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July2005 Vol.42 Issue:      2 Table of Contents
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Ovulatory Dysfunction in Epileptic Women: A Reciprocal Interaction

Gharib Fawi1, M. A. Abd El lah2, A.S. Ait Allah2, A. A. Elsayed3, H. T. Salem4
Departments of Neurology1, Obstetric & Gynecology2, Clinical Pathology3, South Valley University,Obstetric & Gynecology, Assiut University4

ABSTRACT

Objective: To determine the effect of epilepsy on ovulatory function on one hand and the effect of ovulation induction therapy on epilepsy on the other hand. Patients and Methods: Ovulation was assessed over three consecutive menstrual cycles by ovulatory score based on Transvaginal sonography (TVS) and mid-luteal progesterone in day 22, in three groups of patients. Group I (22) patients with temporal lobe epilepsy (TLE), Group II (11) patients with primary generalized epilepsy (PGE), and Group III (26) healthy women. The effect of age, seizure-frequency, degree of depression and anti-epileptic drugs on the incidence of ovulation was evaluated. Also, seizure exacerbation in each phase of the menstrual cycle was assessed. The effect of clomiphene therapy in those with TLE and anovulation was evaluated. Results: Anovulation was more frequent in group I (36.4%) than in group II (0%) and group III (7.7%). Patient age, seizure-frequency and degree of depression did not affect ovulatory function. Polytherapy with anti-epileptic drugs for temporal lobe epilepsy tends to cause anovulatory cycles more than monotherapy, but by non-significant values. Conclusions: Temporal lobe epilepsy appears to be more frequently affected by anovulation. Although anti-epileptic drug polytherapy may increase the likelihood of anovulation, temporal lobe dysfunction appears to be the responsible cause. Those candidates get benefit from added hormonal therapy regarding either reorproductive dysfunction or their epilepsy.

(Egypt J. Neurol. Psychiat. Neurosurg., 2005, 42(2): 323-331).

 




INTRODUCTION

 

Epileptic women are said to show abnormal reproductive function1. They experienced reduced fertility2, decreased sexual desire3, and lowered sexual responsiveness4. Also, menstrual disorders are more common in those patients5. Infertility is more common in epileptic women; which might be attributed to higher incidence of polycystic ovarian disease, oligomenorrhea, or even amenorrhea6,7.

Chronic anovulation may be a cause of infertility in epileptic women8. Temporal lobe epilepsy (TLE); with limbic dysfunction; might alter the release of hypothalamic trophic hormones more than primary generalized epilepsy (PGE), with consequent affection of the pituitary gonadotropins causing anovulation9,10,11.

Temporal lobe partial epilepsy also may promote the development of PCOS and hypothalamic-hypogonadism, two conditions associated with inadequate luteal phase syndrome which further facilitate seizures9.

Epileptic patients are more commonly suffering from clinical depression12. Those with onset of epilepsy at a young age may experience retarded social development and low self-esteem. In general, the stress experienced by patients who must cope daily with a seizure disorder may be associated with a higher incidence of clinical depression. All these psychological variables may contribute to reproductive dysfunction in patients with TLE13.

Anti-epileptic drugs (AEDs), also might cause anovulation by change of the sex steroid hormones metabolism through direct or indirect hypothalamic-hypophysial gonadal axis disruption, direct cortical depressant effect and/or through inducing the hepatic microsomal system with consequent increase metabolism of the sex steroid hormones and increase the synthesis of the sex hormone binding globulins6,14,15.

There are wide spectrums of diagnostic aids that may point to the possibility of ovulation, but many of them are just presumptive16. Transvaginal sonography (TVS) is a well-established method for evaluation and management of infertility17. It has become the method of choice for non-invasive monitoring of follicular development18,19, with increased compliance20. If used in association with mid-luteal plasma progesterone, diagnosis of ovulation is most probable16.

Seizure exacerbation in relation to the phase of the menstrual cycle is described and is termed catamenial epilepsy21. Those with partial epilepsy who showed anovulatory cycles are mentioned to experience exacerbation during the luteal phase of the cycle22. Those patients may get benefit from hormonal therapy to stimulate gonadotropin secretion, ovulation, and fertility, with a secondary anticonvulsant effect23.

