This study was specifically aimed to evaluate the sexual and reproductive health in a group of men with generalized epilepsy. In total, 44 men with generalized epilepsy were included in this study, their ages between 18 and 48 years (29.2±9.9) and duration of illness between 2 and 35 years (11.2±7.4); 34 patients were treated with conventional antiepileptic drugs (AEDs). Sexological and psychological interviews together with serum total testosterone, E2, FSH, LH and prolactin were determined. Hyposexuality was diagnosed in 61.4%. Erectile dysfunction (ED) and premature ejaculation represented 70.4 and 66.7%, respectively. Variables such as hyposexuality, seizure duration and its poor control on AEDs were significantly associated with depressive symptoms. Compared to the normal control group, all patients reported elevated E2 levels (P<0.001), 10 had FSH (n=4) and LH (n=6) levels exceeding that of the normal range for controls and two had hyperprolactinemia. Although the patients’ mean value of total testosterone remained within the normal range, but it was significantly lower in hyposexual men compared to nonhyposexual (P<0.002), only two epileptic patients had markedly reduced level of total testosterone beyond normal control levels. This study strongly supports that: (1) The risk of hyposexuality and reproductive disturbances is high in epileptic patients with GTC convulsions despite the AEDs utilized. The risk for SD is further increased by poor seizure control and the frequently accompanied depressive manifestations. (2) It is possible that elevated E2 could increase the risk of SD by reducing active testosterone through negative feedback and the reduction of active testosterone could increase seizure intractability to antiepileptic medications.
Sexuality and reproductive functions involve complex interactions between different brain areas (cortical, limbic system, hypothalamic, and pituitary) and end organs.1, 2 Epileptic patients frequently exhibited sexual and reproduction dysfunctions. Changes in central control, peripheral hormone levels, and/or antiepileptic drug (AED) medications may all contribute to decreased libido, potency, and fertility in patients with epilepsy.3, 4, 5, 6, 7, 8, 9 Epileptiform discharges may disrupt the function of structures mediating sexual behavior, particularly the limbic cortex, or alter the release of hypothalamic–pituitary hormones.10 Due to enormous limbic system connections with different brain areas, sexual and endocrinologic abnormalities were commonly reported in patients with limbic epilepsies than those with generalized epilepsies.10, 11, 12, 13 AEDs were also demonstrated to modulate hormone release from the hypothalamic–pituitary–gonadal axis and may have direct inhibitory effect on sexual and reproductive functions.7, 12, 14 The resultant neuroendocrine effects with steroid sex hormone alterations may alter epileptogenicity.15, 16, 17 Organic etiologies such as vasculogenic erectile dysfunction (ED) were infrequently reported in men with epilepsy.18 In addition, psychosocial variable can contributed to a great extent as a cause of altered sexual responsiveness in patients with epilepsy.17 Due to the multifactorial nature of sexual and reproductive disturbances in epileptics,18 specific evaluation and treatment protocols for such patients mandate multidisciplinary evaluation.
Aim of the work
Sexual and endocrinologic abnormalities were rarely reported in patients with generalized epilepsies compared to limbic epilepsies. We hypothesize that men with generalized epilepsy have high liability to develop sexual and reproductive dysfunction; hence, we designed this study aiming to evaluate the sexual and reproductive function in a group of adult men with generalized epilepsy through a multidisciplinary team (Neurologist, Psychiatrist and Urologist) together with endocrinological screening. We studied the relationship between sexual dysfunction (SD), depressive manifestations, variables of epilepsy (duration, AEDs, and the degree of seizure control on medications), and the reproductive profile of gonadal hormones.
Patients and methods
This study was performed in the outpatient epilepsy clinic of the Department of Neurology (Assiut University Hospital, Assiut, Egypt) with approval of the local ethical committee. Written informed consent was obtained from both patients and controls. In total, 44 adult male epileptics were investigated. Epilepsy type was defined according to the International League Against Epilepsy.19 All patients had generalized tonic–clonic convulsions. In all, 34 were treated with one or more AED(s) (VPA (n=8), CBZ (n=17), combined CBZ and VPA (n=9)) and 10 were untreated. Also, 30 age-matched healthy volunteer men (selected from the hospital paramedical staff) served as controls (age range was 21–45 years, married/single=2/1).
