Effects of valproate or lamotrigine monotherapy on the reproductive endocrine and insulin-related metabolic profile in Chinese adults with epilepsy: A prospective randomized study
Introduction
Although valproate (VPA) has been used against a broad range of seizure types for more than 40 years, there has been renewed concern over its adverse endocrine and metabolic effects. A number of cross-sectional studies in women have suggested that VPA treatment for epilepsy is associated with hyperinsulinemia/insulin resistance, hyperandrogenism, and other biochemical characteristics of polycystic ovary syndrome, usually among those who had gained weight during treatment [1], [2], [3], [4], [5], [6]. In the few studies including male patients, raised serum insulin in association with obesity [7], reduction in follicle stimulating hormone (FSH) concentration, and changes in serum androgen level have been reported [8], although no change in testosterone level was observed in others [9], [10].
Lamotrigine (LTG) has a similarly broad spectrum of antiepileptic activity and is similar in efficacy to VPA [11]. Unlike VPA, LTG treatment is not associated with weight gain [12], [13], and does not appear to affect the reproductive hormonal profile in women with epilepsy [14]. In a small cohort (n = 12) of 12 women with valproate-induced polycystic ovaries or hyperandrogenism, substituting LTG for VPA for 12 months apparently resulted in improvement of the endocrine abnormalities [2].
These observations made in cross-sectional or prospective but nonrandomized studies were subject to selection bias. In addition, the patients were sometimes receiving VPA or LTG in combination with other antiepileptic drugs (AEDs), making it difficult to separate the effects of individual drugs. To overcome these limitations, several prospective monotherapy studies in adults with epilepsy have been published. In a nonrandomized, 3-month study, serum testosterone, luteinizing hormone (LH) and FSH decreased in women and FSH decreased in men treated with VPA compared with baseline [15]. Stephen et al. [16] found no difference in testosterone, sex hormone-binding globulin, or androstenedione concentrations in patients (male or female) randomized to VPA or LTG monotherapy at 6 and 12 months of treatment. In the study by Morrell et al. [17], which included women only, more patients randomized to VPA developed hyperandrogenism compared with those given LTG, but both groups had similar changes in LH or FSH levels. None of these studies measured insulin and the related metabolic parameters prospectively.
Because of differences in diet, lifestyle, and genetic factors, it is possible that VPA might exert different endocrine and metabolic effects in Chinese patients with epilepsy compared with their Caucasian counterparts. For instance, Chinese women with polycystic ovary syndrome have been shown to have a lower rate of hyperandrogenism but a similarly high rate of insulin resistance [18]. We conducted a prospective, randomized study among Chinese men and women with untreated epilepsy to compare the reproductive endocrine and insulin-related metabolic changes associated with VPA and LTG monotherapy.
Section snippets
Subjects
Chinese patients with epilepsy aged between 18 and 55 years and not receiving AED therapy were recruited from the Prince of Wales Hospital and United Christian Hospital (both regional hospitals with more than 1000 beds) in Hong Kong. Patients had either newly diagnosed, untreated epilepsy or a recurrence of seizures after a period of remission with AED therapy completely withdrawn for at least a year. Seizures and epilepsy syndromes were classified according to international guidelines. Both
Results
A total of 81 subjects were randomized to treatment (44 VPA, 37 LTG). All but four male subjects (two in each group) and one female subject (aged 51 years in the LTG group) were 50 years or younger. All female subjects were premenopausal. There was no significant difference in baseline characteristics between the two treatment groups in terms of age, seizure type, epilepsy syndrome, body weight/BMI, or endocrine and metabolic measures (P > 0.05 for all) (Table 1).
Of the 81 randomized subjects, 56
Acknowledgments
The authors thank all members of the neurology teams in Prince of Wales Hospital and United Christian Hospital for their support in the conduct of this study.
