Dominik Kobylarek1,2*
Katarzyna Zakryś1
Julia Gierszewska1
Bhavana Reddy Pagidela1
Yung-Yi Lan1
Rujith Kovinthapillai1
Aleksander Rajczewski1,2
Wojciech Kozubski1Sławomir Michalak1- 1Institute of Neurological Disorders, Poznan University of Medical Sciences, Poznań, Poland
- 2Poznan University of Medical Sciences, Doctoral School, Department of Neurology, Poznań, Poland
Epilepsy, a chronic neurological condition affecting over 70 million individuals worldwide, has far-reaching effects beyond seizure activity, including a significant impact on reproductive health by posing significant challenges to fertility and hormonal health. Emerging evidence underscores the complex bidirectional interplay between epilepsy, antiepileptic drugs (AEDs), and sex steroid hormones; particularly progesterone, testosterone, and prolactin, which influence both seizure threshold and reproductive function. This paper explores how epilepsy alters hypothalamic–pituitary-gonadal (HPG) axis dynamics, often leading to conditions like polycystic ovary syndrome (PCOS), anovulation, and menstrual irregularities. Moreover, the role of prolactin dysregulation following seizures, as well as the impact of temporal lobe epilepsy on gonadotropin-releasing hormone (GnRH) pulsatility, is examined in relation to infertility outcomes. By integrating current research on neuroendocrine signaling and reproductive physiology, this paper highlights the need for individualized care strategies in individuals with epilepsy to optimize both seizure control and reproductive health.
Introduction
There is a wealth of evidence in the scientific literature supporting the complex relationship between epilepsy and infertility. Infertility is clinically defined as the failure to achieve pregnancy after 12 months of regular unprotected intercourse or as a result of reproductive disorders in one or both partners. Its prevalence is approximately 15% of couples worldwide (1, 2). The etiology of infertility is attributed to male factors in about one-third of cases, female factors in another third, and the remaining cases are considered idiopathic (3, 4).
Epilepsy is one of the most common neurological disorders, affecting over 70 million individuals worldwide (5, 6). Its development and manifestations are multifactorial and often reflect an interplay of genetics, environmental and acquired factors, and hormonal dysregulation (7, 8). Due to its mechanisms of neuronal disruption, epilepsy has a profound systemic impact and can significantly affect reproductive health through disruption of the hypothalamic–pituitary-gonadal (HPG) axis and alterations in circulating sex hormone levels (9, 10).
Women with epilepsy (WWE) commonly exhibit reproductive disturbances, including menstrual irregularities, polycystic ovary syndrome (PCOS), and dysregulation of estrogen, androgen, and prolactin (PRL) levels (11–13). Men with epilepsy (MWE) often present with hypogonadism, reduced testosterone, and impaired spermatogenesis (14). Disruption of the HPG axis, ion channel dysfunction, and anti-seizure medications (ASM)-mediated endocrine interference underlie these impairments (11, 15, 16). Key fertility regulators that are affected include estrogen, progesterone (PROG), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), oxytocin (OT), dehydroepiandrosterone (DHEA), human chorionic gonadotropin (hCG), anti-müllerian hormone (AMH), testosterone, neurosteroids, and insulin (13–15). Despite significant advances in understanding the intersection between epilepsy and infertility, critical gaps remain regarding the mechanisms through which epilepsy and its treatment influence reproductive health. Key unanswered questions include the pathophysiological mechanisms underlying infertility in patients with epilepsy and the effective strategies for preserving fertility in affected individuals to improve quality of life both physiologically and psychosocially.
This review aims to explore the relationship between epilepsy and hormonal dysregulation, particularly emphasizing reproductive outcomes. It consolidates the current evidence regarding the complex interactions among epilepsy, sex hormone regulation, endocrine signaling pathways, and fertility. Additionally, it provides a comprehensive overview of how epilepsy impacts fertility, pregnancy, and fetal development, while considering the 2025 ILAE framework to address previous limitations that have hindered translational research. Furthermore, it discusses emerging strategies aimed at preserving reproductive function within this vulnerable population.
The interplay between reproductive hormones and neuronal activity
The impact of reproductive hormones on seizure occurrence is well documented, especially during physiologic states of high hormonal influence such as menstruation, pregnancy, and menopause. Hormonal fluctuations can alter seizure control due to changes in neuronal excitability and survival, but strangely, pregnancy, a state of high hormonal influence, is not reported to exacerbate seizures (17, 18). Two-thirds of women remain free from seizures during pregnancy, although if seizures are present, there may be a significant worsening of the general condition, especially due to focal seizures. In such cases, close supervision of the treatment regimen and seizure response is required, with modifications such as increased dosages of ASMs or different drug options (17, 18).
Women with epilepsy (WWE) are significantly more likely to experience reproductive and sexual dysfunction than the general population. Sexual disorders affect approximately 20–30% of WWE, with reduced libido being the most common complaint (19). Additional endocrine and reproductive abnormalities frequently reported include polycystic ovary syndrome (PCOS), menstrual irregularities, premature menopause, hyperandrogenism, hypogonadotropic hypogonadism, premature ovarian failure, and hyperprolactinemia (20–26). Approximately 33% of WWE experience seizure exacerbation corresponding with the changes of the menstrual cycle, known as catamenial epilepsy (27). This seizure pattern is sensitive to changes in hormonal levels of estrogen and progesterone (PROG), both key players in modulating neuronal excitation and thereby seizure thresholds (28). Corresponding to the dominant hormone in each phase of the menstrual cycle, three main patterns of catamenial epilepsy have been noted. The C1 (perimenstrual pattern) is guided by a decline in PROG and its metabolites, which reduces GABAergic inhibition, consequently increasing seizure susceptibility. The C2 (perimenstrual pattern) is characterized by a peak in E2 (estradiol) levels, which enhances the excitation of neurons, and lastly, the C3 (anovulatory pattern) is marked by a highly sustained level of estrogen in the absence of PROG entirely, leading to heightened neuronal excitation (29–31). These disruptions in hormonal balance not only reflect underlying endocrine abnormalities but also contribute to reduced fertility. Morrell estimates that 50–66% of WWE may be at risk for impaired fertility compared to women without epilepsy (32).
The hormonal effects of epilepsy are not limited to women, but are highly reported in men as well, with rates of sexual dysfunction ranging between 38 to 71% among men with epilepsy (MWE) (33). Hormonal dysregulation caused by epilepsy results in reduced levels of testosterone, both in its free and albumin-bound state, lower free androgen index (FAI) and increased concentrations of estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) (22, 23, 34). This imbalance and marked decrease in testosterone concentrations manifests as concerns such as delayed sexual development, impaired spermatogenesis, decreased libido, and abnormal testicular morphology (20, 22). MWE have characteristically lower levels of testosterone, even from younger ages, where 11% of individuals under 20 years of age exhibit sub-threshold levels. These manifestations become more pronounced with age as testosterone levels decrease physiologically as well, causing increased sexual dysfunction in MWE (35).
Although both sexes experience epilepsy-related endocrine disturbances, the clinical manifestations differ. These sex-specific factors warrant the need for personalized, comprehensive care that addresses both the neurological and psychosocial challenges associated with epilepsy (3, 11, 12, 34).
The mechanisms of hormonal disturbances caused by epilepsy
The relationship between epilepsy and sex hormones is complex and not yet fully understood and has a multi-faceted interaction since both the condition itself and the use of ASMs can disrupt the hypothalamic–pituitary axis, resulting in abnormal steroid hormone production (20). One theory proposes that alterations in neuronal activity during and between seizures interrupt the release of neurotransmitters glutamate, NE, GABA, and dopamine which interferes with the pulsatility of Gonadotropin-releasing Hormone (GnRH) and consequent hormonal regulation (20, 61). It has been suggested that epilepsy directly affects the hypothalamic–pituitary axis, resulting in altered levels of GnRH, LH, FSH, PRL, and downstream hormones such as estrogen, testosterone, and DHEA (20).
GnRH pulse frequency plays a critical role in determining gonadotropin output. Low-frequency pulses favor FSH secretion, while high-frequency pulses promote LH release. Continuous (non-pulsatile) GnRH secretion suppresses both FSH and LH, inhibiting ovulation and estrogen production. Seizure-related disruptions in this balance can thus result in reproductive dysfunction (64). Abnormal GnRH pulsatility is pathognomonic for several reproductive disorders. In PCOS, persistently high-frequency GnRH pulses shift the LH/FSH ratio toward LH dominance (65). This stimulates ovarian theca cells to overproduce androgens, while insufficient FSH impairs aromatase activity in granulosa cells, reducing estrogen synthesis. Conversely, in hypogonadotropic hypogonadism and hypothalamic amenorrhea, GnRH secretion is diminished, resulting in low FSH and LH levels and impaired gonadal function (66).