Patients with neurologic, psychiatric, systemic or primary endocrine diseases that may result in SD.
Use of any regular medication(s) in addition to AEDs.
Heavy cigarette smoking or regular alcohol consumption.
All patients were subjected to full medical, neurological, and urological history and examination with special emphasis to the duration of illness, type of AED(s), and the degree of response to AEDs. The frequency of seizures was divided as follows: (a) very frequent: seizures occurring several times a day or at intervals shorter than 7 days, (b) frequent: seizures at intervals longer than 7 days but shorter than 30 days, (c) occasional: seizures at intervals longer than 30 days but shorter than 1 year, and (d) rare: seizures at intervals longer than 1 year. Patients were considered controlled when seizure free for ⩾1 year and partially controlled when seizure frequencies were occasional or rare and uncontrolled when seizures were frequent or very frequent.
Interviews about sexual function were carried out to all patients, controls, and their partners by a psychiatrist, urologist, and a third independent investigator. Psychological interview was carried out using a validated sexual questionnaire for assessment of libido, potency, or satisfaction of erection or orgasm (Diagnostic criteria of research of ICD 10, 1992).20 Libido was considered decreased or absent when the subject reported diminished or absence of sexual desire and had frequency of search for sexual intercourse once a month or less. Potency and sexual pleasure were considered reduced or absent when the frequency of sexual intercourse that culminates in orgasm was at least less than once a month and/or when there was a failure to persistent or recurrent partial or complete obtaining and/or maintaining penile erections until the end of sexual activity. Premature ejaculation (PE) is usually defined as an ejaculation occurring <60 s after initiation of intercourse. Hyposexuality was defined in those who presented with decreased or absent sexual potency and/or libido lasting a period greater than 6 months and were completely unsatisfied with their sexual experience. Global hyposexuality was defined when the patients exhibited impairment in desire, erection, and ejaculation.
Depressive manifestations were screened in all patients, control subjects, and their partners, utilizing the self-report standardized Beck Depression Inventory,21 including: mood, pleasure of activity, appetite, energy, concentrations and attention, psychoperformance, sleep disturbances, suicide or death wishes, and associated performance anxiety.
Routine lab blood tests were carried out for all patients, including: complete blood count, blood sugar curve, kidney, and liver function tests.
Blood samples of all patients and control subjects were drawn at (0800–1000 h) after an overnight fast and patients were seizure free for at least 72 h, as any postictal central hormonal dysfunction is recognized to reverse within hours,22 for analysis of serum LH, FSH, total testosterone, prolactin, and E2 using protocols recommended by the manufacturers. For confirmation, the serum hormone levels for all patients and control subjects were obtained and assessed twice at two different days. The hormonal levels were combined with the cross-sectional assessment of psychological and sexual interviews of all patients and control subjects. No seminal analyses were performed. Owing to financial causes, we were unable to measure the levels of free testosterone and sex hormone-binding globulin (SHBG). The concentration of serum LH was measured by immunoenzymetric assay kit obtained from Biosource Europe SA, as described by the manufacturer. The concentrations of serum prolactin, FSH, testosterone, and E2 were measured by IMMULITE reproductive hormone assays from Diagnostic Product Cooperation (Los Angeles, CA, USA), as described by the manufacturer.
The serum levels of AEDs were determined in the therapeutic drug-monitoring (TDM) lab (Assiut University Hospital, Assiut, Egypt) using the fluorescence polarization immunoassay system of Abbott (EPIA), using TDxFLX apparatus (Abbott Lab, Wiesbaden, Germany) as described before,23 and they were measured as part of the investigation in batched assays.
Data are expressed as means±s.d. Statistical comparison among patients and control subjects and different groups of patients was evaluated using ANOVA tests. The logistic t-test was used to evaluate the difference in the descriptive data of the patients and the control group. Moreover, Pearson's and Spearman's correlations were performed between different biochemical parameters. Calculations were performed with the statistical package SPSS for windows, version 10.0. Statistical significance was defined as P<0.05.
