|Year : 2016 | Volume
| Issue : 2 | Page : 79-83
A study on serum levels of testosterone and prolactin hormones in male epileptic adolescents
Mohamed Osman Rabie1, El-Sayed Ali Tag El-din1, Khaled H Rashed1, Wafik S Bahnasy1, Hesham A El-Serogy2
1 Department of Neuropsychiatry, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Tanta University, Tanta, Egypt
|Date of Submission||20-Jan-2016|
|Date of Acceptance||15-May-2016|
|Date of Web Publication||2-Jun-2016|
Wafik S Bahnasy
MD Department of Neuropsychiatry, Tanta University, Tanta, Gharbia
Source of Support: None, Conflict of Interest: None
Testosterone and prolactin hormone abnormalities have been noticed in some epileptic patients and were attributed to either the direct effect of the disease or the effect of antiepileptic drug therapy.
The aim of this study was to evaluate the potential endocrinal dysfunction in nonmedicated male adolescents with idiopathic generalized epilepsy as well as those on valproate treatment.
Patients and methods
This study was performed on 40 epileptic patients, 20 newly diagnosed nonmedicated and 20 treated with valproate, who attended the epilepsy clinic in the Department of Neuropsychiatry, Tanta University Hospital. Twenty age-matched male healthy controls were also included. Patients were subjected to full history taking, neurological examination, evaluation of testosterone and prolactin blood levels, and electroencephalography.
The serum levels of both free and total testosterone were higher in valproate-treated patients compared with nonmedicated patients and healthy controls. The levels were significantly lower in the nonmedicated group compared with the control group. The serum level of prolactin in both patient groups was significantly higher when compared with the healthy control group, with no statistically significant difference between the two patient groups.
The exact etiology of hormonal abnormalities in men with epilepsy appears to be multifactorial, including the disease and antiepileptic drug effects. Neuroendocrine regulation in men with epilepsy may be important not only for reproductive function but also for optimal management of seizure disorders.
Keywords: Adolescent male, epilepsy, prolactin, testosterone
|How to cite this article:|
Rabie MO, El-din ESA, Rashed KH, Bahnasy WS, El-Serogy HA. A study on serum levels of testosterone and prolactin hormones in male epileptic adolescents. Egypt J Neurol Psychiatry Neurosurg 2016;53:79-83
|How to cite this URL:|
Rabie MO, El-din ESA, Rashed KH, Bahnasy WS, El-Serogy HA. A study on serum levels of testosterone and prolactin hormones in male epileptic adolescents. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2020 Oct 20];53:79-83. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/2/79/183407
| Introduction|| |
Epilepsy during adolescence is a significant neurologic burden, with a prevalence of 1.5-2%. Adolescence is a time of great changes, with preparation for employment, driving, relationships, and marriage, and epilepsy can affect all these aspects . Reproductive endocrine dysfunction is not uncommon among epileptic patients and may be related to the effect of epilepsy and/or antiepileptic drugs (AEDs). Epileptic discharges and AEDs may stimulate or inhibit the hypothalamus, altering the hypothalamic and pituitary hormones, gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone, and luteinizing hormone (LH), through alteration in the input of the cerebral cortex, amygdala, and hippocampus to the hypothalamic-pituitary-gonadal axis .
Epileptic discharges may stimulate or inhibit the hypothalamic release of GnRH, which in turn alters the release of corresponding pituitary hormones. Moreover, the release of GABA and glutamate during seizures also influences hypothalamic and pituitary hormone release ,. Moreover, experimental animal investigations have shown that generalized seizures disrupt normal gonadal structure, physiology, and serum androgen levels in male rats, and the induction of seizures in the amygdala produces hyposexuality. At the same time, epileptiform discharges are accompanied by acute changes in patterns of LH secretion .
Testosterone metabolites may exert proconvulsant and anticonvulsant actions depending on their levels within the brain . Testosterone metabolite estradiol promotes seizures, whereas androstanediol has a powerful antiseizure effect . Androstanediol and estradiol act as positive and negative allosteric modulators of GABA-A receptors, respectively . Activation of these receptors leads to the influx of chloride ions and hyperpolarization of the membrane that dampens the excitability and vice versa . Recent evidence indicates that neurosteroids are present mainly in the hippocampus and neocortex . Prolactin secretion and its serum level have also been affected by epilepsy. The postictal serum prolactin measurement has been used in the differentiation between psychogenic and epileptic seizures, and the interictal epileptic activity seems to have an influence on prolactin release ,.