In the present study we attempted to evaluate the effect of epilepsy on ovulatory function, and explain the possible mechanism for this effect. Also, to evaluate the effect of clomiphene citrate therapy on those epileptic women with anovulatory cycles.

 

PATIENTS AND METHODS

 

            This prospective study was done in Sohag University hospital, during the period from October 1997 to august, 2001. It included 3 groups of infertile women, selected from those attending the infertility and neurology clinics. They were informed of the aim of the study; ethical approval for the study was obtained from the hospital ethics committee, and informed consent was obtained.

Group I (n=22): women with temporal lobe epilepsy (TLE).

Group II (n=11): women with primary generalized epilepsy (PGE).

Group III (n=26): “control group” healthy women.

 

*              Tubal and male factors were excluded as other causes of infertility.

*      History and EEG were used to diagnose patients in both group II and I. Women in group III were with no history of seizures and normal EEG and not receiving any medications.

*      Significant medical, or other neurological diseases, history of contraceptives, hormonal therapy and gynecologic surgery were excluded.

 

Regularity of menstrual cycling was observed for three consecutive menstrual cycles during which ovulatory function was assessed in the 3 groups. Epileptic patients were also given a seizure calendar to record fits. To determine the exact time occurrence of seizures in relation to the menstrual cycle; the cycle was divided into 4 phases as following “ using the onset of the period as day 0”:

-               Menstrual phase: -3 to +3

-               Follicular phase: +4 to + 9

-               Ovulation phase: +10 to + 16

-       Luteal phase: + 17 to  -4 “4 days before the next period”.

 

The number of seizures in each phase was counted. The average daily number of seizures for each phase was compared to that for the rest of the cycle. Seizure exacerbation at a certain phase was defined as daily seizure frequency of 2 times or more as that of the remainder of the same cycle.

The degree of depression in the 3 groups was determined by the Beck Depression Inventory (BDI)24.

All women underwent T.V.S. on days 10, 12, 14 and 22 of each menstrual cycle; using an Acuson XP/4 vaginal probe with a 5.0 MHz (Acuson corp. comp. USA). It was done in the lithotomy position with an empty bladder by the same gynecologist. Both ovaries were thoroughly examined for folliculometry.

In the clinical pathology department, venous blood samples were collected on day 22 of each menstrual cycle, after 10 minutes of semi-recumbent resting with measurement of blood pressure. This was done between 07.00 and 09.00 a.m. after an overnight (> 12 hours) fasting. All samples were centrifuged to separate sera, which were analyzed within 48 hours for determination of serum progesterone levels by means of commercially available Chemoleuminescence (Immulite DPC, USA).25 The laboratory was blinded to the origin (patient group) of the samples. A progesterone level > 3ng/ml was considered the strongest evidence for ovulation26.

            A score was used for each cycle “depending on TVS and mid-luteal progesterone” to provide an overall reflection of ovulatory function in each woman to accommodate missing data due noncompliance and minimize the chance of type I error occurrence. Total scores ranged from 0 to 4 as following:

0 = anovulatory cycle: mid-luteal progesterone < 3 ng/ml

1 = probable anovulatory cycle: TVS signs of anovulation, but no confirming mid- luteal progesterone.

2 = neutral score: no TVS data or confirming mid-luteal progesterone.

3 = probable ovulatory cycle: TVS signs of ovulation, but no confirming mid-luteal progesterone.

4 = ovulatory cycle: mid-luteal progesterone > 3 ng/ml

 

Women with TLE who were proved to be with anovulatory cycles were given clomiphene citrate in a dose of 50mg/day, on days 5-9 of the following 3 cycles. Reevaluation of regularity of menstrual cycling, ovulatory scores, seizure-frequency, and seizure exacerbation was done.

Data obtained were analyzed by IBM computer using statistical program "Excel version 5" to obtain the mean (x) and standard deviation (SD). Then student t-test to compare two independent means and the "t" distribution probability table were used to get the "p" value. (p>0.05 = not significant, p<0.05 = significant and p< 0.001 = highly significant).

