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Keywords:

  • Epilepsy;
  • Female;
  • Androgenic hormones;
  • PCOS;
  • Endocrine functions

Abstract

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary: Purpose: This study investigated the effect of epilepsy and/or antiepileptic drugs (AEDs) on the physical growth, pubertal development, and androgenic status of girls with epilepsy between ages 8 and 18 years.

Methods: Sixty-six female patients with epilepsy, their mean ages 13.47 ± 3.5 years, were included. Anthropometric measurements, staging of pubertal maturation, and clinical manifestations of hyperandrogenism were assessed, as well as measurement of serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone–binding globulin (SHBG), and free androgen index (FAI). Of the included patients, 44 had transabdominal ultrasonic examination of the ovaries and fasting serum insulin levels were measured. Forty healthy age-matched females served as a control group.

Results: Patients showed reduced mean height percentile compared with controls (z = 2.07; p = 0.04), which was negatively correlated with the duration of their epilepsy. Patients showed increased frequency of obesity, especially postpubertal girls taking valproate (VPA; 67%), who also showed higher insulin levels (t = 8.01; p = 0.0003). Patients showed increased frequency of clinical hyperandrogenemia in the different stages of puberty. High levels of testosterone and DHEAS were found in female patients with epilepsy, especially pubertal and postpubertal girls. Hyperandrogenism (clinical and/or laboratory) was most affected by the types of AEDs, with higher incidence in patients taking VPA compared with those taking enzyme-inducing AEDs (χ2= 9.16; p = 0.01). Eighteen percent of the patients were diagnosed as having polycystic ovary syndrome (PCOS). No difference was found in the types of seizures, degree of seizure control, type of AEDs, or insulin levels between patients with and those without PCOS.

Conclusions: Longer duration of the disease has a negative impact on the stature of female patients with epilepsy. Postpubertal girls taking VPA are more liable to obesity, which is associated with increased incidence of hyperinsulinemia. Clinical and/or laboratory evidence of hyperandrogenism is seen at a high frequency in patients, especially with the use of VPA. Furthermore, female patients with epilepsy especially in the postpubertal stage of sexual maturation, have a high prevalence of PCOS, independent of the type of AED or the characteristics of the epilepsy disorder.

Reproductive and endocrine functions are of major concerns for clinicians who treat patients with epilepsy. An increased frequency of reproductive endocrine disorders has been reported in women with epilepsy (1). Considerable data pertaining to changes in the hormonal milieu of women with epilepsy and suggest that these individuals are more likely to have derangements of the menstrual cycles and polycystic ovary syndrome (PCOS) (2).

A possible role of the seizure disorder or, alternatively, of the use of antiepileptic drugs (AEDs) has been suggested as the pathogenic mechanism (3). Evidence exists for a role for central mechanisms, hyperinsulinemia, local factors within the ovary, and environmental factors such as weight gain that may be critical for the expression of the PCOS (4).

The aim of the study was to investigate the probable effect of epilepsy and/or AEDs on the physical growth, pubertal development, and androgenic status of females with epilepsy between ages 8 and 18 years through assessing anthropometric measurements, pubertal maturation, clinical manifestations of hyperandrogenism, and measurement of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone–binding globulin (SHBG), free androgen index (FAI), and insulin levels together with ultrasonic examination of the ovaries.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subjects

The study included 66 female patients with epilepsy (age ranging between 8 and 18 years) whose diagnosis was based on the criteria of clinical and electroencephalographic (EEG) classification of epileptic seizures according to the International League Against Epilepsy (5). The patients were recruited randomly from those attending the Outpatient Pediatric Neurology Clinic and Epilepsy Clinic of Neurology Department, Ain Shams University Hospitals, in the period from May 2002 through January 2003. All patients had been taking regular AEDs for a period of 1 to 5 years. Patients with evidence of disease or underlying disorder that might influence the neuroendocrinal systems were excluded from the study.

A group of 40 female subjects (large numbers of them were relatives of the included patients with epilepsy) were included as the control group. They were chosen from apparently healthy females with no obvious history suggesting epilepsy or other medical, neurologic, or psychiatric disorders. They were age matched with the studied group.

Methods

The study was approved by the local ethical committee, and consents were taken from included subjects and their parents. Detailed history was taken from each patient by interviewing her or her parents and by examining her hospital records, with special emphasis on the characteristics of the epilepsy disorder including the age at onset of seizures, underlying etiology, types of seizures, drugs received, and control of seizures with therapy. Patients were considered controlled if they were seizure free for 6 months.

