The Effects of Valproate, Carbamazepine, and Oxcarbazepine on Growth

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DOI:10.1542/peds.103.3.5881999;103;588-593PediatricsIsojrvi

Johanna Rtty, Leena Vainionp, Mikael Knip, Peter Lanning and Jouko I.T.Sexual Maturation in Girls With Epilepsy

The Effects of Valproate, Carbamazepine, and Oxcarbazepine on Growth and

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The Effects of Valproate, Carbamazepine, and Oxcarbazepine on Growthand Sexual Maturation in Girls With Epilepsy

Johanna Rattya, MD*; Leena Vainionpaa, MD, PhD; Mikael Knip, MD, PhD; Peter Lanning, MD, PhD;

and Jouko I. T. Isojarvi, MD, PhD*

ABSTRACT. Objective. Antiepileptic drugs (AEDs)have endocrine effects that may interfere with growthand sexual maturation in children. The aim of this studywas to evaluate the effects of AEDs on growth and pu-bertal development in girls with epilepsy.

Study Design. Forty girls taking valproate (VPA), 19girls taking carbamazepine (CBZ), and 18 girls takingoxcarbazepine (OXC) for epilepsy and 49 healthy controlgirls participated in the study, which included a cross-sectional clinical examination when the girls were 8 to 18years old and a longitudinal growth analysis from the

age of 1 year.Results. VPA, CBZ, or OXC did not affect lineargrowth or pubertal development in girls with epilepsy.However, the patients taking VPA gained weight, and anincrease in relative weight was seen in girls who startedtheir medication before as well as during puberty. Thebody mass index of the VPA-treated girls (19.8 4.8kg/m2) was higher than that of the control girls (18.0 2.5kg/m2) at clinical examination. The weight of the girlstaking CBZ or OXC for epilepsy was similar to that of thecontrol girls. Plasma insulin-like growth factor-I (IGF-I)levels were higher in girls treated with CBZ and OXCthan in the control girls, but AEDs did not affect fastingserum insulin, IGF-binding protein-1, or IGF-bindingprotein-3 concentrations in girls on VPA, CBZ, or OXCmedication during the period of exposure (average 2.8,4.1, and 1.9 years, respectively) in this study.

Conclusions. AEDs do not seem to have any adverseeffects on linear growth or sexual maturation in girlswith epilepsy. VPA-related weight gain can be seen al-ready in prepuberty and it is not associated with hyper-insulinemia in these young patients. The clinical signif-icance of high circulating concentrations of IGF-I inpatients taking CBZ or OXC remains to be defined.Pediatrics 1999;103:588593; girls, epilepsy, antiepilepticdrugs, growth, sexual maturation, insulin, insulin-likegrowth factor-I, insulin-like growth factor binding pro-teins -1 and -3.

ABBREVIATIONS. AED, antiepileptic drug; VPA, valproate; CBZ,carbamazepine; IGFBP, insulin-like growth factor binding protein;OXC, oxcarbazepine; BMI, body mass index; SDS, standard devi-ation score; IGF, insulin-like growth factor; RIA, radioimmunoas-say; GH, growth hormone.

Reproductive endocrine disorders are morecommon among patients with epilepsy than inthe average population of similar age.1 These

disorders have frequently been attributed to epilepsyitself,2,3 especially to partial epilepsy of temporal lobeorigin, but also antiepileptic drugs (AEDs) have var-ious effects on endocrine functions in adult patientswith epilepsy.4 7 Because growth and sexual matura-tion in adolescence are regulated by a complex neu-roendocrine system,8 potential AED-related endo-

crine abnormalities may be reflected in growth andpubertal development in young patients with epi-lepsy.

