Even if the woman involved does nothing to alter the prospects of her becoming pregnant, could antiepileptic drug intake in her male partner increase or decrease the prospects of her achieving pregnancy if the drugs were to alter his sexual capacity or behaviour? There seems to be little in the medical literature to suggest that antiepileptic drug intake may be responsible for male sexual hyperactivity , though Grabowska-Grzyb et al. (2006) did describe two males who, after lamotrigine was added to their current antiepileptic drug (in one oxcarbazepine and the other carbamazepine ), developed dose-related but reversible hypersexuality. In appropriate circumstances, this could have increased the likelihoods of pregnancy in any female partners that they had.

Much more commonly, the literature has reported that males taking antiepileptic drugs exhibit diminished sexual function . For instance, Artama et al. (2006) found a statistically significantly lower birth rate to males with epilepsy who were treated with carbamazepine , oxcarbazepine or valproate , as compared with the birth rate in a reference population of males who did not have epilepsy. In many of the reports, the interpretation of the lower birth rate in relation to antiepileptic drug-treated males is confounded by the fact that the drugs were used to treat epilepsy, and epilepsy itself might have altered male fertility . Overt and also probably subclinical focal seizures , particularly ones arising in mesial temporal lobe structures, can spread into the hypothalamus . In that brain region, the epileptic discharges may alter neuroendocrine function and, through this mechanism, possibly influence male fertility . If the degree of reduced fertility correlated with changes in the dose or circulating concentration of the antiepileptic drug or drugs concerned, one could be moderately confident that the drugs played a causal role in decreasing male fertility. Even then, the possibility remains that intracerebral spread of epileptic seizure discharges to neuroendocrine nuclei may also have contributed.

Over 40 years ago, Livingstone (1972), in his monograph, described the occurrence of sexual impotence in a few men treated with primidone . Later Mattson et al. (1985), in their large-scale study of US male war veterans, reported that use of this drug was sometimes associated with a decreased libido and with complaints of impotence . Unfortunately, it is difficult to know whether at the time of the Mattson et al. study the primidone had been prescribed in awareness of the long elimination half-life of the phenobarbitone that is formed from it within the body. Too rapid primidone dosage escalation might have produced excessive sedation , thereby decreasing libido. The subsequent literature has not infrequently contained the statement that males with epilepsy tend to be less fertile than their fellows and have diminished libidos. However, there has been at least one report to the contrary, in relation to continued intake of carbamazepine and valproate (Røste et al. 2003). By way of contrast, Reis et al. (2013) compared reports of sexual function in 63 males taking carbamazepine and in 55 healthy male control subjects. There was an increased occurrence of erectile dysfunction and decreased coital frequency in the antiepileptic drug-exposed males. Luef et al. (2009) observed that previously persisting sexual dysfunction improved in 79.4 % of 228 antiepileptic drug-treated men when agents that did not induce drug-metabolising enzymes were substituted for antiepileptic drugs that did induce the enzymes .

The possible hormonal background to diminished male sexual function associated with antiepileptic drug intake was investigated by Isojärvi et al. (2004), who were aware of the reported decreased fertility of males with epilepsy. They studied 15 men taking carbamazepine , 18 taking oxcarbazepine and 27 taking valproate , comparing the concentrations of certain circulating sex hormones in these men with the concentrations that were present in 41 normal male control subjects. They found that carbamazepine use was associated with decreased circulating concentrations of dehydroepiandrosterone sulphate and valproate use with increased concentrations of androstenedione . There were increased tendencies for low sperm counts and the presence of more functionally abnormal sperm in the males taking carbamazepine. Valproate exposure was also associated with sperm abnormalities. As well, men taking this drug tended to have smaller testes. Verrotti et al. (2011) pointed out that antiepileptic drugs which induced the body’s drug-metabolising enzyme systems also tended to cause increased formation of sex hormone-binding globulin , whose higher concentrations would result in decreased circulating levels of free (i.e. plasma protein unbound) relative to total testosterone . This reduction in free hormone levels might cause a lessened libido and potency. These authors also knew that valproate use was associated with increased circulating concentrations of dehydroepiandrosterone and decreased concentrations of gonadotropins . At much the same time, Sivaraaman and Mintzer (2011) described how the proposed hypothalamic disturbance that resulted from the spread of clinical and subclinical mesial temporal seizure discharges mentioned above might alter gonadotropin secretion. They also pointed out that use of the older enzyme-inducing antiepileptic drugs would produce increased blood levels of sex hormone-binding globulin , resulting in lower circulating concentrations of unbound relative to total testosterone. This pair of authors recognised that substituting the newer, generally non-inducing, antiepileptic drugs for the older inducing ones would avoid the alteration in circulating unbound testosterone concentrations and thereby might decrease hormone-related impairment of male sexual function . However, Najafi et al. (2012) noticed that decreased circulating testosterone concentrations also occurred when the non-inducing antiepileptic agent lamotrigine was being taken and mentioned that valproate use was associated with increased circulating concentrations of androstenedione .