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Cited by (13)
Polycystic ovary syndrome and the new antiepileptic drugs: A systematic review
2022, Epilepsy ResearchCitation Excerpt :References were obtained, of which 22 articles were initially included by title and abstract (Morrell et al., 2001; Taubøll et al., 2009; Leach et al., 2006; Reuber et al; Stephen et al., 2001; Löfgren et al., 2006; Sahota et al., 2008; Morrell et al., 2003; Kwan et al., 2009; Svalheim et al., 2009; Löfgren et al., 2007; Betts et al., 2003; Lamotrigine, 2021; Ribacoba-Montero et al., 2003; Mikkonen et al., 2004; Sidhu et al., 2018; Khatami and Henrich, 2000; Luef et al., 2002; Morrell et al., 2008; Isojarvi et al., 1997; Isojärvi et al., 1998; Morrell et al., 2002; Rauchenzauner et al., 2010), but only four (Morrell et al., 2008; Stephen et al., 2001; Löfgren et al., 2006; Sidhu et al., 2018) met all of the established criteria. Articles were excluded for the following reasons: they only measured sex hormones with or without a study of ovarian morphology, but did not establish whether the patients met the criteria for PCOS (n = 5); (Morrell et al., 2001; Morrell et al., 2002; Morrell et al., 2003; Kwan et al., 2009; Svalheim et al., 2009); they were associated with other anticonvulsants and the analysis was not performed individually for antiepileptics (n = 5); (Luef et al., 2002; Sahota et al., 2008; Löfgren et al., 2007; Mikkonen et al., 2004; Betts et al., 2003); only the abstract was available since they were published in congresses but not as articles (n = 4); (Leach et al., 2006; Reuber et al; Isojarvi et al., 1997; Khatami and Henrich, 2000); the study was performed on human ovarian cells ( n = 1); (Taubøll et al., 2009); the study was not found in any database (n = 1); (Lamotrigine, 2021) the study population was not of reproductive age (n = 1); (Rauchenzauner et al., 2010); and the study did not clearly show whether the drug causes PCOS (n = 1) (Isojärvi et al., 1998). The four included studies provided a total of 276 women of reproductive age, 223 of whom were exposed to LTG and 19 to OXC.
Reproductive health in patients with epilepsy
2020, Epilepsy and BehaviorCitation Excerpt :Lamotrigine is a widely used AED in women of childbearing age with low teratogenesis rates [71]. Lamotrigine has not been associated with sex hormonal alterations [79,83]. Isojarvi et al. [62] studied 16 women with polycystic ovaries taking VPA and they found that the first year after VPA replacement with lamotrigine, the mean ovaries’ volume decreased but not significantly.
Effects of valproate on reproductive endocrine function in male patients with epilepsy: A systematic review and meta-analysis
2018, Epilepsy and BehaviorCitation Excerpt :As shown in our study, when compared with the healthy controls, the level of the testosterone was decreased, even though it was either increased or unchanged when compared with the level of testosterone in patients with epilepsy before VPA treatment, since these may already be much lower than the levels in healthy controls [32]. The confusing variation in the effects of VPA on sex hormones might also be due to the mismatch of the treatment duration, average age of the treated patients, subject population, and sample size among different studies [16,17,28,33]. In our study, VPA caused a significant decreased in the level of FSH in the male patients, which is consistent with previous studies [28,33–35].
The steroid metabolome in lamotrigine-treated women with epilepsy
2011, SteroidsCitation Excerpt :For a better illustration of the pathways involved, a scheme for the biosynthesis of common steroids and reduced progesterone metabolites is shown in Fig. 1, and Fig. 2 displays a scheme for the biosynthesis of reduced androstane metabolites. We selected WWE on lamotrigine monotherapy, as lamotrigine appeared to have a minimum effect on gonadal steroidogenesis [13–16]. In contrast to previous studies that included a greater number of patients and focused on particular steroids, we have selected a limited number of lamotrigine-treated WWE and a wider spectrum of analytes.
Effects of valproate and carbamazepine monotherapy on neuroactive steroids, their precursors and metabolites in adult men with epilepsy
2010, Journal of Steroid Biochemistry and Molecular BiologyAntiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data
2022, Cochrane Database of Systematic Reviews