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- SUBJECTS AND METHODS
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.
- Top of page
- SUBJECTS AND METHODS
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