Verrotti et al. (2011), in their review of the topic, pointed out the difficulties in distinguishing between the roles of having epilepsy, of taking antiepileptic drugs and of these two factors in combination, in explaining the increased likelihood that abnormal concentrations of reproductive steroid hormones may occur in men with epilepsy. A potential hormonal basis thus appears to exist that could contribute to the diminished sexual activity , libido and fertility reported in males with antiepileptic drug-treated epilepsy. Also, because there is a little published evidence that the altered sexual behaviour tends to vary with the antiepileptic drug dose and with the enzyme-inducing capacity of drug used, it seems likely that antiepileptic drug intake can interfere with male sexual function . Nonetheless, it seems likely that various psychosocial factors , such as limitations on lifestyle and possible earning capacity consequent on suffering from epilepsy, also play significant roles in the situation. The available medical literature contains relatively little detailed information dealing with the contributions made by such psychosocial factors.

As in the male, theoretical possibilities exist that antiepileptic drug therapy in the female may enhance or diminish sexual activity and that these alterations may influence her possibility of becoming pregnant. In the literature, almost all the available data pertain to decreased female sexual activity or lowered female fertility .

The statement has often been made that women with epilepsy, which in practice will nearly always be antiepileptic drug-treated epilepsy, exhibit decreases in fertility , libido , sexual arousal and orgasm and increases in the incidences of menstrual irregularity , tendencies to early menopause or premature ovarian failure and also face a heightened risk of suffering from the polycystic ovary syndrome . All these changes would militate against the chances of becoming pregnant (Klein et al. 2001; Harden 2006; Pennell 2009). However, in their material, Klein et al. could not correlate premature ovarian failure manifestations with antiepileptic drug intake. Some quantitative data are available in relation to the lowered fertility aspect. In females with epilepsy aged 15–44 years, Wallace et al. (1998) found a live birth rate of 47.1 per 1000 per year as compared with the national 1993 England and Wales live birth rate of 62.6 per 1000 per year. Artama et al. (2006), in two cohorts from the Finnish population, also found a lower birth rate in women with epilepsy treated with carbamazepine , oxcarbazepine and valproate as compared with a reference cohort, though the reduction in rate was not statistically significant. Kariuki et al. (2008) found a 3-year fertility rate of 46 live births per 1000 women with established epilepsy, a reduction by two-thirds as compared with the expected rate for the local African population. Jalava and Sillanpää (1997) followed up a cohort of childhood epilepsy sufferers and showed that, in the longer term, they had a lower marriage rate than would have been expected and also a lower rate of fertility .

The above alterations in fertility and in other aspects of female sexual function appear to have a hormonal basis. In three women, Isojarvi and Tapanainen (2000) drew attention to an apparent association between intake of valproate and the presence of polycystic ovaries and hyperandrogenism . Replacing the valproate with lamotrigine caused the polycystic ovaries to disappear in two of the women, and plasma testosterone concentrations fell in all three. Bilo et al. (2001) noted the presence of various reproductive disorders in 32 % of 50 women with (treated) epilepsy, the disorder encountered being polycystic ovaries in 26 %. These authors failed to detect a correlation between the abnormalities and the intake of any particular antiepileptic drug. They therefore suggested that having epilepsy per se might be responsible. Despite the latter suggestion, it seems to have become fairly widely accepted that there is a real association between the use of valproate and the occurrence of polycystic ovaries (Crawford 2009).

The use of antiepileptic drugs that induce drug-metabolising enzymes increases the concentration of sex hormone-binding globulin in women as well as in men. This increase may decrease the concentrations of circulating unbound (and therefore biologically active) oestrogen relative to total oestrogen concentrations, an effect which could contribute to the presence of menstrual disorders in some women with epilepsy (Isojärvi 2008). As well, the use of valproate in women causes increased circulating testosterone concentrations, which also might disturb the menstrual cycle and as well contribute to the development of polycystic ovaries . These various altered circulating steroid hormone concentrations may contribute to the decreased fertility of women with epilepsy. Hamed (2008) suggested that antiepileptic drugs may also modulate hormone release from the hypothalamic–pituitary axis and, through this additional means, diminish fertility in women.

Jankovic et al. (2006) investigated a further matter that might be relevant to impaired fertility in antiepileptic drug-treated women. In a laboratory study, they found that carbamazepine and lamotrigine , at concentrations within the ranges encountered in the treatment of epilepsy, inhibited motility in surgically removed human fallopian tubes . This effect could contribute to the diminished fertility of women with epilepsy, by reducing the opportunity for contact between the sperm and the ovum at an appropriate time and anatomical site.

It is highly probable that various psychological and social factors that vary between individual women with epilepsy will also have major influences on fertility and also on some of the other aspects of altered sexual function that have been mentioned above. For instance, it is not difficult to appreciate that a woman with uncontrolled seizures may have problems in sustaining enduring personal relationships and may also be reluctant to undertake pregnancy because of uncertainties about her ability to care for a young infant.