**5. Epilepsy and menopause**

Ovarian reserve shrinks throughout life and reaches a critical threshold level at the inception of the menopause. At this point, a woman notes her rst skipped menstrual period. The menopausal transition begins with the onset of rst menstrual irregularity, or skipped menses, and ends with the nal menstrual period. Progressive loss of ovarian follicles results in decreased production of inhibin and a loss of restraint on FSH secretion. The monotropic increase in FSH leads to variable hormonal patterns, depending on the available ovarian follicles and their degree of responsiveness. Once follicles reach a critically low level, ovulation becomes progressively less likely and prolonged amenorrhea ensues. In addition to ovarian factors that contribute to reproductive senescence in women, there is accumulating evidence that as in rodents, hypothalamic-pituitary dysfunction accompanies reproductive aging and contributes to the process. As knowledge about the menopausal

The Impact of Epilepsy on Reproductive Functions 63

As vitamin D and calcium metabolism can be affected by AEDS, supplements should be considered. Herbal preparations should be avoided as their efficacy is uncertain and they

The cessation of ovarian function at the menopause is associated with a phase of rapid bone loss which probably lasts from 5 to 10 years (Genant et al, 1982; Recker et al, 2000). This rapid bone loss results from an increase in bone turnover in association with a negative remodelling imbalance (Compston, 2001); whilst reduced bone formation undoubtedly contributes to the latter, there is evidence that increased osteoclastic activity also plays a role, particularly in the earlier stages of menopausal bone loss (Compston et al, 1995). The combination of increased bone turnover and increased resorption depth results in disruption of bone microarchitecture, with loss of connectivity of cancellous bone and

Osteoporosis and fractures may increase due to hypoestrogenism in menopause and cytochrome P450 inducing AEDs. Recent studies suggest lower bone mineral density (BMD)

Both idiopathic epilepsy and symptomatic epilepsy are associated with reduced BMD, with the greatest reduction in symptomatic generalized epilepsy (Sheth & Hermann, 2008). However, the pathophysiological underlying mechanisms are far from understood and likely multifactorial. Potential risk or predisposing factors include physical impairment, genetic factors, AED treatment with enzyme-inducing drugs, AED polytherapy, impact of seizures on the hypothalamus-hypophysis-adrenal (HPA) axis, and vitamin D deficiency/insufficiency. As growth and sexual maturation in adolescence are regulated by a complex neuroendocrine system including the HPA axis, potential AED-related abnormalities may be reflected in growth and bone metabolism in childhood epilepsy. In adults and children treated with enzyme-inducing AEDs, vitamin D deficiency/insufficiency (up to 50% of patients) and low BMD have been reported in most, but not all, studies (Petty et al, 2007; Farhat et al, 2002; Pack

However, and in particular in children, it is unclear whether non-enzyme-inducing AED monotherapy (lamotrigine, sulthiame) or minimal enzyme-inducing AED monotherapy (oxcarbazepine) seem to have any adverse effects on linear growth or to cause vitamin D deficiency in otherwise healthy children with epilepsy (Luef & Rauchenzauner, 2008). In contrast to adults, there is controversy over the association of chronic AED use with an increased incidence of fractures in children (Souverein et al, 2005; Petty, et al, 2007). Recent studies suggest lower BMD in adults and children with epilepsy, irrespective of AED treatment (Pack, 2008; Sheth et al, 2008a, 2008b; Pack & Walczak, 2008; Sheth & Hermann,

In conclusion, in gynecological practice, women with epilepsy deserve special care with a multidisciplinary approach. Women with epilepsy should be questioned routinely about menstrual cycles, infertility, excessive weight gain, hirsutism, galactorrhea, and changes in sexual life. If abnormalities are detected, hormone determinations, pelvic ultrasound, and neuroimaging of pituitary gland should be assessed. If the cause of the problem is AED-

may interact with AEDs (Erel et al, 2010).

thinning of the cortices, which also show increased porosity.

in adults and children with epilepsy, irrespective of AED treatment.

**6. Epilepsy and osteoporosis** 

et al, 2005; Verrotti et al, 2000).

2008).

**7. Conclusion** 

transition increases, it may turn out that the ovary is not the only area that should be studied—the brain may undergo changes as well (Santoro, 2005).

During the perimenopausal period, the frequency of catamenial epileptic seizures may increase (probably due to hyperestrogenism) and then decrease after menopause. According to current data, hormone replacement therapy (HRT) may increase the frequency of epileptic seizures. Changes in serum concentrations of sex steroid hormones are frequently observed when enzyme-modulating AEDs (VPA, CBZ, phenytoin, or phenobarbital) are used. It is generally accepted that long-term treatment with VPA and CBZ may lead to reproductive endocrine disorders in patients with epilepsy. VPA can increase biologically active sex hormone levels (e.g., hyperandrogenism) independent of associated weight gain, more commonly seen in women before the age of 20. In contrast, CBZ may decrease free serum testosterone concentrations through the induction of SHBG. If the woman is taking AEDs, which reduce steroid hormone levels, OCs must contain a minimum of 50 μg of EE. If there is a hemorrhage, the dose should be raised to 75 or 100 μg.

Indications for HRT are dealing with menopausal symptoms and conservation of bone mass and fracture prevention. As epilepsy is affected by sex steroids, careful consideration must be given to the regimen used. However, the data are extremely limited (Harden et al, 2006; Shen & Stearns 2009). The details of the only randomized trial double-blind, placebocontrolled trial are now described (Harden et al, 2006). This was undertaken in postmenopausal women with epilepsy who are taking stable doses of AEDs and are within 10 years of their last menses. After a 3-month prospective baseline, subjects were randomized to placebo, Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA) daily, or double-dose CEE/MPA daily for a 3 month treatment period. Twenty-one subjects were randomized after completing baseline. The subjects' ages ranged from 45 to 62 years (mean, 53 years), and the number of AEDs used ranged from none to three (median, one). Five (71%) of seven subjects taking double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared with four (50%) of eight taking single-dose CEE/MPA, and one (17%) of six taking placebo (p = 0.05). An increase in seizure frequency of the subject's most severe seizure type was associated with increasing CEE/MPA dose (p = 0.008). An increase in complex partial seizure frequency also was associated with increasing CEE/MPA dose (p = 0.05). Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25–30% while taking CEE/MPA. The authors concluded that CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels. There are no data with other regimens with different estrogens and progestogens or transdermal or vaginal administration. It is not known whether women with epilepsy need higher doses of estrogen or whether transdermal rather than oral therapy is preferred depending on their AED use. Based on the randomized trial, it would be prudent to closely monitor women who start HT as their AED needs may change (Erel et al, 2010).

Non-estrogen based treatments are used to treat hot flushes and symptoms of urogenital atrophy (Erel et al, 2010). Drug interactions need to be carefully assessed before using pharmacotherapy. Interventions to consider include clonidine, selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs), gabapentin, and vaginal lubricants and mosturizers (Shen et al, 2009). While bisphosphonates will conserve bone mass, there are little data in women with epilepsy and there are concerns about the safety of long term use (Drezner, 2004).

As vitamin D and calcium metabolism can be affected by AEDS, supplements should be considered. Herbal preparations should be avoided as their efficacy is uncertain and they may interact with AEDs (Erel et al, 2010).