The pattern and location of seizures affect the prevalence of specific hormonal disturbances. This suggests that there is a direct link between epilepsy and endocrine dysfunction (21, 37–42). Present research is largely acquired by conducting investigations in animal models utilising electrical stimulation, and human studies using electroconvulsive therapy. Both models have demonstrated altered pituitary hormone secretion caused by altered neuron firing in response to epilepsy (43, 44). Hormonal changes have been noted both in response to seizures and during interictal periods, especially with increased levels of PRL and LH in both sexes (20, 37).
Dana-Haeri et al. (39) found that PRL and LH levels increased significantly 20 min after the seizure. Following a 60-min period, PRL returned to its initial level, while LH continued to demonstrate elevated levels for a longer duration of time. FSH was also noted to be increased both immediately after a seizure and following a 60-min period, but only in women. In a similar vein, Nappi et al. (45) reported a higher frequency of LH surges in both focal and generalised epilepsy cases. Elevated PRL levels may cause decreased libido and impotence in men, and anovulatory cycles in women (46, 47).
Beyond the disease itself, ASMs also contribute to GnRH dysregulation by modulating neurotransmitters such as gamma-aminobutyric acid (GABA), NMDA, and glutamate in the limbic system (50). Epilepsy impacts hormonal regulation through feedback loops involving the hypothalamus, pituitary gland, and peripheral endocrine organs. Disruptions in these circuits, whether during seizures or interictal periods, impairs hormonal balance and regulation (51) (Figures 1–4).
Figure 1. Neurotransmitters (glutamate, NE, GABA, dopamine) and hormonal pathways (GnRH, LH, FSH) involved in epileptic seizures, highlighting abnormal GnRH pulsatility as a potential factor in seizure-related endocrine disruptors. Created in BioRender (2025).
Figure 2. An overview of hypothalamic and anterior pituitary hormones, their endocrine targets, and key physiological processes such as ovulation, spermatogenesis, and pregnancy. The image highlights the roles of dopamine, oxytocin, GnRH, prolactin, FSH, LH, and other hormones in regulating bodily functions. Created in BioRender (2025).
Figure 3. Metabolic pathways of androgen and estrogen biosynthesis, including cholesterol-derived intermediates and the roles of estrogen isoforms (E1–E4) across various reproductive stages. Created in BioRender (2025).
Figure 4. Brain regions with estrogen receptors and their roles in seizure susceptibility. Estrogen increases neuronal excitability in the cerebral cortex (promoting generalized seizures), modulates hormone-sensitive rhythms in the hypothalamus (linked to catamenial epilepsy), reduces GABAergic inhibition in the amygdala (enhancing emotional triggers), and enhances glutamate signaling in the hippocampus (a key focus in temporal lobe epilepsy). These mechanisms collectively lower the seizure threshold under hormonal fluctuations. Created in BioRender (2025).
FSH, LH, and the HPG axis in epilepsy
Seizures affect the HPG axis which mainly regulate the release of sexual hormones. The downstream effect of the preoptic nucleus neurons activation in the hypothalamus result from the secretion of GnRH into the portal circulation and anterior pituitary gland activation (55). GnRH signal transduction to G-protein coupled receptors on the gonadotroph cells, generates LH and FSH release in the anterior pituitary (56, 57). Both hormones bind to receptors in the gonads and promote the production of sex hormones such as estrogen (E2), testosterone, and PROG (52, 58). Not only are these steroid hormones and their neuroactive metabolites highly influenced by seizures, they also modulate neuronal excitability through genomic and non-genomic mechanisms, thus influencing seizure susceptibility (18, 59). The bidirectional impact of endocrine dysregulation causes higher levels of hormonal and reproductive disruption in individuals with epilepsy when compared to their healthy counterparts, in both men and women (20, 53, 54). The dysfunction is not limited to any subtype of epilepsy, but is rather observed in the vast majority of cases, including focal and generalized onset seizures as well as secondary generalized focal onset seizures (20) but is most commonly associated with temporal lobe epilepsy (TLE) (53, 54).
TLE, a specific subtype of focal epilepsy affecting mainly the temporal lobe, exerts a more profound effect on the HPG axis, leading to significant dysregulation of gonadotropin secretion, especially impacting FSH and LH (8). TLE can trigger seizure activity in different hemispheres, each exerting lateralized effects on neuroendocrine regulation. Left-sided TLE is consistently associated with elevated GnRH pulse frequency, triggering higher LH/FSH ratios resulting in hyperandrogenism, and clinical features resembling PCOS (8). In contrast, right-sided TLE is more often linked to hypogonadotropic hypogonadism, characterized by reduced LH and FSH secretion resulting in amenorrhea (48). Essentially, left temporal foci contribute to hypergonadotropic states, whereas right temporal foci contribute to hypogonadism. In addition to the chronic region-specific impact of epilepsy on the HPG axis, acute ictal and postictal events also produce immediate hormonal disturbances. Postictal surges of neuronal activity trigger surges of LH and FSH translating immediately to short-term endocrine imbalances. Chronic instability of these hormones often terminates in altered LH pulse frequency and amplitude, causing anovulatory cycles and menstrual irregularities (49).
Up to 50% of WWE experience reproductive disturbances such as oligomenorrhea, amenorrhea, and infertility. These effects are more pronounced in women with left-sided epileptiform discharges, which may more directly impact limbic-hypothalamic pathways responsible for GnRH regulation (63).
Seizure disorders and ASMs, particularly valproic acid (VPA), can further exacerbate GnRH dysregulation. VPA has been shown to elevate androgen levels and worsen LH/FSH imbalances, contributing to PCOS-like features in women and hormonal suppression in men (15, 42, 48, 62, 68).
In MWE, elevated LH levels may reflect increased pituitary drive in response to testicular dysfunction. Increased FSH and LH levels are markers of gonadal damage and impaired spermatogenesis. Epileptic discharges may interfere with hypothalamic control of testosterone production via Leydig cell suppression and disruption of negative feedback loops. Clinically, this manifests as reduced libido, delayed sexual development, and infertility (69).
The clinical consequences of HPG axis disruption in epilepsy are extensive. Menstrual irregularities, infertility, and premature menopause are observed frequently in women, especially those with TLE and VPA exposure. Men are similarly affected, with hypogonadism and sexual dysfunction being the typical manifestations of reproductive disruption. These findings emphasize the importance of integrated treatment strategies that address seizure control and reproductive health.
Seizure activity during ictal and postictal phases can interfere with the pulsatile release of GnRH, likely due to disrupted neurotransmitter signaling involving GABA, glutamate, and NMDA receptor pathways (60). Ictal events in TLE have been shown to trigger transient postictal surges in both LH and FSH, leading to acute hormonal fluctuations (49). This disruption contributes to altered levels of LH, FSH, PRL, estrogen, and testosterone (20, 61).
Generalized seizures are also associated with acute elevations in PRL and LH in both sexes, while FSH levels tend to rise predominantly in women. PRL typically returns to baseline within an hour, but LH may remain elevated for longer periods (37, 62). Chronic seizure activity can lead to persistent alterations in the frequency and amplitude of LH pulses, often resulting in anovulatory cycles and menstrual dysfunction.
Estrogen
Estrogens are a group of sex steroid hormones that include estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4), the latter being produced exclusively during pregnancy. These hormones are synthesized from cholesterol, the main precursor to all steroid hormones, including testosterone and androstenedione, which are immediate precursors to estrogen, via the enzyme aromatase. The biosynthesis is tightly controlled by alterations in LH and FSH levels, secreted by the anterior pituitary in response to GnRH (70). The production of estrogens in women occurs primarily in the ovaries, while in men, 20% of estrogen is derived from the testes but predominantly produced through peripheral aromatization of adipose tissue, bone, brain, and skin (71).
Based on the physiological state of the body, the prevailing estrogen varies. E2 is the main estrogen during reproductive years, E1 dominates after menopause, and E3 becomes prominent during pregnancy (72–74). While estrogen is highlighted as the main hormone regulating female reproductive physiology, its importance in males is often overlooked but very critical. Inadequate estrogen signaling in the testes can impair spermatogenesis and contribute to infertility (70).
Beyond their reproductive roles, estrogens exert a significant influence on brain function. These hormones are locally synthesized in the brain via aromatization and play a key role in modulating cognitive and neuroendocrine process in key regions of the brain especially the hypothalamus and temporolimbic system, including the medial and cortical amygdala (75, 76). In these regions, estrogens highly influence emotional regulation, fear and anxiety processing as well as neuronal excitability via estrogen receptors ESR1, ESR2, and G-protein coupled estrogen receptor (GPER) (70, 77). E2 in particular is implicated in altering seizure susceptibility in regions such as the hippocampus, cerebral cortex, amygdala, and hypothalamus by altering key neurotransmitters such as GABA and glutamate (77).
Historically, estrogens were believed to be purely proconvulsant based on early animal and clinical data. However, accumulating evidence suggests that estrogens can exhibit both proconvulsant and anticonvulsant properties, with their effects modulated by factors such as sex, hormonal status, seizure type, brain region, dosage, and duration of exposure (78, 79). This duality as well as the influence of various external factors, complicates predictions of their influence on seizure activity.
