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Previous Volume 329:1383-1388 November 4, 1993 Number 19 Next

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ABSTRACT

Background Reproductive endocrine disorders are more common among women with epilepsy than among normal women. These disorders have been attributed to epilepsy itself, but could be related to antiepileptic-drug therapy.

Methods We studied 238 women with epilepsy who were seen regularly at the Outpatient Department of the University Hospital, Oulu, Finland. Their mean age was 33 years (range, 18 to 45), and the mean duration of therapy was 9 years (range, 0 to 31). Twenty-nine (12 percent) were treated with valproate, 120 (50 percent) with carbamazepine, 12 (5 percent) with valproate and carbamazepine, and 62 (26 percent) with other medications; 15 (6 percent) were untreated. Vaginal ultrasonography was performed to determine ovarian size, and serum sex-hormone concentrations were measured in 41 women with epilepsy and menstrual disturbances, 57 women with epilepsy and regular menstrual cycles, and 51 normal women.

Results Menstrual disturbances were present in 13 of the women receiving valproate alone (45 percent), 3 of the women receiving valproate in combination with carbamazepine (25 percent), 23 of the women receiving carbamazepine (19 percent), and 8 of those receiving other medications (13 percent). Forty-three percent of the women receiving valproate had polycystic ovaries, and 17 percent had elevated serum testosterone concentrations without polycystic ovaries; 50 percent of the women receiving valproate and carbamazepine had polycystic ovaries, and 38 percent had elevated serum testosterone concentrations without polycystic ovaries. Eighty percent of the women treated with valproate before the age of 20 years had polycystic ovaries or hyperandrogenism.

Conclusions Menstrual disturbances, polycystic ovaries, and hyperandrogenism are often encountered in women taking valproate for epilepsy.

Antiepileptic-drug therapy is associated with changes in the serum concentrations of sex hormones. Antiepileptic medications that induce liver enzymes also increase the serum concentrations of sex hormone-binding globulin, resulting in decreases in serum free androgen concentrations. Moreover, serum dehydroepiandrosterone concentrations decrease^7,8,9. The endocrine disorders that occur in women with epilepsy may therefore be caused by the therapy rather than the epilepsy itself. With respect to particular antiepileptic drugs, menstrual cycles appear to remain ovulatory in women treated with carbamazepine despite alterations in serum sex hormone concentrations,⁷ whereas amenorrhea has been recognized as a side effect of valproate therapy¹⁰. The possible underlying hormonal effects of valproate, however, have not been studied.

The reports of reproductive endocrine disorders in women with epilepsy are based on studies of relatively small numbers of women and therefore do not allow the evaluation of possible associations between the antiepileptic medications and the reproductive disorders^2,3. The purpose of this study was to determine the frequency and types of reproductive endocrine disorders in a large group of women with epilepsy and to analyze the effects of the type of seizure, the frequency of seizures, and antiepileptic therapy on the occurrence of these disorders.

Methods

Study Subjects

This cross-sectional study was carried out with the approval of the Ethics Committee of the Medical Faculty, University of Oulu, Oulu, Finland, and informed consent was obtained from all the women.

Between April 1991 and March 1992 all 273 women between 18 and 45 years old with all types of epilepsy who were being followed in the Outpatient Department of the University Hospital of Oulu were interviewed (Table 1). We obtained the medical history of each woman by interviewing her and examining her hospital records. Thirty-five women were excluded because they were taking an oral contraceptive or other medication, had illnesses that interfered with pituitary-gonadal function, or had undergone hysterectomy.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the 273 Women with Epilepsy Considered for the Study.

 
Of the remaining 238 women, 200 (84 percent) had idiopathic epilepsy. The type of seizure was classified according to the recommendations of the International League against Epilepsy¹¹. Other clinical characteristics of these women are shown in Table 2. The medication used was chosen according to accepted European guidelines; carbamazepine (Neurotol or Tegretol) was the most commonly used drug in women with both primary generalized and partial seizures, followed by valproate. Combination therapy was used mostly in refractory cases in which the woman did not become seizure-free with single-drug therapy.

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics of the 238 Women with Epilepsy Who Were Studied.

 
The mean (±SD) dose of valproate was 1043 ±306 mg per day, and the mean serum valproate concentration at the time of this study was 65 ±30 mg per liter in the women treated with valproate alone; the respective values were 1309 ±381 mg per day and 53 ±26 mg per liter in the women treated with valproate and carbamazepine. The doses of carbamazepine and serum carbamazepine concentrations were 553 ±188 mg per day and 6.5 ±1.6 mg per liter, respectively, in the women treated with carbamazepine alone and 750 ±265 mg per day and 6.4 ±1.7 mg per liter in those treated with carbamazepine and valproate.

