AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY 28:231-234 © 1992 MUNKSGAARD
Estrogens and Rheumatoid Arthritis J.w.J. BIJLSMA ANDH.R. VAN DEN BRINK Department ofRheumatology, University Hospital, Utrecht, The Netherlands ABSTRACT: Epidemiological and immunological evidence has suggested that female sex hormones may playa role in the etiology and course of autoimmune diseases such as rheumatoid arthritis (RA). In this review the present clinical data with regard to estrogens and RA are discussed, with emphasis on the possible preventive effect of oral contraceptives on the incidence of RA and on the possibility of using estrogens as adjuvant therapy in RA. It is concluded that oral contraceptives may mitigate or postpone the onset of RA slightly, but that estrogens are not able to alleviate the symptoms of RA. Presently there is no evidence to promote the use of estrogens in preventing or treating RA in females. (Am J Reprod Immunol. 1992; 28:231-234.) Key words: Oral contraceptives, menopause, progesterone INTRODUCTION
Epidemiological and immunological evidence has suggested that female sex hormones may playa role in the etiology and course of rheumatoid arthritis (RA). In this article the present clinical data, especially with regard to estrogens, are reviewed. GENDER AND RA
RA is seen three times more often in women than in men. The age of disease onset in women adopts a Gaussian type distribution with a peak at age 45-54 years and a relative decline in later life.' This peak age implies a possible relationship to menopause. While the susceptibility to RA seems to fall in women with increasing age, it seems to rise in men. Thus, in later onset of the disease the ratio female:male equals 1.4:1, while this ratio is 3.5:1 in the under-60-years age group.f The mechanisms underlying the different expression ofRA in males and females are incompletely understood. Immune reactivity is stronger in females than in males. In both experimental animals and in man there is a preponderance of autoimmune diseases in females, compared to males. Sex steroids are believed to influence the immune system, although the precise mechanisms are unknown. It is thought that gonadal steroids may mediate their effects on the immune system directly by binding to lymphocytes, or perhaps more likely indirect via the thymus-hypothalamus-pituitary-gonadal axis. This latter field of research has been named immunoendocrinology, and several reviews about this subject have been published.v" In vitro effects of sex steroids on the' activation and
Received June 23, 1992; accepted June 30, 1992. Address reprint requests to Prof. Dr. J.W.J. Bijlsma, Dept. of Rheumatology, F02.223, University Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
proliferation of human mononuclear cells have been studied by different groups. There is some evidence that estrogens, as well as androgens and progesterone, may suppress T-cell proliferation, but T-helper and T-suppressor cell activity may be influenced differently. Most studies have used a specific stimulation with phytohaemagglutinin (PHA). We used specific method for activating T-Iymphocytes with immobilized anti-CD3 monoclonal antibodies to investigate the influence of estradiol, progesterone, testosterone, and cortisol on lymphocytes of postmenopausal women with RA. The results show that estradiol, progesterone, and testosterone, even in high doses, do not influence lymphocyte proliferation when stimulated with anti-CD3 monoclonal antibodies. However cortisol is able to suppress lymphocyte proliferation even at physiological concentrations." This supports the recent observation that it is doubtful whether there are indeed receptors for estrogens on 'I'-Iymphocytes.f PREGNANCY AND MENSTRUAL CYCLE
The effect of pregnancy on RA is beneficial in the majority of patients. A pregnancy-induced remission is experienced by 75% of the patients, but a flare-up occurs in nearly 80% after delivery.8 Apart from a beneficial effect of pregnancy on existing RA there is also some evidence suggesting that pregnancy may decrease the risk of developing RA, or at least postpone the onset ofRA. 9 ,1O Morning stiffness and pain in women suffering from RA are often reduced in the postovulatory phase of the menstrual cycle, indicating that fluctuations of RA in females may relate to the menstrual cycle. 11 However, it should be noted that the potential beneficial effect of pregnancy and the second half of the menstrual cycle on disease activity may be due to estrogens, but also to progesterone. It has been shown that progesterone can depress cellular immune response in vitro, 12 and some investigators believe it to be a more potent immunomodulator than estrogens. LEVELS OF GONADAL HORMONES IN RA
