CONTRACEPTION

Effects of female sex hormones on caffeine-induced epileptiform activityin rats

BUNYAMIN BOREKCI1, METIN INGEC1, MEHMET YILMAZ2, OSMAN KUKULA3,

MEHMET KARACA4, AHMET HACIMUFTUOGLU5, ZEKAI HALICI5, &

HALIS SULEYMAN5

1Faculty of Medicine, Department of Obstetrics and Gynecology, Ataturk University, Erzurum, Turkey, 2Ministry of Health,

Nenehatun Obstetrics and Gynecology Hospital, Erzurum, Turkey, 3Samsun Mehmet Aydin Hospital, Pharmacology,

Samsun, Turkey, 4Faculty of Medicine, Department of Obstetrics and Gynecology, Kafkas University, Kars, Turkey, and5Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey

(Received 30 July 2009; accepted 2 November 2009)

AbstractResearch on female sex hormones has demonstrated that estrogen aggravates epileptogenesis. Theoretically, this means thatthe frequency of epileptic attacks should be decreased in epileptic women during menopause. However, although epilepsyattacks are reported to decrease in some women during menopause, they may not change in others. Increases in attackfrequency have even been reported during menopause in some epileptic women. This study has investigated the effects ofestrogen, progesterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) on caffeine-induced epileptiformactivity in rats. Estrogen was found to increase epileptiform activity in a dose-dependent manner via its own receptors. Incontrast, progesterone had no effect on epileptiform activity. FSH and LH suppressed epileptiform activity at low doses;however, at high doses they enhanced it. In conclusion, we suggest that the occurrence or aggravation of epilepsy, despiteestrogen deficiency in the menopausal or post-menopausal period, is related to excessive accumulation of FSH and LH.

Keywords: Estrogen, progesterone, FSH, LH, caffeine, epilepsy

Introduction

Epilepsy is a reaction of the brain that has a focal or

generalised characteristic. Several factors (inflamma-

tion, trauma, increased glutamatergic activity, in-

creased levels of cortisol, etc.) are known to have roles

in its pathogenesis [1–3]. Although the overall

prevalence of epilepsy is similar in both men and

women [4], some additional factors such as preg-

nancy, menopause, hormone replacement therapy

and oral contraceptive usage may affect the epilepsy

process in females [5]. Studies on female sex

hormones have demonstrated that estrogen is an

epileptogenic factor [4]. This finding may suggest, at

least theoretically, that the frequency of attacks should

be decreased in epileptic women during menopause.

However, although epilepsy attacks are reported to

decrease in some women with the onset of meno-

pause, in other women there is no change. An

increased attack frequency in menopausal women

has even been reported [6–10]. Some of these studies

also reported the occurrence of epilepsy after meno-

pause in women with no previous epileptic anamnesis

[9].

Joels [11] demonstrated anti-convulsant effects of

progesterone in both acute and chronic epilepsy

models. This finding has also been supported by

other studies that showed progesterone to have anti-

convulsive properties [12]. Progesterone apparently

causes its anti-convulsant outcomes via its own

receptors, as the effects of progesterone were shown

to disappear in rats given RU-486 [13]. However,

some research has demonstrated that progesterone

increases epileptic attack frequency in epileptic

women [14]. In another study, the combined admin-

istration of estrogen and progesterone or administra-

tion of progesterone alone decreased the frequency of

epileptic seizures, while administration of estrogen

Correspondence: Halis Suleyman, Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum 25240, Turkey. Tel: þ90-442-231-65-58.

Fax: þ90-442-236-09-62. E-mail: halis.suleyman@gmail.com

Gynecological Endocrinology, May 2010; 26(5): 366–371

ISSN 0951-3590 print/ISSN 1473-0766 online ª 2010 Informa UK Ltd.

DOI: 10.3109/09513590903511513

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alone had no anti-epileptic effects [15]. Studies

demonstrating that estrogen prevents status epilepti-

cus-induced hippocampal injury have also been

published [16–18].