A high frequency of hyperandrogenism, hyperin-sulinemia, and polycystic ovaries has recently beenreported among women taking valproate (VPA) forepilepsy. These disorders seem to be more commonamong women who have gained weight duringtreatment.5,6 Furthermore, VPA seems to exert someinfluence on thyroid hormone function in both gen-ders.9 Increased relative weight has also been re-ported during VPA treatment in children with epi-lepsy, although some authors have suspected that

the weight gain may not be a consequence of VPAtherapy.10,11

Carbamazepine (CBZ) medication is associatedwith altered serum concentrations of sex steroids,thyroid hormones, sex hormone binding globulin,and insulin-like growth factor binding protein 3(IGFBP-3) in adults.1214 These endocrine changesmay result in hyposexuality, impotence, andmenstrual disorders in patients with epilepsy.1214

Oxcarbazepine (OXC) is not known to induce anyendocrine dysfunction.15,16

CBZ and OXC are the first-line drugs in the treat-ment of epilepsies of focal origin in both adult and

pediatric patients in Finland. VPA, on the otherhand, is a widely used drug in primary generalizedepilepsies during childhood and adolescence. Theaim of this study, therefore, was to evaluate growthand sexual maturation in girls taking VPA, CBZ, orOXC monotherapy for epilepsy.

PATIENTS AND METHODS

The study was conducted in the Outpatient Departments ofPediatrics and Neurology, Oulu University Hospital, with theapproval of the Ethics Committee of the Medical Faculty, Univer-sity of Oulu, and according to the principles of the Declaration ofHelsinki. Epilepsy type was classified according to the recommen-dations of the International League Against Epilepsy.17

From the Departments of *Neurology, Pediatrics, and Radiology, Univer-

sity of Oulu, Oulu, Finland.

Received for publication May 5, 1998; accepted Sep 8, 1998.

Reprint requests to (J.R.) Department of Neurology, University of Oulu,

Kajaanintie 50, 90220 Oulu, Finland.

PEDIATRICS (ISSN 0031 4005). Copyright 1999 by the American Acad-

emy of Pediatrics.

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growth curve of the control group from the age of 3years (data not shown). The growth spurt occurred

between ages 11 and 15 years both in VPA-treatedgirls and in the controls. The patients were, on aver-age, 9.7 3.5 (standard deviation) years old whenthe medication was started. The growth charts,which were drawn with this age as time 0, did notshow any change in relative height after the start ofthe medication (Fig 1A). However, the patientsstarted to gain weight slowly but progressively after

medication was initiated (Fig 1B). The prevalence ofobesity increased during medication from a fre-quency of 17.5% at the initiation of therapy to 50%after 6 years of therapy (P .04). This increase could

be seen for the first time after the fourth year oftreatment. Weight gain was similar in patients whostarted VPA therapy before puberty and in thosewho started VPA during puberty (data not shown).The weight gain was not reflected in an increasedgrowth velocity in girls with epilepsy. The relativeweight of the control group decreased sharply whenthe growth velocity increased (data not shown).

Sexual maturation did not differ between the pa-tients taking VPA for epilepsy and their controls

Fig 1. Mean relative height (SEM) (A) and mean relative weight(B) in patients taking valproate for epilepsy (-f-), and in thecontrols (-F-) at the same ages, in relation to duration of therapy.Time point zero is the onset of medication, and the negativenumbers represent the time in years before medication wasstarted. The patients and the control girls were 9.7 years old atthe time point zero. The number of study participants at varioustime-points are expressed as numbers along the curves in A. *P .05, ** P .001.T

ABLE

2.

AnthropometricMeasuresoftheGirlsWithEpilepsyandTheirControlsatClinicalExamination*

Study

Participants

No.of

Pairs

Age(y)

Height

(cm)

Relative

Heig

ht

(SDS)

Target

Height

(SDS)

Weight

(kg)

Relative

Weight

(%)

BMI

(kg/m2)