Subjects with established menstrual cycles were considered to have a menstrual disorder if they had any of the following for ≥6 months: amenorrhea (no menstruation), oligomenorrhea (cycle length >35 days), or irregular menstrual cycles (length varying >4 days from cycle to cycle, between 22 and 35 days), and polymenorrhea (menstrual cycles lasting <24 days) (6).

Values of anthropometric measurements, including weight and height, were compared with the percentile reference (7). The body mass index (BMI; the weight in kilograms divided by the square of the height in meters) was calculated; those with a BMI exceeding 25 were considered obese (6).

Staging of pubertal maturation was done according to Tanner and Whitehouse (7), and accordingly, the patients and control groups were further divided into three groups: Prepubertal, if no clinical signs of puberty were seen, that is, breast (B1) and pubic hair (PH1). This group included 20 patients, their ages ranging from 8 to 16 years (mean age, 9.80 ± 1.82 years), and 10 controls, their ages ranging from 9 to 11 years (mean age, 10.00 ± 0.94 years). Pubertal, if they have clinical signs of puberty (B2-4 or PH2-4). This group included 25 patients, their ages ranging from 10 to16 years (mean age, 12.80 ± 1.76 years), and 14 controls, their ages ranging from 12 to 16 years (mean age, 14.00 ± 1.66 years). Postpubertal, if they have full sexual maturation (B5PH5). This group included 21 patients, their ages ranging from 16 to18 years (mean age, 17.76 ± 0.54 years), and 16 controls, their ages ranging 16 to 18 years (mean age, 17.75 ± 1.00 years).

Clinical manifestations of hyperandrogenism were considered if any of the following were noted: hirsutism, acne, male-pattern balding, or male distribution of body hair (8). Acne was considered present if currently active and involving the face, neck, or upper trunk, or if evidence was found of facial, neck, or upper trunk scarring (9). Hirsutism is defined as an excessive hair growth, characteristically of dark color and coarse texture, which occurs in androgen-dependent areas of the skin. According to the Ferriman-Gallwey (F-G) scale, a total score >8 indicates hirsutism (10).

Investigations

Interictal wake and sleep EEG tracings with photic and (whenever possible) hyperventilation provocation were performed for all patients. Neuroimaging studies [computed tomography (CT) brain and in some cases, magnetic resonance imaging (MRI) of the brain] were done for all included patients.

Venous blood samples were withdrawn between 8 and 10 a.m. after an overnight fast. Serum blood samples were stored at –20°C. Serum levels of testosterone, DHEAS, and SHBG were determined in all studied subjects by competitive immunoassay, Immulite (11,12).

Laboratory hyperandrogenemia was defined as a total testosterone and/or DHEAS levels above the upper 95th percentile of the matched control group, as shown in Table 1 (1).

Table 1. The 5th and 95th percentiles of the studied hormones in different pubertal subgroups of the control subjects
 5th95th
  1. The FAI was calculated for all included subjects according to the formula 100 × Testosterone/SHBG.

  2. DHEAS, dehydroepiandrosterone; SHBG, sex hormone–binding globulin.

PrepubertalTestosterone (ng/dl)13.231.3
 DHEAS (μg/dl)33.264.7
 SHBG (nM)161182
PubertalTestosterone (ng/dl)28.741.8
 DHEAS (μg/dl)14.392.4
 SHBG (nM)132182
PostpubertalTestosterone (ng/dl)27.170.3
 DHEAS (μg/dl)23.789.3
 SHBG (nM)151185

Abdominal ultrasonic examination of the ovaries was done for 44 of the studied females; the rest of the patients did not give their consent. Their ages ranged between 8 and 18 years (mean age, 13.61 ± 3.64 years). For those who are menstruating (32 patients), it was done on day 10 to 14 of the menstrual cycle.

The ovaries were considered polycystic if they contained a total of ≥10 cysts, 2 to 8 mm in diameter, arranged peripherally with a dense core of ovarian stroma or scattered throughout an increased amount of stroma. Typically, the multiple follicles resemble a “pearl necklace” on ultrasound examination (13).

For patients who had pelviabdominal ultrasound done, their serum fasting insulin levels were determined by competitive immunoassay, Immulite, as well as in the control group. Hyperinsulinemia was defined as insulin level above the 95th percentile of the control group.

PCOS was defined according to the National Institutes of Child Health and Human Development (NICHHD) and The National Institutes of Health (NIH) Consensus Conference (14) as the presence of echographic picture of polycystic ovaries, the presence of ovulatory dysfunction (polymenorrhea, amenorrhea, or oligomenorrhea), clinical and/or biochemical evidence of hyperandrogenism, and the exclusion of other endocrinopathies

Statistical analysis

Data were analyzed by computer with IBM (SPSS for Windows). Results were expressed as mean ± SD (for parametric data), median (interquartile range) for nonparametric data, number, and percentage.