These data are not adequate for allowing decisions

to be made regarding which female sex hormones are

pro-epileptic and which are anti-epileptic. Untreated

women with epilepsy, in whom both an abnormal

luteinizing hormone (LH) pulsatility pattern and a

significant rise of gonadotropin secretion during

increase of subclinical paroxysmal activity have been

reported [19]. However, literature search did not

provide conclusive evidence regarding anti-epileptic

effects of other female hormones, such as LH and

follicle stimulating hormone (FSH). The aim of this

study was therefore to investigate the effects of

estrogen, progesterone, LH and FSH on caffeine-

induced epileptiform activity in rats.

Material and methods

Animals

A total of 210 female Albino Wistar rats weighing

210–215 g were obtained from the Ataturk Univer-

sity Medicinal and Experimental Application and

Research Centre for use in this study. The animals

were divided into treatment groups prior to initiation

of the experimental procedures. The animals were

housed and fed under standard conditions in a

laboratory at a temperature of 228C. Animal experi-

ments were performed in accordance with the

national guidelines for the use and care of laboratory

animals and were approved by the local animal care

committee of Ataturk University.

Chemicals

Estrogen from Novo-Nordisk (Turkey), progester-

one from Deva (Turkey), LH and FSH from Serono

(Switzerland), tamoxifen from Astra-Zeneca (Tur-

key) and caffeine were purchased from Sigma-

Germany.

Caffeine-induced epileptiform activity in intact and

ovariectomised rats

In this part of the study, 300 mg/kg of caffeine was

injected intraperitoneally (i.p.) into intact and

ovariectomised rats (the ovaries had been removed

7 days before by the method of Kelly and Robert

[20]). After injection, the animals were immediately

placed into a glass box, and observation was started.

The time (latent period) was assessed by chron-

ometer from caffeine injection until tonic-clonic

convulsions started. Anti-convulsant (anti-epilepti-

form) activity was evaluated by comparing the results

of the intact rats and the ovariectomised rats [21].

Effects of estrogen and progesterone on caffeine-induced

epileptiform activity in ovariectomised rats

In this experiment, groups of six ovariectomised rat

groups received estrogen (1, 2 or 5 mg/kg doses) or

progesterone (1, 2 or 5 mg/kg doses) by oral gavage.

The ovariectomised control group received the same

volume of distilled water as a vehicle. One hour after

drug administration, a 300 mg/kg dose of caffeine

was administered to all rats in all groups via i.p.

injection. The effects of these drugs on epileptiform

activity were then determined as described earlier.

Effects of FSH and LH on caffeine-induced epileptiform

activity in intact rats

In this series of experiments, FSH (25, 50, 100 or

200 U/kg doses) or LH (10, 20 or 40 U/kg doses)

were administered to intact rat groups via i.p.

injection. The control group received the same

volume of distilled water as vehicle by i.p. injection.

One hour after drug administration, a 300 mg/kg

dose of caffeine was administered i.p. to all rats in all

groups. The effects of these drugs on epileptiform

activity were determined as described earlier.

Effects of estrogen on caffeine-induced epileptiform activity

in ovariectomised rats treated with tamoxifen

In this experiment, rat groups received a 10 mg/kg

dose of tamoxifen by oral gavage 1 h prior to oral

estrogen administration at 1, 2 or 5 mg/kg doses.

The control group received the same volume of

distilled water as vehicle by i.p. injection. One hour

after estrogen administration, a 300 mg/kg dose of

caffeine was administered i.p. to all rats in all groups.

The effects of estrogen on epileptiform activity were

determined as described earlier.

Effects of estrogen, progesterone, FSH and LH on blood

noradrenaline, adrenaline and corticosterone levels in

intact rats

To evaluate effects of female sex hormones on

catecholamine levels, estrogen (1, 2 or 5 mg/kg),

progesterone (1, 2 or 5 mg/kg), FSH (25, 50, 100 or

200 U/kg) and LH (10, 20 or 40 U/kg) were adminis-

tered to rat groups as described earlier. One hour after

administration of the drugs, blood samples were

collected from all rats and transferred to a biochemistry

laboratory for determination of noradrenaline, adrena-

line and corticosterone levels. Results were evaluated

by comparison to those of a healthy control group.

Measurement of adrenaline and noradrenaline levels in rats

Blood samples were collected from the hearts of rats

into 2-ml EDTA vacuum tubes for determination of

Sex hormones and epilepsy 367

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adrenaline and noradrenaline levels. Within 15 min

of venesection, the EDTA samples for adrenaline,

noradrenaline and dopamine measurements were

placed on ice and centrifuged at 3500g for 5 min.

