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General Hospital Psychiatry 34 (2012) 529 533

Antidepressants and menstruation disorders in women:

a cross-sectional study in three centers
Faruk Uguz, M.D. a,, Mine Sahingoz, M.D. a , Seyit Ali Kose, M.D. b , Ozgur Ozbebit, M.D. c ,
Cem Sengul, M.D. d , Yavuz Selvi, M.D. e , Ceyhan Balci Sengul, M.D. f ,
Medine Gynas Ayhan, M.D. a , Adnan Dagistanli, M.D. a , Rustem Askin, M.D. a
a
Department of Psychiatry, Meram Faculty of Medicine, Konya University, Konya, Turkey
b
Department of Obstetrics and Gynecology, Faculty of Medicine, Duzce University, Duzce, Turkey
c
Department of Psychiatry, Van Ipekyolu State Hospital, Van, Turkey
d
Department of Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey
e
Department of Psychiatry, Faculty of Medicine, Yuzuncuyil University, Van, Turkey
f
Department of Psychiatry, Denizli State Hospital, Denizli, Turkey
Received 10 January 2012; accepted 20 March 2012

Abstract

Objective: The relationship between menstruation disorders and antidepressant drugs usage in women remains unclear. In this study, we
aimed to investigate the incidence rate of antidepressant-related menstruation disorders and to examine whether or not antidepressant use is
associated with menstrual disorders in women.
Methods: The study sample was gathered from three centers and four hospitals. A total of 1432 women who met the criteria of inclusion
were included in the study. The sample was divided into two groups: the antidepressant group (n=793) and the control group (n=639). The
menstruation disorders were established with reports from the study participants on the basis of related gynecological descriptions.
Results: The prevalence of menstrual disorders was significantly higher in the antidepressant group (24.6%) than the control group (12.2%).
The incidence of antidepressant-induced menstruation disorder was 14.5%. The antidepressants most associated with menstrual disorders
were paroxetine, venlafaxine, sertraline and their combination with mirtazapine. Overall, the incidence rate was similar in women receiving
selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors.
Conclusions: The results of the present study suggest that menstruation disorders are frequently observed in women taking antidepressants
and that it appears to be associated with antidepressant use at least in some women.
2012 Elsevier Inc. All rights reserved.

1. Introduction premenstruum or menstruation, and the effects of psychotro-

Menstrual cycle is a notable hormonal function in women
during their reproductive period. In addition to hormonal
fluctuations, some mental changes may be observed in this
period. The association between psychiatric problems and
menstruation include mainly two points: the association with
the onset or course of mental symptoms or disorders of
Corresponding author. Konya niversitesi Meram Tp Fakltesi,
Psikiyatri Anabilim Dal, Akyoku, 42080, Konya, Turkey. Tel.: +90 332
223 6306.
E-mail address: farukuguz@gmail.com (F. Uguz).
0163-8343/$ see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.genhosppsych.2012.03.014
pics on menstrual cycle. The premenstrual phase is frequently
related to mood, behavioral and somatic symptoms. Premen-
strual dysphoric mood symptoms including depressed mood,
affect lability and irritability are not rare [1]. In addition,
menarche and premenstrual period are associated with mental
disorders in at least some women [2,3].
The relationship between psychotropics and menstrual
function in women has been focused on mostly antipsy-
chotics. The impact of antidepressant drugs, the most
commonly used psychotropics, on menstrual cycle is
unclear. Conversely, it is observed by clinicians that some
women patients attending the psychiatry outpatient clinic
report abnormalities in menstrual bleeding or regularity
530 F. Uguz et al. / General Hospital Psychiatry 34 (2012) 529533