Infertility problems and menstrual disturbances were identified. The following were considered menstrual disorders if they had been present for at least six months: amenorrhea (no menstruation), oligomenorrhea (cycle length longer than 35 days), prolonged menstrual cycles (cycle length varying from less than 35 days to more than 35 days), or irregular menstrual cycles (length varying more than 4 days from cycle to cycle, between 22 and 35 days)¹². All the women who had a history of menstrual disorders then underwent a pelvic examination, an examination for hirsutism, vaginal ultrasonography of the ovaries, and laboratory studies, with the exception of three women who were pregnant at the time of the study and three women who declined to undergo these examinations (Table 1). The ovaries were considered polycystic if they contained a total of at least 10 cysts 2 to 8 mm in diameter arranged either peripherally around a dense core of stroma or scattered throughout an increased amount of stroma¹³. Venous-blood samples were obtained at 8 a.m. after an overnight fast during the early follicular phase of the menstrual cycle from the women who did not have amenorrhea. Samples were taken at random from the women with amenorrhea. We also performed the same studies in 57 women with epilepsy who had regular menstrual cycles to determine the prevalence of possible subclinical disorders. Among them were 13 women treated with valproate, 28 treated with carbamazepine, 5 treated with valproate and carbamazepine, and 11 treated with other medications. The basis for the selection of these 57 women was their use of valproate therapy alone or together with carbamazepine (18 women) or was random. We also studied 51 normal women (mean age, 35 years; range, 22 to 45) who volunteered to participate as a control group.

The body-mass index (the weight in kilograms divided by the square of the height in meters) was calculated. Women with a body-mass index exceeding 25 were considered obese¹².

Assays

Serum samples were kept frozen at -20 °C until analyzed. Serum testosterone and estradiol concentrations were measured by radioimmunoassay with kits obtained from Orion Diagnostica (Turku, Finland). The sensitivity of the testosterone assay was 0.07 ng per milliliter (0.24 nmol per liter), and the intraassay and interassay coefficients of variation were 4.5 percent and 6.4 percent, respectively. The respective values for the estradiol assay were 8.2 pg per milliliter (30.1 pmol per liter) and 6.0 and 8.0 percent. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin concentrations were measured by two-site fluoroimmunometric methods with kits obtained from Wallac Oy (Turku, Finland). The sensitivity of the FSH assay was 0.05 mIU per milliliter, and the intraassay and interassay coefficients of variation were 3.9 percent and 4.1 percent, respectively. The respective values for the LH assay were 0.05 mIU per milliliter and 5.0 and 5.3 percent, and the respective values for the sex hormone-binding globulin assay were 0.07 µg per milliliter (0.8 nmol per liter) and 6.7 and 6.4 percent. Serum free testosterone, dehydroepiandrosterone sulfate, and prolactin concentrations were measured by radioimmunoassay with kits obtained from Diagnostic Products (Los Angeles). The sensitivity of the free testosterone assay was 0.15 pg per milliliter (0.52 pmol per liter), and the intraassay and interassay coefficients of variation were 4.3 percent and 5.5 percent, respectively. The respective values for dehydroepiandrosterone sulfate were 22.1 ng per milliliter (0.06 µmol per liter) and 4.5 and 5.5 percent, and for prolactin they were 1.4 ng per milliliter (1.4 µg per liter) and 3.2 and 7.5 percent. Serum carbamazepine, phenytoin (Hydantin), and valproate concentrations were assayed by a fluorescence polarization immunoassay system (TDX, Abbott Diagnostic Division, Irving, Tex.). The sensitivity of the carbamazepine assay was 0.5 mg per liter (2.1 µmol per liter), and the intraassay and interassay coefficients of variation were 1.5 percent and 2.5 percent, respectively. These values were 0.3 mg per liter (1.3 µmol per liter) and 2.0 and 2.6 percent, respectively, for the phenytoin assay, and 0.7 mg per liter (0.005 mmol per liter) and 2.3 and 3.1 percent for the valproate assay.

Statistical Analysis

Chi-square tests and analysis of variance with the Bonferroni correction (two-tailed) were used to analyze the results.

Results

The mean age of the 238 women was 33 years, and the mean duration of therapy for epilepsy was 9 years (range, 0 to 31). Forty-seven of the women (20 percent) had menstrual disturbances (Table 1). Their frequency was unrelated to the type of epilepsy, being 21 percent in women with primary generalized seizures, 18 percent in women with partial seizures, and 21 percent in women with partial seizures leading to secondary generalization. None of the 15 women who were not taking any antiepileptic medication had menstrual disturbances. The frequency of menstrual disturbances in the normal women was 16 percent. The relation between menstrual disturbances and the type of antiepileptic therapy is shown in Table 3. Thirteen (45 percent) of the women receiving valproate alone had menstrual disturbances, as compared with 23 (19 percent) of those receiving carbamazepine alone (P = 0.004). Six women receiving valproate alone or combined with carbamazepine (15 percent), 21 women taking medication not including valproate (11 percent), and 2 women not taking any medication (13 percent) reported being infertile.