After centrifugation, the plasma adrenaline and

noradrenaline concentrations were measured by

isocratic high-performance liquid chromatography

(HPLC) (model Hewlett Packard Agilent 1100)

(flow rate 1 ml/min, injection volume: 40 ml, analy-

tical run time: 20 min) using an electrochemical

detector. We used a reagent kit for HPLC analysis of

catecholamines in the plasma serum (Chromsystems,

Munich, Germany).

Measurement of blood corticosterone levels

Blood samples were collected from the hearts into 2-

ml EDTA vacuum tubes to determine the corticos-

terone levels. Samples were centrifuged at 3500g for

10 min. The samples for the measurement were

frozen and kept at –808C until analysis. The plasma

was separated and extracted with 5 ml of ethyl

acetate (betamethasone as the internal standard),

and then the extract was washed with sodium

hydroxide (0.1 M) and water. After evaporation of

the ethyl acetate, the residue was dissolved in mobile

phase (acetonitrile-water-acetic acid-TEA,

22:78:0.1:0.03, v/v). Plasma corticosterone was

separated and measured by isocratic HPLC (model

Hewlett Packard Agilent 1100 system with a UV

detector set at 254 nm) (flow rate: 1 ml/min, injec-

tion volume: 150 ml). The corticosterone in the

samples was quantified by comparison with a pure

corticosterone standard (Sigma, St. Louis, MO)

dissolved in ethyl acetate [22].

Statistical analyses

Data were subjected to one-way ANOVA using SPSS

13.0 software. Differences among groups were

attained using LSD option, and significance was

declared at p5 0.05.

Results

Severity of caffeine-induced epileptiform activity in female

intact and ovariectomised rats

Epileptiform activity (tonic-clonic convulsions) was

seen within 2.6 min (latent period) following caffeine

injection into intact rats. Epileptiform activity

occurred approximately 4.8 min after caffeine injec-

tion in ovariectomised rats (Figure 1).

Estrogen and progesterone test in ovariectomised rats

The latent period of epileptiform activity in control

rats was determined as 4.1 min. The latent periods

were 3.3, 2.9 and 1.9 min in rats receiving estrogen

at 1, 2 and 5 mg/kg doses, respectively. Latent

periods were 3.9, 4.3 and 4.2 min in rats receiving

progesterone at 1, 2 and 5 mg/kg doses, respectively

(Table I).

FSH and LH test in intact rats

As seen in Table II, the latent period was determined

as 4.2, 3.3, 3.0 and 1.5 min in rat groups receiving

25, 50, 100 and 200 mg/kg doses of FSH, respec-

tively. In rats receiving 10, 20 and 40 U/kg LH, the

latent periods were determined as 4.3, 3.8 and

2.0 min, respectively. In the rat group that received

caffeine only, the latent period was 3.2 min.

Estrogen test in ovariectomised rats treated with

tamoxifen

The mean of the latent periods was 9.2 min in the rat

group receiving tamoxifen only. In the rats that were

post-treated with estrogen at 1, 2 and 5 mg/kg doses

after tamoxifen application, the latent periods were

6.7, 5.1 and 4.4 min, respectively. In the control

group that received caffeine alone, the latent period

was 3.6 min (Table III).

Effects of estrogen, progesterone, FSH and LH on blood

noradrenaline, adrenaline and corticosterone levels in

intact rats

As seen in Table IV, there were no significant

changes in the blood adrenaline, noradrenaline and

corticostreone levels of the rats receiving estrogen,

progesterone, FSH or LH at any of the doses tested.

Discussion

Scientific research performed to date has not yet

conclusively demonstrated whether female sex hor-

mones are pro-epileptic or anti-epileptic. The data

Figure 1. Comparison of caffeine-induced epileptiform activity in

intact and ovariectomised rats. *Significant at p50.01 when

compared to intact group.

368 B. Borekci et al.

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from the literature on this topic are inconsistent

[6–10]. In this study, we investigated the effects of

different doses of estrogen, progesterone, FSH and

LH on caffeine-induced epileptiform activity in rats.