 

RESULTS

 

Clinical criteria of women in the 3 groups are shown in table (1). Irregular menstrual cycles were present in 7/22 (31.8%) cases with TLE, compared with 2/26 (7.7%) healthy women while all cases with PGE experienced regular cycles. Also, patients with TLE were significantly more obese than those with PGE (27.5±1.1 vs. 23.2±0.9 kg/m2, p<0.001) and control group (27.5±1.1 vs. 22.9±0.8 kg/m2, p<0.001)

Compliance of women and missed data in the 3 groups are shown in table (2). Ovulatory function in the 3 groups is shown in table (3). Anovulatory cycle occurred in 8/22 (36.4%) patients with TLE (9/56 cycles), with their mean age was 32.8 ±3.2 years compared to 33.9±2.1 years for those who were all ovulatory, with no significant difference. The control group showed anovulatory cycle in 2/26(7.7%) patients (2/75 cycles) with their mean age was 24.5±1 years compared to 28.1±1.3 years for those who were all ovulatory. Patients with PGE were all ovulatory. Collectively, patients with TLE showed significantly greater number of anovulatory cycles with lower ovulatory scores than those with PGE (3±0.2 vs. 3.8±0.2, p<0.001) and control group (3±0.2 vs. 3.8±0.1, p< 0.001).

Seizure-free patients during the study were 4/22 (18.2%) patients with TLE compared with 6/11(54.5%) patients with PGE. However, there was no significant difference between seizure-free patients and those who suffered from seizures during the period of the study as regards the mean ovulatory scores.

Seizure frequency in either group of patients did not affect ovulatory function. Patients with TLE showed seizure frequency/cycle less than those with PGE (9.7±1.1 vs. 44.3±3.3) despite that they showed more frequent anovulation. Ovulatory function between different patients with TLE was not correlated with seizure frequency. Also, Spearman rank analysis of month-to-month seizure pattern of each patient with TLE showed that there was no correlation in each cycle.

There was no significant difference between both types of epilepsy as regards the degree of depression, despite that both showed significantly higher BDI scores (10.2 ±2.1 for group I and 11.3±3.4 for group II) than the control group  (2.2±0.5, p<0.001 for both). There was no association between BDI score and seizure frequency. Even epileptic patients who were seizure-free showed significantly higher BDI scores than the control group (p<0.05). Also, patients with anovulatory cycles showed comparable BDI scores to those with exclusively ovulatory cycles.

Patients who received AED polytherapy showed a slightly lower; but statistically insignificant ovulatory scores (2.9±0.3 for group I and 3.3±0.6 for group II) than those who received monotherapy (3.1±0.2 for group I and 3.9±0.1 for group II) (Table 4).

Seizure frequency/ each phase of the menstrual cycle is shown in table (5). Patients with TLE and ovulatory cycles showed seizure exacerbation in the menstrual phase (4.6±1.1) and ovulation phase (3.9±0.8) while those with anovulatory cycles experienced seizure exacerbation in the luteal phase (6.5±1.2).

Clomiphene therapy of patients with TLE who showed anovulation resulted in regulation of their cycles with ovulation in 7/8 (87.5%) of them. Also reduction of their seizures frequency/cycle (9.8±1.2 vs. 1.5±0.5, p<0.001) with change of their seizure exacerbation to be in the menstrual and ovulatory phases instead of the luteal phase (Table 6).


 

Table 1. Clinical criteria of women in the 3 groups.

     

 

Group I (n=22)

Group II (n=11)

Group III (n=26)

Age (Ys.)

33.3±1.6

24.5±2.3

27.3±1.1

Parity

nulligravida

nulligravida

nulligravida

Regularity of menstrual cycling: -regular

                                                    -irregular

15(68.2%)

7(31.8%)

11(100%)

0(0%)

24(92.3%)

2(7.7%)

Weight(kg)

Height(m)

Body mass index (kg/m2)

75±3.3

1.65±0.4

27.5±1.1*

63.9±2.1

1.66±0.2 23.2±0.9**

64±2.2

1.67±0.3

22.9±0.8**

 

* p< 0.001 for the other 2 groups                                               ** NS.

 

Table 2. Compliance of women and missed data in the 3 groups.

