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Systemic lupus erythematosus induced by ovulation induction treatment.

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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.
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SLE AND OVULATION INDUCTION THERAPY
7. Meirow D, Laufer N, Schenker JG: Ovulation induction in
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