At a cellular level, E2 enhances excitatory neurotransmission by stimulating NMDA receptor-mediated glutamate activity, thereby increasing neuronal firing rates (80). It augments the excitability of hippocampal CA1 pyramidal neurons and weakens inhibitory control by reducing GABA synthesis and downregulating glutamic acid decarboxylase in the corticomedial amygdala (76, 81). E2 also elevates acetylcholine levels and increases choline acetyltransferase activity, further potentiating excitatory activity (82).
Conversely, E2 has demonstrated anticonvulsant and neuroprotective effects in several preclinical studies. Due to its ability to counteract cyclosporin A-induced inhibition of GABAergic signaling in the hippocampus, estrogen thereby reduces seizure susceptibility (84). In ovariectomized female rats, estrogen administration attenuated seizures induced by NMDA, kainic acid (KA), cyclosporin A, and picrotoxin, supporting its role in enhancing GABAergic tone and modulating excitatory input (77, 83–86). Additionally, E1 reduced KA-induced seizures and mortality in male mice (87), and E2 pre-treatment in female rats protected against hippocampal damage following status epilepticus (SE) (88, 89).
Clinically, estrogen imbalance has profound consequences for individuals with epilepsy, particularly during states such as pregnancy or menopause, where hormonal regulation is strictly controlled and plays a key role in physiological processes. Variations in E1, E2, and E3 levels can modulate neuronal excitability and thus affects seizure thresholds. Creating a feedback loop and hormonal fluctuations cause bidirectional influence. Moreover, hormone replacement therapy (HRT) and certain contraceptives may influence seizure patterns, depending on their formulation and estrogenic content (90).
Progesterone
Progesterone (PROG) is a key sex steroid hormone involved in reproductive and neuroendocrine function. In females, it is primarily secreted by the corpus luteum during the luteal phase of the menstrual cycle and in early pregnancy, while placental production dominates from the second trimester onward. PROG facilitates implantation, supports gestation, and contributes to maintaining pregnancy. In males, smaller amounts of PROG are synthesized by the testes and adrenal glands, where it plays critical roles in spermatogenesis, sexual function, and neuroprotection (91).
The effects of PROG are mediated by progesterone receptors (PRs), which are expressed throughout the CNS. These receptors play a pivotal role in the brain’s reward circuitry and modulation of dopamine dependent sexual behaviors, implicating the psychosocial impacts of reproductive hormones (92, 93). PROG also exerts neuroprotective effects, reducing oxidative damage in the CNS and supporting neuronal strength and plasticity, indicating its importance in the regulation of epilepsy (94, 95).
PROG is widely recognized for its anticonvulsant properties, primarily through its enhancement of GABA-A receptor-mediated chloride conductance causing neuronal hyperpolarization and reduced excitability (96–98). In addition to potentiating GABAergic inhibition, PROG also diminishes acetylcholine activity as well as amplifies the effects of adenosine, a neuromodulator with potent inhibitory effects. These mechanisms are relevant in syndromes such as autosomal dominant nocturnal frontal lobe epilepsy (99, 100).
A critical mediator of PROG’s anticonvulsant action is allopregnanolone (ALLO), a neuroactive metabolite that acts as a positive allosteric modulator of GABA-A receptors. ALLO concentrations rise significantly following PROG treatment and have been inversely correlated with seizure frequency due to the augmentation of GABA-A receptors, especially in women experiencing premenstrual seizure exacerbations (106, 107). Conversely, reduced ALLO levels in the cerebrospinal fluid have been associated with catamenial epilepsy and menstrual migraine, highlighting the clinical relevance of neurosteroid fluctuations in seizure susceptibility (108).
Clinical evidence supports the anticonvulsant effects of PROG in both focal and generalized epilepsies. Several studies have demonstrated reductions in interictal epileptiform discharges and seizure frequency following intermittent PROG administration, particularly in women with catamenial epilepsy (48, 101–103). However, the effectiveness of PROG appears to be dose-dependent, with insufficient levels showing minimal benefit (104, 105).
Testosterone
Testosterone is the dominant male androgen and a steroid sex hormone integral to both reproductive and systemic health. Synthesized primarily in the Leydig cells of the testes under LH stimulation, testosterone is also produced in smaller quantities by the adrenal glands, ovaries, and placenta in both sexes. In the body, testosterone can exist in several main forms, the majority being inactive and bound to sex hormone binding globulin (SHBG), and a small active portion found unbound or weakly bound to albumin. The most biologically active form, 5a-dihydrotestosterone (5a-DHT) converted from testosterone via 5a-reductase, is vital to the development and functioning of primary and secondary male sexual characteristics. 5a-DHT exerts effects through both cytoplasmic and nuclear androgen receptors resulting in development of male secondary sexual characteristics, maintenance of spermatogenesis, muscle growth, libido, and mood regulation. While this hormone is also found in females to a much lower extent, excessive androgen levels can contribute to masculinization and hirsutism (46, 109).
Beyond its role in sexual development, testosterone contributes significantly to psychological well-being due to its role in mood regulation, self-esteem, and perceived quality of life (QOL), particularly in aging men. Conversely, testosterone deficiency is linked to sexual dysfunction, fatigue, and diminished QOL, all of which can extend the burden of epilepsy (109).
Emerging epidemiological evidence indicates a substantial link between androgen-related disorders and epilepsy in men. Both factors are implicated in a bidirectional relationship due to mechanisms causing a feedback influence via the hormones metabolic pathways. Testosterone can be aromatized to E2, which is mostly associated with proconvulsant properties, or metabolized by 5α-reductase into 5α-DHT, which exhibits anticonvulsant effects (110). Since 5a-DHT is the principal circulating male androgen, which is known to be an anticonvulsant, it can be estimated that there is a positive net impact of testosterone on seizure activity. However, MWE are known to have hypogonadism, characterized by reduced levels of free testosterone and its urinary metabolites, thus diminishing any potential anticonvulsant effects. Temporal lobe seizures (TLS) can disrupt the HPG axis, impairing gonadotropin secretion and subsequently reducing testosterone synthesis resulting in proconvulsant states. Furthermore, serum testosterone levels are affected by hormone-binding protein concentrations, which enzyme-inducing ASMs can alter. Newer ASMs appear to have a lesser effect on this mechanism (111). These hormonal imbalances have remarkable clinical implications for both sexes, albeit with differing outcomes.
The effects of testosterone on mood and reproductive function are complex in WWE. A recent study correlating elevated levels of testosterone, lower prolactin concentrations and increased depression scores connects any associations between the imbalance of androgens and their negative effects on mood and sexual desire (112). In MWE, hormonal therapies may offer dual benefits for both seizure control and sexual health. A comparative study evaluating the effects of anastrozole plus testosterone versus placebo plus testosterone for the treatment of sexual dysfunction and hypogonadism demonstrated a reduction in seizure frequency in both treatment arms (113). In this study, forty men with focal epilepsy, hyposexuality and hypogonadism were randomized into two groups and observed for three months. The improvement of seizure control was remarkably associated with decreased serum E2 levels and lowered scores in Beck Depression Inventory-II (BDI-II). Such an observation indicates a potential link between estrogen suppression, mood stabilization, and induced libido.
Prolactin
Prolactin (PRL), a polypeptide hormone secreted by the anterior pituitary gland regulates lactation, reproductive physiology and immune modulation. It is also known to affect the central nervous system and can influence mood, emotions and behavior. Its pulsatile secretion pattern plays an essential role in homeostasis and reproductive balance and any alterations to this pulsatility often seen in neurological disorders such as epilepsy can trigger menstrual irregularities, infertility, as well as metabolic and immunologic imbalances (114).
Physiologically, PRL exhibits a well-defined circadian rhythm often mimicking the patterns of melatonin. Serum PRL levels surge during the onset of sleep and often return to baseline levels within one to two hours of waking. Baseline PRL concentrations are typically higher in women than in men, reflecting differences in endocrine regulation and reproductive physiology (116, 122). Stressors including pregnancy, lactation and trauma can also result in increased PRL levels (115, 116). The regulation of PRL secretion is primarily governed by the ventromedial and arcuate nuclei of the hypothalamus, which exert consistent inhibitory influence over the anterior pituitary through dopaminergic signaling pathways (115, 116). Disruptions in these inhibitory mechanisms, such as those caused by epileptic discharges can lead to transient elevations in serum PRL levels causing activation of many anterior pituitary hormones. The elevations in the hypothalamus receive input from key limbic regions, particularly the hippocampus and amygdala, structures frequently affected by epilepsy. These regions also play key influential roles on the dynamics of PRL dynamics through distinct anatomical pathways: hippocampal projections via the fornix and stria terminalis are predominantly inhibitory, while amygdaloid efferents through the amygdalofugal tract often exert excitatory effects (117–121).
In TLE where seizure activity typically originates in the mesial temporal structures, dissociation of epileptiform discharges from the temporal lobe to the hypothalamus may result in a post-ictal surge in PRL levels, as observed in both clinical and experimental settings (118, 120, 122, 123). This immediate surge in PRL levels, known as postictal hyperprolactinemia, serves as an indicator for generalized or focal seizures involving the limbic system. Elevations in hormone levels caused by ictal episodes are generally more pronounced in intensity and duration compared to those associated with stress, allowing PRL to be a reliable biomarker for seizures (115, 116, 124).