Student's t test or the Mann–Whitney test was used in comparing the anthropometric measurements and hormonal profile of the patients and the control subjects.

The χ2 test was used to determine the percentage of obesity, menstrual disturbances, and clinical manifestations of hyperandrogenism. Fisher's exact test (FET) was further used in measurement and calculation of small numbers.

Correlation coefficient analysis was used to determine the relation between duration of epilepsy, anthropometric measurements, and hormonal profile in different age groups. In all tests, the p value was considered statistically significant at <0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Clinical characteristics of the included patients

The study was conducted on 66 female patients with epilepsy, with a mean age of 13.47 ± 3.53 years, and on 40 apparently healthy females in the same age range (mean age, 14.50 ± 3.34 years) serving as the control group.

Twenty-eight (42.4%) of the patients were diagnosed as having symptomatic epilepsy; the commonest causes were CNS infection (28.5%), perinatal asphyxia (21.4%), neurodegenerative disorders (17.8%), and head trauma (17.8%). Eighteen of the patients in our study had idiopathic epilepsy syndromes, whereas in 20 (30.3%) patients, no definite CNS insult could be defined; they did not fit into the definition of idiopathic epilepsy and thus were categorized as having cryptogenic epilepsy. Of the included patients, 33 were receiving monotherapy [17 taking carbamazepine (CBZ) and 15 taking valproate (VPA)] and 33, polytherapy (Table 2).

Table 2. Clinical characteristics of patients with epilepsy
Patients (n = 66) 
  1. VPA, valproate; CBZ, carbamazepine; PCOS, polycystic ovary syndrome.

Age (yr): Mean ± SD13.47 ± 3.53 
Etiology of epilepsy:
 Symptomatic28 (42.42%)
 Idiopathic18 (27.27%)
 Cryptogenic20 (30.3l%) 
Type of seizure
 Focal 7 (10.60%)
 Focal with secondary generalization42 (63.63%)
 Generalized17 (25.77%)
Type of drug therapy
 Monotherapy:32 (48.48%)
  CBZ17 (53.12%)
  VPA15 (46.88%)
 Polytherapy34 (51.51%)
Control of seizure on drug therapy
 Controlled33 (50.00%)
  on monotherapy23 (69.69%)
  on polytherapy10 (30.31%)
 Uncontrolled33 (50.00)  
Patients who had ultrasonic examination of the ovaries (n = 44)
Age (yr)
 Median14
 Interquartile range 8.0
Ultrasound finding
 Polycystic ovaries22 (50%)   
 PCOS8 (18%)  
 Normal ultrasound finding22 (50%)   
Insulin level (μIU/ml)
 Range4.7–32.3
 Mean ± SD16.52 ± 7.31
Insulin status
 High28 (64%)   
 Normal16 (36%)   

Comparison between patients with epilepsy and their matched controls as regards the values of anthropometric measurements, prevalence of menstrual disturbances, and the clinical manifestations of hyperandrogenism

The height percentiles of the patients were significantly reduced [median (interquartile range), 10.00 (20.00)] compared with controls [25.00 (43.75)] (z = 2.07; p = 0.0388). Conversely, a higher prevalence of obesity was noted among the studied patients (37%) compared with only 10% of the control group (χ2= 4.52; p = 0.0335). This was especially evident in postpubertal female patients with epilepsy, who were significantly more obese (mean BMI, 26.14 ± 6.28) compared with their matched controls (22.11 ± 3.75; p = 00.0293; Table 3). When comparing patients exclusively taking VPA with those taking enzyme-inducing AEDs, patients taking VPA were significantly more frequently obese (27%; χ2= 5.46; p = 0.0194*), which was especially evident in the postpubertal female patients taking VPA (χ2= 4.44; p = 0.0350).

Table 3. Comparison between patients with epilepsy and their matched controls as regards the values of anthropometric measurements and the clinical manifestations of hyperandrogenism in the different pubertal stages
GroupVariablePatientsControlsTest value
  1. ap < 0.05 (S).