This work aimed to study testosterone and prolactin levels in male epileptic adolescents and to study endocrinal functions in long-term valproate users.
| Patients and methods|| |
The present study was conducted on 40 male patients between 12 and 18 years of age with idiopathic generalized epilepsy according to the ILAE classification 2010  attending the epilepsy clinic of the Department of Neuropsychiatry, Tanta University Hospitals, during the period from October 2013 to April 2014. Patients were divided into two groups: group I included 20 nonmedicated patients and group II included 20 patients with stable treatment regimen on valproate. Twenty healthy relatives of the patients matched with the same age and sex were taken as a control group (group III).
The study protocol was approved by our local ethics committee. Participation was voluntary, and all participants and their parents received detailed information concerning the aims of this research work. Informed consent was obtained from the parents of all participants before the commencement of the study.
Patients with endocrinal dysfunction, hepatic diseases, and those on enzyme-modulating drugs or hormonal therapy were excluded from the study.
Patient groups were subjected to clinical evaluation, history taking, predesigned epilepsy sheet, and neurological examination. Testosterone and prolactin blood levels were assessed in both patients and controls. Electroencephalography, brain computed tomography, and/or MRI were performed, if needed.
After an overnight fasting and a seizure-free period of at least 1 week, 5 ml of venous blood was taken from every investigated participant under complete aseptic conditions. The sample was transferred into a disposable plastic tube and allowed to clot, and then was centrifuged at 1200 rpm for 15 min to separate the serum. The obtained sera were stored at −20°C until used for different estimations. Total serum testosterone levels were measured using Elecsys and Cobas electrochemiluminescence immunoassay kit for quantitative measurement of total testosterone level . Serum (Roche Diagnostics Corporation, 7988 Centerpoint Dr, Indianapolis, IN 46256, United States) free testosterone levels were assayed using Genway ELISA kit for quantitative measurement of free testosterone level . Serum prolactin levels were detected using Elecsys and Cobas electrochemiluminescence immunoassay kit for quantitative measurement of prolactin level .
Statistical presentation and analysis was conducted using the mean, SD, c2 -test, and analysis of variance test using SPSS V18 (IBM Inc., Chicago, Illinois, USA). Correlation analysis was performed using Pearson's correlation test. P value less than 0.05 was considered as statistically significant.
| Results|| |
The study showed a nonsignificant difference between the three studied groups with regard to age [Table 1]. Electroencephalography showed epileptic discharge in 16 cases (80%) from group I and six cases (30%) from group II. Patients from rural areas constituted 85% of group I, 80% of group II, and 70% of group III participants.
Prodromal symptoms in group I included headache in 25% of cases, smell abnormalities in 10% of cases, blurred vision in 30% of cases, and apprehension in 15% of cases compared with 20, 15, 20, and 5% in group II, respectively.
Postictal manifestations were as follows: tiredness in 100% of cases from groups I and II, headache in 90% of cases from group I and 100% of patients from group II, sleep in 85% of group I and 80% of group II patients, confusion in 90% of group I and 75% of group II patients, and emotional disturbances in 35% of group I and 40% of group II patients.
Results of the present study revealed the following: the serum level of free testosterone in group I was significantly lower when compared with both groups II and III, whereas group II showed significantly higher levels when compared with both groups I and III [Table 2], [Figure 1].
|Figure 1: Free and total testosterone and prolactin levels among studied groups (ng/ml).|
Click here to view
The serum level of total testosterone in group I was significantly lower when compared with both groups II and III, whereas group II showed significantly higher levels when compared with both groups I and III [Table 2].
The serum level of prolactin in group I was significantly higher when compared with group III. Moreover, group II showed significantly higher levels when compared with group III, with no statistically significant difference between groups I and II [Table 2].