Increased PRL levels following seizures and during the interictal period may play a role in anovulatory cycles by interfering with other regulatory hormones secreted by the hypothalamus and anterior pituitary, in WWE. Elevated PRL concentrations have been observed after both electroconvulsive therapy and spontaneous seizures and studies have consistently shown that PRL levels are higher in individuals with focal epilepsy compared to their healthy counterparts (125). This increase in PRL has been documented in a significant proportion of generalized tonic–clonic seizures (GTCS) as well as focal seizures with secondary generalization (21, 126). Furthermore, clinical observations suggest that interictal brain activity may contribute to the sustained elevation of PRL levels in the blood, providing additional insight into its potential impact on reproductive health in WWE (127).
Oxytocin
Oxytocin (OT), a peptide hormone produced in the supraoptic and paraventricular nucleus of the hypothalamus and secreted from the posterior pituitary, plays a critical role in the female reproductive system regulation, mainly during labor and lactation. It facilitates the milk ejection reflex, uterine contractions and constricts blood vessels after child-birth to prevent excessive bleeding (128). Beyond its effects on reproduction, OT influences a range of physiological and psychological processes, including social behavior, anxiety, appetite regulation, memory, learning, pain modulation (antinociception), social recognition, and the stress response by functioning as a neurotransmitter and neuromodulator by activating central OT receptors in the brain (129).
Both OT and vasopressin mRNA expressions are upregulated in the paraventricular hypothalamic nucleus during seizures (131). This suggests that the rapid rise in OT levels during or immediately following a seizure may represent a neuroprotective mechanism aimed at regulating hypothalamic activity in response to seizure-related stress (132, 133). For example, after KA-induced status epilepticus, increased activation of OT-expressing magnocellular neurons, but not vasopressin-expressing neurons, was observed in the PVN (133). Although OT and vasopressin share structural similarities, they likely serve distinct roles in the pathophysiology of epilepsy.
Due to the potential neuroprotective role of oxytocin following seizures, specific reports suggest that OT may have a therapeutic effect in neuropsychiatric disorders, including but not limited to epilepsy (131, 130).
Discussion
The relation between epilepsy, reproductive hormones, the HPG axis and their complex pathways has been long recognized and studied, with plenty of documentation supporting the bidirectional influence between seizures and hormones. The interactions between seizures and the mechanisms of the HPG axis has a pivotal role in the functioning of the reproductive system thereby influencing fertility, libido and overall QOL. Estrogen is primarily proconvulsant enhancing glutamatergic excitation and reducing GABAergic inhibition, especially with exogenous estrogens associated with hormonal replacement therapy (HRT) or in-vitro fertilization (IVF). Seizures can disrupt GnRH/FSH pulsatility disrupting estrogen and progesterone levels thereby producing cycle irregularity and anovulation, however, utilization of HRT or exogenous hormones to treat any cycle irregularities can further exacerbate seizures. ALLO enhances GABA-A currents behaving as an anticonvulsant in the setting of seizures, however, epilepsy reflects low progesterone levels and are found to be associated with an increased estrogen to progesterone ratio. A luteal phase deficiency marked by lower levels of progesterone may result in difficulty for the fetus to implant and remain in the uterus (134). Hormonal fluctuations directly influence fertility outcomes such that luteal insufficiency and hyperprolactinemia contribute to anovulation and hypogonadism, while hyperandrogenic states, including polycystic ovary syndrome, are more prevalent in women with epilepsy. Conversely, reproductive hormonal therapies can exacerbate seizure risk, as demonstrated by case reports of seizure worsening during estrogen-based ovulation induction.
Much of the current documentation regarding this relation stems from animal based studies conducted in the 1990s, posing a translational challenge to humans due to the vast difference in epileptic properties and manifestations between both groups. These properties may depend on various factors such as on sex, treatment duration, time from seizure to testing, method of administration, hormonal status, brain region involved, and seizure type. According to the revised International League against Epilepsy (ILAE), the updated classification of seizures has removed the term ‘onset’ from ‘generalized-onset seizures’, acknowledging evidence that even generalized seizures may have focal origins. Essentially, this challenges any previous assumptions about the uniformity of seizures or hormonal responses to seizures as their focal nature may change. This nuance is critical when studying the pro or anticonvulsant properties of hormones, which may vary by seizure onset type (78, 79, 135). Importantly, the type and localization of seizures dictate the extent to which endocrine and reproductive hormones can be altered. Among focal epilepsies, temporal lobe epilepsy is recorded to have a significant impact on GnRH pulsatility by causing disruptions to the HPG axis, where right sided temporal foci are associated with hypogonadotropic hypogonadism causing reduced gonadotropin secretion, while left-sided temporal foci are associated with hyperandrogenic and PCOS causing increased LH to FSH ratios and chronic anovulation (48, 49). In contrast, generalized clonic–tonic seizures are associated with elevations in neuroendocrine hormones such as prolactin and cortisol which can also influence fertility outcomes which contribute to anovulation and hypogonadism (116, 115). The postictal rises in hormonal levels are dependent on the hormone, where prolactin is detected and measured 10–20 min after an epileptic episode, returning to baseline in 2–6 h (117–121). Due to this, prolactin serves as both a diagnostic biomarker and a marker of acute hypothalamic–pituitary stress activation in the setting of epilepsy. In terms of chronic reproductive dysfunction caused by epilepsy, a thorough endocrine evaluation comprising measurements of gonadotropins, estrogen, luteal phase progesterone, early morning testosterone in men, prolactin and cortisol are necessary to highlight the complex interplay of hormones that rise to reproductive dysfunction. Taken together, reproductive dysfunction in epilepsy emerges not from a single factor but from a convergence of seizure-related hypothalamic disruption, acute postictal hormonal surges, chronic alterations in HPGl feedback, and iatrogenic drug effects. Recognition of these multidirectional pathways highlights the importance of both acute and longitudinal endocrine monitoring, tailored by seizure type and patient sex, especially in individuals with fertility aspirations.
The new framework also shifts seizure observations which were previously categorized as motor and non-motor responses, to observable vs. unobservable manifestations. In essence, small changes as facial flushing or tachycardia which were previously overlooked phenomena can now be acknowledged as such as stress-induced sympathetic activation and be systematically linked to postictal endocrine disruptions (135).
The current understanding of epilepsy’s effects on hormonal balance relies predominantly on animal studies, with limited data regarding the impacts on humans. This poses a concern toward the validity of these studies as the metabolic demands, hormonal regulation and even seizure manifestation differs significantly between animals and humans. Currently, many of the studies regarding reproductive hormones and their role versatility in epileptic states are based on rodent models, which experience estrous cycles that last 4–5 days, with a considerable overlap between estrogen and PROG levels. This contrasts with the human menstrual cycle, which spans 28–35 days and features more distinct hormonal phases (136). Animal based studies have also indicated that PROG and its active metabolite, ALLO, both possess anticonvulsant properties and can lead to decreased seizure occurrence (106, 103), however, a 2012 clinical trial found that cyclic PROG was ineffective in treating partial refractory epilepsy in women (18). This clinical trial also paved the understanding regarding the differences in types of seizures and exacerbations and how they can manifest with various responses to hormones or treatments. It was noted that women with higher perimenstrual seizure exacerbations showed minimal response to PROG, but those with lower exacerbations showed some response to treatment., highlighting the inconsistencies of extrapolating animal data to human treatment and the need for further clinical research. Moreover, such discrepancies suggest the need to examine the hormonal responsiveness in relation to seizure type and timing within the menstrual cycle. The effects of medications observed around periods of menstruation further raise questions regarding the role of fluctuating hormones in seizure exacerbation and treatment efficacy. Much of the current literature focuses on acute postictal hormone measurements, often overlooking the physiological, chronic fluctuations of hormones, as the hormonal cycles do not follow a daily pattern but are subject to varying amplitudes based on the cyclic period. Studies by Bauer et al. (126) and Molaie et al. (127) identified acute PRL spikes following seizures and altered levels during interictal periods, suggesting persistent hormonal disruptions in epilepsy, though the long-term impact on seizure thresholds or fertility remains unclear. This constrains our ability to draw precise correlations and conclusions applicable to human healthcare.
Catamenial epilepsy, where seizures cluster around specific menstrual phases, highlights the need for longitudinal hormone monitoring, yet most studies measure hormones only postictally or within narrow windows, neglecting the full cyclical variation across the menstrual cycle (18). Consequently, the broader relationship between seizure patterns and chronic effects of hormonal fluctuations remain poorly understood (37, 62). Hormones naturally fluctuate in response to both extrinsic and intrinsic stimuli, and the inability to account for these variations weakens claims about their relationship to epilepsy. While acute postictal hormone changes are well established, long-term hormonal imbalances require longitudinal investigation.