PrepubertalAge (yr) 9.80 ± 1.8210.00 ± 0.94t = 0.40
 20 patientsBMI16.17 ± 4.7916.72 ± 2.11t = 0.34
 10 controlsObesity  1 (5%)0 (0)χ2 = 0.52 
 Clinical manifestations of hyperandrogenemia   3 (15%)0 (0)χ2= 1.67  
PubertalAge12.80 ± 1.76 14.0 ± 1.66 t = 2.08a
 25 patientsBMI20.43 ± 6.0420.81 ± 2.46t = 0.23
 14 controlsObesity   5 (20%)0 (0)χ2 = 3.21 
 Menstrual disturbances   4 (16%) 1(7%)χ2= 0.02  
 Clinical manifestations of hyperandrogenemia   5 (20%)0 (0)χ2= 3.21  
PostpubertalAge   17 ± 0.5417.75 ± 1.00t = 0.04
 21 patientsBMI26.14 ± 6.2822.11 ± 3.75 t = 2.27a
 16 controlsObesity  12 (57%)   4 (25%)χ2= 3.82 
 Menstrual disturbances  10 (48%)    2(12.5%)χ2= 1.98 a
 Clinical manifestations of hyperandrogenemia   7 (33%)   4 (25%)χ2= 0.30 

Comparing patients in the different stages of puberty with their matched control groups, it was found that pubertal patients were significantly younger (mean age, 12.80 ± 1.76 years) than the matched controls (mean, 14.0 ± 1.66 years), and menstrual disturbances were significantly more frequent in postpubteral patients with epilepsy (48%) than with their matched controls (12.5%).

Regarding the clinical manifestations of hyperandrogenism, it was found to be more prevalent in the patients group in the three stages of puberty (15%, 20%, and 33%) compared with their controls (only in 25% of the postpubertal female controls); however, the difference was not statistically significant (see Table 3). A significantly higher number of patients taking VPA had clinical manifestations of hyperandrogenism compared with those taking enzyme inducers (χ2= 5.46; p = 0.0194).

Comparison of the values of the studied hormones between patients with epilepsy and their matched controls

The mean testosterone levels were higher in patients with epilepsy in the pubertal and postpubertal stages (52.3 ± 38.5 and 78.2 ± 28.69 ng/dl, respectively) compared with the controls (34.04 ± 4.82 and 45.86 ± 13.71 ng/dl, respectively) (t = 2.34 and 4.53; p = 0.025 and 0.0002, respectively). As to DHEAS, although its mean levels were higher in the patients in different pubertal subgroups compared with their matched controls, the difference was not statistically significant (Fig. 1). Regarding SHBG, its mean values were significantly higher in patients in the different pubertal stages (182.55 ± 11.44, 177.28 ± 17.29, and 177.33 ± 7.47 nM, respectively) compared with their matched controls (169.80 ± 10.10, 160.86 ± 16.58, and 163.25 ± 13.68 nM, respectively) (t = 2.99, 2.89, and 3.72, respectively, and p = 0.006, 0.007, and 0.0007, respectively). The values of FAI were significantly increased in postpubertal patients [median (interquartile range): 45.93 (22.18)] compared with their matched controls [26.39 (12.59)] (z = 3.19; p = 0.001).

image

Figure 1. Mean values of testosterone (ng/dl) and dehydroepiandrosterone sulfate (μg/dl) in patients and controls in different pubertal subgroups.

Download figure to PowerPoint

When comparing patients exclusively taking VPA to those taking enzyme-inducing AEDs, the levels of testosterone were significantly higher in patients taking VPA (mean, 5.29 ± 43.37 ng/dl), whereas those of SHBG were significantly lower (mean, 166.07 ± 16.38 nM) than those taking enzyme inducers (mean = 36.86 ± 26.75 ng/dl and 188.56 ± 8.75 nM, respectively) (t = 2.21 and 4.78, respectively; p = 0.0345 and 0.0002, respectively). The values of FAI were significantly higher in patients taking VPA [median (interquartile range), 41.18 (44.13)] compared with those taking enzyme-inducing AEDs [13.63 (23.52)] (z = 2.24; p = 0.025). Of the patients taking VPA, 53% (25% of the prepubertal, 63% of the pubertal, and 67% of the postpubertal patients) had high testosterone levels compared with 17% of those taking enzyme-inducing AEDs (χ2= 4.95; p = 0.026), whereas none of the patients had high SHBG compared with 67% of those taking enzyme-inducing AEDs (χ2= 15.71; p = 0.0001).

Comparison between patients with and those without clinical and/or laboratory hyperandrogenism

Patients with clinical and/or laboratory hyperandrogenism were older (mean age, 14.42 ± 3.54 years) than were those without evidence of hyperandrogenism (12.63 ± 3.43 years). Neither age at onset, type of seizure, duration of disease, number of AEDs, nor the control of therapy showed any significant effect on development of hyperandrogenism. However, hyperandrogenism was significantly affected by the types of AEDs. Patients taking VPA had a higher incidence of clinical and/or laboratory hyperandrogenemia compared with those taking enzyme-inducing AEDs (χ2= 9.15; p = 0.0103).

