ARTICLE
Interest in thalidomide has intensified in recent years as it
has been shown to be successful in the treatment of severe dermatological
conditions unresponsive to other agents [1]. Compared with thalidomide's
other side effects, amenorrhea has been relatively poorly investigated
although it was first reported in 1989 [2]. We studied this side effect
retrospectively in a consecutive series of women treated with thalidomide.
Patients and methods
From January 1995 to December 1999, 23 women received thalidomide in
our institution. Two were excluded from the study due to prior hysterectomy
or menopause. The other 21 women had the following refractory dermatological
conditions: discoid and/or subacute lupus erythematosus (15 cases), complex
aphthosis (6 cases). The mean age at treatment initiation was 35.2 years
(range: 16-49 years). Pregnancy was ruled out before the onset of thalidomide
treatment. All women concomitantly received progestin contraception with
either chlormadinone acetate (10 mg/day, 21 consecutive days/28, 20 cases)
or norethisterone (0.6 mg/day, 1 case). Other treatments were kept unchanged
for at least six months before thalidomide initiation: hydroxychloroquine
(200 to 400 mg/day: 10 cases), chloroquine (100 to 200 mg/day: 2 cases),
prednisone (5 to 20 mg/day: 11 cases), colchicine (1 mg/day: 5 cases).
The initial dose of thalidomide was 100 mg/day in all patients, followed
by progressive tapering when dermatological lesions disappeared. Data
concerning their genital life were retrospectively analyzed and systematically
checked by phone with a simple questionnaire. When amenorrhea occurred,
pregnancy was excluded and serum levels of follicle-stimulating hormone,
luteinizing hormone and prolactin were determined by an ELISA technique.
Results
Five women developed transient secondary amenorrhea. Table
I summarizes their main characteristics. Data from patient 1, who
had complex aphthosis, have been previously reported [3]. Other women
had refractory discoid lupus erythematosus associated in one case with
subacute cutaneous lupus. Three of them satisfied at least four 1997 ACR
criteria for systemic lupus erythematosus in the absence of severe organ
involvement [4]. Before thalidomide institution, none had experienced
extra-dermatological flare for more than six months, and all had regular
menses. Treatment with thalidomide induced complete (3 cases) or partial
remission (2 cases) of dermatological manifestations. Two patients developed
clinical sensitive peripheral neuropathy confirmed by electrical studies.
The mean delay between the beginning of treatment with thalidomide and
onset of amenorrhea was 14.2 months (1-42 months). Amenorrhea persisted
for 3 to 10 months according to the duration of thalidomide treatment.
Menses resumed 2 to 3 months after thalidomide withdrawal although progestin
contraception was stopped simultaneously in 3 patients. Patient 4 had
a full-term pregnancy 16 months after thalidomide withdrawal. Recurrence
of amenorrhea occurred in patient 3, 12 months after thalidomide was reinitiated
without change of progestin contraception. During amenorrhea, the serum
follicle-stimulating hormone (FSH) levels of all women were in the post-menopausal
range and returned to normal pre-menopausal values after reappearance
of menses. Serum luteinizing hormone (LH) and prolactin (3 cases) levels
were normal.
Discussion
Interest in thalidomide has intensified in recent years since its anti-inflammatory,
immunomodulatory, and anti-angiogenic properties have been identified
[1]. Its usage in dermatological practice appears to be increasing for
a large variety of refractory conditions [5]. In this study, it was only
prescribed for severe aphthosis or refractory discoid/subacute lupus.
Its effectiveness in these conditions has been demontrated by randomized
trials [6, 7] or multiple open series [8, 9]. The most common side-effects
of thalidomide are fetal phocomelia and peripheral neuropathy. Among other
side-effects, transient amenorrhea was noticed as early as 1989 in a 33
year-old woman treated for rheumatoid arthritis [2] but not mentioned
in recent reviews [10, 11]. Amenorrhea frequently occurs when used in
patients with lupus erythematosus. Indeed, in1998, Ordi reported that
5 of 14 women treated with thalidomide for refractory cutaneous lupus
developed amenorrhea after a cumulative dose of 9-18 gm [12]. Menses resumed
2-3 months after cessation of treatment [13]. In one of these patients,
an ovarian biopsy showed severe ovarian atrophy and absence of ova and
follicles [13]. Many causes may induce amenorrhea in women with lupus,
i.e. lupus flares, end-stage renal disease, autoimmune oophoritis,
immunosuppressive therapy such as cyclophosphamide, or progestin contraception.
The responsibility of thalidomide for amenorrhea in these patients is
however suggested by increased endogenous levels of FSH despite progestin
contraceptive, reappearance of menses 2 to 3 months after thalidomide
withdrawal and further recurrence of amenorrhea in one previously reported
case [13] and in one case of this series. A premenopausal state was unlikely
in the 39 year-old patient who noticed amenorrhea only 1 month after the
beginning of treatment. Indeed, amenorrhea persisted for 10 months during
thalidomide treatment; this patient had regular menses after thalidomide
withdrawal with a follow up of 4 years. Thalidomide-induced amenorrhea
has also been reported in women suffering from complex aphthosis, a condition
which is not associated with primary spontaneous ovarian failure [3].
The mechanism of amenorrhea induced by thalidomide is still unclear, though
high serum FSH levels suggest reversible ovarian failure. The initial
dosage of thalidomide, the duration of treatment and the cumulative dose
did not differ in women with or without amenorrhea (data unshown). This
side-effect is not correlated with other side-effects of thalidomide,
especially peripheral neuropathy, which was present in 2 cases, while
it is detected in between 21% and 50% of all patients depending upon the
series [14]. Whatever its mechanism, thalidomide-induced amenorrhea is
a transient and reversible condition, with possible further pregnancy
as in one case of this series. Further studies are required to clarify
its prevalence according to the underlying disease and its mechanism.
Article accepted on 31/8/01
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