 

 

Group I (n=22)

Group II (n=11)

Group III (n=26)

Recorded cycles:-3 cycles[no(%)]

-2 cycles[no(%)]

-1 cycle  [no(%)]

-total

14/22(63.6%)

6/22(27.3%)

2/22(9.1%)

56

10/11(90.9%)

1/11(9.1%)

0/11(0%)

32

24/26(92.4%)

1/26(3.8%)

1/26(3.8%)

75

T.V.S. :-3 cycles[no(%)]

-2 cycles [no(%)]

21/22(95.5%)

1/22(4.5%)

11/11(100%)

0/11(0%)

26/26(100%)

0/26(0%)

Progesterone assay:-3 cycles[no(%)]

-2 cycles[no(%)]

-1 cycle  [no(%)]

-0 cycle  [no(%)]

7/22(31.8%)

8/22(36.4%)

6/22(27.3%)

1/22(4.5%)

8/11(72.7%)

0/11(0%)

2/11(18.2%)

1/11(9.1)

15/26(57.7%)

9/26(34.6%)

2/26(7.7%)

0/26(0%)

Table 3. The ovulatory function in the 3 groups.

 

Group III

(No = 26)

Group II

(No =11)

Group I

(No =22)

 

Ovulating

Non ovulating

All were ovulating

Ovulating

Non ovulating

24 (92.3%)

2 (7.7%)

14 (63.6%)

8 (36. 4%)

Number (%) of case

 

2/75

 

9/56

Number of cycles

28.1±1.3

24.5 ±1

33.9±2.1

32.8±3.2

Mean of age (years)

 

 

Table 4. Effect of AEDs on the mean ovulatory scores in the 3 groups.

 

Group I (n=22)

Group II (n=11)

Group III (n=26)

3±0.2*

3.8±02

3.8±01

Monotherapy

(n=9)

Polytherapy

(n=13)

Monotherapy

(n=8)

Polytherapy

(n=3)

3.1±0.2**

2.9±0.3**

3.9±0.1

3.3±0.6

* p<0.001for the other 2 groups.                              ** NS                               NS

 

 

Table 5. Seizures frequency/each phase of the menstrual cycles (mean ± SD).

 

 

       Group I (n=22)

Group II (n=11)

Type of the cycle

Ovulating

Non ovulating

Ovulating

Number of patients

14/22

8/22

11/11

Number of cycles

47/56

9/56

32/32

-Menstrual phase

-Follicular phase

-Ovulatory phase

-Luteal phase

4.6±1.1

1.1±0.6

3.9±0.8

0

1.4±0.6

0

1.9±0.7

6.5±1.2

13.3±1.8

9.1±1.3

12.2±1.6

9.8±1.4

Total

9.7±1.1

44.3±3.3

 

 

Table 6. Effects of clomiphene therapy on women with TLE and anovulation .

 

 

Before therapy

After therapy

Regularity of menstrual cycling

irregular

regular

Ovulation

0/8(0%)

7/8(87.5%)

Seizures frequency: - Total/cycle
                                   - Menstrual phase

                                   - Follicular phase

                                   - Ovulatory phase

                                   - Luteal phase

9.8±1.2

1.4±0.6

0

1.9±0.7

6.5±1.2

1.4±0.1

0.77±0.4

0

0.66±0.5

0

 

 


DISCUSSION

 

Epileptic women appear to suffer from lowered fertility rates which was attributed to chronic anovulation. To evaluate this problem, patients’ recruitment and compliance represented a point of difficulty that tried to be solved by the use of different ovulatory scores. In this study, a score for each cycle; included TVS and mid-luteal progesterone; was used. Cummings et al.13, used; in stead of TVS; a chart to determine the basal body temperature in their study. However, it was a relatively subjective method that required women literacy, which was deficient in some of the recruited women.

In the present study, chronic anovulation was significantly higher in patients with TLE than in those with PGE (p<0.001) and control group (p<0.001). This suggests that chronic anovulation in those with TLE might be caused by limbic dysfunction, namely the amygdala27. This may disrupt the normal modulation of lutinizing hormone releasing hormone (LHRH) pulse generator28. Consequently, LH pulse secretion is altered resulting in abnormal ovulation29. Similar data were mentioned by Cummings et al.13.

The claimed other potential mechanisms for anovulation in patients with TLE as age, and relative seizure frequency did not appear to be related to the problem either in this study or in that of Cummings et al.13.

