 30% of people with RA, 10% withSLE and 1% with scleroderma. A particular problem for women with SS is the decrease intearing and increase in vaginal dryness which accompanies menopause. As in SLE, there maybe some concerns regarding the use of estrogen replacement, but benefits need to beseriously considered. 

Scleroderma occurs with a frequency of about 1 in 10,000and a 10-to-1 female-to-male ratio in the age group 15-44. Little is published about theeffects of hormones on this disease. With regard to pregnancy, it appears that the extentof diffuse skin disease and systemic involvement (particularly lung, cardiac, and renalinvolvement) may be more important than the length of the disease; limited disease carriesa better prognosis. The third trimester is the most dangerous period, the risks beingsudden hypertension and renal failure. Although pregnancy is possible, it may be lesslikely than in the normal population, and in most studies the spontaneous abortion rate isincreased.

Despite a now reasonable large body of availableinformation, critical gaps remain. Women with rheumatic diseases (and their families)continue to seek answers from their physicians, who in turn seek answers from basic andclinical research. Through this complex partnership, we can hope to address questionsconcerning birth control, fertility, the impact of adjunctive hormonal manipulation tostimulate ovulation, maternal and fetal outcomes of pregnancy, skeletal sequelae ofpregnancy, and appropriate management of the menopause.

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