Included in this study were 44 epileptic men with generalized tonic–clonic convulsions (Table 1). In all, 34 epileptics were treated with AEDs (CBZ=17, VPA=8 and CBZ and VPA=9) and 10 were untreated. Regarding the response to AED treatment: eight patients (23.5%) were controlled on ⩾1 AED(s), six (17.7%) were partially controlled, while near half of the patients were uncontrolled (n=20 or 58.8%). All treated patients gave history of compliance to AEDs. The serum levels of AEDs were within the normal reference range.
On sexological and psychological interviews: all married control subjects (n=20) apparently reported healthy and happy sexual relationship with regular sexual relation (at least once per month), and single control subjects (n=10) reported intact desire with adequate self-esteem. All patients’ couples were having stable marriages and reported healthy relationship with their partners; however, 25% of them reported lack of sexual relations for periods averaging 8 weeks due to lack of desire from the husband's side. All married patients had children (range 3–7). In all, 80% of the unmarried patients reported low self-esteem, fear of marriage, lack of desire, and no previous experiences with sex. Compared to control subjects, 27 patients (61.4%) reported one or more manifestations of SD (P<0.001). Self-reported ED and PE represented 70.4 and 66.7%, respectively (Table 2). Global hyposexuality was diagnosed in 59.3% (16/27). None of the married patients reported low fertility rate. SD was more among the treated group of epileptics than untreated. All AEDs utilized as either monotherapy or polytherapy were associated with noticeable sexual disturbances (Table 2). Compared to controls, most patients demonstrated one or more depressive symptoms (Table 2). Depressed mood was present in 72% (n=32 versus 13 for controls) (P<0.0001), diminished pleasure of activity was present in 56.8% (n=25 versus 13 for controls) (P<0.001), diminished psychoperformance was present in 59.1% (n=26 versus 13 for controls) (P<0.001), and sleep disturbances were present in 68.2% (n=30 versus 13 controls) (P<0.0001). The partially controlled and uncontrolled epileptics demonstrated more depressive manifestations than the controlled and untreated group of epileptics (Tables 2 and 5). A significant correlation was identified between different depressive manifestations and SD (depressive mood and SD, P=0.01, diminished pleasure of activity and SD, P=0.004, sleep disturbance and SD, P=0.03, and diminished psychoperformance SD, P=0.05). A positive association was identified between patients with associated anxiety and PE (P<0.001). The treated group of epileptics demonstrated more reproductive hormonal abnormalities than the untreated group. The CBZ-treated group of epileptics, either as monotherapy or polytherapy, demonstrated more reproductive hormonal abnormalities than the VPA-treated group (Table 2).
Compared to the normal control group, all patients had significantly increased levels of E2 (P<0.001). Only two CBZ-treated patients demonstrated marked reduction in total testosterone level beyond that of the normal control range (76.3 and 182 ng/dl). However, total testosterone mean level remained within the normal range, but was significantly lower in hyposexual compared to nonhyposexual men (554.5±136.0 versus 603.6±197.9; P<0.002), but there were no significant differences between the levels E2 among hyposexual and nonhyposexual patients. In all, 10 patients showed elevated FSH (n=4) and LH (n=6) on endocrinologic screening. Hyperprolactinemia was reported in only two patients (21.7 and 37.7 ng/ml) (Table 3). Patients with global hyposexuality had significantly lower level of total testosterone (P<0.01) compared to other hyposexual men (Table 4). Hyposexuality and endocrinologic abnormalities were significantly higher in all treated groups of epileptics, particularly those with poor seizure control (partially controlled and uncontrolled groups) (P<0.001) (Table 5). Global hyposexuality was found among patients with poor drug responders compared to good drug responders (P<0.001). Significant association was identified between the duration of illness and history of depressive manifestations (P=0.02); however, no significant association was identified between the duration of illness and hormonal changes.