Female sex hormone levels have been studied in women and men with active RA. No difference whatsoever was found when these patients were compared with healthy and disease controls. Androgen levels in women with RA have been reported to be lower than in controls in most studies, but equal or even increased in some studies. 13 - 16 These lower levels of androgens were more apparent in postmenopausal women, in whom these androgens are mainly produced by the adrenals. It is relevant to note that similar hormonal changes have been described as a non-specific effect of severe disease.!" In above mentioned studies serum hormone concentrations ofRA patients (with more or less disease activity) were compared with age-matched controls (healthy and/or disease controls). Recently we investigated the
232
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influence of disease activity on hormonal status in a logitudinal study. RA patients were evaluated when their disease activity was low and later during a flare oftheir disease. In postmenopausal women no change was found in the serum levels of estrogens, but a nonstatistical significant decrease in the levels of testosterone and dehydroepiandrosterone was noted.l" These findings are in line with a previous observation that serum concentrations of dehydroepiandrosterone sulphate are inversely correlated with disease activity. 19 In male patients with RA, serum levels of androgens were depressed during active disease while these levels returned to normal when disease activity diminished.P? This observation led to a study in which male RA patients were given androgens and some beneficial effect was reported.21 In conclusion there is a suggestion of hypoandrogenism in male and postmenopausal female patients with active RA, but it is unknown whether this is a consequence of the active disease or a predisposing factor. There is no evidence for a change in the level offemale hormones in RA patients. ORAL CONTRACEPTIVES AND RA
Much interest has been generated by the Royal College of General Practitioner's study on the use of oral contraceptives (OCs), suggesting a protective effect of OCs on the incidence of RA. 22 Compared to those who have never used OCs the relative risk for current OC users was 0.49 (95% CI 0.29-0.83) and for former users 0.84 (0.53-1.34). This observation seemed to be supported by an American study showing a decrease in the incidence rate of RA in females among the residents of Rochester since 1962. This decrease coincided with a sharp increase in the use of OCs in that period, leading the authors to suggest that this reduction in RA mi~ht be due to the use of exogenous female sex ,hormones. 3 Since then several analytic epidemiological studies have been reported: half of the studies showing a reduction of the incidence of RA of about 50% and half of them showing no protective effect of OCs. In order to try to solve the controversy based on these conflicting results two metaanalyses were performed. lO,24 In the first metaanalysis nine case-control studies were used; the relative risk ofRA for those who had ever used was 0.79 (95% CI 0.58-1.10), for current users 0.98 (0.34-2.77), and for past users 0.73 (0.49-1.08): no definite protective effect was found.P" In the second, Spector calculated an overall pooled odds ratio for all the studies ofO.73 (95% CI 0.61-0.85), thus showing a modest preventive effect ofOCs. When he divided the studies by the type of case source he found a relative risk of 0.49 (0.39-0.63) for studies using hospital-based cases ofRA, which was considerably less than that of the studies using population-based cases: 0.95 (0.78-1.16). This striking difference can indeed be explained by the selection of cases in the different studies: patients with mild or transient RA are quite often not seen in hospital. Hospitalbased studies tend to include the more severe cases of RA. This was confirmed in a study in the Netherlands in which patients with definite or classical RA were divided in two groups with mild and severe disease. The relative risk for mild disease was 0.79 (95% CI 0.21-2.79) and for severe disease 0.33 (0.19-0.57). The protective effect of OCs was only found in the more severe cases of
RA; this group of patients had also a higher proportion of rheumatoid factor-positive and HLA-DR4-positive persons.f" both predictive of a more severe disease outcome. Recently the original study from the British General Practitioners was updated.F" The incidence ofRA among those who had formerly and those who had never used OCs had declined, but not among current users. No protective effect of OCs on the incidence of RA could be demonstrated: relative risk 0.82 (95% CI 0.59-1.15). Unfortunately nearly two-thirds of the original study subjects have been lost for follow-up and these findings are thus difficult to interpret. Other epidemiological studies also suggest a declining incidence of RA among women over time, independent of the use ofOCs,27 and one may wonder whether RA itself has changed in the population, in terms of incidence as well as of severity. The reported decline in incidence ofRA is unlikely to be due to the use of OCs, since this decline coincided with a decrease in the use of OCs among married women. Looking at the data on OC use one should bear in mind that the use of OCs may be a marker for some other causal factor and that also reproductive factors distinct from contraceptive practice or factors such as sexual lifestyle may be important in terms of the risk of developing RA. 9 The present conclusion with regard to the use of OCs and the development of RA is that OCs, or other factors associated with the use of OCs, may mitigate, or possibly postpone, the onset of RA. However, this effect is very modest and OCs are, if any, only weak modulators ofthe disease. ESTROGENS AS (ADJUVANT) THERAPY IN RA