Despite that epileptic patients showed significantly higher BDI scores than the control group  (p< 0.001 for both groups), this did not contribute significantly to the ovulatory dysfunction in women with TLE. This was in agreement with data mentioned by Cummings et al.13, but contrary to what was suggested by Robertson30, Domar et al.8, and Indaco et al.12. This variation in the results seems to be due to variation in the onset of diagnosis and consequently receiving the AEDs.

The total or individual effect of AEDs on ovulation was not established in this study, despite that the frequency of anovulatory cycles increased with polytherapy more commonly in patients with TLE. This was not in agreement with the data mentioned by Cramer et al.6, Ramsay et al.14, and Wallace et al.31, but confirmed the results reported by Cummings et al.13. However, AEDs could not be the main mechanism responsible for anovulation, because patients with PGE on AEDs showed normal ovulatory function. Also, AEDs used for the treatment of both groups were qualitatively different; as patients with TLE received carbamazepine mainly, while those with PGE treated by valproate. However, both of them were proved to have effect on reproductive hormones32,33.

In a women with anovulatory cycles, estrogen levels rise at the end of the follicular phase and stay elevated throughout the luteal phase untill premenstrually, as in normally menstruating women; but there is little or no progesteron secretion. Thus, there is estrogen progesteron imbalance with relative excess of estrogen (or difficiency of progesteron) throughout the whole second (luteal) half of menstrual cycle, with associated seizure exacerbation.21              

Catamenial seizure exacerbation; with its 3 known patterns21; occurred in this study. Previous studies reported that catamenial epilepsy could be shown in about 1/3 of women with intractable epilepsy21,22. It was explained by the observation that estrogens facilitate seizures34,35 whereas progesterone protects against them36,37. This fact was considered as a rationale for the use of ovulation inducing drugs in epileptic patients with chronic anovulation to stimulate gonadotropin secretion, ovulation, and fertility, with a secondary anticonvulsant effect23.

Clomiphene citrate is an estrogen analogue, in its clinical use it acts primarily as an antiestrogen at the hypothalamic and pituitary level to stimulate gonadotropin secretion, ovulation and fertility. Remarkable reduction in seizure frequency has been reported in epileptic men and women with normalization of the menstrual cycle and of luteal progesteron secretion in those women23.

Our results confirmed these data by the use of clomiphene therapy in patients with TLE who showed anovulation. Regulation of their cycles and ovulation was obtained in 87.5% of them. Also, their seizures became significantly less frequent (p<0.001) with their exacerbation changed to be in the menstrual and ovulatory phases instead of the luteal phase.

 

Conclusions

Epileptic women with TLE are more prone to suffer from irregular menstruation, anovulatory cycles, lower ovulatory scores and chronic anovulation with consequent lowered fertility rate.

Polytherapy with AEDs may increase the likelihood anovulation where it was associated with slightly lower ovulatory score.

Individual effects of AEDs, EEG changes, seizure frequency and age of onset of epilepsy were with no definite significant reciprocal effects.

Patients with TLE and ovulatory cycles showed seizure exacerbation in the menstrual and ovulation phases respectively while those with anovulatory cycles experienced seizure exacerbation in the luteal phase.

Patients with TLE are associated with chronic anovulation and seizure exacerbation mainly during the luteal phase. Those patients appear to get benefit from hormonal therapy, which directed to stimulate gonadotropins secretion leading to ovulation and fertility with a secondary anticonvulsant effects.

 

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 الملخص العربي

 

اضطراب التبويض في مريضات الصرع : تفاعل متبادل

 

تعتبر الوظيفة الإنجابية من الأشياء التى يصيبها الاضطراب في السيدات اللائى يعانين من الصرع ويتضح ذلك في صورة اختزال  في معدل الخصوبة مع اضطرابات في الطمث الشهري وقد يكون ذلك مصحوبا بانخفاض في الغلمة ،  وقد ثبت أن مرض الصرع لدى السيدات يصاحبه  بعض الظواهر مثل  الزيادة في معدلات الإصابة بتكيس المبيضين وتباعد الطمث وربما الانقطاع الثانوي للطمث.

