Epilepsy, Sex Hormones, and Antiepileptic Drugs

Summary: Many factors associated with hormone function have an impact on the course of epilepsy. Patients with epilepsy may have disturbances in sexual function such as anovulatory cycles in women and decreased libido and potency in men. Data indicate seizures, especially those arising in the limbic system, may influence the hypothalamic pituitary axis. Antiepileptic drugs also influence sexual function through direct brain effects as well as through induced changes in pharmacokinetics of the sex steroid hormones. Pregnancy has been reported to be a time of increased seizures; however, this has often been associated with low drug levels, for reasons that include inadequate drug dose, possible changes in pharmacokinetics, and noncompliance. Some evidence suggests that hormones affect seizure frequency. Changes in seizures during the menstrual cycle (catamenial epilepsy) have been found in some women: seizures were fewer during the luteal phase but increased when progesterone levels declined. Some improvement in seizure frequency has been shown in pilot studies using medroxyprogesterone acetate, a synthetic progesterone. Current concepts of the interrelationship among epilepsy, sex hormones, and antiepileptic drugs are discussed.     

Antidepressant medications, mood and male fertility

By modulating the activity of central neurotransmitters, psychotropic agents may affect reproductive functioning in men and women. Many neurotransmitters influence the hypothalamic-pituitary-gonadal (HPG) axis and can consequently affect menstrual cycling in women and spermatogenesis in men. Emotional state similarly may disrupt reproductive functioning through the effects of stress hormones on the HPG axis. While some data exist on the relationship between stress and menstrual cyclicity in women of reproductive age, little is known regarding the potential effect of emotional state on reproductive function in men. This paper will review: (1) aspects of male reproductive function that may be vulnerable to medication-induced influences; (2) the impact of emotional state on male reproductive function; and (3) the literature on the possible effects of antidepressant medications on male fertility.     

Neuropeptidase activity is down-regulated by estradiol in steroid-sensitive regions of the hypothalamus in female mice

Thimet oligopeptidase (TOP) and prolyl endopeptidase (PEP) are neuropeptidases involved in the hydrolysis of gonadotropin-releasing hormone, a key component of the hypothalamic-pituitary-gonadal axis. GnRH is regulated in part by feedback from steroid hormones such as estradiol. Previously, we demonstrated that TOP levels are down-regulated by estradiol in reproductively-relevant regions of the female rodent brain. The present study supports these findings by showing that TOP enzyme activity, as well as protein levels, in the ventromedial hypothalamic nucleus of female mice is controlled by estradiol. We further demonstrate that PEP levels in this same brain region are down-regulated by estradiol in parallel with those of TOP. These findings provide evidence that these neuropeptidases are part of the fine control of hormone levels in the HPG axis.     

Endocrinologic adverse effects of psychotropic drugs

Psychotropic drugs affect the regulatory mechanisms of different neuroendocrine axis. This chapter reviews the interactions between psychotropic drugs and prolactin, the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-gonadal axis. Hyperprolactinemia can cause galactorrhea, amenorrhea, sexual disfunction, impaired spermatogenesis and increased risk for osteoporosis and fractures. Atypical antipsychotics cause less hyperprolactinemia than conventional antipsychotics. Lithium has important effects on thyroid function. During lithium treatment, affectively ill patients show, in varying degrees and combinations, reduced levels of thyroid hormones and clinical evidence of subclinical hypothyroidism, overt hypothyroidism and goiter. Recent literature reports suggest that valproic acid, may be associated with polycistic ovarian syndrome. Until additional data is available, women starting valproate therapy should be warned about the possibility of endocrinology side effects.     

