Changes in circulating thyroid hormones during short-term hepatic enzyme induction with carbamazepine

Connell, John; Rapeport, WG; Gordon, Stuart R.; Brodie, Martin J.

doi:10.1007/bf00542140

Cited by 59 publications

(27 citation statements)

References 9 publications

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“…The finding of low serum T 4 and fT 4 concentrations in epileptic patients receiving CBZ is coherent with earlier reports (12,13,(19)(20)(21)(22)(23)(24)(25)(26). The large majority of these studies and also our data demonstrate that serum T 4 and fT 4 decreased whereas TSH levels remained unchanged.…”

Section: Discussionsupporting

confidence: 82%

“…Blank and Joffe (33,45) suggested that CBZ may alter thyroid hormone levels affecting directly TSH or TRH, but our data do not support this possibility. In agreement with other authors (5,19,26), TSH levels do not increase in CBZ-treated patients, the cause is not activated by the positive feedback mechanism, which should result from low serum thyroid hormone concentrations and serum thyroid hormone levels remain low. Moreover, TRHstimulated secretion of TSH is not increased during CBZ medication.…”

Section: Discussionsupporting

confidence: 76%

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Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate

Verrotti

Laus

Sereno

et al. 2009

European Journal of Endocrinology

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Objective: This study evaluates the effects of long-term carbamazepine (CBZ) and valproate acid (VPA) therapy on thyroid function in epileptic children. Design: A prospective study performed in 32 newly diagnosed pediatric patients, subdivided into two groups: 18 patients treated with CBZ and 14 patients treated with VPA. Thirty-two sex-and agematched subjects served as controls. Methods: Serum TSH, thyroxine (T 4 ), triiodothyronine (T 3 ), free thyroxine (fT 4 ), free triiodothyronine (fT 3 ), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (TG-Ab) were evaluated at baseline and at the 3rd, 6th, and 12th month in all patients and in the control group. A TRH stimulation test was performed in all epileptic patients at baseline and at the 3rd, 6th, and 12th month evaluations while in controls only baseline assessment was carried out. Results: At baseline evaluation, thyroid function was normal in all epileptic children. After 3 months, CBZ-treated patients showed serum T 4 and fT 4 levels significantly lower than baseline evaluation and control subjects. Serum T 4 and fT 4 concentrations were unaffected by VPA monotherapy. Serum T 3 and fT 3 were normal in both CBZ-treated and VPA-treated patients. TRH test was normal in all patients. At 6th and 12th month evaluations, the same alterations were present in CBZ-treated patients while thyroid function remained normal in VPA-treated patients. TRH test responses were normal in all epileptic patients. TPO-Ab and TG-Ab were always absent in all patients. Conclusions: Our data suggest that VPA monotherapy does not alter thyroid hormones. On the contrary, alterations of thyroid hormones occur in CBZ-treated children. However, the patients are euthyroid and thyroid hormone alterations are not associated with clinical or subclinical hypothyroidism.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 76%

Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate

Verrotti

Laus

Sereno

et al. 2009

European Journal of Endocrinology

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“…(1 2-14, 16,19,20,22,[23][24][25]27) T,, triiodothyronine; T,, thyroxine; IT4, free thyroxine, TSH, thyroid-stimulating hormone; TBG, thyroxine-binding globulin; CBZ, carbamazepine; VPA, valproate; PB, phenobarbital.…”

Section: Discussionmentioning

confidence: 99%

“…E-mail: pdcastro@uscmail.usc.es marked protein-binding activity, such as DPH and carbamazepine (CBZ) ( 3 3 , typically cause reduced levels of thyroxine (T,) and free thyroxine (FT,), but have variable effects on triiodothyronine (T3), free triiodothyronine (FT,), and thyroxine-binding globulin (TBG) levels, and no effect on TSH levels (12-14, 16,19,20,[22][23][24][25]. The effects of AEDs with enzyme-inducing activity but only weak protein-binding activity, such as phenobarbital (PB) (36,37), are typically similar to those of DPH and CBZ, although of smaller magnitude (1 3, 20,24,29).…”

mentioning

confidence: 99%

Long‐Term Treatment of Children with Epilepsy with Valproate or Carbamazepine May Cause Subclinical Hypothyroidism