When the first female sex hormone preparations became available in the early 1960s the effect of these hormones on the course of RA was studied. Norethynodrel, a mixture of ethinylestradiol and progesterone, gave an improvement in all of the initial treated six patients.i" The same authors later reported on 44 patients: 11 abandoned the study due to side effects, and of the 33 remaining, 18 improved.f" A placebo-controlled cross-over study with the same hormone showed an improvement in only four of the 17 patients studied.'? At that time it was thought that this rather crude hormone product also contained glucocorticosteroids'" and this line of investigation was not further explored. Since new information on a potential beneficial effect of estrogens became available in the mid 1980s5,22 new studies were started. In 1987 a pilot study was reported in ten women (seven post- and three premenopausal) with active RA.32 In this prospective double-blind placebocross-over study during 24 weeks 12.5 f-Lg ethinylestradiol was used. This dosage was chosen because of the proven beneficial effect on bone-density and on the alleviation of perimenopausal symptoms such as hot flashes. A significant improvement during the estrogen period was found in 30-m walking time, hemoglobin concentration, and platelet count. Erythrocyte sedimentation rate and C-reactive protein deteriorated in both periods but less in the estrogen period; grip strength improved in both periods. The number of swollen joints decreased, whereas the joint tenderness score increased during the estrogen period. The small number of patients and the short duration of the treatment period make the interpretation of
ESTROGENS AND RHEUMATOID ARTHRITIS
these results difficult. In an open study ten premenopausal women with moderately active RA received a highdose oral contraceptive (2.5 mg lynestrenol and 50 /-Lg ethinylestradiol) during 6 months. Four patients stopped the treatment due to inefficacy and side effects. Evaluation of the remaining six patients showed a statistical significant decline in the number of swollen joints, and a tendency of decline in the number of painful joints: the Ritchie articular score fell from 18 to 10. No other clinicalor laboratory parameter improved, leading the authors to conclude that estrogens have no disease modifying effect. 33 Since the number of patients was small, the disease activity limited, and the study open, no definite conclusion can be drawn. Based on the studies so far a double-blind placebocontrolled study was started in 1989. 34 Forty postmenopausal women with active RA were treated with 2 mg estradiol-valerate (equivalent to 25 /-Lg ethinylestradiol) or placebo in four cycles of 90 days. During the last 10 days ofthis cycle progesterone was added to induce a withdrawal bleeding. Seven patients withdrew from the study (five in the estrogen group and two in the placebo group). Not all data are available yet, but preliminary analysis shows that there was no improvement in the following outcome parameters: joint score, pain score, disability score, or ESR,35.However, bone density improved in the estrogen treated group. With regard to the effect of estrogens in women with RA it can be concluded that in premenopausal women the beneficial effect, if any, is only marginal, and in postmenopausal women there is no effect at all. Thus it seems unlikely that estrogens can be used as an adjuvant treatment in patients with RA to alleviate the symptoms of the disease. CONCLUSION
Though epidemiological and immunological evidence has suggested that femal-e sex hormones may playa role in the etiology and course ofRA, there is no evidence for a beneficial effect of estrogens on disease activity once RA has occurred. Based on epidemiological studies it is likely that estrogens may, in a modest way, mitigate or postpone the onset of the disease; some have also suggested that the outcome ofRA in females is better than in males.f It is possible that a beneficial effect of estrogens on (postmenopausal) bone density improves the outcome ofRA, especially whenjoint surgery is needed. The striking relation between gender and autoimmune diseases, such as most of the rheumatic diseases, remains clear. Perhaps we must investigate other mechanisms involved, such as the influence of gonadal hormones, or perhaps other hormones, on production of cytokines and/or growth factors to understand this relationship. , From a practical, clinical point of view, there is at present no evidence to promote the use of estrogens in preventing or treating RA in females. ACKNOWLEDGMENTS
2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
24. 25. 26. 27.