Waist-Hip

Ratio

Waist-Thigh

Ratio

PatientsonVPA

40

1

2.4

3.1

149.5

15.3

0.05

1.1

0.11

0.7

45.8

18.5

109.8

22.5

19.8

4.8

0.80

0.06

1.87

0.15

Controls

1

2.4

3.0

150.2

14.8

0.04

1.0

0.41

0.6

41.5

11.8

100.6

11.2

18.0

2.5

0.77

0.09

1.82

0.21

P

value

.1

.1

.07

.06

.04

.03

.1

.1

PatientsonCBZ

18

1

2.7

3.3

152.7

14.3

0.46

1.2

0.13

0.6

44.5

12.6

104.4

16.8

19.0

3.3

0.80

0.07

1.90

0.20

Controls

1

2.6

3.2

154.4

14.5

0.59

1.0

0.52

0.4

43.1

12.4

99.3

10.9

17.9

2.5

0.73

0.14

1.74

0.31

P

value

.1

.1

.1

.1

.1

.1

.1

.1

PatientsonOXC

18

1

2.7

3.0

146.5

12.5

0.20

1.0

0.06

0.7

40.8

10.0

101.4

11.9

18.0

2.3

0.78

0.04

1.86

0.12

Controls

1

2.7

3.0

152.5

10.8

0.21

0.6

0.34

0.6

42.4

9.6

99.6

11.5

18.0

2.4

0.79

0.07

1.86

0.15

P

value

.05

.1

.1

.1

.1

.1

.1

.1

Abbreviations:SDS,standarddeviation

score;BMI,bodymassindex;VPA,valproate;CBZ,carbamazepine;OXC,oxcarb

azepine.

*Valuesaremeans

standarddeviations(SD).

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(Table 3), and there were no differences in bone age(data not shown). Plasma concentrations of IGF-I andserum concentrations of insulin, IGFBP-1, andIGFBP-3 were similar in VPA-treated girls and inthe control group (Table 4).

Patients on CBZ

The girls taking CBZ for epilepsy were as tall astheir age-matched controls at clinical examination,and there were no differences in BMI or relative

weight between the two groups (Table 2).According to the growth curves, the growth spurtin the CBZ group seemed to begin at the age of 13years, while the control group started their growthspurt 2 years earlier (data not shown). The growthcharts, which were drawn with the age when CBZwas started as time 0, did not show any change inrelative height or weight after the start of the medi-cation (Fig 2.A, B).

The bone age and the pubertal stage did not differbetween the girls taking CBZ for epilepsy and theircontrols at clinical examination (Table 3). The plasmaconcentrations of IGF-I were increased in the CBZgroup (P .001), but the serum insulin, IGFBP-1, andIGFBP-3 levels were similar to those of the controlgroup (Table 4).

Patients on OXC

The height of the patients who started OXC inpuberty was similar to that of the controls, but thegirls who had started OXC in prepuberty were 5.5cm shorter (P .03) than the control group at clinicalexamination, although there was no significant dif-ference in their target height. The girls taking OXCfor epilepsy and the controls had similar relativeweight, BMI, and waist-hip and waist-thigh ratios(Table 2).

The linear growth curve of OXC-treated girls ranat a level 0.3 to 0.5 SDS lower than that of the controlgroup, and the patients were significantly (P .006)shorter at the age of 15 to 17 years (data not shown).The growth charts, which were drawn with the agewhen OXC was started as time 0, did not show anychange in relative height after the start of the medi-cation (Fig 3A, B).

The pubertal development of girls who startedOXC in prepuberty was delayed: the clinical signs ofpuberty, ie, pubic hair and breast stages, were moreimmature (P .04 and .02, respectively) at the timeof clinical examination in patients compared with

those of the control group. However, the sexual mat-uration in the mothers of the OXC-treated patientsalso tended to be delayed according to an older ageat menarche. Sexual maturation did not differ be-tween the girls who started OXC in puberty and thecontrols, and bone age was similar in both groups(data not shown).

The plasma concentrations of IGF-I were higher inOXC-treated girls with epilepsy than in the controlgirls (P .004). There were no differences in the

serum concentrations of insulin, IGFBP-1, or IGFBP-3 between the patients taking OXC and the controlgroup (Table 4).

DISCUSSION

The results of this study show that relative weightincreases in girls taking VPA for epilepsy when com-pared with the control group, whereas it remainsunchanged during CBZ and OXC treatment. Thegirls, who started OXC in prepuberty were shorterthan their controls. Serum concentrations of insulin,IGFBP-1, and IGFBP-3 were normal in all threegroups of patients, but plasma concentrations ofIGF-I were high in those treated with OXC or CBZ.

The weight gain in VPA-treated girls was similarregardless of whether the medication was started

before or during puberty. Accordingly, these datasuggest that an adult mature endocrine system is notneeded for the development of VPA-related obesity.Although VPA-related weight gain has been studiedextensively, the present study is the first to compareVPA-related weight gain between girls who startedVPA before puberty and those who started VPA inpuberty.

