Highlights
- •AED treatment can alter the levels of different sex hormones.
- •EIAEDs increase sex hormone binding globulin concentrations in men and women.
- •VPA can increase serum testosterone, give menstrual disturbances and polycystic ovaries.
- •EIAEDs can reduce bone strength and promote osteoporosis.
- •EIAEDs can reduce T3, T4 and fT4, but patients are euthyroid.
Abstract
Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries.
Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation.
It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation.
Keywords
1. Introduction
Epilepsy can have major impacts on several important aspects of life. The severity of the disease varies from good seizure control or seizure freedom (50–60%) with minor side effects from medication, to a debilitating disease with several daily seizures, the need for polytherapy, the occurrence of major side effects, and problems with drug interactions. Many patients also suffer from an underlying brain disease and co-morbidity, with depression or psychiatric disorders, for example, occurring frequently.
The epilepsy itself, with frequent epileptic discharges, can interact with cerebral function and affect memory and other cognitive aspects. Alterations in hormone levels are a direct effect of epileptic discharges, both in animals and humans [
1
, 2
, 3
, 4
, 5
].Distinguishing the side effects of antiepileptic drugs (AEDs) from the many other factors that influence the patients can be difficult. In vitro experimental studies, in vivo animal studies, and studies in humans using the same medication for diagnoses other than epilepsy, can be helpful. In order to avoid the possible complexity from multiple interactions, monotherapy studies are important.
Despite these investigative difficulties, AEDs have been clearly demonstrated to have several hormonal side effects that can influence important areas in life, such as fertility, sexual function, and bone health. Some side effects may also be of a more cosmetic nature, such as weight gain, hair loss, acne, or a more masculine hair distribution in women. The various drugs affect the hormonal system differently, and cause specific and different types of hormonal disturbances.
2. Reproductive endocrine function in men
2.1 Enzyme-inducing drugs
The AEDs phenobarbital (PB), phenytoin (PHT), and carbamazepine (CBZ) are all inducers of hepatic microsomal enzymes, and thus accelerate the metabolism of other drugs, and also the breakdown and production of sex hormone binding globulin (SHBG). This increases SHBG concentrations and reduces concentrations of free, circulating androgen and estrogen, resulting in decreased levels of biologically active sex hormones [
6
, 7
, 8
, 9
]. Elevated estradiol levels have also been found in men with epilepsy taking PHT [7
, 10
].Low serum dehydroepiandrosterone sulfate (DHAES) concentrations have also been reported in men and women taking PHT and CBZ [
6
, 8
, 11
]. DHAES is a weak androgen that is secreted from the adrenal cortex, but the clinical implication of low DHAES levels is unknown.Associations between high estradiol levels and sexual dysfunction have been found in men taking PHT [
[10]
]. In some men, sexual dysfunction has also been described after long-term CBZ or PHT treatment and is related to low bioactive testosterone levels [[12]
]. Furthermore, both CBZ and PHT have been associated with changes in semen quality [[13]
] and CBZ has been linked with reduced sperm motility and increased frequency of morphologically abnormal sperm [14
, 15
].Despite these findings, there is no obvious significant reduction in fertility in patients using enzyme-inducing AEDS (EIAEDs) [
[16]
].Oxcarbazepine: Oxcarbazepine (OXC) has a different metabolic pathway to that of CBZ. Instead of oxidation, OXC is metabolized by reduction to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine, and induces the liver P450 enzyme system only at high doses [
[17]
]. OXC taken in high doses may affect serum testosterone and SHBG levels, and may also induce changes in sperm morphology [[18]
]. However, these findings should be confirmed in further studies before conclusions on their clinical significance can be reached.2.2 Valproate
Valproate (VPA) does not induce liver enzymes, but, nevertheless, does reduce serum gonadotropin levels and increase concentrations of serum androstenedione [
15
, 19
]. These effects may be caused either by a centrally mediated modification of GABA-ergic neurotransmission in the hypothalamus or by a direct effect of VPA on endocrine tissue, in particular in the testis. A direct effect on the testis is supported by studies in dogs, rats, and goats that have demonstrated a reduction in testicular size and altered testicular morphology after VPA treatment [14
, 19
, 20
]. Similarly, small testicular volumes have also been found in some [[14]
], but not all [[14]
], studies of men taking VPA. Further, semen morphology and motility are affected by VPA. In humans, the number of motile sperms is reduced, and several morphological parameters are changed [14
