Interhemispheric integration during the menstrual cycle: failure to confirm progesterone-mediated interhemispheric decoupling

A recent theory proposed that high levels of progesterone during the menstrual cycle may lead to functional decoupling of the cerebral hemispheres [Neuropsychologia 38 (2000) 1362]. The present study tested this theory with a well-validated behavioral measure of interhemispheric communication administered to 55 naturally-cycling women at the luteal or menstrual phase of the cycle. Neither between-subjects nor within-subjects analyses found significant differences in interhemispheric communication between the menstrual and luteal phases (F < 1). Correlations between salivary progesterone levels and interhemispheric communication also failed to support the theory. Although negative affect (NA) was associated with decreased effectiveness of interhemispheric communication, mood variables could not account for the lack of relationship between hormonal and interhemispheric variables. In summary, despite a rigorous and valid test, the theory that progesterone leads to interhemispheric decoupling found no support.     

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.     

Three Patterns of Catamenial Epilepsy

Summary: Purpose: On the basis of the neuroactive properties of estradiol and progesterone and the menstrually related cyclic variations of their serum concentrations, we propose the existence of three hormonally based patterns of seizure exacerbation. Because previous reports both support and refute the concept of catamenial epilepsy, we test the hypothesis by charting seizures and menses and measuring midluteal serum progesterone levels to estimate the frequency of epileptic women with catamenial seizure exacerbation. Methods: One hundred eighty-four women with intractable complex partial seizures (CPS) charted their seizure occurrence and onset of menstruation on a calendar for one cycle during which they had a midluteal blood sample taken for serum progesterone determination on day 22. Levels >5 ng/ml were considered ovulatory. The cycle was divided into four phases with onset of menstruation being day 1: menstrual (M) = -3 to +3, follicular (F) = 4 to 9, ovulatory (O) = 10 to -13, and luteal (L) =?12 to ?4. Average daily seizure frequency for each phase was calculated and compared among phases by repeated-measures analysis of variance (ANOVA) and the Student-Newman-Keul's test, separately for ovulatory and anovulatory cycles. Results: The 1,324 seizures recorded during 98 ovulatory cycles occurred with significantly greater (p < 0.001) average daily frequency during the M (0.59) and O (0.50) phases than during the F (0.41) and L (0.40) phases, offering support for perimenstrual (catamenial 1) and preovulatory (catamenial 2) patterns of seizure exacerbation. The 1,523 seizures recorded during 86 anovulatory cycles occurred with significantly lower (p < 0.001) average daily frequency during the F phase (0.49) than during all other phases (M = 0.78, O = 0.74, L = 0.74), offering support for seizure exacerbation throughout the second half of inadequate luteal phase cycles (catamenial pattern 3). Although 71.4% of the women with ovulatory cycles and 77.9% with inadequate luteal phase cycles had seizure exacerbation in relation to one of the three patterns of catamenial epilepsy, approximately one third of the women showed at least a twofold increase in average daily seizure frequency. We propose a twofold or greater increase as a reasonable definition of catamenial epilepsy. Conclusions: Charting of seizures and menses and determination of day 22 progesterone levels during each cycle may be sufficient to establish the existence of three distinct patterns of catamenial epilepsy. Approximately one third of women with intractable CPS may have catamenial epilepsy.     

Self-poisoning and the menstrual cycle

A study of the menstrual cycle phase on day of admission was conducted on 156 women with regular menstruation admitted for self-poisoning to a medical department. No relation of statistical significance was found between the day of self-poisoning and the menstrual cycle phase. This was also the case when a distinction was made between suicidal and non-suicidal attempts and between the main toxic agents taken. The findings are partly in contrast to earlier investigations.     

Reproductive Endocrine Considerations and Hormonal Therapy for Women with Epilepsy

Summary: Animal experimental and human clinical investigations show that estrogens lower and progestins raise many seizure thresholds. In women, seizure frequency varies with the serum estradiol to progesterone ratio. The fluctuation of this ratio during the menstrual cycle is a major factor in catamenial epilepsy. A decline in serum antiseizure medication levels premenstrually may be another factor. Estradiol to progesterone ratios are elevated in anovulatory or inadequate luteal phase cycles. This may explain a propensity for seizure onset at the time of menarche and the exacerbation of seizures during the months or years leading up to menopause. It may also be an important factor in the association between reproductive endocrine disorders and epilepsy. Specifically, polycystic ovarian syndrome and hypogonadotro-pic hypogonadism are significantly overrepresented among women with epilepsy. Epilepsy may promote the development of these disorders. These disorders, in turn, are characterized by inadequate luteal phase cycles that may promote the development or occurrence of seizures. In the setting of catamenial epilepsy or reproductive endocrine disorders, progestins, such as natural progesterone and parenteral medroxyprogesterone, or antiestrogenic agents, such as clomi-phene, constitute rational and effective adjuncts to therapy.     

Phenytoin Levels in Catamenial Epilepsy

We studied the fluctuations in phenytoin (PHT) levels during ovulatory and menstrual phases of the cycle, in eight patients with catamenial epilepsy and in eight age-matched controls. Pharmacokinetic studies of PHT were done in five patients with catamenial epilepsy. The difference in PHT levels during menstrual and ovulatory phase in catamenial group was 3.44 +/- 3.25 micrograms/ml as compared with 0.91 +/- 2.03 micrograms/ml in controls. The mean fall during menstrual phase was significant (p less than 0.05) in the catamenial group. There was also rapid though statistically nonsignificant clearance of PHT during menses as compared with the ovulatory period. It is presumed that the fall in plasma PHT levels during menses, though still within therapeutic range, may be responsible for catamenial exacerbation of epilepsy.     