View this table: [in this window] [in a new window]   Table 3. Frequency of Menstrual Disturbances in 238 Women with Epilepsy and 51 Normal Women.

 
One woman receiving valproate alone (3 percent), one woman receiving carbamazepine alone (1 percent), two women receiving valproate and carbamazepine (17 percent), and none of the women receiving other medications or not taking any antiepileptic drug were hirsute. The results of the gynecologic and laboratory examinations in relation to the medication being taken are shown in Table 4. Polycystic ovaries and elevated serum testosterone concentrations with normal ovaries were the most frequent findings in women with menstrual disturbances. Almost all the women receiving valproate alone who had menstrual disturbances had either polycystic ovaries or an elevated serum testosterone concentration. Two of the three women receiving valproate and carbamazepine who had menstrual disturbances had polycystic ovaries. In the women whose medication did not include valproate, polycystic ovaries were less common (P = 0.02). Among the normal women, seven of the eight (88 percent) with menstrual disorders had polycystic ovaries. None of the women who had menstrual disturbances had elevated serum prolactin concentrations.

View this table: [in this window] [in a new window]   Table 4. Number of Women with Epilepsy Who Had Polycystic Ovaries or Elevated Serum Testosterone Concentrations, According to Whether Their Menstrual Cycles Were Normal or Abnormal.

 
No woman taking medication other than valproate who had normal ovaries had an elevated serum testosterone concentration. Three women receiving combination therapy other than valproate and carbamazepine and one woman receiving carbamazepine alone had premature menopause, defined as the cessation of menstruation before the age of 40 years, together with elevated serum gonadotropin concentrations. Another woman receiving carbamazepine alone had hypergonadotropic hypogonadism presenting as primary amenorrhea.

Polycystic ovaries, elevated serum testosterone concentrations, or both were also associated with valproate therapy in women with regular menstrual cycles. They were found in 10 of the women receiving valproate alone or in combination with carbamazepine (56 percent). The frequency of polycystic ovaries was lower (13 percent) in women with regular menstrual cycles who were receiving other medications (P<0.001). Two of the normal women with regular menstrual cycles (5 percent) had polycystic ovaries.

Of the 31 women receiving valproate alone or combined with carbamazepine, 21 (68 percent) had polycystic ovaries or high serum testosterone concentrations. The frequency of polycystic ovaries in the women receiving carbamazepine alone was 22 percent, and it was 18 percent in the normal women.

The presence of polycystic ovaries was associated with elevated serum testosterone concentrations or obesity in all women with menstrual disturbances who were taking valproate and in 83 percent of the women with regular menstrual cycles who were taking valproate. The comparable values for women with polycystic ovaries who were taking other medications were 62 percent and 40 percent, respectively.

The hormonal results in the women with epilepsy and the normal women are shown in Table 5. The serum testosterone (P<0.001), free testosterone (P = 0.008), and dehydroepiandrosterone sulfate (P<0.001) concentrations were higher in the women receiving valproate alone than in the normal women. The valproate-treated women with menstrual disturbances had higher serum free testosterone concentrations (P<0.001) and lower serum sex hormone-binding globulin concentrations (P = 0.03) than the valproate-treated women who had regular menstrual cycles. Serum free testosterone concentrations were also elevated in the women taking valproate and carbamazepine (P = 0.006 for the comparison with values in normal women). The women taking carbamazepine alone or valproate and carbamazepine had elevated serum sex hormone-binding globulin concentrations (P<0.001). The women taking other medications (mainly long-term combination therapy including carbamazepine or phenytoin) had elevated serum sex hormone-binding globulin (P<0.001), LH (P = 0.004), and FSH concentrations (P = 0.002) and decreased serum dehydroepiandrosterone sulfate concentrations (P = 0.001). The high serum sex hormone-binding globulin and gonadotropin concentrations in women with menstrual disorders in this group were due to the elevated levels in three women with premature menopause.

View this table: [in this window] [in a new window]   Table 5. Serum Sex Hormone and Sex Hormone-Binding Globulin Concentrations in Women with Epilepsy and Normal Women.