There was a statistically significant positive correlation between the serum levels of both free and total testosterone in the two patient groups (I and II) [Figure 2].
|Figure 2: Positive correlation between free and total testosterone among groups I and II.|
Click here to view
There was a statistically significant negative correlation between serum levels of prolactin and both free and total testosterone in group I [Figure 3], with no statistically significant correlation between them in the group II.
|Figure 3: Negative correlation between prolactin and free testosterone in the nonmedicated group.|
Click here to view
| Discussion|| |
Reproductive endocrine disorders are more common among epileptic patients than among the general population, which is attributed to epilepsy itself, AEDs, or both . An understanding of these relationships are important for better management of epileptic patients . This study aimed to explore the inter-relationship between puberty and epilepsy. Therefore, we tried to study serum level of testosterone and prolactin hormones in male epileptic adolescents to find their relationship with epileptic seizures in this age. We also studied whether the long-term use of valproate could interfere with reproductive endocrine functions.
The study showed that free and total testosterone levels were significantly lower in the nonmedicated epileptic group compared with both the medicated and control groups. These results are in accordance with those of Herzog et al. (2004) , who explained on the basis of altered LH pulse, frequency, and amplitude of secretion, and thus support the notion that epilepsy itself may contribute to reproductive abnormalities in epileptic patients .
As regards prolactin, it was significantly higher in the nonmedicated epileptic group compared with healthy controls. These results are in agreement with those of Xiaotian et al. (2013)  but in contrast with the results of Hamed (2013) . These results are attributed to seizure-induced abnormal neuronal discharge, which stimulates the hypothalamus and alters prolactin secretion by the pituitary gland. Prolactin levels are elevated due to altered regulation of GABAergic, noradrenergic and serotonergic neurons, which in turn modulate dopamine release . The observed state of hyperprolactinemia in the nonmedicated epileptic group of the current study may be related to the low level of testosterone as evidenced by a statistically significant negative correlation between the serum levels of prolactin and both free and total testosterone. The possible explanation is that high prolactin level has inhibitory effect on hypothalamic GnRH neurons and/or on the pituitary gland to reduce secretion of the gonadotropins LH and follicle-stimulating hormone, resulting in a reduction in both the amplitude and frequency of LH pulses .
The valproate-treated epileptic group showed a higher serum free and total testosterone levels compared with healthy controls and the nonmedicated epileptic group. In accordance with these results, Rδttyδ et al. (2001)  concluded that valproate increases serum androgen concentrations involving testosterone in men with epilepsy. However, Roste et al. (2005)  and Mikkonen et al. (2004)  found no significant differences, either in the total or free testosterone serum levels, in valproate-treated male patients compared with the control group. Moreover, Najafi et al. (2012)  and Xiaotian et al. (2013)  demonstrated that men receiving valproate had significantly lower mean testosterone levels.
Valproate-associated hyperandrogenemia may be attributed to the inhibition of the enzymatic conversion of testosterone to estradiol by aromatase. Moreover, valproate may cause inappropriate LH secretion through its effect on gonadotropin pulsatility, thus increasing the levels of testosterone. The described hormonal change is considered to be a part of valproic acid antiepileptic action, as valproate enhances dehydroepiandrosterone sulfate concentrations, a precursor of testosterone, which can be metabolized to GABAergic steroid, in addition to inhibition of conversion of testosterone to estradiol, which is considered to be a proconvulsant .
As regards the valproate-treated epileptic group, they showed higher prolactin level as compared with healthy participants. These findings are in agreement with those of Xiaotian et al. (2013)  and Hamed et al. (2013) . It was speculated that valproate-mediated changes in prolactin levels result from altered regulation of GABAergic, noradrenergic, and serotonergic neurons, which in turn modulate dopamine release .
| Conclusion|| |
The exact etiology of hormonal abnormalities in men with epilepsy is not well known and appears to be multifactorial, including the effects of disease state and its treatment on hormone levels, the hypothalamic-pituitary axis, and testicular function, in addition to psychosocial factors that affect people with epilepsy.
- Further studies with longer duration of AED uses are needed
- Regular evaluation of epileptic patients by an endocrinologist is necessary.
If hormonal therapy is needed, testosterone must be combined with an aromatase inhibitor to block its transformation to estradiol and thus avoid seizure induction.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Parachuri V, Inglese C. Neurological problems in the adolescent population. Adolesc Med State Art Rev 2013; 24(1):1-28.