Dr. Van den Brink is supported by a 'grant from the Dutch Arthritis Foundation (National Reumafonds). 28. REFERENCES 1. Goemaere S, Ackerman C, Goethals K, De Keyser F, Van der Straeten C, Verbruggen G, Mielants H, Veys EM. Onset of symp-
29.
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toms of rheumatoid arthritis in relation to age, sex and menopausal transition. J Rheumatol. 1990; 17:1620-1622. Da Silva JAP, Hall GM. The effects of gender and sex hormones on outcome in rheumatoid arthritis. Baillieres Cloin Rheumatol. 1992; 6:193-219. Lahita RG. Sex steroids and the rheumatic diseases. Arthritis Rheum. 1985; 28:121-126. Bhalla AK. Hormones and the immune response. Ann Rheum Dis. 1989; 48:1-6. Grossman CJ. Regulation of the immune system by sex steroids. Endocr Rev. 1984; 5:435-455. Lahita RG. The effects of sex steroids on the rheumatic diseases. [Report of this conference]. Brink HR van den, Wijk MJG van, Bijlsma JWJ. Influence ofsteroid hormones on proliferation of peripheral blood mononuclear cells in patients with rheumatoid arthritis. Br J Rheumatol. 1992; in press. Ostensen M, Aune B, Husby G. Effects of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol. 1983; 12:69-72. Hazes JMW. Pregnancy and its effect on the risk of developing rheumatoid arthritis. Ann Rheum Dis. 1991; 50:71-72. Spector TD. Rheumatoid arthritis an pregnancy: An overview. [Report of this conference]. Latman NS. Relation of menstrual cycle phase to symptoms of rheumatoid arthritis. Am J Med. 1983; 74:957-960. Clemens LE, Siiteri PK, Stitis DP. Mechanism of immunosuppression of progesterone on matenallymphocyte activation during pregnancy. J Immunol. 1979; 122:1978-1985. Feher KG, Feher T, Merety K. Interrelationship between the immunological and steroid hormone parameters in rheumatoid arthritis. Exp Clin Endocrinol. 1980; 87:38-42. Sambrook PN, Eisman JA, Champion GD, Pocock NA. Sex hormone status and osteoporosis in postmenopausal women with rheumatoid arthritis. Arthritis Rheum. 1988; 31:973-979. Cutolo MN, Balleari E, Siusti M, Monachesi M, Accardo S. Sex hormone status in women suffering from rheumatoid arthritis. J Rheumatol. 1986; 13:1019-1023. Spector TD, Perry LA, Tubb G, Huskisson EC. Androgen status of females wth RA. Br J Rheumatol. 1987; 25:316-318. WoolfePD, Hamill RW, McDonald JV, Lee LA, Kelly M. Transient hypogonado-trophic hypogonadism caused by critical illness. J Clin Endocrinol Metab. 1985; 60:445-450. Brink HR van den, Blankenstein MA, Koppeschaar HPF, Bijlsma JWJ. Influence of disease activity on steroid hormone levels in peripheral blood of patients with rheumatoid arthritis. Submitted. Feher KG, Feher T, Merety K. Interrelationship between immunological and steroid hormone parameters in rheumatoid arthritis. Exp Clin Endocrinol. 