ARTHRITIS & RHEUMATISM Volume 37 Number 11, November 1994, pp 1614-1617 8 1994, American College of Rheumatology 1614 SYSTEMIC LUPUS ERYTHEMATOSUS INDUCED BY OVULATION INDUCTION TREATMENT AVRAHAM BEN-CHETRIT and ELDAD BEN-CHETRIT Infertile women are treated with various regimens for ovulation induction. The ultimate end-result of these treatments is a significant rise in levels of serum gonadotropins and estradiol-the most potent natural estrogen. Estrogens may affect diverse biologic functions, including immune and inflammatory reactions. A role for estrogens in the development or exacerbation of systemic lupus erythematosus (SLE) has been suggested by many studies. In this report, we present 3 cases of otherwise healthy women who received ovulation induction agents and subsequently developed full-blown SLE. The possible association between this treatment and SLE is discussed. The vast majority of patients presenting with systemic lupus erythematosus (SLE) are women (1). Several physiologic and pharmacologic states incriminate estrogens in the development or the exacerbation of the disease. Among these are the association between synthetic estrogen in oral contraceptives and SLE exacerbation (2), the menstrual period effect on disease activity (3), the adverse effect of pregnancy on SLE (4),and the observation of a high incidence of SLE among patients with Klinefelter's syndrome (5) and a low incidence of disease after menopause (1). The most obvious effect of sex steroids is the development of secondary sex characteristics at puberty. However, they also influence diverse biologic functions throughout life (1). Sex steroids may affect behavior, intelligence, sexual preference, physical Supported by the Adolfo and Evelyn Blum Fund for Arthritis Research. Avraham Ben-Chetrit, MD: Shaare Zedek Medical Center, Jerusalem, Israel (current address: Toronto General Hospital, Toronto, Ontario, Canada); Eldad Ben-Chetrit, MD: Hadassah University Hospital, Jerusalem, Israel. Address reprint requests to Eldad Ben-Chetnt, MD, Rheumatology Unit, Division of Medicine, Hadassah University Hospital, Jerusalem, Israel. Submitted for publication April 11, 1994; accepted in revised form June 30, 1994. stature, and immunity. The effect of sex steroids on immunity may be quite profound and long lasting. These steroids affect the maturation of various immune cell systems and may influence susceptibility to disease by modulating immune populations of cells. While estrogens have been found to stimulate the T cell response and increase immunoglobulin levels, androgens do the opposite (6). Infertile women may be treated for ovulation induction by several regimens which stimulate follicular development and thereby increase the level of circulating estrogens (7). Therefore it would be anticipated that these drugs could exacerbate existing SLE or induce development appearance in predisposed individuals. However, in a review of the Englishlanguage medical literature, we were unable to find reports describing such a side effect of ovulation induction therapy. Herein we report 3 cases of otherwise healthy women in whom SLE developed after several cycles of ovulation induction treatment. CASE REPORTS Patient 1. Patient 1, a 31-year-old woman, was hospitalized because of fever and pleuritic pain. Three months previously, she had developed a classic butterfly rash with symmetric arthritis in her hands. Her earlier medical history was unremarkable except for antinuclear antibody (ANA)negative Raynaud's phenomenon for the last 16 years. Obstetric history disclosed that she had had 2 pregnancies, of which the first progressed to full term with delivery of a healthy baby, and the second was terminated artificially in the third gestational month. For the last 4 years she had had secondary infertility, and during the last 10 months she underwent ovulation induction therapy with 6 cycles of clomiphene citrate (CC) and human chorionic gonadotropin (hCG). Following this treatment, her estradiol levels rose to 2,135 pmolesfliter. One month after the sixth cycle, the facial rash and arthritis developed. On admission, the relevant physical findings included fever (38"C), malar flush, mild cervical lymphadenopathy, 1615 SLE