Effects of Ovariectomy on GnRH Neuronal Morphology inRhesus Monkey (Macaca mulatta)

Gonadotropin releasing hormone (GnRH) neurons are typically simple, fusiform cells; however, over the course of prepubertal development increasing numbers take on a 'spiny' appearance. Following gonadectomy there is a decrease in the frequency of these spiny GnRH neurons. These observations which were made in the rat suggest that GnRH neurons are directly affected by the gonadal steroid milieu, though they do not themselves contain receptors for these steroidal hormones. In that there are important species differences in the hypothalamic-pituitary-gonadal axis between rats and primates, the present study was undertaken to determine whether a reduction in ovarian hormones would produce similar changes in the morphology of GnRH neurons in the monkey. A further aim was to determine whether such changes were localized to a specific brain region.     

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

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

Hypothalamic-Pituitary-End-Organ Axes: Hormone Function in Female Patients with Major Depressive Disorder

Classic hypothalamic-pituitary-end-organ feedback loops – the hypothalamic-pituitary-adrenal axis (HPAA), hypothalamic-pituitary-thyroidal axis (HPTA), and hypothalamic-pituitary-gonadal axis (HPGA) – are associated with the neuroendocrine and immune systems in major depressive disorder (MDD). Female patients with MDD present with evident neuroendocrine and immunological changes. Glucocorticoid, thyroid hormone, and reproductive steroid levels fluctuate with menstrual cycles, which might lead to glucocorticoid receptor resistance, impairment of triiodothyronine conversion, and sex hormone secretion disorders. In this review, we summarize the independent and interactive functions of these three axes in female MDD patients. The similar molecular structure of steroids implies an interrelationship between the hypothalamic-pituitary-end-organ axes and the competitive inhibitory effects at the receptor level, especially when considering the HPAA and HPGA.     

Autonomic activity in epilepsy: Diagnostic considerations and implications

Autonomic function is usually disrupted to some degree during epileptic seizures. This loss of control has multiple clinical expressions. Some autonomic changes that accompany seizures are subtle and of little importance, while other changes may be life-threatening. In some cases, the autonomic accompaniments of epilepsy overshadow the cerebral effects of the seizures. In doing so, they tend to hamper correct diagnosis and treatment. In this article I will review some of the autonomic changes that accompany seizures. I will focus primarily upon those changes that affect the neurocardiac axis and the neurorespiratory axis. Other autonomic accompaniments affecting the gastrointestinal tract, urinary bladder, and skin are also discussed.     

Epilepsy and reproductive disorders: the role of the gonadotropin-releasing hormone network

Individuals with temporal lobe epilepsy have an increased incidence of reproductive dysfunction. The comorbidity may be due to the acute effects of the seizures, the chronic effects of the epilepsy, and/or the use of antiepileptic drugs on the gonadotropin-releasing hormone network and the hypothalamic-pituitary-gonadal axis. This review provides a brief overview of evidence from experimental animal and clinical studies exploring the basis for epilepsy-associated reproductive abnormalities.     

Epilepsy and hormones

The paper contains a review of reports concerned with how for hormones, epileptic seizures and antiepileptic drugs can be influenced by one another. Hormones influence brain excitability but, on the other hand, both epileptic seizures and antiepileptic drugs may alter hormone secretion and metabolism. Effect of hormones on seizures--Experimental studies revealed the properties which inhibit or stimulate convulsive reactivity of different hormones. Progesterone, testosterone, adrenocorticotropin and desoxycorticosterone are responsible for an increase in seizure threshold, while estradiol, cortisol and thyroid hormones cause a reduction. Effect of seizures on hormones--Epileptic seizures, chiefly tonic-clonic, also complex partial and sometimes simple partial seizures, result in "the hormonal storm". Immediately after an epileptic seizure, an increase is found in serum concentrations of prolactin, cortisol, adrenocorticotropin, triidothyronine, thyroxin, thyrotropin, luteotropin, follicular stimulating hormone and growth hormone. These changes may persist for two hours, while prolactin concentration even for 24 hours after a seizure. Effect of antiepileptic drugs on hormones--Antiepileptic drugs may affect hypothalamus-pituitary function directly or indirectly through neurotransmitter system. By induction of hepatic microsomal enzymes, some antiepileptic drugs cause acceleration of hormone metabolism, reducing hormone serum concentrations. Moreover, antiepileptic drugs enhance sex hormone binding globulin SHBG/synthesis, increase binding of these hormones and reduce their active fraction concentration in serum. Recognition of the relationship between epilepsy and hormonal system is necessary to obtain better understanding of this disease.     