We first compared the severity of caffeine-induced

epileptiform activity between intact and ovariecto-

mised rats. Ovariectomy resulted in removal of

estrogen and progesterone from the body, as these

Table I. Effects of estrogen and progesterone on caffeine-induced epileptiform activity in ovariectomised rats.

Drugs

Dose

(mg/kg)

Number of

animals

Latent

period (min) p

Pro-epileptiform

activity versus

control (%)

Antiepileptiform

activity versus

control (%)

Estrogen 1 6 3.3+ 0.44 0.74 19.5 –

Estrogen 2 6 2.9+ 0.43 0.003 29.3 –

Estrogen 5 6 1.88+ 0.52 0.0001 53.7 –

Progesterone 1 6 3.86+ 0.66 0.16 4.9 –

Progesterone 2 6 4.3+ 0.55 0.33 – 4.7

Progesterone 5 6 4.2+ 0.53 0.45 2.1 –

Caffeine (Control) 300 6 4.1+ 0.30 – – –

Table II. Effects of FSH and LH on caffeine-induced epileptiform activity in intact rats.

Drugs Dose

Number of

animals

Latent

period (min) p

Pro-epileptiform

activity versus

control (%)

Antiepileptiform

activity versus

control (%)

FSH 25 (U/kg) 6 4.2+0.55 0.0001 – 24

FSH 50 (U/kg) 6 3.3+0.49 0.69 3.1 –

FSH 100 (U/kg) 6 3.0+0.59 0.42 6.3 –

FSH 200 (U/kg) 6 1.8+0.21 0.0001 43.8 –

LH 10 (U/kg) 6 4.3+0.50 0.0001 – 25.6

LH 20 (U/kg) 6 3.8+0.36 0.024 – 15.8

LH 40 (U/kg) 6 2.0+0.19 0.0001 37.5 –

Caffeine (Control) 300 (mg/kg) 6 3.2+0.36 – – –

Table III. Effects of estrogen on caffeine-induced epileptiform activity in ovariectomised rats treated with tamoxifen.

Drugs

Dose

(mg/kg)

Number of

animals

Latent

period (min) p

Pro-epileptiform

activity versus

control (%)

Antiepileptiform

activity versus

control (%)

Estrogenþ tamoxifen 1þ 10 6 6.7+ 0.46 0.0001 – 46.3

Estrogenþ tamoxifen 2þ 10 6 5.1+ 0.53 0.0001 – 29.4

Estrogenþ tamoxifen 5þ 10 6 4.4+ 0.3 0.007 – 18.2

Tamoxifen 10 6 9.2+ 0.5 0.0001 – 60.9

Caffeine (Control) 300 6 3.6+ 0.49 – – –

Table IV. Effects of estrogen, progesterone, FSH and LH on blood noradrenaline, adrenaline and corticosterone levels in intact rats.

Drugs Dose N Noradrenalin p Adrenalin p Corticosterone p

Estrogen 1 (mg/kg) 6 2131.1 40.05 2659 40.05 10.6 40.05

Estrogen 2 (mg/kg) 6 2477.7 40.05 2281.2 40.05 9.9 40.05

Estrogen 5 (mg/kg) 6 2392.3 40.05 2370.1 40.05 9.5 40.05

Progesterone 1 (mg/kg) 6 2350.3 40.05 2131.7 40.05 8.8 40.05

Progesterone 2 (mg/kg) 6 1893.5 40.05 2095.2 40.05 10.7 40.05

Progesterone 5 (mg/kg) 6 2418.1 40.05 2152.3 40.05 11.2 40.05

FSH 25 (U/kg) 6 1992.1 40.05 2147.7 40.05 9.3 40.05

FSH 50 (U/kg) 6 2236.1 40.05 2265.1 40.05 8.4 40.05

FSH 100 (U/kg) 6 1801.3 40.05 2195.2 40.05 10.1 40.05

LH 10 (U/kg) 6 2075.6 40.05 2521.2 40.05 10.3 40.05

LH 20 (U/kg) 6 2346.5 40.05 2467.3 40.05 8.1 40.05

LH 40 (U/kg) 6 2096.2 40.05 2352 40.05 9.4 40.05

Intact (control) – 6 2057.6 – 2473.1 9.19

Sex hormones and epilepsy 369

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female sex hormones are synthesised and released

from the ovaries. Epileptiform activity was reduced in

ovariectomised rats compared to intact rats.