Hamed SA. Neuroendocrine hormonal conditions in epilepsy: relationship to reproductive and sexual functions. Neurologist 2008; 14(3):157-169.
Montouris G, Morris GL III. Reproductive and sexual dysfunction in men with epilepsy. Epilepsy Behav 2005; 7:Suppl 2:7-14.
Taubøll E, Røste LS, Svalheim S, Gjerstad L. Disorders of reproduction in epilepsy - what can we learn from animal studies?. Seizure 2008; 17(2):120-126.
Reddy DS. Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy. Front Endocrinol (Lausanne) 2011; 2:38.
Velíšková J, Desantis KA. Sex and hormonal influences on seizures and epilepsy. Horm Behav 2013; 63(2):267-277.
Reddy DS, Jian K. The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors. J Pharmacol Exp Ther 2010; 334(3):1031-1041.
Carver CM, Reddy DS. Neurosteroid interactions with synaptic and extrasynaptic GABA(A) receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. Psychopharmacology (Berl) 2013; 230(2):151-188.
Reddy DS, Rogawski MA. Neurosteroids endogenous regulators of seizure susceptibility and role in the treatment of epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors Jasper′s basic mechanisms of the epilepsies
. 4 th
ed. Bethesda: National Center for Biotechnology Information (US); 2012. 667-674.
Aydin S, Dag E, Ozkan Y, Arslan O, Koc G, Bek S, et al.
Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients. Peptides 2011; 32(6):1276-1280.
Chen DK, So YT, Fisher RS. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005; 65(5):668-675.
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al.
Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51(4):676-685.
Blackburn GF, Shah HP, Kenten JH, Leland J, Kamin RA, Link J, et al.
Electrochemiluminescence detection for development of immunoassays and DNA probe assays for clinical diagnostics. Clin Chem 1991; 37(9):1534-1539.
Marcus GJ, Durnford R. A simple enzyme-linked immunosorbent assay for testosterone. Steroids 1985; 46(6):975-986.
Smith CR, Norman MR. Prolactin and growth hormone: molecular heterogeneity and measurement in serum. Ann Clin Biochem 1990; 27:542-550.
Isojärvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms. Seizure 2008; 17(2):111-119.
Herzog AG. Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure 2008; 17(2):101-110.
Herzog AG, Drislane FW, Schomer DL, Pennell PB, Bromfield EB, Kelly KM, et al.
Differential effects of antiepileptic drugs on sexual function and reproductive hormones in men with epilepsy: interim analysis of a comparison between lamotrigine and enzyme-inducing antiepileptic drugs. Epilepsia 2004; 45(7):764-768.
Xiaotian X, Hengzhong Z, Yao X, Zhipan Z, Daoliang X, Yumei W. Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy. J Clin Neurosci 2013; 20(11):1492-1497.
Hamed SA, Ahmad HK, Youssef AH, Metwaly NA, Hassan MM, Mohamad HO. Erectile function in men with epilepsy: relationship to demographic-, clinical endocrinal, psychosocial-related variables. J Neurol Neurosci 2013; 4:1-12.
Kaiser UB. Hyperprolactinemia and infertility: new insights. J Clin Invest 2012; 122(10):3467-3468.
Rättyä J, Turkka J, Pakarinen AJ, Knip M, Kotila MA, Lukkarinen O, et al
. Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology 2001; 56(1):31-36.
Røste LS, Taubøll E, Mørkrid L, Bjørnenak T, Saetre ER, Mørland T, Gjerstad L. Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy. Eur J Neurol 2005; 12(2):118-124.
Mikkonen K, Tapanainen P, Pakarinen AJ, Päivänsalo M, Isojärvi JI, Vainionpää LK. Serum androgen levels and testicular structure during pubertal maturation in male subjects with epilepsy. Epilepsia 2004; 45(7):769-776.
Najafi MR, Ansari B, Zare M, Fatehi F, Sonbolestan A. Effects of antiepileptic drugs on sexual function and reproductive hormones of male epileptic patients. Iran J Neurol 2012; 11(2):37-41.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]