1986; 87:38-42. Gordon C, Beastall GM, Thomson JA, Sturrock RD. Prolonged hypogonadism in male patients with rheumatoid arthritis during flares in disease activity. BrJ Rheumatol. 1988; 27:440-444. Cutolo M, Balleari E, Giusti M, Intra E, Accardo S. Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum. 1991; 34:1-5. Wingrave SJ, Kay CR. Royal College of General Practioners study. Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet 1978; i:569-571. Linos A, Worthington JW, O'Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: A study of its incidence, prevalence and mortality. Am J Epidemiol. 1980; 111:87-98. Romien I, Hermandez-Avila M, Liang MH. Oral contraceptives and the risk of rheumatoid arthritis: A meta-analysis of conflicting literature. BrJ Rheumatol. 1989; 28(suppl1):13-17. van Zeben D, Hazes JW, Vandenbroucke Jp, Dijkmans BAC, Cats A. Diminished incidence of severe rheumatoid arthritis associated with oral contraceptive use. Arthritis Rheum. ;1.990; 33:1462-1465. Hammerford PC, Kay CR, Hirsch S. Oral contraceptives and rheumatoid arthritis: New data from the Royal college of General Practioners' oral contraception study. Ann Rheum Dis. 1990; 49:744-746. Dugowson CE, Koepsell TD, Voigt CF, Bley L, Nelson JL, Daling JR. Rheumatoid arthritis in women. Incidence rates in group health cooperative. Seattle, Washington 1987-1989. Arthritis Rheum. 1991; 34:1502-1507. Blais JA, Demers R. The use of norethynodrel (Enovid) in the treatment of rheumatoid arthritis. Arthritis Rheum. 1962; 5:284. Demers R, Blais JA, Pretty H. Arthrite rheumatoide traitee par norethynodrel associee mestranol: Aspects cliniques et tests de laboratoire. Can Med Assoc J. 1966; 95:350-354.
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30. Gilbert M, Rotstein J, Cunningham C, Estrin I, Davidson A, Pinaus G. Norethylnodrel with mestranol in treatment ofRA. JAMA 1964; 190:235. 31. Waine H, Frieden EH, Caplan HI, Cole T. Metabolic effects of Enovid in rheumatoid patients. Arthritis Rheum. 1963; 6:796. 32. Bijlsma JWJ, Huber-Bruning 0, Thijssen JHH. Effect of oestrogen treatment on clinical and laboratory manifestations of rheumatoid arthritis. Ann Rheum Dis. 1987; 46:779-779. 33. Hazes JMW, Dijkmans BAC,Vandenbroucke JP, Cats A. Oral con-
traceptive treatment for rheumatoid arthritis: An open study in 10 female patients. Br J Rheumatol. 1989; 28(Supplll:28-30. 34. Brink HR van den, Bijlsma JWJ. Can oestrogens be used as adjuvant in therapy in female patients with rheumatoid arthritis? Br J Rheumatol. 1989; 28(Supplll:24-27. 35. Brink HR van den, Everdingen AA, Wijk MJG van, Jacobs JWG, Bijlsma JWJ. Adjuvant estrogen therapy does not influence disease activity in postmenopausal female patients with rheumatoid arthritis. Submitted.