Effect of the etiology of epilepsy, its duration, and control of seizures on the studied parameters

No significant difference was found between patients with idiopathic epilepsy and those with either symptomatic or cryptogenic syndromes or between patients with controlled and those with uncontrolled seizures in any of the studied parameters in the three groups of patients studied.

No significant correlation was seen between the duration of epilepsy and either the weight, BMI, or any of the androgenic hormones studied; however, a significant negative correlation occurred between the duration of epilepsy and the height percentiles of the studied patients in the prepubertal (r=–0.47; p = 0.037) and postpubertal (r=–0.52; p = 0.015) stages of sexual maturation.

Comparison between patients with and those without PCOS

Only 44 of the included patients had ultrasonic examination of the ovaries. It revealed evidence of polycystic ovaries in 22 (50%) of the patients; eight of them were considered to have PCOS according to the NICHHD and the NIH Consensus Conference (14) (see Table 2).

Comparing patients with PCOS with those without, no significant difference was noted regarding the weight and height percentiles, BMI, or the percentage of obesity. Similarly, the type of seizure, duration of epilepsy, types of AEDs, and the degree of seizure control did not differ in patients with PCOS compared with those without. Conversely, patients with PCOS were significantly older [median (interquartile range): 17.5 (2.75) years] than were those without PCOS [12 (7.75) years] (z = 2.4; p = 0.014). Most of the patients with PCOS (75%) were in the postpubertal stage of sexual maturation, compared with those without PCOS (only 27.8%) (χ2= 7.03; p = 0.03; Table 4).

Table 4. Comparison between patients with PCOS and patients without PCOS
VariableCases without PCOS (n = 22)Cases with PCOS (n = 8) Test value
  1. BMI, Body mass index; F, focal seizure; G, Primary generalized seizure; FG, focal seizure with secondary generalization; VPA, valproate; ED, enzyme-inducing antiepileptic drug.

Age (yr)12 (7.75)17.5 (2.75)z = 2.4a
Height percentile10 (20.0)30 (45.0)z = 0.891
Weight percentile50 (72.5)62.5 (55.0)z = 0.355
BMI21.6 ± 6.5623.65 ± 7.23t = 0.768
Obesity10 (27.8%)3 (37.5%)x2= 0.297
Type of seizure
 F 4 (11.1%)4 (50%)x2= 5.6
 FG27 (75.0%)4 (50%) 
 G 5 (13.9%) 
Etiology of epilepsy
 Idiopathic11 (30.6%)3 (37.5%)x2= 0.146
 Others25 (69.4%)5 (62.5%) 
Seizure control
 Controlled21 (58.3%)4 (50%)x2= 0.158
 Uncontrolled15 (41.7%)4 (50%) 
Drug therapy
 Monotherapy19 (52.8%)4 (50%)x2= 0.02
 Polytherapy17 (47.2%)4 (50%) 
Duration (yr)6.54 ± 4.127.13 ± 3.87t = 0.366
Type of drug
 VPA (with/without ED)26 (72.2%)5 (62.5%)x2= 0.297
 ED10 (27.8%)3 (37.5%) 
Pubertal stages
 Prepubertal12 (33.3%) x2= 7.03a
 Pubertal14 (38.9%)2 (25%) 
 Postpubertal10 (27.8%)6 (75%) 
Insulin status
 High21 (58.3%)7 (87.5%)x2= 2.41
 Normal15 (41.7%)1 (12.5%) 
Insulin levels (μIU/ml)16.3 ± 7.817.36 ± 4.75t = 0.356

The insulin levels were higher in the patient group (mean of 16.52 ± 7.3 μIU/ml) than in the control group (mean, 6.92 ± 2.98 μIU/ml) (t = 8.01; p = 0.0003). No significant difference in its levels was found between patients with and those without PCOS (see Table 4). Comparing serum insulin levels in patients taking different AEDs, we found it to be significantly higher in patients taking VPA (mean, 18.51 ± 6.96 μIU/ml) compared with those not taking VPA (mean, 11.77 ± 5.97 μIU/ml) (t = 3.05; p = 0.04). Obese patients taking VPA had higher insulin levels (mean, 21.78 ± 5.83 μIU/ml) compared with lean patients taking VPA (mean, 16.16 ± 6.90 μIU/ml) (t = 2.38; p = 0.024); however, the incidence of menstrual irregularity, clinical hyperandrogenism, or biochemical hyperandrogenemia was not different in both groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Assessment of anthropometric measurements in female patients with epilepsy revealed that the height percentiles of the patients were significantly lower than those of the control group. Our results are in agreement with those of Novac et al. (15) and Guo et al. (16), who reported that long-term AED therapy is associated with short stature. It is worth noting that El Khayat et al. (17), who studied male patients with epilepsy between 8 and 18 years old, found that patients were significantly shorter when compared with their matched controls. It is possible that AEDs or epilepsy itself has some effect on the hormones of growth.