AND OVULATION INDUCTION THERAPY and arthritis of the wrist and the proximal interphalangeal joints of both hands. The heart sounds were normal, and no pleural friction rub was heard. Laboratory testing showed an elevated erythrocyte sedimentation rate (ESR) (70 m d hour), 4,500 white blood cells (WBC)/mm3, and a hemoglobin value of 10.8 gm%. ANA testing gave a positive result (titer 1:320), as did testing for anti-Sm antibodies. Serum levels of C3 and C4 were normal, while the Coombs’ test result was positive. Findings of kidney and liver function tests were within normal limits. A chest radiograph showed mild pleural effusion. The patient was diagnosed as having SLE and was treated with 10 mg prednisone and 400 mg hydroxychloroquine daily. Patient 2. Patient 2 was a 42-year-old nulliparous woman who was hospitalized because of fever, malaise, and diffuse arthritis. The patient had primary infertility, and over the previous 2 years had undergone 10 cycles of ovulation induction with human menopausal gonadotropin (hMG) accompanied by hCG. Following the ovulation induction treatment, her serum estradiol concentration had reached a maximal level of 1,560 pmolesiliter. Two months after the last cycle, she began to experience arthralgia in her elbows, wrists, and temporomandibular joints. Later she noted the development of progressive alopecia. On physical examination, she was febrile (to 38.4”C), and manifested tenderness in both temporomandibular joints, cervical and axillary lymphadenopathy, and arthritis of all interphalangeal joints. There was no hepatosplenomegaly. Laboratory tests revealed an ESR of 40 m d h o u r , 2,900 WBC/mm3, 200,000 platelets/mm3, and a hemoglobin value of 12 gm%. Testing for ANA gave a positive result (titer 1:640) as did testing for anti-double-stranded DNA and anti-SS-A antibodies. There were no anticardiolipin antibodies, and the Coombs’ test result was negative. Chest radiography, electrocardiography, and echocardiography all gave normal results. Findings on kidney and liver function tests were within normal limits. The patient was diagnosed as having SLE and was treated with 30 mg prednisone daily, with immediate response. She was discharged with no symptoms, with a recommendation to taper the steroid treatment. Patient 3. This patient, a 34-year-old nulliparous woman, presented to our outpatient clinic with a diffuse erythematous rash. On physical examination, the only relevant finding was a maculopapular rash on her face and limbs. Laboratory findings included 5,500 WBC/mm3, 220,000 platelets/mm3, and a hemoglobin value of 13.8 gm%. ANA was positive (titer 1:320), but anti-double-stranded DNA and anti-Sm antibodies were negative. Results of a lupus band test were also positive. Discoid lupus was diagnosed, and treatment with hydroxychloroquine was instituted. Two years previously, she had been referred to the infertility clinic, and had undergone 8 cycles of ovulation induction, consisting of CC and hMG accompanied by hCG. Following the CC treatment, the estradiol level rose to a maximal level of 2,850 pmoles4iter. Three months subsequent to the last course, the skin rash developed. Treatment with hydroxychloroquine was beneficial, but the patient wished to continue her attempts to conceive. Therefore, the hydroxychloroquine was stopped, and following the second course of hMG and hCG, she conceived. However, in the twentieth gestational week, she had a spontaneous abortion. Two weeks later, she was hospitalized because of shortness of breath and severe peripheral edema. On examination, her blood pressure was measured at 180/120 mm Hg, and bilateral pleural effusions and pitting edema of both calves were detected. Laboratory tests revealed a hemoglobin level of 8 gm%, total protein level of 62 gdliter, serum albumin level of 20 gmiliter, serum creatinine level of 320 pmolesfliter, urea level of 85 mmolesiliter, creatinine clearance rate of 21 mlhinute, and proteinuria of 4 g d 2 4 hours. The Coombs’ test result was positive. ANA and anticardiolipin antibodies were also detected in the serum. A kidney biopsy disclosed rapidly progressive glomerulonephritis. The patient was treated with pulse intravenous methylprednisolone 1 gm daily, since she refused