following the initiation of an antidepressant drug. To our
knowledge, there is no published study examining the
prevalence of disorders of menstruation secondary to
antidepressant treatment. This study aimed to investigate
the following: (a) the prevalence of disorders in menstruation
due to treatment with specific antidepressants, (b) the
differences in prevalence of menstrual disorders among
women taking antidepressants compared to controls who are
not on antidepressants and (c) the association of socio-
demographic factors with antidepressant-induced menstrua-
tion disorders.
2. Methods
The study was conducted among women who presented
at psychiatric outpatient clinics of four hospitals in Turkey:
The Training and Research Hospital of Meram Faculty of
Medicine of Konya University in Konya, The Meram
Training and Research Hospital in Konya, The Denizli
State Hospital in Denizli and Ipekyolu State Hospital in Van.
The study included 1432 consecutive women who were
between 18 and 42 years of age and who were admitted to
these four outpatient clinics between February 2010 and
September 2010. We divided the study population into two
groups: (a) the antidepressant group which was composed of
793 women receiving an antidepressant treatment for at least
3 months and (b) a control group comprising of 639 women
who did not use any antidepressant or other psychotropic
drugs for at least the previous 6 months.
Subjects with a history of gynecological surgery or
disease, the existence of a neurological disease, uncontrolled
endocrine abnormalities, cardiovascular and pulmonary
system disease, and a history or existence bipolar mood
disorder, schizophrenia or other psychotic disorders, and
mental retardation were excluded from the study. The study
sample included women using combination of selective
serotonin reuptake inhibitors (SSRIs) and venlafaxine with
mirtazapine . In contrast, women taking other antidepressant
combinations (e.g., SSRI or venlafaxine plus bupropion;
SSRI plus SSRI; SSRI or venlafaxine plus tricyclic or
tetracyclic antidepressants) and combination of antidepres-
sants with antipsychotics, anxiolytics and mood stabilizers
were also excluded from the study. The study sample also
did not include women who used an intrauterine device or a
hormonal contraceptive method. The objectives and pro-
cedures of the study were explained to all the patients, and all
participants provided written informed consent.
A semistructured interview form developed by the in-
vestigators was used to determine sociodemographic features,
the presence of menstrual disorders and use of antidepressant
drugs. The existence and type of menstrual dysfunction were
established based on reports from the study participants
according to the following descriptions [47]: normal
menstrual cycle: 2135 days in duration, with bleeding lasting
an average of 7 days and flow measuring 2580 ml;
menorrhagia: menstruation at regular cycle intervals but with
excessive flow exceeding 80 ml per cycle or duration lasting
longer than 7 days; metrorrhagia: irregular or frequent menses
that are not excessive; menometrorrhagia: bleeding occurs at
irregular, noncyclic intervals and with heavy flow (80 ml) or
duration (7 days); dysfunctional uterine bleeding: irregular
uterine bleeding that occurs in the absence of pathology or
medical illness; hypomenorrhea: abnormally low bleeding,
substantially less than 30 ml per menstrual cycle in a cycle of
normal duration; amenorrhea: failure to menstruate for 90 days

Table 1
Frequencies of antidepressant drugs used and prevalence of menstrual disorders in antidepressant group (n=793)
Drug n Prevalence of menstrual P value a Odds ratio b (95% Cl)
disorders, n (%)
Sertraline 165 44 (26.7) .000 2.61 (1.723.97)
Citalopram 83 12 (14.5) .595 1.21 (0.632.34)
Paroxetine 98 32 (32.7) .000 3.49 (2.155.66)
Fluoxetine 69 19 (27.5) .001 2.73 (1.534.88)
Fluvoxamine 23 2 (8.7) 1.000 0.68 (0.162.98)
Escitalopram 115 24 (20.9) .017 1.89 (1.143.15)
Clomipramine 9 1 (11.1) 1.000 0.90 (0.117.29)
Venlafaxine 123 33 (26.8) .000 2.64 (1.664.19)
Mirtazapine 23 5 (21.7) .193 2.05 (0.765.60)
Duloxetine 28 4 (14.3) .767 1.20 (0.413.55)
Milnacipran 23 4 (17.4) .513 1.51 (0.564.57)
Sertraline+mirtazapine 7 3 (42.9) .046 5.39 (1.1824.55)
Paroksetine+mirtazapine 8 4 (50.0) .011 7.19 (1.7629.34)
Citalopram+mirtazapine 10 4 (40.0) .027 4.79 (1.3217.37)
Venlafaxine+mirtazapine 10 4 (40.0) .027 4.79 (1.3217.37)
Only SSRI 562 134 (23.8) .000 2.25 (1.663.06)
Only SNRI 174 41 (23.6) .000 2.22 (1.453.38)
CI, confidence interval.
a
Statistical value for comparisons of prevalence rate of menstrual disorders between women receiving specific antidepressant drugs and the control group.
b
Risk estimate for prevalence rate of menstrual disorders in women receiving specific antidepressant drugs compared to the control group.
 F. Uguz et al. / General Hospital Psychiatry 34 (2012) 529533 531