Dysregulation of the hypothalamic-pituitary-gonadal axis with menopause and andropause promotes neurodegenerative senescence

Senescence is characterized neurologically by a decline in cognitive function, which we propose is the result of degenerative processes initiated by the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis with menopause and andropause. Compelling epidemiologic evidence to support this assertion includes the increased prevalence of Alzheimer disease (AD) in women, the correlation of serum HPG hormones with disease and the decreased incidence, and delay in the onset of AD following hormone replacement therapy. Dysregulation of the axis at this time leads to alterations in the concentrations of all serum HPG hormones (decreased neuronal sex steroid signaling, but increased neuronal gonadotropin releasing hormone, luteinizing hormone, and activin signaling). Hormones of the HPG axis, receptors for which are present in the adult brain, are important regulators of cell proliferation and differentiation during growth and development. Based on this, we propose that dysregulated HPG hormone signaling with menopause/andropause leads to the abortive reentry of differentiated neurons into the cell cycle via a process we term "dyosis." Interestingly, the major biochemical and neuropathologic changes reported for the AD brain also are intimately associated with neuron division: altered AbetaPP metabolism, Abeta deposition, tau phosphorylation, mitochondrial alterations, chromosomal replication, synapse loss, and death of differentiated neurons. Recent evidence supports the premise that AD-related biochemical changes are likely the combined result of increased mitotic signaling by gonadotropins and GnRH, decreased differentiative and neuroprotective signaling via sex steroids, and increased differentiative signaling via activins. This results in a hormonal milieu that is permissive of cell cycle reentry but does not allow completion of metaphase. Partial resetting of the axis following administration of normal endogenous sex steroids delays the onset and decreases the incidence of AD. Ideally, supplementation with HPG hormones should mimic closely the serum concentrations of all HPG hormones in reproductive men and cycling women to prevent dyotic signaling and attempted neuron division.     

Effects of quetiapine on gonadal axis hormones in male patients with schizophrenia: a preliminary,open study

PURPOSE: The authors investigated the effects of a novel antipsychotic agent, quetiapine administration on hypothalamo-pituitary-gonadal (HPG) axis hormones in patients with chronic schizophrenia. METHODS: In this prospective, open-label study, the subjects were nine male inpatients. We tried to switch the patients from typical antipsychotics to quetiapine. The patients took a mean dose of 636.1 mg quetiapine daily for a mean period of 104.7 days. RESULTS: (i) Although the total Brief Psychiatric Rating Scale score did not show significant changes, no patients needed anticholinergic medications after the switch. (ii) Before the switch, only the prolactin concentration showed a significant difference between the patients and normal subjects. After the switch, neither prolactin nor HPG axis hormone concentrations showed significant differences between the groups. CONCLUSIONS: Our preliminary results indicated that quetiapine might not affect prolactin and HPG axis hormones at least in chronic schizophrenia patients with normal levels of HPG axis hormones.     

Treatment of women with epilepsy

Epilepsy is equally prevalent in men and women. However, for women there are unique concerns related to hormone effects on seizures and the effects of seizures and antiepileptic drugs (AEDs) on reproductive health. Steroid hormones affect neuronal excitability and seizure frequency. Some AEDs reduce the efficacy of oral contraceptive agents, increasing the probability of unplanned pregnancies. AEDs affect bone density. AEDs may alter reproductive hormones resulting in polycystic-appearing ovaries, anovulatory cycles, and infertility. Seizure frequency may change during pregnancy, seizures may cause pregnancy complications, some AEDs are teratogenic, and many cross into breast milk. The treatment of a woman with epilepsy must consider all these issues.     