, 15
]. In contrast to findings with CBZ, sperm from men that have been treated with VPA have been found to show increased tail pathology [[14]
]. A number of studies of infertile men without epilepsy have shown these types of sperm tail abnormalities; bent or coiled sperm tails were found to occur significantly more frequently when pregnancy did not occur [20
, 21
, 22
]. These findings suggest that sperm tail changes observed with VPA may affect fertility. Carnitine is important for sperm motility, and reduced sperm motility has been noted in men on VPA, and in whom the free versus total carnitine ratio is reduced [23
, 24
].2.3 Lamotrigine
To date, lamotrigine (LTG) has not been associated with reproductive endocrine disturbances in men with epilepsy nor in non-epileptic animals [
12
, 25
, 26
, 27
, 28
].2.4 Levetiracetam
The mode of action levetiracetam (LEV) is mostly unknown, and differs from that of other AEDs. The drug binds to a synaptic vesicle protein, SV2A, which is widely distributed in the central nervous system and in most endocrine tissues. In a paper from Harden et al. [
[29]
] from 2010 testosterone levels increased in eight men after LEV treatment. However, this study was uncontrolled and included a very heterogeneous group of patients. In a clinical study by Svalheim [[28]
], 30 men treated with LEV did not differ from controls regarding reproductive hormones or sexual function. Normal levels of sexual hormones were also found in a recent Chinese study by Xiaotian [[30]
], but more sperm abnormalities were reported in LEV-treated males. Further studies are therefore needed before any conclusions can be drawn regarding the effects of LEV on reproductive endocrine function in men.2.5 Topiramate
Sexual dysfunction has rarely been described in association with treatment with the newer AEDs, but there has been growing evidence of a correlation between topiramate (TPM) treatment and erectile dysfunction [
31
, 32
, 33
] and dose dependent reversible anorgasmia (both men and women) [34
, 35
]. A non-hormonal, vasogenic mechanism has been suggested to explain these associations [[33]
].3. Reproductive endocrine function in women
3.1 Enzyme-inducing drugs
As in males, EIAEDs in females reduce the free fractions of steroid hormones, increase SHBG, and may also lower DHEAS. No consistent abnormalities in basal or stimulated serum gonadotropin or prolactin levels have been reported [
[36]
]. The clinical consequences of these endocrine changes are unknown. To date, no large study has demonstrated any increased frequency of menstrual disorders or other reproductive endocrine disorders in women treated with these drugs [[27]
].3.2 Valproate
The first report suggesting a high incidence of menstrual disorders linked to obesity, hyperandrogenism, and polycystic ovaries (PCO) in women taking VPA for epilepsy was published in 1993 by Isojärvi et al. [
[37]
]. This was a cross-sectional study of 238 women on VPA monotherapy. These women had significantly more menstrual disorders than controls, and these were frequently associated with PCO and/or hyperandrogenism. PCO and hyperandrogenism were especially common if VPA medication had been started before the age of 20 years. Moreover, the serum mean androgen levels were increased in women on VPA. These findings have been confirmed in later studies [[38]
]. In a large, three-center study, with patients from Finland, Norway and Netherlands, hyperandrogenism and/or PCO were detected in 70% of VPA-treated women, 20% of CBZ-treated women, and 19% of women acting as controls. Menstrual disorders were reported by 59% of women on VPA, compared with 12% of CBZ-treated women and 15% women in the control group [[39]
].The age dependency, found by Isojärvi in 1993 [
[37]
] was later confirmed by others [[38]
]. Furthermore, increases in serum androgen levels were detected before and during pubertal development in young girls taking VPA for epilepsy [[40]
]. A five-year follow-up of these girls showed that of the girls/women who were still on VPA 5 years later (during the follow-up study), 60% had polycystic ovary syndrome (PCOS) as compared with 25% of the girls/women who had stopped taking VPA and switched to other AEDs [[41]
]. These observations indicate that the young ovary is more vulnerable to the effects of VPA.Similar endocrine changes induced by VPA were also seen in non-epileptic rats in a long-term monotherapy study [
[25]
]. A significant, dose-dependent increase in the number of follicular cysts in the ovaries was observed after VPA treatment, together with a reduction in the number of corpora lutea. Blood samples showed a marked increase in the testosterone: estrogen ratio and a decrease in estrogen levels, with an absence of, or only minor, effects on gonadotropins [[42]
].Endocrine side effects of VPA have also been seen in women using VPA for bipolar disorders [
43
, 44
]. Endocrine side effects caused by VPA seem to be at least partly reversible [45
, 46
] (Table 1).Table 1Endocrine effects of antiepileptic drugs.
Published with permission from: Taubøll et al.