or longer; oligomenorrhea (infrequent menses): the interval is

greater than 37 days but less than 90.
All statistical analyses were performed using the
Statistical Package for the Social Sciences, version 13.0,
for Windows. Differences with regard to continuous vari-
ables, 3 or more2 categorical variables and 22 categorical
variables between the groups were analyzed with t test, 2
test and Fisher's Exact Test, respectively. All significant
levels were two-tailed and set at the level of .05.

3. Results

The mean age of the sample (n=1432) was 31.7712.87

years. Most subjects were married (n=1102, 77.0%),
housewives (n=1186, 82.8%) and primary school graduates
(n=964, 67.3%). Of all the participants, 267 (18.6%) had a
history of abortion. The mean number of children was 1.85 Fig. 1. Prevalence and incidence of menstruation disorders in women using
1.37. The antidepressant group and the control group were antidepressant drugs.
statistically similar with regard to age (t=0.77, P=.44),
number of children (t=1.04, P=.30), marital status ( 2=3.28,
P=.19), educational level ( 2=2.96, P=.23), employment pine and clomipramine compared to the control subjects
status (Fisher's Exact Test, P=.67) and history of abortion (Table 1). There was no significant difference between the
(Fisher's Exact Test, P=.16). groups for the types of menstruation disorders (Table 2).
Frequencies of antidepressant use in the study sample are Fig. 1 presents the prevalence and incidence of menstru-
presented in Table 1. Among the subjects in the antidepres- ation disorders with respect to the usage of specific
sant group, 562 (70.9%) used only SSRIs or clomipramine, antidepressant drugs. The incidence rate of antidepressant-
174 (21.9%) used only serotonin noradrenaline reuptake induced menstruation disorder was 14.5% (n=115). Menstru-
inhibitors (SNRIs), 22 (2.8%) used only mirtazapine, 25 ation disorders secondary to antidepressant use were most
(3.2%) used SSRIs plus mirtazapine, and 10 (1.3%) used commonly reported by women receiving combinations of
SNRIs plus mirtazapine. Specifically, the antidepressant mirtazapine and paroxetine (n=3, 37.5%), venlafaxine (n=3,
drug most commonly used in this study group was sertraline 30.0%), sertraline (n=2, 28.6%) and citalopram (n=2, 20.0%).
(n=165, 20.8%) followed by escitalopram (n=115, 14.5%). As monotherapy, the antidepressants most commonly associ-
The prevalence of menstruation disorders was 24.6% ated with the emergence of menstruation disorders were
(n=195) in the antidepressant group and 12.2 (n=78) in the paroxetine (n=22. 22.4%), venlafaxine (n=23, 18.7%) and
control group (Fisher's Exact Test, P=.000). The overall sertraline (n=28, 17.0%). The incidence of menstruation
prevalence rate of menstruation disorders was significantly disorders among subjects using other antidepressants were as
higher in women taking paroxetine, sertraline, fluoxetine, follows: 13.0% (n=3) for milnacipran, 11.1% (n=1) for
escitalopram, venlafaxine, paroxetine plus mirtazapine, clomipramine, 10.7% (n=3) for duloxetine, 9.6% (n=11) for
sertraline plus mirtazapine, citalopram plus mirtazapine escitalopram, 8.7% (n=6) for fluoxetine, 6.0% (n=5) for
and venlafaxine plus mirtazapine compared to the control citalopram and 4.3% (n=1) for fluvoxamine. Overall, the
group. This rate, however, was similar in women taking incidence rate was statistically similar in women receiving
fluvoxamine, citalopram, duloxetine, milnacipran, mirtaza- SSRIs (13.2%) and SNRIs (16.7%) (P=.26).
Among the participants who reported menstrual disorders
Table 2 related to antidepressant use (n=115), the mean onset time of
The types of menstruation disorders in antidepressant and control groups antidepressant-induced menstruation disorder was 8.798.03
Menstruation Antidepressant Control P value weeks, and the mean number of cycles was 2.161.86.
disorders, n (%) group n=195 group n=78 Among the same group, most (88.8%) reported the onset of
Metrorrhagia 71 (36.4) 21 (26.9) .157 dysregulated menstruation within three menstrual cycles
Oligomenorrhea 58 (29.9) 29 (37.2) .253 following the initiation of antidepressant drugs, with the
Menorrhagia 26 (13.3) 12 (15.4) .700