Although the BMI was not significantly different in the patients compared with controls, the number of obese patients (37%) was significantly higher than obese controls (10%). VPA was associated with obesity due to increased appetite by stimulating the hypothalamus (2). This may occur through lowering blood glucose level, or through an enhancing effect of γ-aminobutyric acid (GABA)–mediated neurotransmission, which may increase appetite for carbohydrates and reduce energy expenditure (18). Decreased sensitivity to leptin may be another factor that is partly responsible for VPA-induced weight gain (19). In accordance with the previous theories, patients taking VPA were found to have higher percentage of obesity compared with those taking enzyme-inducing AEDs only.

In our study, postpubertal patients were especially prone to obesity; this was again seen in postpubertal VPA-treated patients compared with those taking enzyme-inducing AEDs. A similar finding was reported by Vainionpää et al. (20), who found significantly higher BMIs only in postpubertal VPA-treated girls. These data may suggest that a mature endocrine system of the adult type may be necessary for the development of VPA-related obesity.

Female pubertal patients were found to be younger than the matched controls. This result was contrary to the suggested effect of epilepsy per se or hormonal disturbances on the hypothalamic-pituitary axis (21). However, an accelerated pubertal maturation also was reported by Nalin et al. (22), who found that the onset of stage II puberty was significantly earlier in female treated patients than in healthy controls. Conversely, Rättyä et al. (23) and Genton et al. (2) reported that AEDs do not seem to have any adverse effects on sexual maturation in girls with epilepsy.

A possible explanation of our results is provided in the report of Genazzani et al. (24), who stated that DHEA, allopregnanolone, and GABA-agonist neurosteroids may be important in the onset of gonadarche and concluded that the onset of puberty is derived from the complex interplay among neuropeptides, neurotransmitters, and neurosteroids that occurs in the awakening of hypothalamic-pituitary-ovarian axis. Whether the results in our study may be explained by the effect of hyperandrogenemia, especially the increase in DHEA on pubertal maturation or the possible role of AEDs in GABA modulation, cannot be concluded from our results.

In the present study, menstrual disorders were significantly more frequent in postpubertal girls with epilepsy (48%) compared with their matched controls (12.5%). No effect of the type of AED (whether enzyme inducers or inhibitors) on the prevalence of menstrual disturbance could be detected in our study. In their study, Isojärvi et al. (25) and Luef et al. (26) reported menstrual disturbance in 28% and 16%, respectively, of patients taking CBZ, whereas the reported prevalence was 11% and 45%, respectively, in those taking VPA (26,27).

The occurrence of menstrual disorders with the use of CBZ was attributed to its enzyme-inducing effect, increasing serum SHBG levels and thus lowering the estradiol/SHBG ratio (25). In addition, SHBG can modify the effect of testosterone and estradiol on their target cells by binding to its own receptors at the cellular membrane, in addition to binding them in the circulation, which may interfere with the feedback regulation of pituitary luteinizing hormone (LH) secretion (28).

However, patients taking VPA had also menstrual disorders. VPA seems to inhibit the conversion of testosterone to estradiol, and this may act locally in the ovary to block ovulation or may accomplish this through negative feedback on follicle-stimulating hormone (FSH) secretion (22).

Furthermore, it was previously suggested that reproductive disorders could be attributed to epilepsy itself rather than to AEDs. This may occur through spreading of generalized paroxysmal activity into the hypothalamic areas that control the pituitary reproductive hormones. Alterations in gonadotropin-releasing hormone (GnRH) secretion may cause neurotransmitter dysfunction between the hypothalamus-pituitary and the ovaries, which maintains normally menstrual cyclicity (29).

Although clinical manifestations of hyperandrogenism were higher in patients in different stages of puberty (15%, 20%, and 33%, respectively) compared with controls (0, 0, and 25%, respectively), the difference was not statistically significant. Herzog et al. (30) and Isojärvi et al. (27) reported a prevalence of 25% and 21%, respectively, of hirsutism in female patients with epilepsy. The different results in the studies may be due to the different effects of the individual AEDs on androgenic hormones. Although VPA is known to increase testosterone and DHEAS (30,27), enzyme inducers are known to decrease DHEAS (32). This was evident in our study in which the clinical manifestations of hyperandrogenism were seen in 27% of the patients taking VPA compared with none of those taking the enzyme-inducing AEDs. Furthermore, significantly higher levels of testosterone were found in female patients taking VPA (53%) compared with those taking enzyme-inducing AEDs (17%).