[80]
.| Drug | Men | Women | |
|---|---|---|---|
| EIAED | Tot. testosterone | ↔ | ↔ |
| Tot. estradiol | ↔ (↑?PHT) | ↔ | |
| SHBG | ↑ | ↑ | |
| FAI | ↓ | ↓ | |
| DHEAS | ↓ | ↓ | |
| FSH | ↔ | ↔ | |
| LH | ↔ | ↔ | |
| VPA | Tot. testosterone | ↔ | ↑ |
| Tot. estradiol | ↓ (?) | ||
| SHBG | ↔ | ↑ | |
| Androstenedione | ↔/↑ | ↑ | |
| DHEAS | ↑ | ||
| FAI | ↔ | ↑ | |
| Insulin | ↑ | ↑ | |
| FSH | ↓ | ↔ | |
| LH | ↓ | ↔ | |
The table shows the most frequently reported findings. Differences between studies do occur. EIAED: enzyme inducing antiepileptic drugs; VPA: valproate; PHT: phenytoin; FAI: total testosterone/SHBG × 100.
PCO and hyperandrogenism are not only caused by the weight gain that many VPA users experience, as they also occur in lean VPA-treated women without hyperinsulinemia [
[39]
]. However, obesity and related hyperinsulinemia can be caused by VPA and may exacerbate the VPA-related reproductive endocrine disorders [[38]
].VPA is thought to have a direct effect on follicular steroidogenesis in the ovary. This was studied by Taubøll et al. [
47
, 48
, 49
, 50
], in a series of studies using both porcine and human ovary cells that were exposed to different concentrations of VPA, which was shown to increase testosterone and reduce estradiol secretion. The conversion of testosterone to estradiol at therapeutically relevant concentrations was reduced, indicating an effect on aromatase activity. A direct effect of VPA is further supported by the work of Hattori et al. [[51]
] who demonstrated the presence of the enzyme microsomal epoxide hydrolase (mEH) in human ovaries. mEH is important in detoxification of several substances. Hattori and co-workers showed that human granulosa cells expressed mEH and that inhibition of mEH suppressed conversion of testosterone to estradiol. Given that VPA is a mEH inhibitor, this may be a mechanism by which VPA reduces serum estrogen levels and thereby increases the testosterone: estrogen ratio. This effect would result in an androgen-dominant microenvironment in the ovary and thereby possibly lead to polycystic changes without an increase in levels of luteinizing hormone.VPA has also been found to affect gene expression. Nelson-DeGrave et al. [
[52]
] found that VPA increased expression of CYP17 and CYP11A genes. This occurs in PCOS and implies that VPA treatment may convert normal ovarian theca cells to a PCOS phenotype. In line with this, Gustavsen et al. [[53]
] used a model of human adrenal carcinoma cells, which are capable of full steroidogenesis, to show that VPA resulted in a general down-regulation of expression of genes encoding for enzymes early in steroidogenesis. Using the same cell line, gene analyses suggested that VPA affects NR0BI expression [[54]
], inhibiting promoters of other genes involved in steroidogenesis. Altered expression of NR0BI might explain the observed down-regulation in hormone production.3.3 Lamotrigine
Lamotrigine has not been found to have endocrine side effects [
26
, 27
, 28
, 55
]. On the contrary, switching from VPA treatment to LTG treatment resulted in normalization of endocrine function during a one-year follow-up of women with a previously identified reproductive endocrine disorder that was likely to be related to VPA medication [[46]
].3.4 Levetiracetam
In a paper from 2006, we showed for the first time that LEV affected basal, but not gonadotropin-stimulated, testosterone and estrogen secretion from porcine ovarian follicular cells [
[49]
]. This observation suggests that LEV may affect reproductive endocrine function. The clinical consequences of this observation are difficult to determine, but it is possible that LEV might only affect reproductive endocrine function in prepubertal female subjects with low serum gonadotropin levels, whereas fertile-aged women might not be at risk because the ovaries are stimulated by higher levels of gonadotropins. In a paper from 2009, no endocrine changes were found in 21 LEV-treated women [[28]
].3.5 New AEDs
Randomized studies on newer AEDs are lacking, and little is known about their possible endocrine side effects. There have only been a few case reports, and this provides a positive indication that such side effects are rare. However, further studies are required.