disorder occurring in the first cycle in 53 (45.7%) women, in
Menometrorrhagia 19 (9.7) 6 (7.7) .717
Hypomenorrhea 11 (5.7) 8 (10.3) .194 the second cycle in 32 (27.6%) women and in the third cycle
Dysfunctional uterine bleeding 5 (2.6) 1 (1.3) .678 in 18 (15.5%) women. The most common menstruation
Amenorrhea 5 (2.6) 1 (1.3) .678 disorders observed following antidepressant use were
Interval disorder 139 (71.3) 53 (67.9) .660 metrorrhagia (n=40, 34.8%), oligomenorrhea (n=39,
Flow disorder 56 (28.7) 24 (32.1) .665
33.9%) and menorrhagia (n=15, 13.0%). Menometrorrhagia
532 F. Uguz et al. / General Hospital Psychiatry 34 (2012) 529533
(n=9, 7.8%), hypomenorrhea (n=7, 6.1%), dysfunctional
uterine bleeding (n=3, 2.6%) and amenorrhea (n=2, 1.7%)
were less frequent. Statistical tests suggested that antide-
pressant-induced menstruation disorders were unrelated to
age (t=1.61, P=.11), number of children (t=1.79, P=.07),
marital status ( 2=1.67, P=.43), educational level ( 2=1.58,
P=.45), employment status (Fisher's Exact Test, P=.28) and
history of abortion (Fisher's Exact Test, P=.48).
4. Discussion
To our knowledge, this is the first study examining the
connection between specific antidepressant drug usage and
menstrual disorders in reproductive women. The present
study suggests that antidepressant agents, especially parox-
etine, sertraline, venlafaxine and their combination with
mirtazapine, appear to be associated with an increased risk of
menstruation disturbances in women of reproductive age.
There are several case and small study reports on this topic.
Previous two case reports presented vaginal bleeding
associated with sertraline use in postmenopausal women
[8,9]. Linnebur et al. [10] reported that a 41-year-old woman
developed vaginal bleeding with the usage of venlafaxine. In
a subgroup analysis of 93 women hospitalized due to
primarily abnormal uterine bleeding (e.g., metrorrhagia,
menorrhagia and postmenopausal bleeding), Meijer et al.
[11] noted an increased risk of abnormal uterine bleeding in
women using antidepressants.
In our sample, the prevalence of menstruation disorder
was significantly higher in the antidepressant group
compared to the control group. Among the women receiving
antidepressant medication, 14.5% described the onset of
menstrual abnormalities following the initiation of the
antidepressant drug. The pathogenesis of the relationship
between antidepressants and menstruation disorders reported
in this study is currently unknown. This could be due to
antidepressant, particularly serotonin reuptake inhibitors
(SRIs), -related hematological adverse reactions. A recent
review suggested that SSRIs and venlafaxine, which is a
relatively new dual-action drug that also potently inhibits
serotonin reuptake, are associated with an increased risk of
abnormal bleeding, especially from the upper gastrointesti-
nal tract [12]. In addition, serotonin reuptake potency
appears to be related to an increased risk of bleeding
[11,12]. Similarly, in our sample, antidepressant-induced
menstrual abnormalities were frequently observed in women
receiving paroxetine, sertraline and venlafaxine, which have
a high degree of serotonin reuptake inhibition [13,14].
SSRIs have a negative effect on platelet aggregation via
a decrease in platelet serotonin storage [15,16]. This may be
the underlying mechanism of antidepressant-induced men-
strual dysfunction. If so, antidepressant-related bleedings
should be reported from almost all organ systems.
However, the previous reports include mostly upper
gastrointestinal tract bleeding, with no adequate evidence
of antidepressant-associated abnormal bleeding from other
systems [12]. In addition, this factor does not explain
menstruation abnormalities such as hypomenorrhea and
oligomenorrhea, which are associated with infrequent and
decreased vaginal bleeding.
Another explanation includes hyperprolactinemia sec-
ondary to antidepressant medication. Although hyperpro-
lactinemia is most commonly associated with antipsychotics
within psychotropics, it is a potential side effect of SSRIs due
to interactions between serotonergic and dopaminergic
pathways. However, the available data on the relation
between SSRIs and serum prolactin level are controversial