Eirís-Puñal¹,

Río-Garma²,

Río-Garma

et al. 1999

Epilepsia

103

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Summary:Purpose: The aim of the study was to evaluate serum thyroid hormone balance in children receiving long-term therapy with carbamazepine (CBZ), valproate (VPA), and phenobarbital (PB).Methods: We determined serum levels of triiodothyronine (TJ, thyroxine (TJ, free thyroxine (FT,), thyroxine-binding globulin (TBC), and thyroid-stimulating hormone (TSH) in 148 healthy children and 141 children with epilepsy who had been receiving CBZ (61 patients), VPA (51 patients), or PB (29 patients) for 12-161 months. In view of TSH values, three categories of subclinical hypothyroidism were considered: I, TSH greater than the control-group mean + 2 SD (4.37 mIUL in our study) and <6 mIU/L; 11, TSH between 6 and 12 mIUL; and 111, TSH >I2 mIU/L.Results: In all treated groups, mean T, and f14 levels were lower than in the control group, whereas the CBZ-and VPAtreated children additionally showed reduced mean T, and TBC levels and increased mean TSH levels. In the group receiving CBZ, 8.2% had TSH values higher than the normalrange maximum, by comparison with only 3.6% of healthy children. The increase in TSH levels was particularly marked in VPA-treated children, accounting for 26% of patients with subclinical hypothyroidism. Conclusions: Our results, in contrast to previous reports, suggest that CBZ and particularly VPA may induce subclinical hypothyroidism. This suggests a need for careful monitoring of TSH levels in children receiving CBZ or VPA.

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“…8 CBZ-related endocrine changes have been attributed to the induction of the hepatic P450-enzyme system by the drug. 9,10 Oxcarbazepine (OXC), a keto-derivative of CBZ, is a new AED that closely resembles CBZ in structure. 11 However, it has a different metabolic pathway in the liver; instead of by oxidation, it is mainly metabolized by reduction, and does not appear to induce the oxidative P450-enzyme system to the same extent as CBZ.…”

Section: Neurology 2001;56:31-36mentioning

confidence: 99%

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

Rättyä¹,

Turkka²,

Pakarinen³

et al. 2001

Neurology

175

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Article abstract-Background: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. Methods: Reproductive endocrine function was evaluated in 90 men taking VPA (n ϭ 21), CBZ (n ϭ 40), or OXC (n ϭ 29) as monotherapy for epilepsy and in 25 healthy control men. Results: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormonebinding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (Ͻ900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose Ն900 mg. Conclusions: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not. NEUROLOGY 2001;56:31-36 Reproductive endocrine disorders and sexual dysfunction have frequently been attributed to epilepsy itself, but antiepileptic drugs (AED) also have various effects on endocrine function.1-7 Valproate (VPA) has been implicated to have only minor effects on the hormonal system in men with epilepsy.3,4 However, there is growing evidence that VPA therapy induces endocrine disorders in women with epilepsy, which are characterized by hyperandrogenism and hyperinsulinemia that are related to obesity. 5,6 Carbamazepine (CBZ) is one of the most widely used first-line AED. The use of CBZ is associated with a progressive increase in circulating levels of sex hormone-binding globulin (SHBG) and, consequently, in a decreased proportion of free, bioactive testosterone, which may result in sexual dysfunction in some men with epilepsy after long-term CBZ treatment.8 CBZ-related endocrine changes have been attributed to the induction of the hepatic P450-enzyme system by the drug. 9,10Oxcarbazepine (OXC), a keto-derivative of CBZ, is a new AED that closely resembles CBZ in structure.11 However, it has a different metabolic pathway in the liver; instead of by oxidation, it is mainly metabolized by reduction, and does not appear to induce the oxidative P450-enzyme system to the same extent as CBZ.12 Previous studies have shown that the CBZ-induced changes in endocrine and metabolic function equilibrate after CBZ is replaced with OXC.13,14 Thus, OXC has been suggested to be a safe AED with regard to endocrine and metabolic effects. However, there is evidence that OXC may also induce liver enzymes when prescribed at higher doses. 15 Endocrine effects of OXC have not been previously assessed...

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Changes in circulating thyroid hormones during short-term hepatic enzyme induction with carbamazepine

Cited by 59 publications

References 9 publications

Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate

Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate

Long‐Term Treatment of Children with Epilepsy with Valproate or Carbamazepine May Cause Subclinical Hypothyroidism

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

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