This study demonstrated an unusual higher frequency of SD among the group of epileptic men (n=44) with generalized tonic–clonic convulsions. Approximately 2/3 (61.4%) of the studied patients had SD. Many experimental and human studies demonstrated that SD is more common in partial (particularly temporal) lobe epilepsy, as the limbic system is extensively interconnected with the hypothalamic nuclei involved in regulating gonadal function. In support: (1) increased neuronal activity in the amygdala and other parts of the temporal lobe might cause hyposexuality,13 (2) amygdala lesion or removal can produce hypersexuality,24 and (3) temporal lobectomy in epileptic patients has been reported to restore normal sexual function and normal serum androgen levels.24, 25 In contrast, many studies reported SD and hormonal disturbance in epileptic men with partial epilepsy, particularly if followed by secondary generalization.12, 26, 27
Most of our patients (61.4%) demonstrated hyposexuality, among whom 59.3% were considered to have global hyposexuality. ED and PE represented 70.4 and 66.4% of patients’ sexual complaints. It has been demonstrated that men with epilepsy appear to have an approximately fivefold increase in risk of ED.28 Hyposexuality was the most frequent interictal abnormality previously reported in men with epilepsy (28–67%).3, 4, 5, 11, 12, 18
All studied patients exhibited one or more depressive manifestations, among whom 65.9% demonstrated performance anxiety. It has been observed that depressive manifestations, which are frequently noticed in patients with epilepsy, may cause SD. However, endocrinologic dysfunction and depression could complicate the patient status. Previous studies demonstrated that nocturnal penile tumescence in men who are clinically depressed may demonstrate an absence of or minimal nocturnal erections.29 Patients commonly consider epilepsy as a stigma. Epileptic patients are faced with unexpected seizures, the consequences of the disease and the use of drugs, series of losses in health and employment, feelings of insecurity, low self-esteem, as well as dependence and rejection by others. Epilepsy signifies anxiety and depression, low self-esteem and immaturity as a result of the seizure, and this could lead to avoid situations that call for affective sexual involvement.17, 30, 31 The prevalence of depression was found to increase among patients having epilepsy with secondary generalization, mainly when correlated with duration of disease, intractability, and polymedication.17 The high prevalence of performance anxiety (65.9%) among our patients could be attributed to response to the fear of failure and this may result in psychogenic ED. In support: (1) 16 patients had ED, PE, and diminished sexual desire. A positive association was identified between PE and associated anxiety (P<0.001). It is well known that some patients may complain with ED when the primary problem is PE.31, 32 The man may ejaculate before penetration and is unable to immediately regain his erection. (2) Negative association was identified between the duration of the illness, SD, and hormonal changes, which is consistent with many studies,7 while positive association existed between different depressive manifestations and SD and the duration of the illness.33 Demerdash et al.34 reported that long history of illness could result in sexual alterations. (3) Uncontrolled and partially controlled epileptics reported more depressive manifestations than the controlled and untreated group of epileptics. (4) Global hyposexuality was found among patients with poor drug responders compared to those with good drug responders (P<0.001). This is consistent with many studies.3 Satisfaction and sexuality were better in operated epileptics free of seizures.35
However, we cannot exclude the biological cause of depression among epileptics, that is, the relationship between epilepsy and depression is bidirectional. Experimental studies in animal models of epilepsy suggest that serotonin and noradrenaline play fundamental roles in the pathogenesis of epilepsy;36 further evidence of the common pathogenesis of epilepsy and depression may be found in studies regarding the effect of some AEDs on serotonin and norepinephrine. CBZ and VPA have been found to increase synaptic secretion of serotonin.36
In addition to the strong previously described relationship between generalized epilepsy and sexual and psychological states of patients with epilepsy, the effect of generalized epilepsy (epileptiform discharge itself) on the reproductive profile of men is high. Androgens are important for the maintenance of libido and sexual potency.37, 38 It seems that generalized epilepsy has a greater biological effect on the level of reproductive hormones and hence attributes to hyposexality.39 In support: (1) All patients had high levels of estradiol, a metabolite of biologically active testosterone. It is highly possible that elevated E2 could increase the risk of SD by increasing the turnover of testosterone and reducing active testosterone by negative feedback. Reduced free testosterone, which