As a rule, FSH and LH levels increased in

ovariectomised rats, as a consequence of the decrease

in estrogen and progesterone [23]. The reduction of

the epileptiform activity in ovariectomised rats may

therefore be a result of either an increase in FSH and

LH levels or a decrease in estrogen and progesterone

levels. Therefore, in the second series of our

experiments, the effects of estrogen and progesterone

on epileptiform activity were investigated in ovar-

iectomised rats. Results showed that estrogen

increased severity of the epileptiform activity in a

dose-dependent manner. However, no significant

alteration was observed in epileptiform activity in rats

that received progesterone. Røste et al. [24] have

demonstrated that lamotrigine produced anti-epilep-

tic activity by decreasing estrogen levels and not by

affecting progesterone levels, which is in agreement

with the results reported in this study. We have

shown that none of the doses of progesterone tested

(1, 2 or 5 mg/kg) caused alteration in the severity of

epileptiform activity. Although a low dose of estrogen

(1 mg/kg) shortened the latent period when com-

pared to control group, its pro-epileptic activity was

insignificant. In contrast, higher doses of estrogen

(2 and 5 mg/kg doses) produced significant pro-

epileptic activity. This indicated that epileptiform

activity was reduced in ovariectomised rats because

of estrogen deficiency.

In pilocarpin-induced convulsions, the levels of

FSH and LH have been reported to decrease [25].

For this reason, we also investigated the effects of

FSH and LH on epileptiform activity in female intact

rats. Intact rats were studied because it is known that

excessive accumulation of these hormones occurs in

ovariectomised rats. Our results demonstrated that

low doses of FSH and LH reduced epileptiform

activity. In parallel with the increase in dose of FSH

or LH, the anti-epileptiform activities of these

hormones were lost and were replaced by pro-

epileptiform activities. In a previous study, LH levels

were found to increase, while FSH levels were not

altered following picrotoxin-induced convulsions

[26]. This suggested that the convulsant effects of

picrotoxin were at least partially related to increases

in LH levels.

Of the female sex hormones, estrogen has

been indicated as producing more evident pro-

epileptiform activity. Therefore, we investigated

whether the pro-epileptiform activity of estrogen is

mediated via its own receptor. For this purpose, we

investigated epileptiform activity of estrogen in

ovariectomised rats treated with tamoxifen, a partial

antagonist for estrogen receptors. In the rat group

receiving tamoxifen alone, epileptiform activity was

suppressed by 60.9%. However, this anti-epileptiform

activity of tamoxifen was reduced as the level of the

applied estrogen dose was increased. Pro-epileptiform

activity of estrogen therefore appeared to be mediated

via its own receptors.

It has been reported that the convulsant effects of

estrogen are related to induction of the formation of

new excitatory synapses in the CA1 region of the

hippocampus and involves activation of N-methyl-D-

aspartate (NMDA) receptors [27]. Caffeine, the

agent we used to induce epileptiform activity, is

known to produce its central effects and convulsant

effects at high doses via GABAA/benzodiazepine

receptors [28]. Adrenergic receptors have been

shown to play important roles in anti-epileptic

activity [29,30]. A decrease in catecholamine levels

and an excessive increase in cortisol level promote

the severity of epilepsy [31–33]. In light of these

known effects, we determined levels of adrenaline,

noradrenaline, and cortisol (corticosterone in rats) in

rats treated with estrogen, progesterone, FSH or LH.

However, none of these hormone treatments resulted

in any significant alteration in the serum levels of

adrenaline, noradrenaline or corticosterone.

In conclusion, estrogen was shown to increase

epileptiform activity in a dose-dependent manner

and via its own receptors. In contrast, progesterone

had no effect on epileptiform activity. FSH and LH

suppressed epileptiform activity at low doses but

higher doses enhanced this activity. The hormones

we investigated did not affect levels of blood

adrenaline, noradrenaline or corticosterone.

We can therefore suggest that the occurrence or

aggravation of epilepsy, despite the estrogen defi-

ciency induced during the menopausal or post-

menopausal period, is related to the excessive

accumulation of FSH and LH.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

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