Although hormonal influences in women have been more extensively studied due to the clear cyclic patterns, hormones like testosterone and PRL also fluctuate in men and may modulate seizure activity, particularly in conditions like stress or sleep deprivation. Epilepsy manifests differently between sexes, not only in terms of seizure frequency or type, but also in terms of drug response, psychiatric comorbidities, and endocrine profiles. For instance, lower testosterone levels were associated with increased seizure susceptibility, and hormone replacement therapy with testosterone has shown potential in reducing seizure outcomes. However, the precise role of testosterone remains unclear due to its dual metabolic mechanism in the brain, underscoring the need for further investigation of hormonal fluctuations in men.
In addition to the methodological limitations of conducting human studies, the lack of sex-specific analyses, longitudinal studies, and inadequate translation from animal research to human studies hinder our understanding of the role of epilepsy on hormonal imbalance. The physiological variations of hormones, the heterogenic manifestation of epilepsy, and sample size limitations pose significant challenges in conducting human research and performing analyses. Given the variability in reproductive hormones across age groups and menstrual cycles, along with diverse epilepsy phenotypes, large, meticulously stratified cohorts are essential to account for the diversity and identify clinically meaningful patterns.
Future research should aim to address the bidirectional relationship between seizures and the reproductive endocrine system through more precise, longitudinal studies. Careful monitoring of hormonal measurements in respect to seizure onset, menstrual cycle phase, and ASM exposure would allow for stronger comparisons across cohorts, especially with human studies and long term analyses. Advances in hormonal monitoring and imaging of hypothalamic–pituitary activity could refine our understanding of how seizure localization affects endocrine function. Personalized hormonal therapies, such as progesterone supplementation for catamenial epilepsy or androgen supplementation in men with hypogonadism to mitigate seizures and increase fertility outcomes could represent promising avenues to address issues regarding epilepsy and fertility. Advancements in this field could yield a deeper understanding of these mechanisms that will not only refine treatment strategies but also enhance the QOL for patients confronting difficulties of epilepsy and hormonal dysfunction.
Author contributions
DK: Supervision, Project administration, Writing – original draft, Writing – review & editing, Methodology, Validation. KZ: Writing – review & editing, Writing – original draft. JG: Writing – original draft, Writing – review & editing. BP: Visualization, Writing – original draft, Writing – review & editing. Y-YL: Writing – review & editing, Writing – original draft. RK: Writing – original draft, Writing – review & editing. AR: Writing – review & editing, Writing – original draft. WK: Writing – review & editing, Writing – original draft. SM: Writing – original draft, Writing – review & editing.
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References
1. Sharlip, ID, Jarow, JP, Belker, AM, Lipshultz, LI, Sigman, M, Thomas, AJ, et al. Best practice policies for male infertility. Fertil Steril. (2002) 77:873–82. doi: 10.1016/s0015-0282(02)03105-9
2. Zegers-Hochschild, F, Adamson, GD, Dyer, S, Racowsky, C, de Mouzon, J, Sokol, R, et al. The international glossary on infertility and fertility care, 2017. Fertil Steril. (2017) 108:393–406. doi: 10.1016/j.fertnstert.2017.06.005
3. Thonneau, P, Marchand, S, Tallec, A, Ferial, ML, Ducot, B, Lansac, J, et al. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Hum Reprod. (1991) 6:811–6. doi: 10.1093/oxfordjournals.humrep.a137433
4. Isidori, AM, Pozza, C, Gianfrilli, D, and Isidori, A. Medical treatment to improve sperm quality. Reprod Biomed Online. (2006) 12:704–14. doi: 10.1016/s1472-6483(10)61082-6
5. Thijs, RD, Surges, R, O'Brien, TJ, and Sander, JW. Epilepsy in adults. Lancet. (2019) 393:689–701. doi: 10.1016/S0140-6736(18)32596-0
6. Fisher, RS, van Emde Boas, W, Blume, W, Elger, C, Genton, P, Lee, P, et al. Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. (2005) 46:470–2. doi: 10.1111/j.0013-9580.2005.66104.x
7. Borowicz-Reutt, K, Czernia, J, and Krawczyk, M. Genetic background of epilepsy and antiepileptic treatments. Int J Mol Sci. (2023) 24:16280. doi: 10.3390/ijms242216280
8. Taubøll, E, Sveberg, L, and Svalheim, S. Interactions between hormones and epilepsy. Seizure. (2015) 28:3–11. doi: 10.1016/j.seizure.2015.02.012
9. Morrell, MJ. Reproductive and metabolic disorders in women with epilepsy. Epilepsia. (2003) 44:11–20. doi: 10.1046/j.1528-1157.44.s4.2.x
10. Khan, M, Bankar, NJ, Bandre, GR, Dhobale, AV, and Bawaskar, PA. Epilepsy and issues related to reproductive health. Cureus. (2023) 15:e48201. doi: 10.7759/cureus.48201
11. Bosak, M, Słowik, A, and Turaj, W. Menstrual disorders and their determinants among women with epilepsy. Neuropsychiatr Dis Treat. (2018) 14:2657–64. doi: 10.2147/NDT.S179438
12. Ebraheim, A, Shamloul, R, and Talaat, S. Hormonal profile and clinical characteristics of epileptic females with abnormal ovarian morphology. Egypt J Neurol Psychiatr Neurosurg. (2016) 53. doi: 10.4103/1110-1083.202388
13. Octaviana, F, Sumapraja, K, Wiratman, W, Indrawati, LA, and Budikayanti, A. Characteristics of menstrual disorders and reproductive hormones in women with epilepsy at an Indonesian national referral hospital. Front Neurol. (2022) 13:964761. doi: 10.3389/fneur.2022.964761
14. Manchukonda, S. Sex hormonal profile in men and women with epilepsy on enzyme-inducing antiepileptic drugs: a case-control study. Int J Epilepsy. (2018) 5:38–43. doi: 10.1055/s-0038-1667210
15. Verrotti, A, Loiacono, G, Laus, M, Coppola, G, Chiarelli, F, and Tiboni, GM. Hormonal and reproductive disturbances in epileptic male patients: emerging issues. Reproductive Toxicol. (2011) 31:519–27. doi: 10.1016/j.reprotox.2011.02.002
16. Lai, W, Shen, N, Zhu, H, He, S, Yang, X, Lai, Q, et al. Identifying risk factors for polycystic ovary syndrome in women with epilepsy: a comprehensive analysis of 248 patients. J Neuroendocrinol. (2023) 35:e13250. doi: 10.1111/jne.13250
17. Velíšková, J, and Desantis, KA. Sex and hormonal influences on seizures and epilepsy. Horm Behav. (2013) 63:267–77. doi: 10.1016/j.yhbeh.2012.03.018
18. Herzog, AG, Fowler, KM, Smithson, SD, Kalayjian, LA, Heck, CN, Sperling, MR, et al. Progesterone vs placebo therapy for women with epilepsy: a randomized clinical trial. Neurology. (2012) 78:1959–66. doi: 10.1212/WNL.0b013e318259e1f9
20. Hamed, SA. Neuroendocrine hormonal conditions in epilepsy: relationship to reproductive and sexual functions. Neurologist. (2008) 14:157–69. doi: 10.1097/NRL.0b013e3181618ada
21. Bauer, J. Interactions between hormones and epilepsy in female patients. Epilepsia. (2001) 42:20–2. doi: 10.1046/j.1528-1157.2001.042suppl.3020.x
22. Montouris, G, and Morris, GL. Reproductive and sexual dysfunction in men with epilepsy. Epilepsy Behav grudzień. (2005) 7:7–14. doi: 10.1016/j.yebeh.2005.08.026
23. Murialdo, G, Galimberti, CA, Magri, F, Sampaolo, P, Copello, F, Gianelli, MV, et al. Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy. J Endocrinol Investig. (1997) 20:519–26.