represents 2% of total testosterone, was found to be associated with decreased sexual interest and potency.5, 40 This possibility is supported by the previously reported improved seizure control achieved with the adjunctive use of the aromatase inhibitor testolactone or the antiestrogen clomiphene than testosterone alone.41 (2) Poor seizure control and untreated groups of epileptics exhibited more hormonal abnormalities than the controlled group on AED(s). Many evidences support our findings, including the following: free testosterone levels are usually low in reproductive endocrine disorders that are associated with TLE in men and therefore favor the occurrence of epileptiform activity,26 testosterone has been found to raise the threshold of some induced seizures in experimental animals,15, 16 and previous studies demonstrated that patients with refractory epilepsy had improved sexual performance after temporal lobectomy.37
AEDs has been incriminated for hormonal abnormalities among epileptic patients, which seem to be more among enzyme inducer-treated patients, for example, CBZ, utilized as monotherapy or combined with VPA. It has been highly suggested that AEDs, which induce enzyme synthesis, may enhance the conversion of testosterone to estradiol by aromatase. In addition, AEDs can also act through competition of binding plasma protein, making the free fraction ready for metabolism.42
In addition to changes in androgen levels among epileptic patients, secondary hormonal changes can occur due to negative feedback loop between the testosterone and pituitary hormone. LH and FSH (n=10) were found to be increased in some of our patients, which indicates that affection is at the level of the gonades rather than the hypothalamic or pituitary levels.26 Prolactin levels were found to be normal in most of our patients, which is consistent with many studies.43 In contrast, several studies suggested that there is a clear relationship among hyperprolactinemia, low testosterone levels, and impotence, although the mechanisms responsible for ED with hyperprolactinemia are not solely secondary to decreased testosterone levels.26, 44, 45 However, there have been a number of reported incidences of elevated prolactin values with normal serum testosterone levels.46
However, and in contrast to our study, the previously reported results about serum estradiol in patients with epilepsy and SD are controversial. It is known that the majority of plasma testosterone is linked to proteins, 43–45% to albumin, 53–55% to SHBG.47 Murialdo et al.48 found increased levels of estradiol, Duncan et al.8 did not find altered levels of estradiol in epileptics with SD, but increased SHBG and reduced free androgen index (FAI) in patients with epilepsy and hyposexuality.49, 50, 51 Increased SHBG would expect to produce SD by decreasing serum levels of free testosterone and/or albumin-bound testosterone. Also, SHBG is the most important regulator for the biologic effect of the testosterone on the target tissue (i.e. it does decrease the activity of the testosterone on the target cells.7, 26
In conclusion, the strong association between hyposexuality and gonadal hormonal disturbances demonstrated in this study among patients with GTC epilepsy has led us to the following speculations: (1) GTC epilepsy may promote the development of reproductive endocrine disorders with decreased biologically active testosterone, a potent stimulator of libido and potency. It is possible that elevated E2 could increase the risk of SD by reducing active testosterone by negative feedback. In addition, reduced active testosterone could increase seizure intractability to antiepileptic medications. (2) Our study showed that the risk of generalized epilepsy per se overweighted that of AEDs utilized. In other words, SD appears to be related to poor seizure control, and reproductive endocrine disorders may furthermore promote the seizure intractability to AED medications; however, the effect of AEDs on hormonal profile of epileptic cannot be excluded. (3) The strong association between the generalized epilepsy and the psychological variables (depression and anxiety) leads us to suggest that such variables may contribute to SD to some extent in epileptic patients. This should be kept in consideration while treating epileptic patients with SD. One goal includes changing dysfunctional thoughts and behaviors and interactions that are found to inhibit sexual arousal. (4) Lastly, the multifactorial nature of sexual disorder in epilepsy mandates the need for a multidisciplinary approach.
follicle stimulating hormone
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Hamed, S., Mohamed, K., El-taher, A. et al. The sexual and reproductive health in men with generalized epilepsy: a multidisciplinary evaluation. Int J Impot Res 18, 287–295 (2006). https://doi.org/10.1038/sj.ijir.3901406
- antiepileptic drugs
- depressive manifestations
Sexual dysfunction and associated factors among patients with epilepsy at Amanuel Mental Specialty Hospital, Addis Ababa – Ethiopia
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