Disorders of reproduction in patients with epilepsy: Antiepileptic drug related mechanisms

Clinical Development, Neurology, Jazz Pharmaceuticals, Palo Alto, CA 94304, USA.
Seizure (Impact Factor: 1.82). 04/2008; 17(2):111-9. DOI: 10.1016/j.seizure.2007.11.007
Source: PubMed


Epilepsy, antiepileptic drugs (AEDs), and the reproductive system have complex interactions. Fertility is lower in both men and women with epilepsy than in the general population. Moreover, reproductive endocrine disorders are more common among patients with epilepsy than among the population in general. These disorders have been attributed both to epilepsy itself and to AEDs. The use of the liver enzyme inducing AEDs phenobarbital, phenytoin and carbamazepine increases serum sex hormone binding globulin (SHBG) concentrations in both men and women with epilepsy. Over time the increase in serum SHBG levels leads to diminished bioactivity of testosterone and estradiol, which may result in diminished potency in men and menstrual disorders in some women, and, thus, to reduced fertility. Valproate (VPA) medication may have effects on serum androgen concentrations and it reduces serum follicle stimulating hormone levels in men with epilepsy. However, the clinical significance of the VPA related reproductive endocrine changes in men is unknown. On the other hand, in women the use of VPA is associated with a frequent occurrence of reproductive endocrine disorders characterized by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. Young women with epilepsy seem to be especially vulnerable to the effects of VPA on serum androgen levels. The endocrine effects of the new AEDs have not been widely studied. However, it seems they may offer an alternative if reproductive endocrine problems emerge during treatment with the older antiepileptic drugs. On the other hand, it seems that in many cases the reproductive endocrine effects of the AEDs are reversible, if the medication is discontinued.

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    • "In view of considerable evidence that women undergoing VPA treatment for epilepsy and bipolar disorder show an increased incidence of PCOS-like symptoms including hyperandrogenemia and menstrual cycle disturbances (reviewed by: [2], [3], [5]), research is clearly warranted to try to clarify the mechanism(s) through which this widely prescribed drug might elicit such an effect on ovarian function. Potentially VPA could perturb ovarian function by acting at one or more levels of the hypothalamic-pituitary-ovarian axis, or by modifying some other organ that influences ovarian function indirectly (e.g. "
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    ABSTRACT: Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC(50) 67±10 µg/ml) and LH-induced (93% suppression; IC(50) 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC.
    Full-text · Article · Nov 2012 · PLoS ONE
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    • "Although women with epilepsy may already have a higher prevalence of reproductive endocrine disorders, the treatment with certain AEDs may increase this risk (Isojärvi, 2008; Luef & Rauchenzauner, 2009; Verrotti et al., 2009). A large body of literature addresses the presence of alterations in sex hormone levels in women on AED therapy (Dana-Haeri et al., 1982; Beastall et al., 1985; Levesque et al., 1986; Isojärvi, 1990; Isojärvi et al., 1993; Murialdo et al., 1998; Bauer et al., 2002; Morrell et al., 2002; Isojärvi et al., 2005; Hamed et al., 2007; Herzog, 2008). "
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    ABSTRACT: Reproductive endocrine dysfunction in women with epilepsy is an important issue, and in recent years there is growing evidence to support the effect on sex hormones of both epilepsy per se and various antiepileptic drugs (AEDs). Focal epileptic discharges from the temporal lobe may have a direct influence on the function of the hypothalamic–pituitary axis, thereby altering the release of sex steroid hormones. The role of laterality and severity of epilepsy is still conflicting. The use of the liver enzyme–inducing AEDs—such as phenobarbital, phenytoin, and carbamazepine—can increase serum sex hormone–binding globulin concentrations, leading to diminished bioactivity of testosterone (T) and estradiol. Valproic acid, an enzyme inhibitor, has been associated with the occurrence of reproductive endocrine disorders characterized by high serum T, free androgen index, androstenedione, dehydroepiandrosterone sulfate concentrations, and with polycystic changes in ovaries and menstrual disorders. A better understanding of the effects of AEDs on sex hormones is key to selecting the appropriate AEDs and is crucial for reproductive health in female patients.
    Full-text · Article · Jan 2011 · Epilepsia
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    • "Testosterone production in the testes is controlled by pituitary secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). Free testosterone levels are regulated by sex hormone binding globulin (SHBG), and levels of SHBG can be influenced by antiepileptic drugs (AEDs) (Isojärvi, 2008). Measurements of SHBG, FSH, and LH should, therefore, provide insight into the physiology of levetiracetam-associated testosterone changes. "
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    ABSTRACT: We sought to determine whether the testosterone increase found with levetiracetam exposure in animal studies also occurs in patients. Adult male patients were evaluated for reproductive hormone levels before and 1 month after levetiracetam therapy. Eight subjects met inclusion/exclusion criteria (mean age 46 years, range 29-75 years). Total testosterone prior to starting levetiracetam ranged from 206-787 ng/dl [mean 445, standard deviation (SD) 227]. The mean total testosterone after levetiracetam therapy increased to 592 ng/dl (range 216-981, SD 297), an increase of 16% (p = 0.036). The free testosterone increased from a mean of 64 pg/ml (range 36-115, SD 30) to a mean of 76 pg/ml (range 35-155, SD 44), an increase of 19% (p = 0.080). The magnitude of change in testosterone levels correlated with the initial testosterone level (p = 0.038, r = 0.734). These results suggest that levetiracetam increases testosterone levels and that an initial testosterone level may predict the magnitude of increase.
    Preview · Article · Nov 2010 · Epilepsia
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