Brazilian Journal of Medical and Biological Research (2001) 34: 1561-1568 Ovarian failure in systemic lupus erythematosus ISSN 0100-879X
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Risk factors for ovarian failure in patients with systemic lupus erythematosus M.M.C. Medeiros, V.A.L. Silveira, A.P.T. Menezes and R.C. Carvalho
Departamento de Clínica Médica, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, Fortaleza, CE, Brasil
Abstract Correspondence M.M.C. Medeiros Rua Paula Ney, 599/302 60140-200 Fortaleza, CE Brasil Fax: +55-85-224-7222 E-mail:
[email protected]
Received May 23, 2001 Accepted September 26, 2001
The aim of the present study was to identify the risk factors for ovarian failure in patients with systemic lupus erythematosus. Seventy-one women aged 17 to 45 years with systemic lupus erythematosus were studied. Patients were interviewed and their medical records reviewed. Demographic characteristics, clinical and serologic profiles, and menstrual and obstetric histories were recorded. Disease activity was measured by the systemic lupus erythematosus disease activity index. Serum FSH, LH, estradiol, progesterone, TSH, prolactin, and antimicrosomal and antithyroglobulin antibodies were measured. Patients who developed ovarian failure were compared to those who did not. Ovarian failure occurred in 11 patients (15.5%) and nine had premature menopause (11.3%). Cyclophosphamide administration and older patient age were found to be associated with ovarian failure. The cumulative cyclophosphamide dose was significantly higher in patients with ovarian failure than in those without this condition (18.9 vs 9.1 g; P = 0.04). The relative risk for ovarian failure in patients with cumulative cyclophosphamide dose higher than 10 g was 3.2. TSH levels were high in 100% of patients with ovarian failure who had received pulse cyclophosphamide. Ovarian failure, and premature menopause in particular, is common in patients with systemic lupus erythematosus, with the most important risk factors being cyclophosphamide dose and age. Thyroid problems may be another risk factor for ovarian failure in patients with lupus.
Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease which mainly affects women of reproductive age. Menstrual alterations ranging from increased cycle flow, generally due to thrombocytopenia, to temporary amenorrhea and premature menopause are fairly common in these patients. The main factors which have been asso-
Key words · ·
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Ovarian failure Systemic lupus erythematosus Risk factors Cyclophosphamide Premature menopause
ciated with the onset of ovarian failure in patients diagnosed with SLE are disease activity (1), anti-ovarian antibodies (2,3), cytotoxic agents (4-8) and, more recently, use of thalidomide (9,10). Other potential causes of ovarian insufficiency not specific for lupus are polyglandular insufficiency, viral infections, smoking, oophorectomy, emotional disorders, and idiopathic origin (11). Cyclophosphamide is the immunosupBraz J Med Biol Res 34(12) 2001
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pressive agent of choice for the treatment of various complications of SLE and, therefore, is the factor most highly associated with ovarian insufficiency. Gonadal toxicity should be of great concern in premenopausal women who take cyclophosphamide. The frequency of ovarian insufficiency in SLE patients treated with this drug ranges from 11 to 59% in different studies and depends on the dose used, the age of the patient and methodological differences (4-8,12-14). Since estrogens have biological effects which protect the cardiovascular system, as well as the skeletal system from bone loss, estrogen deficiency is linked with a greater risk for cardiovascular disease (15) and osteoporosis (16), thus contributing to higher morbidity and mortality among patients diagnosed with lupus. The potential for other risk factors for the reduction of bone mass in this group of patients, such as use of corticosteroids, lower exposure to sunlight, the controversial use of hormone-replacement therapy (17-19), along with hypoestrogenism secondary to cyclophosphamide-induced ovarian failure, renders women diagnosed with SLE far more susceptible to the development of osteoporosis. Thus, it is crucial to identify those factors most often associated with ovarian insufficiency in patients with SLE in order that preventive and therapeutic measures may be taken to minimize the risk of these complications.
Material and Methods Study population
The study population consisted of female patients diagnosed with SLE, in accordance with the criteria of the American College of Rheumatology (20), attended continuously at the Rheumatology Service of the University Hospital of the Federal University of Ceará, from January 1999 to March 2000. All patients with a diagnosis of SLE under Braz J Med Biol Res 34(12) 2001
treatment at the above-mentioned hospital, aged 16 to 45 years, who agreed to participate were included in the study. Exclusion criteria were patients with known causes of secondary amenorrhea, such as chronic renal insufficiency, and reported hysterectomy or oophorectomy. This is a retrospective cohort study. Methods
A questionnaire was administered to patients in order to obtain sociodemographic data (age, race, marital status, education, smoking habit), clinical data (duration of disease, clinical manifestations, drugs used to treat lupus), and gynecologic-obstetric history (age at menarche, date of latest menstrual cycle, number of gestations and abortions, curettages, gynecological surgeries, and methods of birth control used). At the time of the interview, a disease activity score was determined according to SLE disease activity index (SLEDAI) criteria (21). The following laboratory tests were obtained: blood cell count, hemosedimentation rate, measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, prolactin, thyroid-stimulating hormone (TSH), antinuclear factor, antiDNA, anti-Sm, antithyroglobulin, and antimicrosomal antibodies, protein count, creatinine, and urinalysis. Hormonal determinations were performed by radioimmunoassay. The charts of all patients were reviewed exhaustively in order to complement the data collected (disease manifestations, results of laboratory workup, drug usage, and calculation of cumulative dose of cyclophosphamide). The cumulative dose of venous cyclophosphamide was calculated by summing all the dosages registered in the medical prescriptions. Cyclophosphamide pulse therapy schemes followed the classic standards reported in the medical literature (22): seven monthly pulses (0.5-1 g/m2), followed by
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pulses given every three months for 18-24 months (1 g/m2), with doses adjusted according to platelet and leukocyte levels. The protocol was approved by the Hospital Ethics Committee and informed consent was obtained from all patients. Ovarian insufficiency was considered to have occurred in cases of amenorrhea lasting longer than 4 months, excluding pregnancy. Premature menopause was defined as the presence of amenorrhea for at least 12 months, confirmed by estradiol (0-14 pg/ ml), FSH (42-126 mIU/ml) and LH (11-50 mIU/ml) levels, that had occurred before 40 years of age.
P6 months (%) Venous cyclophosphamide use (%) SLEDAI (mean ± SD)
28.9 ± 7.5 4.8 ± 4.2
37.2 ± 5.8 8.7 ± 4.7
32 (53.3) 28 (46.7)
9 (81.8) 2 (18.2)
10 (16.6) 31 (51.7) 18 (30.0) 1 (1.7) 41 (68.3) 15 (25.0) 47 (78.3) 56 (93.3) 7 (11.7) 11 (18.3) 34 (56.7) 9 (15.0) 15 (25.0) 17 (28.3) 29 (48.3) 59 (98.3) 39 (65.0) 9 (15.0) 17 (28.3) 10.8 ± 9.7
2 (18.2) 8 (72.7) 1 (9.1)
P