Estrogens and Rheumatoid Arthritis J.w.J. BIJLSMA ANDH.R. VAN DEN BRINK Department ofRheumatology, University Hospital, Utrecht, The Netherlands ABSTRACT: Epidemiological and immunological evidence has suggested that female sex hormones may playa role in the etiology and course of autoimmune diseases such as rheumatoid arthritis (RA). In this review the present clinical data with regard to estrogens and RA are discussed, with emphasis on the possible preventive effect of oral contraceptives on the incidence of RA and on the possibility of using estrogens as adjuvant therapy in RA. It is concluded that oral contraceptives may mitigate or postpone the onset of RA slightly, but that estrogens are not able to alleviate the symptoms of RA. Presently there is no evidence to promote the use of estrogens in preventing or treating RA in females. (Am J Reprod Immunol. 1992; 28:231-234.) Key words: Oral contraceptives, menopause, progesterone INTRODUCTION
Epidemiological and immunological evidence has suggested that female sex hormones may playa role in the etiology and course of rheumatoid arthritis (RA). In this article the present clinical data, especially with regard to estrogens, are reviewed. GENDER AND RA
RA is seen three times more often in women than in men. The age of disease onset in women adopts a Gaussian type distribution with a peak at age 45-54 years and a relative decline in later life.' This peak age implies a possible relationship to menopause. While the susceptibility to RA seems to fall in women with increasing age, it seems to rise in men. Thus, in later onset of the disease the ratio female:male equals 1.4:1, while this ratio is 3.5:1 in the under-60-years age group.f The mechanisms underlying the different expression ofRA in males and females are incompletely understood. Immune reactivity is stronger in females than in males. In both experimental animals and in man there is a preponderance of autoimmune diseases in females, compared to males. Sex steroids are believed to influence the immune system, although the precise mechanisms are unknown. It is thought that gonadal steroids may mediate their effects on the immune system directly by binding to lymphocytes, or perhaps more likely indirect via the thymus-hypothalamus-pituitary-gonadal axis. This latter field of research has been named immunoendocrinology, and several reviews about this subject have been published.v" In vitro effects of sex steroids on the' activation and
Received June 23, 1992; accepted June 30, 1992. Address reprint requests to Prof. Dr. J.W.J. Bijlsma, Dept. of Rheumatology, F02.223, University Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
proliferation of human mononuclear cells have been studied by different groups. There is some evidence that estrogens, as well as androgens and progesterone, may suppress T-cell proliferation, but T-helper and T-suppressor cell activity may be influenced differently. Most studies have used a specific stimulation with phytohaemagglutinin (PHA). We used specific method for activating T-Iymphocytes with immobilized anti-CD3 monoclonal antibodies to investigate the influence of estradiol, progesterone, testosterone, and cortisol on lymphocytes of postmenopausal women with RA. The results show that estradiol, progesterone, and testosterone, even in high doses, do not influence lymphocyte proliferation when stimulated with anti-CD3 monoclonal antibodies. However cortisol is able to suppress lymphocyte proliferation even at physiological concentrations." This supports the recent observation that it is doubtful whether there are indeed receptors for estrogens on 'I'-Iymphocytes.f PREGNANCY AND MENSTRUAL CYCLE
The effect of pregnancy on RA is beneficial in the majority of patients. A pregnancy-induced remission is experienced by 75% of the patients, but a flare-up occurs in nearly 80% after delivery.8 Apart from a beneficial effect of pregnancy on existing RA there is also some evidence suggesting that pregnancy may decrease the risk of developing RA, or at least postpone the onset ofRA. 9 ,1O Morning stiffness and pain in women suffering from RA are often reduced in the postovulatory phase of the menstrual cycle, indicating that fluctuations of RA in females may relate to the menstrual cycle. 11 However, it should be noted that the potential beneficial effect of pregnancy and the second half of the menstrual cycle on disease activity may be due to estrogens, but also to progesterone. It has been shown that progesterone can depress cellular immune response in vitro, 12 and some investigators believe it to be a more potent immunomodulator than estrogens. LEVELS OF GONADAL HORMONES IN RA
Female sex hormone levels have been studied in women and men with active RA. No difference whatsoever was found when these patients were compared with healthy and disease controls. Androgen levels in women with RA have been reported to be lower than in controls in most studies, but equal or even increased in some studies. 13 - 16 These lower levels of androgens were more apparent in postmenopausal women, in whom these androgens are mainly produced by the adrenals. It is relevant to note that similar hormonal changes have been described as a non-specific effect of severe disease.!" In above mentioned studies serum hormone concentrations ofRA patients (with more or less disease activity) were compared with age-matched controls (healthy and/or disease controls). Recently we investigated the
232
BIJLSMA ET AL.