A gradual but progressive weight gain was ob-served in girls with epilepsy after VPA medicationwas started. It has been suggested previously that

VPA-related weight gain in children may be notice-able shortly after initiating the medication, but thedoses of VPA used in those patients were high: 25 to30 mg/kg.10 In our study, the doses were smaller,averaging 16.5 mg/kg (8.727.5 mg/kg). This mayindicate that the higher the VPA dose, the faster theweight gain.

Previous studies suggest that VPA-related weightgain is progressive in nature,5 which is confirmed bythe weight curve of the VPA-treated girls in thepresent survey. Only early in puberty, when the girlshad their growth spurt, was there a 3-year plateau inweight gain, but at the same time the weight curve of

TABLE 3. Stage of Puberty (Median) and Age of Menarche in Girls With Epilepsy, Their Mothers, and the Controls

Study Participants No. ofPairs

Stageof Breast

Stage ofPubic Hair

Age atMenarche* (y)

Age at Menarchein Mothers* (y)

Patients with VPA 40 2.6 (2) 2.5 (2) 13.0 1.1 13.3 1.5Controls 2.5 (2) 2.5 (2) 12.7 0.8 12.8 1.2P value .1 .1 .1 .1Patients with CBZ 18 2.7 (3) 2.5 (2) 12.5 1.0 13.5 2.0Controls 2.6 (3) 2.6 (3) 12.4 0.8 13.0 1.2P value .1 .1 .1 .1Patients with OXC 18 2.4 (2) 2.4 (2) 13.2 1.0 14.0 1.7Controls 2.7 (2) 2.8 (2) 13.1 0.6 12.9 1.1P value .1 .1 .1 .1

Abbreviations: VPA, valproate; CBZ, carbamazepine; OXC, oxcarbazepine. * Values are means SD.

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the control group decreased sharply. Neither VPAmedication itself nor the associated weight gainseemed to affect linear growth or pubertal develop-ment, because both relative height and sexual matu-ration were similar in patients taking VPA and intheir controls.

Hyperinsulinemia and low serum IGFBP-1 con-centrations have previously been reported as charac-teristic features in obese adult women taking VPAfor epilepsy.5 Thus, it was surprising that the serum

concentrations of insulin and IGFBP-1 were normalin VPA-treated girls with epilepsy in the presentstudy. However, they had taken VPA only for anaverage of 2.8 years, whereas the adult women withhyperinsulinemia had been on VPA for a mean of 7years.5 Furthermore, in adult women, the elevatedserum insulin levels were associated with obesity(mean BMI, 26.0 kg/m2), whereas the average BMI ofour patients was 19.8 kg/m2. These data suggest that

TABLE 4. Plasma Concentrations of IGF-I and Serum Concentrations of IGFBP-3, Insulin, and IGFBP-1 in Girls With Epilepsy and inthe Controls*

Study Participants No. ofPairs

IGF-I(nmol/L)

IGFBP-3(mg/L)

Insulin(mU/L)

IGFBP-1(g/L)

Patients on VPA 38 38.8 18.3 3.3 0.6 5.8 4.0 3.3 0.6Controls 33.6 12.8 3.6 0.6 6.5 3.0 3.6 0.6P values .1 .1 .1 .1Patients on CBZ 17 51.7 20.6 3.8 0.6 7.0 3.4 3.8 0.6Controls 36.2 14.5 3.6 0.6 7.1 3.5 3.6 0.6P values .001 .1 .1 .1Patients on OXC 16 52.9 25.3 3.7 0.6 7.3 4.9 3.7 0.6

Controls 35.9

12.6 3.6

0.7 6.7

3.0 3.6

0.7P values .004 .1 .1 .1

Abbreviations: IGF, insulin-like growth factor; IGFBF, insulin-like growth factor binding protein; VPA, valproate; CBZ, carbamazepine;OXC, oxcarbazepine.*Values are means SD.

Fig 2. Mean relative height (SEM) (A) and mean relative weight(B) in patients taking carbamazepine for epilepsy (-f-), and in thecontrol group (-F-) at the same ages, in relation to duration oftherapy. Time point zero is the onset of medication, and thenegative numbers represent the time in years before medicationwas started. The patients and the control girls were 8.5 years old

at the time point zero. The number of study participants at varioustime-points are expressed as numbers along the curves in A.

