Phenytoin-Induced Elevation of Serum Estradiol and Reproductive Dysfunction in Men with Epilepsy

Reproductive and sexual dysfunction in men with epilepsy has been attributed to androgen deficiency. Low serum free testosterone (FT) levels occur in both hypogonadotropic and hypergonadotropic hypogonadism. Antiepileptic drugs (AEDs) have been implicated. Proposed mechanisms include induction of increased sex hormone binding globulin (SHBG) resulting in decreased FT, as well as dysfunction or premature aging of the hypothalamopituitary-gonadal axis. In an investigation comparing serum reproductive steroid levels among 20 men receiving phenytoin (PHT) monotherapy for complex partial seizures, 21 untreated men with complex partial seizures, and 20 age-matched normal controls, total estradiol levels were significantly higher in the PHT group (56.3 +/- 29.4 pg/ml, mean +/- SD) than in the untreated (32.4 +/- 27.4 pg/ml, p less than 0.01) and normal control (34.3 +/- 12.7 pg/ml, p less than 0.05) groups. The physiologically active non-SHBG-bound serum estradiol levels were also significantly higher in the medicated group (45.1 +/- 21.7 pg/ml) than in the untreated (29.9 +/- 17.2 pg/ml, p less than 0.01) and normal control (31.1 +/- 11.4 pg/ml, p = 0.05) groups. These findings suggest that PHT may lower FT by induction of aromatase, enhancing FT conversion to estradiol, as well as SHBG synthetase. Estradiol exerts a potent inhibitory influence on luteinizing hormone secretion and has been suggested to play a major role in negative feedback in men as well as women. Suppression of LH secretion results in hypogonadotropic hypogonadism. Chronically low FT leads to testicular failure and hypergonadotropic hypogonadism. Finally, estradiol has been shown to produce premature aging of the hypothalamic arcuate nucleus, which secretes gonadotropin-releasing hormone.     

Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms.

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.     

Aromatase inhibition, testosterone, and seizures

The effect of testosterone on brain excitability is unclear. The excitatory aspect of testosterone's action in the brain may be due to its conversion to estrogen via aromatase. We report herein a 61-year-old man with temporal lobe epilepsy and sexual dysfunction due to low testosterone levels. Use of an aromatase inhibitor, letrozole, normalized his testosterone level and improved his sexual functioning. Letrozole, in addition to standard antiseizure medication, was also associated with improved seizure control. This was sustained and, further, was associated with seizure exacerbation after withdrawing letrozole, and subsequent seizure improvement after restarting it. During the course of treatment, his serum testosterone level increased, sex hormone-binding globulin decreased (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels increased, while serum estradiol levels remained undetectable. Letrozole may, therefore, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. This experience suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy.     

The effect of seizures and kindling on reproductive hormones in the rat

Reproductive dysfunction and endocrine disorders are common among both women and men with epilepsy, and, in particular, with temporal lobe epilepsy. In clinical studies, it is hard to separate the effects of seizures from the effects of medication and life style. Studies in rodents, however, suggest that seizures per se can contribute to reproductive dysfunction. In female rats, generalized seizures disrupt normal ovarian cyclicity in adults, and repeated electroshock seizures delay the onset of puberty in juveniles. Right amygdala kindling in adult female rats causes acyclicity, the development of polycystic ovaries and premature aging of the hypothalamic-pituitary neuroendocrine axis, leading to chronic anovulation and continuous estrogen exposure. In adult male rats, repeated electroshock seizures result in transient hypogonadism, characterized by decreased serum testosterone levels and lowered gonadal tissue weight. In contrast, right amygdala kindling increases serum testosterone, estradiol levels and gonadal weight. These findings suggest that reproductive dysfunction in women and men with epilepsy may result from recurrent seizure activity, due to seizure-related interference with the normal functions of the hypothalamic-pituitary-gonadal axis.     

Antiepileptic drugs, sex hormones, and PCOS

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.     

Interictal hyposexuality in male patients with epilepsy

The purpose of this study was to compare the serum levels of androgens between hyposexual and non-hyposexual patients with epilepsy. Adult male patients with epilepsy were investigated. Serum levels of testosterone (T) and free-T, estradiol, and sex hormone binding globulin (SHBG) were measured and the free androgen index (FAI) was calculated. While there were no differences between hyposexual and non-hyposexual patients in the serum levels of T, free-T, and estradiol, or to the FAI, the serum levels of SHBG were significantly higher in hyposexual patients than in non-hyposexual patients. Thus, the effects of increased SHBG upon serum levels of testosterone biologically active in patients with epilepsy and hyposexuality were not detected by the methods used in this study. Four (44%) of nine hyposexual patients who were re-evaluated after two years follow-up improved sexual performance. Thus, clinical treatment that results in good seizure control may improve sexual performance in some patients with epilepsy.     