24. Cummings, LN, Giudice, L, and Morrell, MJ. Ovulatory function in epilepsy. Epilepsia. (1995) 36:355–9. doi: 10.1111/j.1528-1157.1995.tb01009.x
25. Klein, P, Serje, A, and Pezzullo, JC. Premature ovarian failure in women with epilepsy. Epilepsia. (2001) 42:1584–9. doi: 10.1046/j.1528-1157.2001.13701r.x
26. Hamed, SA. Leptin and insulin homeostasis in epilepsy: relation to weight adverse conditions. Epilepsy Res. (2007) 75:1–9. doi: 10.1016/j.eplepsyres.2007.04.001
27. Maguire, MJ, and Nevitt, SJ. Treatments for seizures in catamenial (menstrual-related) epilepsy. Cochrane Database Syst Rev. (2019) 10:CD013225. doi: 10.1002/14651858.CD013225.pub2
28. Voinescu, PE, Kelly, M, French, JA, Harden, C, Davis, A, Lau, C, et al. Catamenial epilepsy occurrence and patterns in a mixed population of women with epilepsy. Epilepsia. (2023) 64:e194–9. doi: 10.1111/epi.17718
29. Reddy, DS, Chuang, SH, Hunn, D, Crepeau, AZ, and Maganti, R. Neuroendocrine aspects of improving sleep in epilepsy. Epilepsy Res. (2018) 147:32–41. doi: 10.1016/j.eplepsyres.2018.08.013
30. Frank, S, and Tyson, NA. A clinical approach to Catamenial epilepsy: a review. Perm J. (2020) 24:1–3. doi: 10.7812/TPP/19.145
31. Harden, CL, Pulver, MC, Ravdin, L, and Jacobs, AR. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia. (1999) 40:1402–7. doi: 10.1111/j.1528-1157.1999.tb02012.x
32. Morrell, MJ. Epilepsy in women. Am Fam Physician. (2002) 66:1489–94. doi: 10.1089/15246090050199982
33. Fenwick, PB, Toone, BK, Wheeler, MJ, Nanjee, MN, Grant, R, and Brown, D. Sexual behaviour in a centre for epilepsy. Acta neurologica Scandinavica. (71) 40:428–435. doi: 10.1111/j.1600-0404.1985.tb03225.x
34. Hamed, S, Mohamed, K, El-Taher, A, Hamed, E, and Omar, H. The sexual and reproductive health in men with generalized epilepsy: a multidisciplinary evaluation. Int J Impot Res. (2006) 18:287–95. doi: 10.1038/sj.ijir.3901406
35. Herzog, AG, Blum, AS, Farina, EL, Maestri, XE, Newman, J, Garcia, E, et al. Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use. Neurology. (2009) 72:911–4. doi: 10.1212/01.wnl.0000344167.78102.f0
36. Reis, RM, de Angelo, AG, Sakamoto, AC, Ferriani, RA, and Lara, LA. Altered sexual and reproductive functions in epileptic men taking carbamazepine. J Sex Med. (2013) 10:493–9. doi: 10.1111/j.1743-6109.2012.02951.x
37. Dana-Haeri, J, Trimble, M, and Oxley, J. Prolactin and gonadotrophin changes following generalised and partial seizures. J Neurol Neurosurg Psychiatry kwiecień. (1983) 46:331–5. doi: 10.1136/jnnp.46.4.331
38. Quigg, M, Kiely, JM, Johnson, ML, Straume, M, Bertram, EH, and Evans, WS. Interictal and postictal circadian and ultradian luteinizing hormone secretion in men with temporal lobe epilepsy. Epilepsia. (2006) 47:1452–9. doi: 10.1111/j.1528-1167.2006.00617.x
39. Baird, AD, Wilson, SJ, Bladin, PF, Saling, MM, and Reutens, DC. The amygdala and sexual drive: insights from temporal lobe epilepsy surgery. Ann Neurol. (2004) 55:87–96. doi: 10.1002/ana.10997
40. Löfgren, E, Mikkonen, K, Tolonen, U, Pakarinen, A, Koivunen, R, Myllyla, VV, et al. Reproductive endocrine function in women with epilepsy: the role of epilepsy type and medication. Epilepsy Behav. (2007) 10:77–83. doi: 10.1016/j.yebeh.2006.09.011
41. Edwards, HE, Burnham, WM, Mendonca, A, Bowlby, DA, and MacLusky, NJ. Steroid hormones affect limbic afterdischarge thresholds and kindling rates in adult female rats. Brain Res. (1999) 838:136–50. doi: 10.1016/S0006-8993(99)01619-4
42. Herzog, AG, Coleman, AE, Jacobs, AR, Klein, P, Friedman, MN, Drislane, FW, et al. Interictal EEG discharges, reproductive hormones, and menstrual disorders in epilepsy. Ann Neurol. (2003) 54:625–37. doi: 10.1002/ana.10732
43. Vigas, M, Stowasserová, N, Németh, S, and Jurcovicová, J. Effect of electroconvulsive therapy without anticonvulsive premedication on serum growth hormone in man. Horm Res. (1975) 6:65–70. doi: 10.1159/000178663
44. Ryan, RJ, Swanson, DW, Faiman, C, Mayberry, WE, and Spadoni, AJ. Effects of convulsive electroshock on serum concentrations of follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone and growth hormone in man. J Clin Endocrinol Metab. (1970) 30:51–8. doi: 10.1210/jcem-30-1-51
45. Nappi, C, Meo, R, Di Carlo, C, Estraneo, A, and Bilo, L. Reduced fertility and neuroendocrine dysfunction in women with epilepsy. Gynecol Endocrinol. (1994) 8:133–45. doi: 10.3109/09513599409058035
47. Clemens, JA, Shaar, CJ, Kleber, JW, and Tandy, WA. Areas of the brain stimulatory to LH and FSH secretion. Endocrinology. (1971) 88:180–4. doi: 10.1210/endo-88-1-180
48. Herzog, AG, Seibel, MM, Schomer, DL, Vaitukaitis, JL, and Geschwind, N. Reproductive endocrine disorders in men with partial seizures of temporal lobe origin. Arch Neurol. (1986) 43:347–50. doi: 10.1001/archneur.1986.00520040035015
49. Singh, P, Singh, M, Cugati, G, and Singh, AK. Effect of epilepsy on female fertility and reproductive abnormalities. J Human Reprod Sci. (2011) 4:100–1. doi: 10.4103/0974-1208.86092
50. Herzog, AG. Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure. (2008) 17:101–10. doi: 10.1016/j.seizure.2007.11.025
51. Cutia, CA, and Christian-Hinman, CA. Mechanisms linking neurological disorders with reproductive endocrine dysfunction: insights from epilepsy research. Front Neuroendocrinol. (2023) 71:101084. doi: 10.1016/j.yfrne.2023.101084
52. Plunk, EC, and Richards, SM. Endocrine-disrupting air pollutants and their effects on the hypothalamus-pituitary-gonadal Axis. Int J Mol Sci. (2020) 21:9191. doi: 10.3390/ijms21239191
53. Quigg, M, Kiely, JM, Shneker, B, Veldhuis, JD, and Bertram, EH. Interictal and postictal alterations of pulsatile secretions of luteinizing hormone in temporal lobe epilepsy in men. Ann Neurol. (2002) 51:559–66. doi: 10.1002/ana.10188
54. Bauer, J, Blumenthal, S, Reuber, M, and Stoffel-Wagner, B. Epilepsy syndrome, focus location, and treatment choice affect testicular function in men with epilepsy. Neurology. (2004) 62:243–6. doi: 10.1212/01.wnl.0000091866.48962.79
55. Stamatiades, GA, and Kaiser, UB. Gonadotropin regulation by pulsatile GnRH: signaling and gene expression. Mol Cell Endocrinol. (2018) 463:131–41. doi: 10.1016/j.mce.2017.10.015
56. Ubuka, T, and Tsutsui, K. Neuropeptidergic control of neurosteroids biosynthesis. Front Neuroendocrinol. (2022) 65:100976. doi: 10.1016/j.yfrne.2021.100976
57. Maguire, M, Singh, J, and Marson, A. Epilepsy and psychosis: a practical approach. Pract Neurol. (2018) 18:106–14. doi: 10.1136/practneurol-2017-001775
58. Atwood, CS, Meethal, SV, Liu, T, Wilson, AC, Gallego, M, Smith, MA, et al. Dysregulation of the hypothalamic-pituitary-gonadal axis with menopause and andropause promotes neurodegenerative senescence. J Neuropathol Exp Neurol. (2005) 64:93–103. doi: 10.1093/jnen/64.2.93
59. Rupprecht, R. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology. (2003) 28:139–68. doi: 10.1016/s0306-4530(02)00064-1
60. Morrell, MJ, and Montouris, GD. Reproductive disturbances in patients with epilepsy. Cleve Clin J Med. (2004) 71:S19–24. doi: 10.3949/ccjm.71.suppl_2.s19
61. Mahesh, VB, and Brann, DW. Regulation of the preovulatory gonadotropin surge by endogenous steroids. Steroids. (1998) 63:616–29. doi: 10.1016/S0039-128X(98)00075-0
62. Luef, G. Hormonal alterations following seizures. Epilepsy Behav. (2010) 19:131–3. doi: 10.1016/j.yebeh.2010.06.026
63. Li, Q, Zhang, Z, and Fang, J. Hormonal changes in women with epilepsy. Neuropsychiatr Dis Treat. (2024) 20:373–88. doi: 10.2147/NDT.S453532
64. Marques, P, De Sousa, Lages A, Skorupskaite, K, Rozario, K, Anderson, R, George, J, et al. Physiology of GnRH and Gonadotrophin Secretion. KR Feingold, SF Ahmed, B Anawalt, MR Blackman, A Boyce, and G Chrousos, et al., Endotext. South Dartmouth, MA: MDText.com, Inc. (2000).