Fig 3. Mean relative height (SEM) (A) and mean relative weight(B) in patients taking oxcarbazepine for epilepsy (-f-), and in thecontrol group (-F-) at the same ages, in relation to duration oftherapy. Time point zero is the onset of medication, and thenegative numbers represent the time in years before medicationwas started. The patients and the control girls were 10.9 years

old at the time point zero. The number of study participants atvarious time-points are expressed as numbers along the curvesin A.

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insulin resistance and hyperinsulinemia are a conse-quence rather than a cause of VPA-related weightgain. However, the pathomechanism of VPA-relatedweight gain has so far remained open.

The growth hormone (GH)-IGF-I-system is themost important regulator of postnatal growth.8 Thecirculating concentrations of IGF-I and IGFBP-3 re-flect the endogenous secretion of GH and are thususeful parameters for clinical purposes when evalu-ating growth disorders.24 Short-term exposure to

VPA is known to stimulate GH release,25

but theresults of the present study suggest that endogenousGH secretion is not increased during long-term VPAtreatment, because linear growth was not acceleratedand the circulating concentrations of IGF-I andIGFBP-3 remained normal. Plasma levels of IGF-Iwere also normal in women taking VPA for epi-lepsy.5

The patients who started to take OXC for epilepsy before puberty were shorter than their controls, al-though their target height and bone age were similar tothose of the control girls. Moreover, their pubertal mat-uration was delayed according to the clinical signs ofpuberty. This may, however, be attributable to geneticfactors, because the mothers of the girls treated withOXC had experienced their menarche an average ofmore than 1 year later than mothers of the controls.

The plasma concentrations of IGF-I were high inpatients taking CBZ or OXC for epilepsy. However,the increased plasma IGF-I levels did not result inaccelerated growth. This suggests that the high IGF-Ilevels are not mediated by an increased GH secretionor nutritional factors. High levels of both IGF-I andIGFBP-3 have previously been reported in the pe-ripheral circulation of women taking CBZ for epilep-sy.5 Both are mainly synthesized in the liver, and theelevated circulating concentrations were attributed

to the liver enzyme-inducing properties of CBZ.5 Inthe present study, the serum concentrations ofIGFBP-3 were normal in the CBZ group as well as inpatients treated with OXC. High serum concentra-tions of IGF-I have not been previously reported inpatients taking OXC for epilepsy. Although OXC isnot as strong an inducer of liver enzymes as CBZ,15 itseems to stimulate the hepatic production of IGF-I tothe same extent as CBZ. The clinical consequences ofthe elevated peripheral IGF-I levels in OXC- or CBZ-treated girls with epilepsy remain to be established.

CONCLUSION

In conclusion, serum concentrations of insulin,IGFBP-1, and IGFBP-3 were normal in girls on VPA,although hyperinsulinemia and low serum IGFBP-1and IGFBP-3 concentrations have been reported ascharacteristic features in adult women taking VPAfor epilepsy.5 Plasma concentrations of IGF-I werehigh in girls on OXC and CBZ, but it was not relatedto accelerated linear growth. Serum insulin, IGFBP-1,and IGFBP-3 levels were normal in patients on CBZ,although they have been observed to be high inwomen on CBZ.5 The girls treated with VPA gainedweight regardless of whether the drug was startedwhen they were prepubertal or pubertal. These datasuggest that a mature endocrine system of the adult

type may not be necessary for the development ofVPA-related obesity. The weight gain in patientstreated with VPA was slow but progressive. Therefore,possible weight gain should be monitored carefully inchildren and adolescents during VPA treatment.

ACKNOWLEDGMENTS

This study was supported by a grant from the Alma and K. A.Snellman Foundation, Oulu, Finland.

We thank Sirpa Anttila for expert technical assistance.

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DOI:10.1542/peds.103.3.5881999;103;588-593PediatricsIsojrvi

Johanna Rtty, Leena Vainionp, Mikael Knip, Peter Lanning and Jouko I.T.Sexual Maturation in Girls With Epilepsy

The Effects of Valproate, Carbamazepine, and Oxcarbazepine on Growth and

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The Effects of Valproate, Carbamazepine, and Oxcarbazepine on Growth

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