 
Polycystic ovaries or elevated serum testosterone concentrations were more common in women who had started taking valproate or other medications in adolescence (Figure 1). Eighty percent of the women treated with valproate before the age of 20 years had polycystic ovaries or an elevated serum testosterone concentration, as compared with 27 percent of the women treated with other antiepileptic drugs (P = 0.002). Among the women who were treated at the age of 20 years or afterward, 56 percent of women receiving valproate had had polycystic ovaries or an elevated serum testosterone concentration, as compared with 20 percent of the women receiving other drugs (P = 0.004).

View larger version (16K): [in this window] [in a new window]   Figure 1. Occurrence of Polycystic Ovaries (Solid Bars) and Elevated Serum Testosterone Concentrations (Open Bars) in Women with Epilepsy, According to the Age at Which Treatment with Valproate (N = 31) or Other Antiepileptic Drugs (N = 67) Was Begun. Differences between groups were analyzed with the chi-square test.

 
Discussion

Menstrual disturbances were found in 20 percent of the 238 women with epilepsy in our study. Among them, polycystic ovaries or elevated serum testosterone concentrations were the most common underlying abnormalities. They were found in a majority of the women receiving valproate and were more common when treatment had been started before the age of 20 years.

Almost half the women receiving valproate alone had menstrual disturbances, whereas the frequency among women taking carbamazepine alone or other medications not including valproate was similar to that in the normal women we studied and that reported previously in the general population¹⁴.

Reproductive endocrine disorders in women with epilepsy have been attributed primarily to their epilepsy^2,3. However, our results indicate that valproate may often be responsible for these disorders, and a large majority of the women receiving valproate alone or in combination with carbamazepine had polycystic ovaries or an elevated serum testosterone concentration. Most of the women with polycystic ovaries or hyperandrogenism had menstrual disturbances. It is not known whether an isolated ultrasonographic finding of polycystic ovaries without symptoms indicates an earlier stage of a symptomatic form of the syndrome; therefore, the clinical importance of such a finding is uncertain.

Polycystic ovaries, hyperandrogenism, obesity, menstrual disturbances, and hirsutism are the clinical characteristics of the polycystic ovary syndrome, although the full-blown syndrome is relatively rare¹⁵. These features also characterize the endocrine disorders associated with valproate therapy among women with epilepsy, especially those who began treatment in adolescence.

The mechanism by which valproate could cause polycystic ovaries and elevated serum androgen concentrations is unclear. -aminobutyric acid neurons seem to modulate noradrenergic inputs to gonadotropin-releasing hormone (GnRH) neurons, which are important in the pulsatile control of and the ovulatory surge in the secretion of GnRH and LH¹⁶. In addition to having a direct action on nerve-cell membranes, valproate modifies -Aminobutyric acid-ergic neurotransmission,¹⁷ through which it could alter the secretion of gonadotropins. However, the polycystic ovary syndrome is usually associated with hyperandrogenism, elevated serum LH concentrations, high ratios of LH to FSH in serum, and enhanced secretory responses of LH to GnRH,^15,18 whereas the valproate-treated women with polycystic ovaries or elevated serum testosterone concentrations did not have increased serum LH concentrations. In addition, in previous studies women receiving valproate had normal or low serum LH concentrations, blunted or normal serum LH responses to GnRH, and normal pulsatile secretion of LH^19,20,21. Therefore, the effect of valproate on ovarian function and androgen production does not seem to be caused by altered pituitary LH secretion. Alternative explanations include an effect on ovarian androgen formation. Serum estradiol concentrations were not elevated in the valproate-treated women despite their elevated serum testosterone concentrations, suggesting that valproate inhibits the conversion of testosterone to estradiol.

The frequency of polycystic ovaries in women receiving medication other than valproate was low and did not differ from that in the normal women we studied. Furthermore, none of the women taking other medications for epilepsy had elevated serum testosterone concentrations. These findings are in accordance with a previous report that serum testosterone concentrations do not change and menstrual cycles remain ovulatory during the first year of carbamazepine treatment⁷.

Valproate is an effective drug in patients with epilepsy, especially children with petit mal epilepsy, and it also is effective in patients with secondarily generalized tonic-clonic seizures²². Nevertheless, our findings of valproate-associated reproductive endocrine disorders raise concern about the use of valproate as antiepileptic therapy in young women with epilepsy.

Supported by a grant from the Epilepsy Research Foundation of Finland.

We are indebted to Mrs. Anja Heikkinen for her excellent assistance in collecting the blood samples and performing the laboratory analyses.

Source Information

From the Departments of Neurology (J.I.T.I., V.V.M.), Obstetrics and Gynecology (T.J.L., K.T.S.J.), and Clinical Chemistry (A.J.P.), University of Oulu, Oulu, Finland.

Address reprint requests to Dr. Isojarvi at the Department of Neurology, University of Oulu, SF-90220 Oulu, Finland.

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