influence of disease activity on hormonal status in a logitudinal study. RA patients were evaluated when their disease activity was low and later during a flare oftheir disease. In postmenopausal women no change was found in the serum levels of estrogens, but a nonstatistical significant decrease in the levels of testosterone and dehydroepiandrosterone was noted.l" These findings are in line with a previous observation that serum concentrations of dehydroepiandrosterone sulphate are inversely correlated with disease activity. 19 In male patients with RA, serum levels of androgens were depressed during active disease while these levels returned to normal when disease activity diminished.P? This observation led to a study in which male RA patients were given androgens and some beneficial effect was reported.21 In conclusion there is a suggestion of hypoandrogenism in male and postmenopausal female patients with active RA, but it is unknown whether this is a consequence of the active disease or a predisposing factor. There is no evidence for a change in the level offemale hormones in RA patients. ORAL CONTRACEPTIVES AND RA
Much interest has been generated by the Royal College of General Practitioner's study on the use of oral contraceptives (OCs), suggesting a protective effect of OCs on the incidence of RA. 22 Compared to those who have never used OCs the relative risk for current OC users was 0.49 (95% CI 0.29-0.83) and for former users 0.84 (0.53-1.34). This observation seemed to be supported by an American study showing a decrease in the incidence rate of RA in females among the residents of Rochester since 1962. This decrease coincided with a sharp increase in the use of OCs in that period, leading the authors to suggest that this reduction in RA mi~ht be due to the use of exogenous female sex ,hormones. 3 Since then several analytic epidemiological studies have been reported: half of the studies showing a reduction of the incidence of RA of about 50% and half of them showing no protective effect of OCs. In order to try to solve the controversy based on these conflicting results two metaanalyses were performed. lO,24 In the first metaanalysis nine case-control studies were used; the relative risk ofRA for those who had ever used was 0.79 (95% CI 0.58-1.10), for current users 0.98 (0.34-2.77), and for past users 0.73 (0.49-1.08): no definite protective effect was found.P" In the second, Spector calculated an overall pooled odds ratio for all the studies ofO.73 (95% CI 0.61-0.85), thus showing a modest preventive effect ofOCs. When he divided the studies by the type of case source he found a relative risk of 0.49 (0.39-0.63) for studies using hospital-based cases ofRA, which was considerably less than that of the studies using population-based cases: 0.95 (0.78-1.16). This striking difference can indeed be explained by the selection of cases in the different studies: patients with mild or transient RA are quite often not seen in hospital. Hospitalbased studies tend to include the more severe cases of RA. This was confirmed in a study in the Netherlands in which patients with definite or classical RA were divided in two groups with mild and severe disease. The relative risk for mild disease was 0.79 (95% CI 0.21-2.79) and for severe disease 0.33 (0.19-0.57). The protective effect of OCs was only found in the more severe cases of
RA; this group of patients had also a higher proportion of rheumatoid factor-positive and HLA-DR4-positive persons.f" both predictive of a more severe disease outcome. Recently the original study from the British General Practitioners was updated.F" The incidence ofRA among those who had formerly and those who had never used OCs had declined, but not among current users. No protective effect of OCs on the incidence of RA could be demonstrated: relative risk 0.82 (95% CI 0.59-1.15). Unfortunately nearly two-thirds of the original study subjects have been lost for follow-up and these findings are thus difficult to interpret. Other epidemiological studies also suggest a declining incidence of RA among women over time, independent of the use ofOCs,27 and one may wonder whether RA itself has changed in the population, in terms of incidence as well as of severity. The reported decline in incidence ofRA is unlikely to be due to the use of OCs, since this decline coincided with a decrease in the use of OCs among married women. Looking at the data on OC use one should bear in mind that the use of OCs may be a marker for some other causal factor and that also reproductive factors distinct from contraceptive practice or factors such as sexual lifestyle may be important in terms of the risk of developing RA. 9 The present conclusion with regard to the use of OCs and the development of RA is that OCs, or other factors associated with the use of OCs, may mitigate, or possibly postpone, the onset of RA. However, this effect is very modest and OCs are, if any, only weak modulators ofthe disease. ESTROGENS AS (ADJUVANT) THERAPY IN RA
When the first female sex hormone preparations became available in the early 1960s the effect of these hormones on the course of RA was studied. Norethynodrel, a mixture of ethinylestradiol and progesterone, gave an improvement in all of the initial treated six patients.i" The same authors later reported on 44 patients: 11 abandoned the study due to side effects, and of the 33 remaining, 18 improved.f" A placebo-controlled cross-over study with the same hormone showed an improvement in only four of the 17 patients studied.'? At that time it was thought that this rather crude hormone product also contained glucocorticosteroids'" and this line of investigation was not further explored. Since new information on a potential beneficial effect of estrogens became available in the mid 1980s5,22 new studies were started. In 1987 a pilot study was reported in ten women (seven post- and three premenopausal) with active RA.32 In this prospective double-blind placebocross-over study during 24 weeks 12.5 f-Lg ethinylestradiol was used. This dosage was chosen because of the proven beneficial effect on bone-density and on the alleviation of perimenopausal symptoms such as hot flashes. A significant improvement during the estrogen period was found in 30-m walking time, hemoglobin concentration, and platelet count. Erythrocyte sedimentation rate and C-reactive protein deteriorated in both periods but less in the estrogen period; grip strength improved in both periods. The number of swollen joints decreased, whereas the joint tenderness score increased during the estrogen period. The small number of patients and the short duration of the treatment period make the interpretation of
ESTROGENS AND RHEUMATOID ARTHRITIS
these results difficult. In an open study ten premenopausal women with moderately active RA received a highdose oral contraceptive (2.5 mg lynestrenol and 50 /-Lg ethinylestradiol) during 6 months. Four patients stopped the treatment due to inefficacy and side effects. Evaluation of the remaining six patients showed a statistical significant decline in the number of swollen joints, and a tendency of decline in the number of painful joints: the Ritchie articular score fell from 18 to 10. No other clinicalor laboratory parameter improved, leading the authors to conclude that estrogens have no disease modifying effect. 33 Since the number of patients was small, the disease activity limited, and the study open, no definite conclusion can be drawn. Based on the studies so far a double-blind placebocontrolled study was started in 1989. 34 Forty postmenopausal women with active RA were treated with 2 mg estradiol-valerate (equivalent to 25 /-Lg ethinylestradiol) or placebo in four cycles of 90 days. During the last 10 days ofthis cycle progesterone was added to induce a withdrawal bleeding. Seven patients withdrew from the study (five in the estrogen group and two in the placebo group). Not all data are available yet, but preliminary analysis shows that there was no improvement in the following outcome parameters: joint score, pain score, disability score, or ESR,35.However, bone density improved in the estrogen treated group. With regard to the effect of estrogens in women with RA it can be concluded that in premenopausal women the beneficial effect, if any, is only marginal, and in postmenopausal women there is no effect at all. Thus it seems unlikely that estrogens can be used as an adjuvant treatment in patients with RA to alleviate the symptoms of the disease. CONCLUSION
Though epidemiological and immunological evidence has suggested that femal-e sex hormones may playa role in the etiology and course ofRA, there is no evidence for a beneficial effect of estrogens on disease activity once RA has occurred. Based on epidemiological studies it is likely that estrogens may, in a modest way, mitigate or postpone the onset of the disease; some have also suggested that the outcome ofRA in females is better than in males.f It is possible that a beneficial effect of estrogens on (postmenopausal) bone density improves the outcome ofRA, especially whenjoint surgery is needed. The striking relation between gender and autoimmune diseases, such as most of the rheumatic diseases, remains clear. Perhaps we must investigate other mechanisms involved, such as the influence of gonadal hormones, or perhaps other hormones, on production of cytokines and/or growth factors to understand this relationship. , From a practical, clinical point of view, there is at present no evidence to promote the use of estrogens in preventing or treating RA in females. ACKNOWLEDGMENTS
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