65. McCartney, CR, and Campbell, RE. Abnormal GnRH Pulsatility in polycystic ovary syndrome: recent insights. Current Opinion Endocrine Metabolic Research. (2020) 12:78–84. doi: 10.1016/j.coemr.2020.04.005
66. Roberts, RE, Farahani, L, Webber, L, and Jayasena, C. Current understanding of hypothalamic amenorrhoea. Ther Adv Endocrinol Metab. (2020) 11:2042018820945854. doi: 10.1177/2042018820945854
67. Drislane, FW, Coleman, AE, Schomer, DL, Ives, J, Levesque, LA, Seibel, MM, et al. Altered pulsatile secretion of luteinizing hormone in women with epilepsy. Neurology. (1994) 44:306–10. doi: 10.1212/wnl.44.2.306
68. Bilo, L, and Meo, R. Polycystic ovary syndrome in women using valproate: a review. Gynecological Endocrinol. (2008) 24:562–70. doi: 10.1080/09513590802288259
69. Dhamodharan, A, Selvaraj, N, and Meenakshi, R. Anticonvulsant effect of Nebivolol alone and in combination with phenytoin against maximal electroshock-induced seizures in mice. J Clin Diagn Res. (2021) 15. doi: 10.7860/JCDR/2021/47167.14669
70. Cooke, PS, Nanjappa, MK, Ko, C, Prins, GS, and Hess, RA. Estrogens in male physiology. Physiol Rev. (2017) 97:995–1043. doi: 10.1152/physrev.00018.2016
71. Vermeulen, A, Kaufman, JM, Goemaere, S, and Van Pottelberg, I. Estradiol in elderly men. Aging Male. (2002) 5:98–102. doi: 10.1080/tam.5.2.98.102
72. Mattsson, C, and Olsson, T. Estrogens and glucocorticoid hormones in adipose tissue metabolism. Curr Med Chem. (2007) 14:2918–24. doi: 10.2174/092986707782359972
73. Parisi, F, Fenizia, C, Introini, A, Zavatta, A, Scaccabarozzi, C, Biasin, M, et al. The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester. Hum Reprod Update. (2023) 29:699–720. doi: 10.1093/humupd/dmad016
74. Castracane, VD, Kraemer, GR, Ogden, BW, and Kraemer, RR. Interrelationships of serum estradiol, estrone, and estrone sulfate, adiposity, biochemical bone markers, and leptin in post-menopausal women. Maturitas. (2006) 53:217–25. doi: 10.1016/j.maturitas.2005.04.007
75. Spool, JA, Bergan, JF, and Remage-Healey, L. A neural circuit perspective on brain aromatase. Front Neuroendocrinol. (2022) 65:100973. doi: 10.1016/j.yfrne.2021.100973
76. Wallis, CJ, and Luttge, WG. INfluence of estrogen and progesterone on glutamic acid decarboxylase activity in discrete regions of rat brain. J Neurochem. (1980) 34:609–13. doi: 10.1111/j.1471-4159.1980.tb11187.x
77. Alam, MN, Ahmad, A, Al-Abbasi, FA, and Ahmad, A. Female ovarian steroids in epilepsy: a cause or remedy. Pharmacological Reports. (2013) 65:802–12. doi: 10.1016/s1734-1140(13)71061-2
78. Reibel, S, Vivien-Roels, B, Lê, BT, Larmet, Y, Carnahan, J, Marescaux, C, et al. Overexpression of neuropeptide Y induced by brain-derived neurotrophic factor in the rat hippocampus is long lasting. Eur J Neurosci. (2000) 12:595–605. doi: 10.1046/j.1460-9568.2000.00941.x
79. Velísková, J. Estrogens and epilepsy: why are we so excited? Neuroscientist. (2007) 13:77–88. doi: 10.1177/1073858406295827
80. Smith, JR, Flanigin, HF, King, DW, Gallagher, BB, Loring, DW, Meador, KJ, et al. Surgical management of epilepsy. South Med J. (1989) 82:736–41. doi: 10.1097/00007611-198906000-00015
81. Wong, M, and Moss, RL. Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons. J Neurosci. (1992) 12:3217–25. doi: 10.1523/JNEUROSCI.12-08-03217.1992
82. Luine, VN, Renner, KJ, Heady, S, and Jones, KJ. Age and sex-dependent decreases in ChAT in basal forebrain nuclei. Neurobiol Aging. (1986) 7:193–8. doi: 10.1016/0197-4580(86)90042-4
83. Schwartz-Giblin, S, Korotzer, A, and Pfaff, DW. Steroid hormone effects on picrotoxin-induced seizures in female and male rats. Brain Res. (1989) 476:240–7. doi: 10.1016/0006-8993(89)91244-4
84. Tominaga, K, Yamauchi, A, Shuto, H, Niizeki, M, Makino, K, Oishi, R, et al. Ovariectomy aggravates convulsions and hippocampal gamma-aminobutyric acid inhibition induced by cyclosporin a in rats. Eur J Pharmacol. (2001) 430:243–9. doi: 10.1016/s0014-2999(01)01377-2
85. Kalkbrenner, KA, and Standley, CA. Estrogen modulation of NMDA-induced seizures in ovariectomized and non-ovariectomized rats. Brain Res. (2003) 964:244–9. doi: 10.1016/s0006-8993(02)04065-9
86. Woolley, CS, Weiland, NG, McEwen, BS, and Schwartzkroin, PA. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J Neurosci. (1997) 17:1848–59. doi: 10.1523/JNEUROSCI.17-05-01848.1997
87. Budziszewska, B, Leśkiewicz, M, Kubera, M, Jaworska-Feil, L, Kajta, M, and Lasoń, W. Estrone, but not 17 beta-estradiol, attenuates kainate-induced seizures and toxicity in male mice. Experimental Clinical Endocrinology Diabetes. (2001) 109:168–73. doi: 10.1055/s-2001-14841
88. Velísková, J, Velísek, L, Galanopoulou, AS, and Sperber, EF. Neuroprotective effects of estrogens on hippocampal cells in adult female rats after status epilepticus. Epilepsia. (2000) 41:S30–5. doi: 10.1111/j.1528-1157.2000.tb01553.x
89. Reddy, DS. The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy. Epilepsy Res. (2009) 85:1–30. doi: 10.1016/j.eplepsyres.2009.02.017
90. Zhu, J, and Tsai, NP. Ubiquitination and E3 ubiquitin ligases in rare neurological diseases with comorbid epilepsy. Neuroscience. (2020) 428:90–9. doi: 10.1016/j.neuroscience.2019.12.030
91. Kolatorova, L, Vitku, J, Suchopar, J, Hill, M, and Parizek, A. Progesterone: a steroid with wide range of effects in physiology as well as human medicine. Int J Mol Sci. (2022) 23:7989. doi: 10.3390/ijms23147989
92. Breton, AB, Austin, KJ, Leedy, MG, and Alexander, BM. Effects of progesterone and RU486 on the development and expression of adult male sexual behaviour and gene expression in the amygdala and preoptic area of the hypothalamus. Reprod Fertil Dev. (2012) 24:916–22. doi: 10.1071/RD12006
93. Hilz, EN, and Lee, HJ. Estradiol and progesterone in female reward-learning, addiction, and therapeutic interventions. Front Neuroendocrinol. (2023) 68:101043. doi: 10.1016/j.yfrne.2022.101043
94. Kawadkar, M, Mandloi, AS, Singh, N, Mukharjee, R, and Dhote, VV. Combination therapy for cerebral ischemia: do progesterone and noscapine provide better neuroprotection than either alone in the treatment? Naunyn Schmiedeberg's Arch Pharmacol. (2022) 395:167–85. doi: 10.1007/s00210-021-02187-y
95. De Nicola, AF, Meyer, M, Garay, L, Kruse, MS, Schumacher, M, Guennoun, R, et al. Progesterone and Allopregnanolone neuroprotective effects in the wobbler mouse model of amyotrophic lateral sclerosis. Cell Mol Neurobiol. (2022) 42:23–40. doi: 10.1007/s10571-021-01118-y
96. Paul, SM, and Purdy, RH. Neuroactive steroids. FASEB J. (1992) 6:2311–22. doi: 10.1096/fasebj.6.6.1347506
97. Majewska, MD, Harrison, NL, Schwartz, RD, Barker, JL, and Paul, SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science (New York, NY). (1986) 232:1004–7. doi: 10.1126/science.2422758
98. Gee, KW, McCauley, LD, and Lan, NC. A putative receptor for neurosteroids on the GABAA receptor complex: the pharmacological properties and therapeutic potential of epalons. Crit Rev Neurobiol. (1995) 9:207–27.