وقد يمثل  اضطراب التبويض في مريضات الصرع السبب المباشر للعقم في هؤلاء السيدات، وربما كانت هناك أسباب عديدة للانقطاع المزمن للتبويض فيهن مثل الاكتئاب واستخدام الأدوية المضادة للصرع وما قد يكون لها من تأثيرات مباشرة أو غير مباشرة على الوظائف الإنجابية، وربما يكون لاضطراب اللحاء اللمباوى دور في ذلك، وعليه فانه يفترض أن اضطراب التبويض ربما يكون أكثر حدوثا في السيدات اللائى يعانين من صرع الفص الصدغي عن أولئك اللائى يعانين من الصرع العام غير مفسر الأسباب. وقد لوحظ أنه في بعض حالات الصرع يتركز حدوث النوبات في وقت معين من الدورة الشهرية وقد سميت هذه الظاهرة بالصرع المرتبط بالطمث (الكتامينى)، وقد ذكرت دراسات سابقة أن مثل هذه الحالات ربما استفادت من العلاج الهرمونى.

وتهدف هذه الدراسة إلى تقييم مدى تأثير مرض الصرع على معدل التبويض ومحاولة إيجاد تفسير لهذا التأثير ،كما تهدف إلى دراسة مدى ارتباط النوبات الصرعية بالأطوار المختلفة للدورة الشهرية، ومدى تأثير العلاج بعقار التاموكسيفن على السيدات اللائى يعانين من اضطراب التبويض مع الصرع.      

شملت هذه الدراسة ثلاث مجموعات من السيدات في عمر الخصوبة:

المجموعة الأولى:- شملت 22سيدة من السيدات المصابات بصرع الفص الصدغي.

المجموعة الثانية:- شملت 11سيدة  من السيدات المصابات بالصرع العام غير مفسر الأسباب.

المجموعة الثالثة:- شملت 26سيدة  من السيدات الصحيحات (كمجموعة ضابطة).

وقد تم قياس التبويض في هؤلاء السيدات باستخدام الفحص بالموجات الفوق صوتية عن طريق المهبل بالإضافة إلى مستوى هرمون البروجيستيرون بالدم في اليوم 22 من الدورة الشهرية.

وقد أثبتت الدراسة الحالية أن معدل عدم حدوث التبويض كان أعلى في السيدات اللائى عانين من صرع الفص الصدغي (3±0.2) عن أولئك اللائى عانين من الصرع العام غير مفسر الأسباب (3.8±0.2) والسيدات الصحيحات في المجموعة الضابطة (3.8±0.1)، ولم يكن هناك تأثير لعمر السيدات أو معدل تكرار النوبات الصرعية أو نسبة الإصابة بالاكتئاب فيهن  على معدل انتظام التبويض، بينما كان استخدام خليط من الأدوية المضادة للنوبات الصرعية لعلاج هذه الحالات مصحوبا بميل إلى ارتفاع نسبة عدم حدوث تبويض بالرغم من أن هذا الأثر لم يصل لمستوى  يمثل دلالة إحصائية واضحة. كما ثبت من هذه الدراسة أنه في حالات صرع الفص الصدغي كان هناك ارتباط بين النوبات الصرعية و الأطوار المختلفة للدورة الشهرية حيث أنه في السيدات اللائى عانين من عدم التبويض تركزت النوبات في الطور المحكوم بالجسم الأصفر (النصف الثاني من الدورة)، كما أن العلاج بعقار التاموكسيفن في هؤلاء السيدات أدى إلى انتظام الدورة الشهرية، وحدوث تبويض في 87,5% منهن، بالإضافة إلى انخفاض بين في معدل حدوث النوبات الصرعية مع تغير واضح في أطوار حدوثها لتتركز في طور الطمث  وطور التبويض.

ونخلص من هذا إلى أنه فىحالات صرع الفص الصدغي هناك ارتباط بين توزيع النوبات الصرعية والأطوار المختلفة للدورة الشهرية، كما أن هناك ارتفاع في معدل عدم حدوث التبويض ربما يعزى بالأساس إلى اضطراب اللحاء اللمباوى بالرغم من أن استخدام خليط من الأدوية المضادة للنوبات الصرعية قد يكون له دور، كما يبدو أن العلاج بعقار التاموكسيفن في هؤلاء السيدات يحمل تأثيرات واضحة على معدل حدوث وتوزيع هذه النوبات مما يوحي بأن العلاقة بين اضطراب الوظيفة الإنجابية والصرع هي عبارة عن تفاعل متبادل.



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