4. Menstrual regularity
Women with epilepsy generally experience more menstrual irregularities than healthy women [
[56]
]. This is thought to be due both to the epilepsy itself and to the use of AEDs. Menstrual disorders are especially frequent in women on VPA treatment and in women using polytherapy [27
, 39
].5. Fertility
Fertility rates have been found to be lower in epilepsy patients than in the general population. In the Rochester study, fertility was considered to be reduced to 80% in males and 85% in females [
[57]
]. However, in a population-based study from Iceland, no difference in birth rate was found between female epilepsy patients and the reference group [[58]
]. However, genuine infertility is not easy to measure in clinical studies because it depends on the frequency of unprotected intercourse. Social and psychological factors will also affect birth rate, which, erroneously, is often taken as being equivalent to fertility. While the frequency of marriage is lower among epilepsy patients, birth rate is also reduced among the married patients [59
, 60
]. Epilepsy is a symptom of an underlying disease in many patients, and it can be that underlying disease (inherited diseases, cancer, cerebrovascular diseases, etc.) that is the cause of reduced fertility, rather than the epilepsy itself.The medication taken for epilepsy can still be of importance. As previously noted, semen quality in men and ovarian function in women can be disrupted by AEDs, and changing medication should be considered for epilepsy patients with genuine fertility problems.
6. Sexuality
Several studies have shown that sexual problems are common in people with epilepsy, and a wide range of different problems has been described [
61
, 62
].The reasons for the sexual problems are multifactorial, and both psychological and epileptological factors are probably important. In a large study on otherwise healthy outpatients on monotherapy and with few seizures, sexual problems were as frequent in the control group as in those being treated with LEV or LTG [
[28]
]. Psychological factors and the burden of seizures are probably critical, and for many patients are probably of greater importance than the drug treatment itself. Therefore, the specific role of the different AEDs is difficult to ascertain. In general, EIAEDs reduce the free fractions of peripheral sex steroid hormone concentrations, and this is well known to affect sexual function, including reduced libido, and potency problems in men. Herzog et al. [[12]
] found reduced sexual function in men using CBZ or PHT for localization-related epilepsy, while sexual function was normal in men on LTG. The decreased sexual function in men on CBZ or PHT correlated with lowered bioactive testosterone levels. In a paper from Svalheim et al. [[28]
], men and women treated with CBZ reported being less satisfied with their sex lives than those treated with LEV or LTG. In a randomized study by Mattson et al. [[63]
], impotence and decreased libido were reported in 16% of epilepsy patients after starting monotherapy with PB, 12% after starting PHT, and 13% after starting CBZ.A few cases of anorgasmia have also been described that are apparently associated with gabapentin treatment [
[64]
]. LTG, however, was shown not to affect sexual function [12
, 28
, 65
]. AEDs can affect sexuality through different mechanisms. First, certain AEDs induce liver enzymes that lead to reductions in the free fractions of peripheral sex steroid hormones. Second, a more general, depressive effect of AEDs on brain excitability may have a negative impact on sexual function. It is possible that the more sedative AEDs have greater impact in this respect than some of the newer AEDs with less sedative effects. A negative impact of AEDs on cognitive function may also be important. In order to obtain a better understanding of the possible impacts of different AEDs on sexuality and to elucidate the underlying mechanisms further research on these aspects is essential.7. Bone health
In comparison with the general population, patients with epilepsy have a 2–6 times greater risk of fractures. In a Danish population-based study from 2004, which included 124,655 fracture cases and 373,962 controls, the fracture risks related to AED exposure were examined [
[66]
]. In an unadjusted analysis, all AEDs were associated with an increased risk of fracture. After adjustment for prior fracture, exposure to corticosteroids, comorbidity, social variables, and diagnosis of epilepsy, some drugs were significantly associated with increased fracture risk: CBZ (odds ratio (OR): 1.18); OXC (OR: 1.14), clonazepam (OR: 1.27); PB (OR: 1.79), and VPA (OR: 1.15). For CBZ, PB, OXC, and VPA, a dose–response association was seen. The risk was more pronounced in those who used EIAEDs than in those who used non-inducing drugs.The results from various studies strongly indicate that AED use may have negative impact on bone health. The older EIAEDs, particularly phenytoin (PHT), are most consistently associated with fractures and reduced bone mineral density (BMD). Pack and Walczak assessed several studies on the effects of individual AEDs on bones [
[67]
]. Decreased BMD was found to be associated with PHT use in four of five studies, PB use in two of two studies, and VPA use in three of four studies. CBZ use was only associated with low BMD in one of five studies. Short-lasting treatment with LTG in 93 premenopausal women was apparently not associated with reduction in BMD or with changes in bone turnover markers.The traditional theory for explaining the bone loss associated with EIAEDs is that turnover of vitamin D and its metabolites is accelerated, owing to increased activity in the cytochrome P-450 system. This results in low vitamin D, reduced intestinal absorption of calcium, low serum calcium, secondary hyperparathyroidism, decreased BMD, and, eventually, fractures [
68
, 69
].Several AEDs, including PHT, PHB, CBZ, and VPA, also appear to have a direct effect on bone cells, resulting in increased bone turnover [
67
, 68
, 70
].Interaction with vitamin K has also been proposed as a possible mechanism for osteoporosis in patients with epilepsy. Vitamin K is an important co-factor in the synthesis of osteocalcin, an important marker of bone formation. Enzyme-inducing AEDs have been found to reduce vitamin K levels [
[71]
].EIAEDs may also increase the metabolism of sex steroids, resulting in decreased levels of bioavailable endogenous estradiol and testosterone. An increased rate of bone loss may therefore be a consequence of this increased steroidal metabolism [
69
, 72
].Several other mechanisms have also been suggested. These include disruption of brain regulation of bone metabolism via increased leptin [
[67]
], AED-induced increase in homocysteine [[73]
], and reduction in insulin-growth factor 1 [[72]
].The mechanisms involved in AED-associated bone loss are likely to be multifactorial and are not yet fully understood. For the individual patient with epilepsy, the risk of developing bone disease is probably determined by a combination of several factors, including genetic factors, epilepsy syndrome, age, gender, lifestyle, and AED treatment.