99. Phillis, JW. Potentiation of the depression by adenosine of rat cerebral cortical neurones by progestational agents. Br J Pharmacol. (1986) 89:693–702. doi: 10.1111/j.1476-5381.1986.tb11173.x
100. Valera, S, Ballivet, M, and Bertrand, D. Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci USA. (1992) 89:9949–53. doi: 10.1073/pnas.89.20.9949
101. Bäckström, T, Zetterlund, B, Blom, S, and Romano, M. Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol Scand. (1984) 69:240–8. doi: 10.1111/j.1600-0404.1984.tb07807.x
102. Herzog, AG. Progesterone therapy in women with complex partial and secondary generalized seizures. Neurology. (1995) 45:1660–2. doi: 10.1212/wnl.45.9.1660
103. Herzog, AG. Catamenial epilepsy: update on prevalence, pathophysiology and treatment from the findings of the NIH progesterone treatment trial. Seizure. (2015) 28:18–25. doi: 10.1016/j.seizure.2015.02.024
104. Kokate, TG, Cohen, AL, Karp, E, and Rogawski, MA. Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice. Neuropharmacology. (1996) 35:1049–56. doi: 10.1016/s0028-3908(96)00021-4
105. Kokate, TG, Juhng, KN, Kirkby, RD, Llamas, J, Yamaguchi, S-i, and Rogawski, MA. Convulsant actions of the neurosteroid pregnenolone sulfate in mice. Brain Res. (1999) 831:119–24 ISSN 0006-8993,. doi: 10.1016/S0006-8993(99)01287-1
106. Reddy, DS. Role of neurosteroids in catamenial epilepsy. Epilepsy Res. (2004) 62:99–118. doi: 10.1016/j.eplepsyres.2004.09.003
107. Herzog, AG, and Frye, CAProgesterone Trial Study Group. Allopregnanolone levels and seizure frequency in progesterone-treated women with epilepsy. Neurology. (2014) 83:345–8. doi: 10.1212/WNL.0000000000000623
108. Rustichelli, C, Bellei, E, Bergamini, S, Monari, E, Baraldi, C, Castro, FL, et al. Serum levels of allopregnanolone, progesterone and testosterone in menstrually-related and postmenopausal migraine: a cross-sectional study. Cephalalgia. (2020) 40:1355–62. doi: 10.1177/0333102420937742
109. Zitzmann, M. Testosterone, mood, behaviour and quality of life. Andrology. (2020) 8:1598–605. doi: 10.1111/andr.12867
110. Mróz, T, Mróz, K, and Tutka, P. Androgeny a padaczka [Androgens and epilepsy]. Przegl Lek. (2010) 67:1186–93.
111. Sivaraaman, K, and Mintzer, S. Hormonal consequences of epilepsy and its treatment in men. Curr Opin Endocrinol Diabetes Obes. (2011) 18:204–9. doi: 10.1097/MED.0b013e328345e533
112. Ogunjimi, L, Alabi, A, Oyenuga, I, Ogunkunle, J, Kasumu, E, Ogunsanya, O, et al. Relationship between depression and sex steroid hormone among women with epilepsy. Front Neurosci. (2024) 18:1370533. doi: 10.3389/fnins.2024.1370533
113. Herzog, AG, Farina, EL, Drislane, FW, Schomer, DL, Smithson, SD, Fowler, KM, et al. A comparison of anastrozole and testosterone versus placebo and testosterone for treatment of sexual dysfunction in men with epilepsy and hypogonadism. Epilepsy Behavior. (2010) 17:264–71. doi: 10.1016/j.yebeh.2009.12.003
114. Freeman, ME, Kanyicska, B, Lerant, A, and Nagy, G. Prolactin: structure, function, and regulation of secretion. Physiol Rev. (2000) 80:1523–631. doi: 10.1152/physrev.2000.80.4.1523
115. Boyd, AE, and Reichlin, S. Neural control of prolactin secretion in man. Psychoneuroendocrinology. (1978) 3:113–30. doi: 10.1016/0306-4530(78)90001-x
116. Wilson, JD, and Foster, DW eds. Williams textbook of endocrinology. 8th ed. Philadelphia, PA: W.B. Saunders (1992).
117. Kliot, M, and Poletti, CE. Hippocampal afterdischarges: differential spread of activation shown by the (14C)deoxyglucose technique. Science. (1979) 204:641–3.
118. Parra, A, Velasco, M, Cervantes, C, Munoz, H, Cerborn, MA, and Velasco, F. Plasma prolactin increase following electrical stimulation of the amygdala in humans. Neuroendocrinology. (1980) 31:60–5.
119. Poletti, CE. Is the limbic system a limbic system? Studies of hippocampal efferents: their functional and clinical implications In: BK Doane and KE Livingston, editors. The limbic system. New York: Raven (1986). 79–94.
120. Renaud, LP. An electrophysiological study on amygdalahypothalamic projections to the ventromedial nucleus of the rat. Brain Res. (1976) 105:45–8.
121. Witter, MP, Groenewegen, HJ, da Lopes Silva, FH, and Lohman, AHM. Functional organization of the extrinsic and intrinsic circuity of the parahippocampal region. Prog Neurobiol. (1989) 33:161–253.
122. Bauer, J, Stefan, H, Schrell, U, Sappke, U, and Uhlig, B. Neurophysiological basics and clinical value of postictal serum-prolactin measurement in epileptic seizures. Fortschr Neurol Psychiatr. (1989) 57:457–68. [In German.]
123. Sperling, MR, and Wilson, CL. The effect of limbic and extralimbic electrical stimulations upon prolactin secretion in humans. Brain Res. (1986) 371:293–7. doi: 10.1016/0006-8993(86)90365-3
124. Trimble, MR. Serum prolactin in epilepsy and hysteria. Br Med J. (1978) 2:1682. doi: 10.1136/bmj.2.6153.1682
125. Bauer, J, Stefan, H, Schrell, U, Uhlig, B, Landgraf, S, Neubauer, U, et al. Serum prolactin concentrations and epilepsy. A study which compares healthy subjects with a group of patients in presurgical evaluation and circadian variations with those related to seizures. Eur Arch Psychiatry Clin Neurosci. (1992) 241:365–71.
126. Bauer, J. Epilepsy and prolactin in adults: a clinical review. Epilepsy Res. (1996) 24:1–7. doi: 10.1016/0920-1211(96)00009-5
127. Molaie, M, Culebras, A, and Miller, M. Effect of interictal epileptiform discharges on nocturnal plasma prolactin concentrations in epileptic patients with complex partial seizures. Epilepsia. (1986) 27:724–8. doi: 10.1111/j.1528-1157.1986.tb03601.x
128. Wang, P, Yang, HP, Tian, S, Wang, L, Wang, SC, Zhang, F, et al. Oxytocin-secreting system: a major part of the neuroendocrine center regulating immunologic activity. J Neuroimmunol. (2015) 289:152–61. doi: 10.1016/j.jneuroim.2015.11.001
129. Kandratavicius, L, Balista, PA, Lopes-Aguiar, C, Ruggiero, RN, Umeoka, EH, Garcia-Cairasco, N, et al. Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat. (2014) 10:1693–705. doi: 10.2147/NDT.S50371
130. Mairesse, J, Gatta, E, Reynaert, ML, Marrocco, J, Morley-Fletcher, S, Soichot, M, et al. Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats. Psychoneuroendocrinology. (2015) 62:36–46. doi: 10.1016/j.psyneuen.2015.07.005
131. Kiss, A, and Mikkelsen, JD. Oxytocin-anatomy and functional assignments: a minireview. Endocr Regul. (2005) 39:97–105.
132. Sun, Q, Pretel, S, Applegate, CD, and Piekut, DT. Oxytocin and vasopressin mrna expression in rat hypothalamus following kainic acid-induced seizures. Neuroscience. (1996) 71:543–54. doi: 10.1016/0306-4522(95)00466-1
133. Piekut, DT, Pretel, S, and Applegate, CD. Activation of oxytocin-containing neurons of the paraventricular nucleus (PVN) following generalized seizures. Synapse. (1996) 23:312–20. doi: 10.1002/(SICI)1098-2396(199608)23:4<312::AIDSYN9>3.0.CO;2-A
134. Ranisavljevic, N, Huberlant, S, Montagut, M, Alonzo, PM, Darné, B, Languille, S, et al. Low luteal serum progesterone levels are associated with lower ongoing pregnancy and live birth rates in ART: systematic review and Meta-analyses. Front Endocrinol. (2022) 13:892753. doi: 10.3389/fendo.2022.892753
135. Beniczky, S, Trinka, E, Wirrell, E, Abdulla, F, Al Baradie, R, Alonso Vanegas, M, et al. Updated classification of epileptic seizures: position paper of the international league against epilepsy. Epilepsia. (2025) 66:1804–23. doi: 10.1111/epi.18338
Keywords: epilepsy, infertility, hormonal dysregulation, sex hormone regulation, endocrine signaling pathways, fertility, pregnancy, fetal development
Citation: Kobylarek D, Zakryś K, Gierszewska J, Pagidela BR, Lan Y-Y, Kovinthapillai R, Rajczewski A, Kozubski W and Michalak S (2025) The neuroendocrine puzzle of epilepsy and infertility: what are we missing? Front. Neurol. 16:1658284. doi: 10.3389/fneur.2025.1658284
Edited by:
Vajir M. Malek, Beckman Research Institute, United StatesReviewed by:
Astri Budikayanti, Universitas Indonesia, IndonesiaMachlusil Husna, Universitas Brawijaya, Indonesia
Copyright © 2025 Kobylarek, Zakryś, Gierszewska, Pagidela, Lan, Kovinthapillai, Rajczewski, Kozubski and Michalak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dominik Kobylarek, ZG9taW5pay5rb2J5bGFyZWtAZ21haWwuY29t