Chronic pain therapy and hypothalamic-pituitary-adrenal axis impairment

Opiates and/or nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most effective therapies for chronic pain, but their prolonged time of use can affect health conditions through physical and psychological side effects. They include the very common gastrointestinal effects and changes that can induce osteoporosis, depression, impaired cognition and a generally poor quality of life, which per se can induce and maintain a chronic painful condition. For this reason it is becoming imperative to expand our knowledge of the interaction of these substances with body functions apparently not directly involved in nociception and pain, such as neuroendocrine functions. The purpose of this study was to determine, in male and female patients suffering from chronic pain, the effect of conventional pain therapy (opiates, NSAIDs) on hypothalamic-pituitary-adrenal (HPA) axis function. This was assessed by measuring the blood levels of adrenal-related hormones (adrenocorticotrophin hormone, ACTH; cortisol; dehydroepiandrosterone, DHEA and dehydroepiandrosterone sulfate, DHEAS). The second purpose of the study was to test the hypothesis that these hormones are associated with the psychological profile shown by the chronic pain patients. The results showed significant changes induced by pain therapy on the HPA axis: ACTH, cortisol, DHEA and DHEAS blood levels decreased in all subjects taking opiates or NSAIDs to treat pain. Moreover these changes showed significant correlations with psychological features of the subjects depending on age and sex.     

Sexual hormones and epilepsy: threat and opportunities

PURPOSE OF REVIEW: This article reviews recent developments in our knowledge of the reciprocal interactions between epilepsy and sex hormones and how these interactions may play a role in the pathophysiology and treatment of both. RECENT FINDINGS: Community studies confirm that menstrual disorders are overrepresented among women with epilepsy, especially among women with high seizure frequency and in those on valproate or polytherapy. Reproductive function is not affected in women with epilepsy who discontinued antiepileptic drug therapy during pubertal maturation. While valproate has been implicated as having particularly notable disruptive effects on reproductive function in women with epilepsy (polycystic ovaries and hyperandrogenemia), this was not evident in non-epileptic primates. The role of epilepsy itself is evident from a study that showed that the laterality of unilateral temporolimbic discharges is associated with predictable directional changes in hormonal secretion at all levels of the reproductive neuroendocrine axis. Epilepsy in men is associated with reduced levels of sexual function, bioactive testosterone and sperm. Various antiepileptic drugs may differ in this regard. SUMMARY: Epilepsy and antiepileptic drugs can alter sex hormone levels to promote the development of reproductive endocrine disorders in both women and men. Reproductive endocrine disorders may adversely affect both reproductive function and seizure control. Treatment of epilepsy and selection of antiepileptic drugs may be important to reproductive health in women and men with epilepsy. Sex steroids and their metabolites may also provide treatment for seizures.     

Glucocorticoids, cytokines and brain abnormalities in depression

Major depression (MD) is a common psychiatric disorder with a complex and multifactor aetiology. Potential mechanisms associated with the pathogenesis of this disorder include monoamine deficits, hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, inflammatory and/or neurodegenerative alterations. An increased secretion and reactivity of cortisol together with an altered feedback inhibition are the most widely observed HPA abnormalities in MD patients. Glucocorticoids, such as cortisol, are vital hormones that are released in response to stress, and regulate metabolism and immunity but also neuronal survival and neurogenesis. Interestingly depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases and at the same time, depressed patients show higher levels of pro-inflammatory cytokines. Since communication occurs between the endocrine, immune and central nervous system, an activation of the inflammatory responses can affect neuroendocrine processes, and vice versa. Therefore, HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance. In addition, increased levels of pro-inflammatory cytokines also induce the production of neurotoxic end products of the tryptophan-kynurenine pathway. Although the evidence for neurodegeneration in MD is controversial, depression is co-morbid with many other conditions where neurodegeneration is present. Since several systems seem to be involved interacting with each other, we cannot unequivocally accept the simple model that glucocorticoids induce neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders. Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life. However, further studies are needed to clarify the relative contribution of glucocorticoids and inflammatory signals to MD and other disorders.     

Hormones and Epilepsy Through the Lifetime

Summary: Hormones influence brain function from gestation throughout life and may affect the seizure threshold by altering neuronal excitability. Estrogen enhances and progesterone diminishes neuronal excitability experimentally, whereas testosterone and corticosteroids have less consistent effects. Hormonal effects in the CNS also depend on the region of brain in which the hormone acts. Sites of action for most steroid hormones include the hypothalamus and limbic cortex, providing a mechanism for modulating behavior and endocrine function. Seizure patterns may change at certain life stages, perhaps as a result of alterations in hormones. At puberty, epilepsy and benign rolandic epilepsy often remit, while juvenile myoclonic and photosensitive epilepsy may arise. Other types of epilepsy do not respond predictably to events in the reproductive life or to advancing age. In some women, fluctuations in hormones over the menstrual cycle appear to increase seizure vulnerability, probably reflecting changes in relative amounts of estrogen and progesterone. Seizure patterns can be altered, for better or worse, during pregnancy. Whether this reflects the effects of hormones or changes in levels of antiepileptic drugs is not resolved. More information is needed about changes in established epilepsy at menopause and in the elderly. Better understanding of endocrine effects on seizures over a lifetime should lead to more effective epilepsy therapies.     

Secondary partial empty sella syndrome in an elite bodybuilder.

The pituitary gland is a hormone-responsive gland and is known to vary in size depending on the hormonal status of the patient and the multifaceted positive and negative feedback hypothalamic-pituitary-gonadal axis. Partial empty sella syndrome with an atrophied pituitary gland is seen in primary neuroendocrinopathies such as growth hormone deficiency, primary hypothyroidism, central diabetes insipidus and hypogonadism. Partial empty sella has also been shown to occur in patients with elevations in intracranial pressure. Secondary partial empty sella syndrome with significant pituitary gland atrophy from negative feedback inhibition of long-term exogenous hormonal use has not been previously reported. We are reporting on a case of partial empty sella syndrome occurring in an elite bodybuilder with a long history of exogenous abuse of growth hormone, testosterone and thyroid hormone. The pathophysiological mechanisms of secondary partial empty sella syndrome from exogenous hormone use and the possibility for elevations in intracranial pressure contributing to this syndrome will be discussed.     

Hormonal considerations in women with seizures

The relationships between seizures in epileptic women and the hormones estrogen and progesterone are under increasing study. Serum concentrations of estrogen and progesterone parallel cerebrospinal concentrations, and circulating sex hormones are concentrated in specific areas of the brain that regulate sexual behavior. These centers include two potentially epileptogenic regions--the amygdala and hippocampus. Many of these structures are physiologically affected in vitro by estrogen and progesterone. Exogenous sex hormones change the seizure threshold in animal models of epilepsy. Cyclical hormonal variations may influence electroencephalographic activity and affect seizure frequency in women with epilepsy. Hormonal therapy may be appropriate adjunctive anticonvulsant treatment, particularly for women with seizures that are catamenial or associated with a menstrual or reproductive endocrine disorder.     

Sexual Dysfunction in Epilepsy

Summary: Sexual dysfunction may arise more frequently in men and women with epilepsy than with other chronic illnesses, manifesting primarily as diminished sexual desire and potency. Studies using retrospective self-report of sexual attitude and behavior find an incidence of sexual dysfunction ranging from 14–66%. Sexual dysfunction may be more common in partial than in generalized epilepsies. Sexual dysfunction in epilepsy may result from a disturbance in social or psychological factors affecting sexual responsiveness. Alternatively, epileptiform discharges may disrupt the function of structures mediating sexual behavior, particularly the limbic cortex, or alter the release of hypothalamic or pituitary hormones. Antiepileptic drugs modulate hormone release from the hypothalamic-pituitary-gonadal axis and may have direct inhibitory effects on sexual behavior. Evidence both supports and refutes each of these etiologies in the sexual dysfunction seen with epilepsy. Specific evaluation and treatment protocols for patients with sexual dysfunction are available.