8. Thyroid function
Some AEDs are associated with alterations in thyroid function. This was first shown in 1981 by Strandjord et al. [
[74]
]. In 42 patients on long-term CBZ treatment, thyroxine (T4), free T4-index (FT4), and triiodothyronine (T3) concentrations in serum were found to be significantly lower than in controls, while T3 uptake and thyrotropin (TSH) concentrations did not differ between patients and controls. A study of 90 men with epilepsy taking either CBZ, VPA, or OXC and 25 control men demonstrated that serum T4 and FT4 concentrations were low in men taking CBZ or OXC, with 45% and 24% falling below the reference range, respectively, but serum T3 and TSH levels were normal. In men taking VPA, the concentrations of thyroid hormones and TSH were normal [[75]
].Another study in children with new-onset epilepsy [
[76]
] was performed prospectively with baseline thyroid testing prior to drug administration, followed by testing at 3, 6, and 12 months after initiation of CBZ or VPA treatment. CBZ-treated patients demonstrated significantly lower serum T4 and FT4 levels than at baseline evaluation and compared with control subjects, but normal serum T3 and TSH response in a thyrotropin releasing hormone (TRH) test. This difference could be identified after only 3 months treatment. Some of the CBZ-treated children were withdrawn from CBZ for other reasons, and reevaluation 6 months later revealed that their thyroid hormone values had normalized. All values remained normal in the VPA treatment group. The patients were found to be clinically euthyroid, also in the CBZ group. The authors conclude that thyroid hormone alterations are not associated with clinical or subclinical hypothyroidism.Another study of 35 patients on long-term PHT or CBZ treatment [
[77]
] reported that the mean concentrations of T4, FT4, FT3, and reverse triiodothyronine (rT3), but not T3, of these patients were significantly lower than those of 19 controls. Clinical examination of these patients did not reveal clinical signs of functional hypothyroidism. The authors also assessed response to thyroxine treatment in a smaller subset of patients, and the clinical parameters they examined were found to be unchanged after treatment. On the basis of the data from the cross-sectional and thyroxine treatment studies, the authors concluded that patients receiving AEDs chronically are eumetabolic and do not need thyroxine supplementation.A recent prospective study on 23 children receiving OXC [
[78]
] showed that FT4, but not FT3, was significantly reduced after 8 and 18 months treatment, while TSH was significantly increased.Alterations in thyroid function seem to be reversible after withdrawal of medication. Lossius et al. [
[79]
] showed significant increases in FT4 serum concentrations 4 months after CBZ withdrawal, in both men and women.For patients with hypothyreosis prior to initiation of AED treatment, use of EIAEDs should probably not be recommended. Otherwise, the clinical importance of the interactions between AEDs and thyroid hormones appears to be minor, if any.
9. Conclusion
Many AEDs may affect an epilepsy patient's hormones and this may result in menstrual disturbances, sexual problems, fertility difficulties, or osteoporosis. In particular, the use of EIAEDs and VPA has been associated with such side effects. The newer drugs, however, have been investigated less and, although current data may imply a lack of such associations, should also be considered if new symptoms arise after initiation of treatment with such drugs. Increased awareness of these side effects will improve the possibility of tailoring treatment regimes to the characteristics of individual patients, paying particular regard to patient age and gender.
Conflict of interest statement
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
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Article info
Publication history
Published online: February 23, 2015
Accepted:
February 12,
2015
Received in revised form:
February 11,
2015
Received:
November 26,
2014
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