Vainionpää et al. (20), in their study on girls taking VPA, reported increased frequency of hyperandrogenemia with the progress of pubertal development and concluded that sensitivity to manifest hyperandrogenism increases as a function of sexual maturation. Similar findings were noted in our study, in which 25% of patients taking VPA in the prepubertal stage, 63% in the pubertal, and 67% of those in the postpubertal stage have laboratory evidence of hyperandrogenemia.

DHEAS was found to be increased in patients compared with controls. Similar to our study is the report of Isojärvi et al. (31), who reported high levels of DHEAS in female patients taking VPA and suggested that a high concentration of serum DHEAS indicates increased androgen synthesis in the adrenal gland.

Although in our study, no significant difference in DHEAS levels was found in patients taking enzyme-inducing AEDs compared with those taking VPA alone, it is worth reporting that low levels of DHEAS were reported in four patients, all of whom were receiving CBZ monotherapy. By comparison, in their study on the effect of CBZ on DHEAS, Stoffel-Wagner et al. (33) and Rättyä et al. (34) reported that the serum concentration of DHEAS was significantly lower with the use of enzyme-inducing AEDs. Several mechanisms may lead to this effect: AEDs (CBZ or phenobarbitone) may induce liver enzymes that metabolize steroids or may stimulate the synthesis of binding proteins and alter the steroid metabolic pathway (35). This was evident in our study, in which patients taking enzyme-inducing AEDs had significantly higher levels of SHBG than did those taking VPA.

Comparing patients with clinical and/or laboratory evidence of hyperandrogenism with the rest of patients, neither the age at onset, type of seizure, etiology of epilepsy, duration of disease, the number of AEDs, nor the control of therapy showed any significant effect on development of hyperandrogenism.

Similar conclusions were previously reported by Bilo et al. (1) and Sverberg et al. (36), who stated that reproductive endocrine disorders were found with similar frequency in women affected by generalized epilepsy and those with focal epilepsy, suggesting that the type of epilepsy is not a relevant factor in determining the occurrence of these conditions.

In 2001, Isojärvi et al. (37) stated that the role of AEDs in the development of reproductive endocrinal disorders may be more important than the type of epilepsy. The role of AEDs was evident in our study, in which 90% of patients with clinical and/or laboratory evidence of hyperandrogenemia were either taking VPA alone (29%) or in combination (61%), which was significantly different from patients without clinical or laboratory evidence of hyperandrogenism.

It is worth noting that patients with clinical and/or laboratory evidence of hyperandrogenism were older than those without hyperandrogenism; this result, together with our previous findings of the predilection for hyperandrogenism in pubertal and postpubertal girls taking VPA, may indicate a special proneness of female patients to hyperandrogenemia with increased age and progress of sexual maturation.

In the present study, 50% of our patients had evidence of PCO in their ultrasound examinations. Our study results are near to the 64% identified by Isojärvi et al. (27); however, it is a far higher percentage than that reported by Luef et al. (26), Bauer et al. (38), and Stephen et al. (39), who reported 27%, 11%, and 17%, respectively in their studies on female patients with epilepsy. The frequency of PCO in our study is also much higher than the 17–22% described in the general population in the U.K. (40), Greece (41), and New Zealand (42).

Using the NIH criteria for definition of PCOS, the prevalence of PCOS in our study was 18%. Previous studies report estimates of the prevalence of PCOS in premenopausal females with epilepsy varying from 5% to 26% (1,27,29,38). The prevalence of PCOS in the general population varies from 4% to 10% (27,43,44), lower than the 18% reported in our patients.

Comparing patients with PCOS and those without, no significant difference was seen regarding the weight and height percentiles, BMI, or the percentage of obesity, a result similar to that of Luef et al. (26). Conversely, Lefebvre et al. (45) reported that women with PCOS had a higher mean body weight and BMI than did women without PCOS.

From our results, it seems that PCOS is more common with increase of age and is more prevalent in female patients in the postpubertal stage, a finding in accordance with the predilection to hyperandrogenemia seen in the pubertal and postpubertal females in our study.

In our study, the type of seizure, the etiology of epilepsy, its duration, and the degree of seizure control did not differ in patients with PCOS compared with those without, and thus the statement postulated by Herzog et al. (46) that women with temporal lobe epilepsy more frequently have disorders of the pituitary-gonad axis could not be supported in the present investigation.