treatment with cyclophosphamide. Following this therapy, the patient improved clinically, but her kidney function remained abnormal with a serum creatinine level of 250 pmolesiliter, creatinine clearance rate of 28 ml/minute, and proteinuria of 1 g d 2 4 hours. Currently, she receives 15 mg prednisone daily. She is in stable condition, with a mild skin rash. DISCUSSION We describe 3 women with primary or secondary infertility, in whom full-blown SLE developed following treatment for ovulation induction. All of the patients were over 30 years old. None had either an ovarian cyst or endometriosis. Apart from Raynaud’s phenomenon in patient 1, none had any clinical finding suggesting connective tissue disease prior to the ovulation induction treatments. All 3 women received at least 6 cycles of ovulation induction therapy. Dynamic relationships between hypothalamic, pituitary, and ovarian hormones regulate the process of the menstrual cycle. Follicle-stimulating hormone (FSH) secreted from the pituitary gland, mainly during the first part of the menstrual cycle, is responsible for follicular development. The developing follicle secretes high levels of estradiol (the most potent natural estrogen), which enhances luteinizing hormone (LH) surge, followed by ovulation. High estrogen and progesterone levels inhibit further FSH and LH release (“negative feedback mechanism”). Ovulation may be induced by several possible methods. The first method most closely mimics the physiologic process. Gonadotropin-releasing hormone (GnRH) is administered in a pulsed manner and stimulates the pituitary gland to secrete endogenous FSH and LH (8). The second technique bypasses the brain and the feedback mechanism. In this method, exogenous FSH/LH mixture (hMG) or purified FSH is administered to directly stimulate follicular development. Human chorionic gonadotropin is then injected 1616 to evoke ovulation (8). The third method is based on interruption of the negative feedback mechanism by applying an estrogen antagonist such as clomiphene citrate. CC is a nonsteroidal agent related to diethylstilbestrol, which exerts a mixed estrogenic and antiestrogenic effect in different tissues (8). The precise mechanism of action of CC has not been fully elucidated; however, it seems to act mainly as an antiestrogen at the level of the hypothalamus, where it binds to estrogen receptors (for weeks), and therefore reduces the number of receptors available for endogenous estradiol binding, This competitive inhibition results in an increase in GnRH pulses, which enhance endogenous FSH release and follicular development (9). Ovulation induction regimens consist of various combinations of these 3 methods. Regardless of the ovulation induction method, a rise in serum gonadotropin (endogenous or exogenous) and serum estradiol levels results. Although high serum gonadotropin levels could be a possible precipitating factor for an SLE flare (lo), there is much more direct and indirect evidence to tie estrogens to the pathogenesis of the disease. In the articles reviewed (1-6,11,12), while estrogen levels were always high, the accompanying gonadotropin levels were either high or low. Sexual dimorphism in the regulation of the immunehnflammatory reaction, including female susceptibility to autoimmune diseases, has been described in various species, such as rat, mouse, and human (13). In male New Zealand black X New Zealand white mice, early castration and estrogen therapy accelerated SLE disease, while administration of androgens to female mice suppressed the disease and allowed them to live a normal life span (11). In humans, there are reports of a relatively high incidence of SLE among patients with Klinefelter’s syndrome (5). In women with SLE, levels of plasma androgens have been reported as being low (14), while in men with the disease, the plasma level of estrogens is relatively high (15). The known deleterious effect of pregnancy and the postpartum period on SLE (4), as well as possible exacerbation of the disease by oral contraceptives (2), may also suggest an important role for estrogens in the pathogenesis of SLE. Furthermore, data suggest that the metabolism of estrogen is altered in SLE patients, resulting in