Aromatase inhibitors as add-on treatment for men with epilepsy

Manipulation of neurosteroids to treat epilepsy has been an area of active research. The effect of testosterone on brain excitability and seizure threshold has been mixed; the estradiol metabolite of testosterone increases brain excitability, while the reduced metabolite of testosterone, 3alpha-androstanediol, decreases brain excitability, likely through an action at the gamma-amino butyric acid A receptor. Therefore, the metabolites of testosterone produce opposite effects on brain excitability in seizure models. Aromatase is the enzyme for the conversion of testosterone to 17beta-estradiol. Aromatase inhibitors could decrease brain excitability by decreasing local estradiol levels and therefore, could be beneficial for the treatment of epilepsy. Aromatase inhibitors are US Food and Drug Administration-approved and have a long history of safe use in menopausal women with breast cancer. This review presents the results of using anastrazole in an open-label, add-on manner in a small group of men with epilepsy in order to improve seizures. The results suggested some effect on reduction of seizures and no side effects. Testosterone levels did increase, but not to above the normal range. Letrozole used in a single case was also beneficial for seizures. It was concluded that aromatase inhibitors may be a useful adjunct to the treatment of epilepsy, but habituation to the treatment may be limiting. Many men with epilepsy have low testosterone, and aromatase inhibition may be helpful in restoring levels to normal. Modulation of reproductive hormones by aromatase inhibition as well as enhancement of the 3alpha-androstanediol pathway may be an avenue of epilepsy treatment that would not produce sedative side effects, which is often a limiting factor with standard antiseizure medications. A further interesting result is that elevated follicle stimulating hormone and luteal stimulating hormone levels were associated with seizure reduction, suggesting that they may be a biomarker for a beneficial effect of aromatase inhibition on brain excitability.     

Sex steroids and sexual desire in a man with a novel mutation of aromatase gene and hypogonadism

Sexual behavior was investigated by a sexological interview in a man with aromatase deficiency and hypogonadism. The study was performed at the end of a long testosterone treatment, during transdermal estradiol treatment and during estradiol and testosterone associated treatment. Sexual behavior did not show abnormalities. As assessed by a sexological interview and by a sexological questionnaire gender-identity was male, sexual orientation was heterosexual and libido was normal. Sexual function was limited to masturbation and was seemingly unaffected by testosterone or estradiol alone; only the associated treatment induced a great increase in libido and in frequency of masturbation and sexual fantasies when both testosterone and estradiol reached the range of normality. Sexual behavior is mainly under the control of cognitive functions in men, but sex steroids may modulate some aspects of male sexuality. Our findings suggest that in men estrogens could play a role in sexual activity.     

Reproductive and sexual dysfunction in men with epilepsy

Disturbances of reproductive and sexual health are common in people with epilepsy. Their etiology is not well understood but appears to be multifactorial, and both epilepsy itself and drugs used to treat it are implicated. Physiologically, sex steroid hormone levels, the hypothalamic-pituitary axis, and testicular function can be affected in men with epilepsy. Psychosocial complications associated with epilepsy can also affect reproductive health and sexuality. Clinicians need to investigate such problems carefully, both because of their multifactorial nature and because patients and physicians alike may often fail to recognize or be reluctant to acknowledge them; in particular, patients whose epilepsy had its onset before puberty may lack subjective awareness of impairments of sexual response and function. Treatments for reproductive and sexual dysfunction in men with epilepsy have been inadequately studied. Modalities such as medications for erectile dysfunction and surgery may be useful. Therapy with exogenous testosterone and an aromatase inhibitor may be helpful for men with epilepsy and sexual dysfunction due to testosterone deficiency.     

A comparison of anastrozole and testosterone versus placebo and testosterone for treatment of sexual dysfunction in men with epilepsy and hypogonadism

Hyposexuality is commonly associated with low bioavailable testosterone (BAT) and relative estradiol elevation in men with epilepsy. This prospective, randomized, double-blind trial compared the effects of depotestosterone + the aromatase inhibitor anastrozole (T–A) versus depotestosterone + placebo (T–P) on sexual function, hormone levels, mood, and seizure frequency in men with epilepsy. Forty men with focal epilepsy, hyposexuality, and hypogonadism were randomized 1:1 to two groups (T–A or T–P) for a 3-month treatment trial of depotestosterone + either anastrozole or matching placebo. Outcomes included both efficacy and safety measures. Normalization of sexual function (S-score) occurred with greater frequency in the T–A (72.2%) than in the T–P (47.4%) group, but the difference was not statistically significant. T–A resulted in significantly lower estradiol levels and S-scores correlated inversely with estradiol levels at baseline and during treatment. Beck Depression Inventory II (BDI-II) scores improved significantly in both groups and changes in S-score correlated inversely with changes in BDI-II score. Changes in seizure frequency correlated with changes in BDI-II score. Seizure frequency decreased with both treatments and showed significant correlations with estradiol levels. Triglyceride levels increased with T–P and decreased with T–A. The difference in triglyceride changes between the two treatments was significant and correlated with changes in estradiol levels. Significant correlations between estradiol levels and S-scores, as well as seizure outcomes and triglyceride levels, suggest further study regarding a potential role for anastrozole in the treatment of men with epilepsy who have hyposexuality and hypogonadism.