[17]. The menstrual abnormalities observed in hyperprolac-
tinemic women are mainly oligomenorrhea and amenorrhea
[18,19]. In the present study, the total frequency of these two
menstruation disorders secondary to antidepressant drug
usage was 35.6%, making hyperprolactinemia as the sole
pathogenesis appear inadequate.
Finally, possible interactions between gonadal steroids
such as estrogen, progesterone, luteinizing hormone,
gonadotropin-releasing hormone, reproductive axis and
monoaminergic effects of antidepressants may be associ-
ated with menstruation disorders in women taking
antidepressant drugs. Estrogen has an enhancement in
serotonergic activity via an increase in serotonin synthesis,
a decrease in serotonin breakdown and desensitization of
serotonin autoreceptors and affects serotonin receptor
subtypes [20]. Experimental studies indicated that seroto-
nin and noradrenaline stimulate gonadotropin release
[21,22]. Rehavi et al. [23] reported the suppression of
serum gonadal steroids in rats by chronic treatment with
SRIs. Similarly, Mennigen et al. [24] found that plasma
estradiol levels were reduced approximately threefold after
fluoxetine treatment in female goldfish. Considering that
menstruation occurs following the withdrawal of estrogen
and progesterone subsequent to normal ovulatory cycle
[25], it may be proposed that antidepressants, especially
serotonergic agents, may trigger menstruation abnormali-
ties by influencing fluctuations of gonadal steroids during
the menstrual cycle in at least some women.
In this study, we found that the highest frequency of
menstrual disturbances was observed during the use of
paroxetine, sertraline, venlafaxine and especially their
combination with mirtazapine. To explain the reasons behind
these findings is difficult. However, when considering other
data generated in the present study showing the relatively
high incidence of menstrual disturbances (9%13%) with
use of mirtazapine, duloxetine and milnacipran, we think that
both serotonergic and noradrenergic potency of antidepres-
sants may be related to frequency of menstruation disorders.
Risk factors for antidepressant-induced menstruation
disorders are unknown. According to the results of the
present study, it was unrelated to sociodemographic
characteristics. Nevertheless, the first 3 months following
antidepressant administration seem to be the high-risk period
for menstruation disorders.
 F. Uguz et al. / General Hospital Psychiatry 34 (2012) 529533
The main limitations restricting the interpretation of
results of this study are as follows: (a) The sample may not
be representative of all women taking antidepressant drugs.
(b) Although the existence of a control group strengthens the
study; its cross-sectional design is a limitation. (c) Other
possible risk factors (e.g., current psychiatric diagnoses,
history of menstruation disorders) except sociodemographic
features were not explored in this study because we primarily
aimed to understand the frequency of menstruation disorders
associated with antidepressant drug usage. (d) It appears to
be difficult to accept of the relationship between the
combination of SSRIs and venlafaxine with mirtazapine
and menstruation disorders because the sample size
including these combinations is very low. (e) This study
does not include an evaluation about what kind of menstrual
irregularity is linked to specific antidepressant.
In conclusion, despite some limitations, the results of the
current study suggest that menstruation disorders are frequently
experienced by women as side effects of antidepressant agents,
especially combinations of SSRIs and venlafaxine with
mirtazapine. Clinicians should carefully interrogate and inform
women about menstruation-related side effects when prescrib-
ing these antidepressants. Furthermore, our results should be
replicated by prospective controlled studies. Further studies
also should examine risk factors for these side effects beyond
sociodemographic features, possible biological mechanisms of
antidepressant-induced menstruation disorders and longitudinal
observation of women who developed menstruation disorder
due to antidepressants.
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