elevation of 16phydroxylated metabolites (16phydroxyesterone and estriol) (12). Having strong estrogenic activity, these metabolites bind estrogen receptors and retain the estrogenic effect. This metabolic abnormality may BEN-CHETRIT AND BEN-CHETRIT contribute to the exacerbation of lupus following ingestion of estrogen-containing oral contraceptives, and in other hyperestrogenic conditions. In the case of CC administration, it is tempting to speculate that this drug may mimic the action of estrogen metabolites in the peripheral tissue, by binding the same receptors and retaining similar activity. Since the incidence of overt SLE among women undergoing ovulation induction therapy is relatively low, it is possible that this association is coincidental. However, the temporal relationship between the ovulation treatment and the onset of the disease in our patients is impressive. Because we have no results of ANA screening prior to the treatment, we do not know whether the treatment exacerbated an underlying silent disease or played a basic role in causing the disease. The infrequent detection of SLE among women undergoing ovulation induction treatment may be due to lack of awareness by physicians of this possible association. Another possible explanation is that SLE may occur following such treatment only in the setting of an appropriate genetic or environmental background. Frequent exposure to ovulation induction agents and the associated prolonged exposure to estrogens may be a prerequisite condition. A prospective study with a large population of infertile women in in vitro fertilization and artificial insemination programs is needed, in order to confirm or refute this association. ACKNOWLEDGMENT We thank Ellen Greenblatt, MD, Division of Reproduction, Toronto General Hospital, for her critical review of the manuscript. REFERENCES 1 . Lahita RG: Sex and age in systemic lupus erythematosus, Systemic Lupus Erythematosus. Edited by RG Lahita. NewYork, Churchil Livingstone, 1988 2. Jungers P, Dougados M, PClissier C, Kuttenn F, Tron F, Lesavre P, Bach J-F: Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum 2k618-623, 1982 3. Rose E, Pillsbury DM: Lupus erythematosus and ovarian function: observation on a possible relatiohship with a report of six cases. Ann Intern Med 21:1022-1034, 1944 4. Petri M, Howard D, Repke J: Frequency of lupus flare in pregnancy: the Hopkins Lupus Pregnancy Center experience. Arthritis Rheum 34:15311545, 1991 5. Tala1 N: Sex steroid hormones and systemic lupus erythematosus. Arthritis Rheum 24:1054-1056, 1981 6. Lahita RG: The effect of sex hormones on the immune system in pregnancy. Am J Reprod Immunol 28:136-137, 1992 SLE AND OVULATION INDUCTION THERAPY 7. Meirow D, Laufer N, Schenker JG: Ovulation induction in in-vitro fertilization. Gynecol Endocrinol6:211-224, 1993 8. Speroff L, Glass RH, Kase NG: Induction of ovulation, Clinical Gynecologic Endocrinology and Infertility. Fourth edition. Baltimore, Williams & Wilkins, 1989 9. Kerin JF, Liu JH, Phillipou G, Yen SSC: Evidence for a hypothalamic site of action of clomiphen citrate in women. J Clin Endocrinol Metab 61:265-268, 1985 10. Athreya BH, Pletcher J, Zulian F, Weiner DB, Williams WV: Subset-specific effects of sex hormones and pituitary gonadotropins on human lymphocyte proliferation in vitro. Clin Immuno1 Immunopathol66:201-211, 1993 11. Roubinian JR, Tala1 N, Greenspan JS, Goodman JR, Siiteri PK: Effect of castration and sex hormone treatment on survival, anti 12. 13. 14. 15. 1617 nucleic acid antibodies, and glomerulonephritis in NZB/NZW F, mice. J Exp Med 147:1568-1583, 1978 Lahita RG, Bradlow L, Fishman J: Increased 16phydroxylation of estradiol in systemic lupus erythematosus. J Clin Endocrinol Metab 53:174-178, 1981 Grossman C: Possible underlying mechanism of sexual dimorphism in the immune response, fact and hypothesize. J Steroid Biochem 34:241-251, 1989 Jungers P, Nahoul K, Pelissier C, Dougados M, Tron F, Bach J-F: Low plasma androgens in women with active or quiescent systemic lupus erythematosus. Arthritis Rheum 25:454-457, I982 Miller M, Urowitz M, Gladman D, Killinger D: Male SLE (abstract). Arthritis Rheum 25 (suppl 4):S58, 1982
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