Our study did not support the association between PCOS and the use of any specific AEDs, in particular, VPA, as previously reported (27,31). Our results are similar to those of Bilo et al. (1) and Luef et al. (26), who found that the prevalence of PCOS is increased in epilepsy independent of the AEDs or the seizure type.

In their two studies, Isojärvi et al. (27,31), reported the association between the use of VPA and PCOS, and the most striking finding was the association of obesity and VPA in those in whom PCOS developed. However, 40% of our patients taking VPA in whom PCOS developed were lean. Furthermore, >60% of our patients in whom PCOS developed were lean, and for those reasons, it seems that the development of obesity is not a prerequisite in the development of the condition, a conclusion that is similar to that offered by Bilo et al. (1).

Hyperinsulinemia may be a key factor in the pathogenesis of PCOS. The hyperinsulinemia is thought to cause hyperandrogenism through stimulation of ovarian steroid synthesis and augmentation of bioactive concentrations of insulin-like growth factor (IGF)-l and androgens (47).

In our study, insulin levels were significantly higher in the patients group than in the control group. Although its levels were higher in patients with PCOS compared with those without, the difference was not statistically significant.

Hyperinsulinemia also may be secondary to insulin resistance, which is thought to result from defects in insulin clearance and peripheral tissue degradation (48). Isojärvi et al. (31) put forward the hypothesis that VPA-induced weight gain leads to increased insulin resistance, with consequent hyperinsulinemia. We compared patients taking different AEDs, and we found insulin levels to be significantly higher in patients taking VPA. Furthermore, its levels were significantly higher in obese patients taking VPA compared with lean ones. Our results support the previous reports of Verrotti et al. (49). These findings may thus point out that patients in whom obesity develops during VPA therapy may be exposed to the risks of these metabolic abnormalities.

In view of the increased prevalence of PCOS in female patients with epilepsy and the fact that neither AEDs nor the types of seizures or its etiology did seem to play a role in its development, it may be suggested that epilepsy itself may play a role in its development. Herzog et al. (50) reported that significant differences exist at all levels of the reproductive neuroendocrine axis, that is, hypothalamus, pituitary, and peripheral gland, between women with epilepsy and healthy controls. In epilepsy patients, ictal and interictal paroxysmal discharges may disrupt GnRH pulsatility, modulating CNS regulation of GnRH neurons by excitatory neurotransmitters (51). Receptors for the excitatory neurotransmitters glutamate and nitric oxide, including N-methyl-d-aspartate receptors, are located in hypothalamic nuclei known to be important for GnRH release. The changes in excitatory neurotransmitter systems associated with epilepsy may potentially increase the risk of PCOS via modulation of GnRH pulsatility (52). The finding that increased menstrual disorders are more common among women with interictal discharges supports this hypothesis (50).

Trying to realize the effect of the duration of epilepsy on the different studied parameters, it was found that the duration of epilepsy did not affect any of the anthropometric measurements, the hormonal profile, or the development of PCOS, except for the height percentile, where the study demonstrated a negative correlation between duration of epilepsy and the height percentile. It seems that the longer the duration of epilepsy, the shorter were the patients.

In conclusion, physical growth is adversely affected in female patients with epilepsy. Longer duration of the disease has a negative impact on their stature, and they are more liable to obesity, especially in postpubertal girls taking VPA. Patients taking VPA in whom obesity develops are especially prone to hyperinsulinemia. Clinical and/or laboratory evidence of hyperandrogenism is seen at a high frequency in female patients with epilepsy, especially in the pubertal and postpubertal stages of sexual maturation and with the use of VPA. Furthermore, female patients with epilepsy, especially in the postpubertal stage of sexual maturation, have a high prevalence of PCOS, independent of the type of AED, the duration, or the characteristics of the epilepsy disorder.

We thus recommend that female patients with epilepsy should be monitored carefully with regard to their height percentiles, weight percentiles, velocity of growth, and evidence of hyperandrogenism or menstrual disturbances, especially so in those taking VPA. If evidence exists of an effect of AED therapy, investigations for sex hormones profile should be considered. If a reproductive endocrine disorder is found, AED treatment should be reviewed to ensure that it is correct for the particular seizure type and that it is not contributing to endocrine problem. The possible benefit of a change in treatment must be balanced against seizure control.

Limitations of the study

In our study, we could not determine BMI or the ultrasonic picture before commencement of therapy; it is possible that some of the patients have had PCOS before exposure to therapy. Again, these studies are all relatively small and cross-sectional in nature, allowing a large role of chance association

REFERENCES

  1. Top of page
  2. Abstract
  3. SUBJECTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES