|Year : 2016 | Volume
| Issue : 4 | Page : 258-262
Hormonal profile and clinical characteristics of epileptic females with abnormal ovarian morphology
Asmaa M Ebraheim MD 1, Reham M Shamloul1, Soha Talaat2
1 Department of Neurology, Cairo University, Cairo, Egypt
2 Department of Radiology, Cairo University, Cairo, Egypt
|Date of Submission||19-Jul-2016|
|Date of Acceptance||03-Sep-2016|
|Date of Web Publication||17-Mar-2017|
Asmaa M Ebraheim
Department of Neurology, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
Women with epilepsy (WWE) tend to have ovarian echographic abnormalities, raising concerns about an interaction between the brain and the ovaries.
This study aims to determine the relationship between abnormal ovarian follicular morphology as detected by ultrasonography (US) and clinical features, hormonal profile, and antiepileptic drugs (AEDs) in epileptic females.
Participants and methods
WWE who attended Kasr Al-Ainy Epilepsy Clinic and fulfilled the inclusion criteria were recruited and assessed clinically. Transabdominal US of the ovaries and the uterus was performed; in addition, serum levels for luteinizing hormone (LH), follicle-stimulating hormone, estradiol, testosterone, and fasting insulin were determined for all the participants. Thirteen WWE who had ovarian echographic abnormalities were compared with 67 epileptic females with normal ovarian US.
Significantly elevated LH was detected in patients with ovarian morphologic abnormality compared with the control group. The clinical parameters, the frequency of use of different AEDs, and the mean values of the other hormones were comparable in both groups.
Elevated LH in patients with an ovarian echographic abnormality points to altered gonadotropin secretion in these patients, which could be explained by the effect of epileptic discharges on the hypothalamus, but not the use of AEDs.
Keywords: epilepsy, ovarian echographic abnormality, reproductive hormones
|How to cite this article:|
Ebraheim AM, Shamloul RM, Talaat S. Hormonal profile and clinical characteristics of epileptic females with abnormal ovarian morphology. Egypt J Neurol Psychiatry Neurosurg 2016;53:258-62
|How to cite this URL:|
Ebraheim AM, Shamloul RM, Talaat S. Hormonal profile and clinical characteristics of epileptic females with abnormal ovarian morphology. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2018 Jun 18];53:258-62. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/4/258/202388
| Introduction|| |
Women with epilepsy (WWE) are exposed to various health hazards, including reproductive disorders . Polycystic appearance of ovaries (PCO) is found to be more common in WWE than in the general population . PCO, which has been included as one of the three diagnostic criteria of polycystic ovarian syndrome (PCOS) in Rotterdam consensus workshop 2003 ,, is not independently a predictor of subfertility. However, it is associated with delayed pregnancy in females with other features of PCOS, if not the full syndrome . In addition to its gynecologic significance, PCOS may exacerbate seizures because of the lack of progesterone cerebral inhibitory effect during anovulatory cycles , a risk that is also possible with anovulation associated with absent follicular activity in the ovaries. Moreover, metabolic disturbances associated with PCOS (dyslipidemia and hyperinsulinism) predispose the patients to atherosclerosis and vascular complications . Therefore, this study aims to determine the relationship between abnormal ovarian follicular morphology as detected by ultrasonography (US) and clinical features, hormonal profile, and antiepileptic drug (AEDs) in epileptic females.
| Participants and methods|| |
This cross-sectional study was carried out in 2011. The patients included were postpubertal epileptic females who were recruited from Kasr Al-Ainy Epilepsy Clinic during a period of about a year. Participants were included when they were of reproductive age and had normal morphology of the pituitary by brain imaging. Exclusion criteria were as follows: pregnancy, lactation, systemic or endocrine disorders, central nervous system illness other than epilepsy, and intake of hormonal or psychotropic medications apart from AEDs. Informed consent was obtained from all participants and the study protocol was approved by the local Ethics Committee.
Careful assessment of medical history was performed for all epileptic participants and data on disease and treatment characteristics were collected. On the basis of clinical information and in accordance with the international classification by the Commission of the ILAE , the epileptic syndromes were classified into primary generalized epilepsy and localization-related epilepsy. According to seizure semiology and the presence of documented focal abnormal unilateral or bilateral paroxysmal activity in temporal leads on electroencephalogram, the latter group was further subdivided into two groups: one with temporal seizures and the other with extratemporal seizures.
Moreover, the menstrual history was obtained including the age of menarche and the regularity of menstrual cycles on the basis of the length of the last three cycles before blood sampling. The age of menarche before 8 years or after 18 years was considered abnormal . Regular cycles were defined as cycle length ranging from 21 to 35 days, with no more than a 4-day variation in length from cycle to cycle . Oligomenorrhea was assumed if cycle length greater than 35 days.
A complete medical and neurological examination was performed. BMI was calculated according to the criteria of Bray et al. .
A hormonal study was carried out with the participants fasting (12 h) in the early follicular phase of the menstrual cycles (days 3–5); serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were determined for all participants: total testosterone for 78 participants and insulin for 79 participants. For one amenorrheic patient, the blood sample was withdrawn randomly. Patients should not experience a seizure within the last 12 h before sampling. The first four hormones were measured on a DPC Immulite 2000 Autoanalyzer (Diagnostic Products Corporation, Los Angeles, California, USA). Insulin was measured on a Roche Elecsys 2010 Autoanalyzer (Roche Diagnostics GmbH, Mannheim, Germany).
The procedure used to determine FSH and LH was a solid-phase enzyme-amplified, two-site chemiluminescent immunometric assay, for E2 and testosterone, a solid-phase, enzyme-amplified, competitive chemiluminescent immunoassay was used, and for insulin a solid-phase, sandwich electrochemiluminescent immunoassay was used.
The population studied underwent a transabdominal US of the ovaries and uterus. The apparatuses used were Hitachi Aloka, Tokyo, Japan (Aloka) for some patients and Philips/ATL HDI 5000 California, USA (ALT 5000) for others. The probe used was 3.5–5.0 MHz. The vaginal approach was precluded by sociocultural constraints. The ovarian morphology was defined as polycystic if there were 10 or more cysts, 2–8 mm in diameter, with a thickened stoma .
Data were analyzed using IBM SPSS advanced statistics version 20 (SPSS Inc., Chicago, IL). Numerical data were expressed as mean±SD, median, minimum, and maximum. Qualitative data were expressed as frequency and percentage. χ2-test (Fisher’s exact test) was used to examine the relation between qualitative variables. For quantitative data, a comparison between two groups was carried out using a nonparametric t-test (Mann–Whitney test) for non-normally distributed variables. Comparison between three groups was carried out using a nonparametric analysis of variance (Kruskal–Wallis test). Then, a post-hoc “Schefe test” on rank of variables was used for pair-wise comparison. Correlations were performed using Pearson’s test. A P-value less than or equal to 0.05 was considered significant.
| Results|| |
The age of the participants ranged from 12 to 46 years. Thirteen participants were found to have ovarian echographic abnormalities and were compared with 67 epileptic females with normal ovarian US.
In terms of the menstrual history, delayed menarche (>18 years) was reported in two patients; however, the age of menarche was comparable in both groups. Menstrual pattern abnormality was reported in eight participants. Six of them had a history of oligomenorrhea, one had primary amenorrhea, and one had irregular menstruation because of more than 4 days of variation from cycle to cycle. The percentages were 15.4% (n=2) in the affected group and 8.9% (n=6) in the group with normal ovarian US. The difference was not statistically significant.
On the basis of the echographic findings, one of the patients (amenorrheic) had an absent uterus on her pelvic US, despite normal ovarian morphology. However, ovarian abnormalities that were encountered in the affected females included PCO, whether unilateral or bilateral (n=12), and undetectable follicular activity (n=1).
No statistically significant differences were detected between both groups in terms of various disease characteristics including age at onset, duration of epilepsy, and its type. However, the frequency of temporal lobe-type seizures among patients with ovarian US abnormality was nearly double that of the other two types. Details are shown in [Table 1].
|Table 1 Clinical profile of epileptic females with and without ovarian ultrasonographic abnormality|
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[Table 2] shows the frequency of AED [carbamazepine (CBZ), phenytoin (PHT), valproate (VPA)] administration, whether alone or in combination, among treated patients with and without ovarian US abnormality. The differences between the two groups were not statistically significant.
|Table 2 Frequency of antiepileptic drug (carbamazepine, phenytoin, valproate) administration, whether alone or in combination, among treated patients with and without ovarian ultrasonographic abnormality|
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In terms of the hormonal profile, the mean values of FSH, E2, and testosterone, and insulin were comparable in patients with and without ovarian US abnormality. However, the mean level of LH was significantly higher in the former group (P=0.039) ([Table 3]).
|Table 3 Comparison of the hormonal profile (mean±SD) in patients with and without ovarian ultrasonographic abnormality|
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A statistically significantly positive correlation was detected between the age of the patients and LH (P=0.015). However, no significant correlation was found between LH and BMI, age at onset, duration of illness, and seizure frequency ([Table 4]). Moreover, neither the dose nor the duration of CBZ, PHT, or VPA was significantly correlated with LH level ([Table 5]).
|Table 4 Correlation of luteinizing hormone with different clinical parameters of the patients|
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|Table 5 Correlation of luteinizing hormone with medication characteristics|
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| Discussion|| |
WWE are at an increased risk of developing PCO and previous studies have documented its association with VPA. This radiological finding alone or in association with other features might reflect anovulation and subfertility . The occurrence of PCO and PCOS is related to various mechanisms. These include central mechanisms with disrupted hypothalamic–pituitary axis, ovarian dysfunction, and hyperinsulinemia .
In the present study, in 13 patients abnormal ovarian follicular morphology was detected by pelvic US. These abnormalities included PCO, whether unilateral or bilateral (n=12), and undetectable follicular activity (n=1). In both conditions, the follicles do not develop and mature properly, and hence, there is impaired ovulation. Patients with abnormal ovarian US had significantly elevated LH compared with patients with normal ovarian US (P=0.039). Folliculogenesis and oocyte maturation is mediated by LH through estrogen synthesis from androgen . Abnormally increased LH has been considered a leading cause for the development of PCOS . LH secretion is mediated by gonadotropin-releasing hormone (GnRH). Therefore, LH levels are affected by disorders abnormally influencing the function of the GnRH pulse generator in the medial preoptic area of the hypothalamus. In epileptic females, the spread of the epileptiform discharges to the hypothalamus and the altered neurotransmission to GnRH neurons  are responsible for disrupted LH pulsatility and consequently follicular immaturation, anovulation, and cystic appearance of the ovary. Moreover, the immature follicle is deficient in aromatase, which converts androgens into estrogens . The higher androgen levels desensitize the hypothalamus to the negative feedback regulation by progesterone . An earlier study reported that focal seizures of limbic origin exerted a more dysfunctional effect on the hypothalamic–pituitary axis compared with generalized seizures . Despite the presence of a higher number of patients with temporal lobe epilepsy among patients with abnormal ovarian US, our results do not support the presence of a significant differential effect of epilepsy type or its characteristics on the ovarian morphology. This is in agreement with Nappi et al. , who reported a significantly high LH pulse frequency in untreated epileptic females who had both partial and generalized types of epilepsy. Moreover, the ovarian US alterations reported by Murialdo et al.  and the incidence of PCOS reported by Zhou et al.  in WWE were not associated with a definite clinical picture. However, Morrell et al.  found that females with generalized epilepsy were significantly more likely to have PCO.
In the present study, no significant differences were reported on the frequency of use of CBZ, PHT, or VPA (either alone or combined with other AEDs) by patients with or without ovarian US abnormality. Furthermore, we did not find any significant correlation between each drug characteristics and LH. Similar to our results, some authors  found that the occurrence of PCO was not significantly related to the use of either valproate, CBZ, or PHT. Moreover, unchanged levels of LH were reported in CBZ-treated epileptic patients  and similar findings were reported with VPA use . No consistent abnormalities in basal or stimulated serum gonadotropins have been reported in women taking PHT for epilepsy ,. In addition, animal studies provide evidence of a disrupting effect of epileptic discharges on GnRH pulsatility and ovarian morphology, independent of the use of AEDs . However, VPA used to be considered to be the cause for the development of PCOS and PCO in WWE, through weight gain and hyperinsulinism ,. The present study failed to support the role of these peripheral mechanisms in the development of PCO in WWE. There was no significant difference between both groups of patients with or without ovarian US abnormality in the values of insulin or BMI. Surprisingly, the values were lower in the former group. Moreover, there was an inverse relation between LH and BMI, but this was not statistically significant. Lower LH levels of women with elevated BMI could be attributed to the increased peripheral conversion of androgens into estrogens by aromatase in adipose tissue, leading to suppression of LH secretion  and consequently reduced likelihood of developing PCO.
Correlational studies were carried out on LH and different clinical parameters to relate its elevation to any of them. A statistically significantly positive correlation was found between LH and the age of patients (P=0.015). However, the correlations with age at onset of seizures, its duration, and frequency were not statistically significant. There is evidence that aging is characterized by attenuated LH surge with delayed onset and peak. In an animal study, this effect was explained by the decreased sensitivity to an E2-positive feedback . The E2-mediated GnRH/LH surge is driven by a balance between stimulatory (glutamate, norepinephrine, and vasoactive intestinal peptide) and inhibitory (gamma aminobutyric acid and opioid peptides) inputs to the hypothalamus. Normally, aging is associated with decline in the stimulatory signals, while the inhibitory signals become elevated or unchanged . Our result indicates that these changes might not take place in WWE, probably due to excessive stimulatory neurotransmission in this disorder.
Finally, our results suggest that ovarian echographic abnormality in WWE could occur through elevation in LH, which itself could result secondary to epileptiform discharges, but not AEDs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Morrell MJ. Reproductive and metabolic disorders in women with epilepsy. Epilepsia 2003; 44 (Suppl 4):11–20.
Luef G, Rauchenzauner M. Epilepsy and hormones: a critical review. Epilepsy Behav 2009; 15:73–77.
Harden CL. Polycystic ovaries and polycystic ovary syndrome in epilepsy: evidence for neurogonadal disease. Epilepsy Curr 2005; 5:142–146.
The Rotterdam ESHRE/ASRM − sponsored PCOS Consensus Workshop Group: The Netherlands. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81:19–25.
Hassan MA, Killick SR. Ultrasound diagnosis of polycystic ovaries in women who have no symptoms of polycystic ovary syndrome is not associated with subfecundity or subfertility. Fertil Steril 2003; 80:966–975.
Heck ET, Cobb WE. The neuropsychology of polycystic ovary syndrome. Arch Clin Neuropsychol 1991; 6:192–193.
Guzick DS, Talbott EO, Sutton-Tyrrell K, Herzog HC, Kuller LH, Wolfson SK Jr. Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case control study. Am J Obstet Gynecol 1996; 174:1224–1232.
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30:389–399.
Okasha M, McCarron P, McEwen J, Smith GD. Age at menarche: secular trends and association with adult anthropometric measures. Ann Hum Biol 2001; 28:68–78.
Polson DW, Adams J, Wadsworth J, Frank S. Polycystic ovaries: a common finding in normal women. Lancet 1988; 1:870–872.
Bilo L, Meo R, Valentino R, Di Carlo C, Striano S, Nappi C. Characterization of reproductive endocrine disorders in women with epilepsy. J Clin Endocrinol Metab. 2001;86(7):2950-6.
Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J 1986; 29:355–359.
Hall JE. Polycystic ovarian disease as a neuroendocrine disorder of the female reproductive axis. Endocrinol Metab Clin North Am 1993; 22:75–92.
Filicori M. The role of luteinizing hormone in folliculogenesis and ovulation induction. Fertil Steril 1999; 71:405–414.
Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 1996; 81:2854–2864.
Spratt DI, Finkelstein JS, Butler JP, Badger TM, Crowley WF Jr. Effects of increasing the frequency of low doses of gonadotropin releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men. J Clin Endocrinol Metab 1987; 64:1179–1186.
Nappi C, Meo R, Di Carlo C, Estraneo A, Bilo L. Reduced fertility and neuroendocrine dysfunction in women with epilepsy. Gynecol Endocrinol 1994; 8:133–145.
Katsikis I, Karkanaki A, Misichronis G, Delkos D, Kandaraki EA, Panidis D. Phenotypic expression, body mass index and insulin resistance in relation to LH levels in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2011; 156:181–185.
Herzog AG. Temprolimbic brain dysfunction − role in reproductive endocrine disorders. Fertil Steril 1996; 65:210–211.
Murialdo G, Galimberti CA, Magri F, Sampaolo P, Copello F, Gianelli MV et al.
Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy. J Endocrinol Invest 1997; 20:519–526.
Zhou JQ, Zhou LM, Chen LJ, Han JD, Wang Q, Fang ZY et al.
Polycystic ovary syndrome in patients with epilepsy: a study in 102 Chinese women. Seizure 2012; 21:729–733
Morrell MJ, Giudice L, Flynn KL, Seale CG, Paulson AJ, Doñe S et al.
Predictors of ovulatory failure in women with epilepsy. Ann Neurol 2002; 52:704–711.
Sahota P, Prabhakar S, Kharbanda PS, Bhansali A, Jain V, Das CP, Modi M. Seizure type, antiepileptic drugs, and reproductive endocrine dysfunction in Indian women with epilepsy: a cross-sectional study. Epilepsia 2008; 49:2069–2077.
Verrotti A, Basciani F, Morresi S, Cutarella R, Morgese G, Chiarelli F. Serum sex hormone levels in young male patients with epilepsy receiving carbamazepine and valproic acid and after their withdrawal. Eur J Pediatr 2000; 159:871–872.
de Varies L, Karasik A, Landau Z, Phillip M, Kiviti S, Goldberg-Stern H. Endocrine effects of valproate in adolescent girls with epilepsy. Epilepsia 2007; 48:470–477.
Franceschi M, Perego L, Cavagnini F, Cattaneo AG, Invitti C, Caviezel F et al.
Effects of long-term antiepileptic therapy on the hypothalamic-pituitary axis in men. Epilepsia 1984; 25: 46–52.
Murialdo G, Galimberti CA, Gianelli MV, Rollero A, Polleri A, Copello F et al.
Effects of valproate, Phenobarbital, and carbamazepine on sex steroid setup in women with epilepsy. Clin Neuropharmacol 1998; 21:52–58.
Scharfman HE, Kim M, Hintz TM, MacLusky NJ. Seizures and reproductive function: insight from female rats with epilepsy. Ann Neurol 2008; 64:687–697.
Isojärvi JI, Rättyä J, Myllylä VV, Knip M, Koivunen R, Pakarinen AJ et al.
Valproate, lamotrigine, and insulin mediated risks in women with epilepsy. Ann Neurol 1998; 43:446–450.
Verrotti A, Mencaroni E, Cofini M, Castagnino M, Leo A, Russo E, Belcastro V. Valproic acid metabolism and its consequences on sexual functions. Curr Drug Metab 2016; 17:573–581.
Wise PM. Estradiol-induced daily luteinizing hormone and prolactin surges in young and middle-aged rats: Correlations with age-related changes in pituitary responsiveness and catecholamine turnover rates in microdissected brain areas. Endocrinology 1984; 115:801–809.
Downs JL, Wise PM. The role of the brain in female reproductive aging. Mol Cell Endocrinol 2009; 299:32–38.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]