Reproductive Function in Epilepsy

Summary: : The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.     

Differential effects of antiepileptic drugs on sexual function and reproductive hormones in men with epilepsy: interim analysis of a comparison between lamotrigine and enzyme-inducing antiepileptic drugs

PURPOSE: We compared sexual function and reproductive hormone levels among men with localization-related epilepsy (LRE) taking various antiepileptic drugs (AEDs) and normal controls (NC). METHODS: Subjects were 63 men with LRE [enzyme-inducing (EI) AEDs, 36; lamotrigine (LTG), 18; no AEDs, 9] and 18 NC. Sexual interest and function (S-score), hormone levels [bioactive testosterone (BAT) and estradiol (BAE)], hormone ratios [BAT/BAE], and gonadal efficiency [BAT/luteinizing hormone (LH)] were compared among the groups. RESULTS: S-scores, BAT levels, BAT/BAE, and BAT/LH were significantly lower in the EIAED group than in NC or LTG groups. Sex hormone-binding globulin (SHBG) was significantly higher in the EIAED group than in all other groups. Of men with LRE, 23.8% had abnormally low S-scores: 33.3% taking EIAEDs, 5.5% taking LTG, and 22.2% taking no AEDs (p < 0.01). BAT was low in 55.6% taking EIAEDs as compared with 33.3% taking LTG and 33.3% taking no AEDs (p < 0.05). Among men with low S-scores, 86.7% had low BAT as compared with 33.3% of men with normal scores (p < 0.01). BAT decline with age was greater among men with LRE than in controls (3.75 vs. 1.80 ng/dl/yr). The slope showed no significant difference among LRE groups. However, 89% of 40- to 50-year-old men taking EIAEDs had low BAT as compared with 33% taking LTG and 33% taking no AED (p < 0.01). CONCLUSIONS: Sexual function, BAT levels, BAT/BAE, and gonadal efficiency are greater with LTG than with EIAED. Abnormally low BAT levels are reached at an earlier age with EIAEDs than with LTG.     

Female reproductive factors and risk of seizure or epilepsy: data from the Nurses' Health Study II

Reproductive factors are associated with seizures in women with epilepsy. We prospectively examined the association between reproductive factors and the risk of adult-onset isolated seizure, epilepsy, or any unprovoked seizure (defined as single unprovoked seizure or epilepsy) among 114,847 Nurses' Health Study II participants followed from 1989 to 2005. Validated seizure questionnaires and medical records were used to confirm incident cases of isolated seizure (n = 95) or epilepsy (n = 151). Overall, there were no significant associations between any reproductive factor and risk of any unprovoked seizure (n = 196). However, menstrual irregularity at ages 18-22 years was specifically associated with an increased risk of epilepsy [relative risk (RR) 1.67, 95% confidence interval (CI) 1.12-2.51]. Menstrual irregularity during follow-up (RR 2.21, 95% CI 1.16-4.20) and early age at menarche (<12 years vs. 12-13 years; RR 1.76, 95% CI 1.10-2.81) increased the risk of isolated seizure. Oral contraceptive use and parity were not associated with isolated seizure or epilepsy. Therefore, menstrual factors were associated with risk of seizure and epilepsy.     

Variation in facial masculinity and symmetry preferences across the menstrual cycle is moderated by relationship context

In women, changes in preference during the menstrual cycle have been documented for attractiveness judgements of odour and various physical and behavioural male traits. Although many studies have demonstrated greater attraction to masculine traits, such as male faces, bodies, and voices, at high fertility, several recent studies present null results for these shifts in preferences. Moreover, evidence for stronger attraction to symmetric faces at high fertility is equivocal. Here we examined variation in preferences across the cycle for both facial masculinity and symmetry according to relationship context. Using both within-subject (Study 1) and between-subject (Study2) designs, we show that women prefer masculinity and symmetry in male faces at times when their fertility is likely to be highest (during the follicular phase of their cycle) when judging the faces for short-term relationship attractiveness. No effect of cycle was seen for long-term judgements. These results indicate that cyclic shifts in women are most apparent when judging for short-term relationships, which may explain the null results in studies where only general attractiveness was assessed. Cyclical preferences could influence women to select a partner who possesses traits that may enhance her offspring's quality at times when conception is most likely and/or serve to improve partner investment when investment is important.     

Facial emotion recognition and amygdala activation are associated with menstrual cycle phase

Converging evidence has accumulated that menstrual cycle and thus hormonal levels can affect emotional behavior, in particular facial emotion recognition. Here we explored the association of ovarian hormone levels and amygdala activation during an explicit emotion recognition task in two groups of healthy young females: one group was measured while in their follicular phase (n=11) and the other during their luteal phase (n=11). Using a 3T scanner in combination with a protocol specifically optimized to reliably detect amygdala activation we found significantly stronger amygdala activation in females during their follicular phase. Also, emotion recognition performance was significantly better in the follicular phase. We observed significant negative correlations between progesterone levels and amygdala response to fearful, sad and neutral faces, further supporting a significant modulation of behavior and neural response by hormonal changes during the menstrual cycle. From an evolutionary point of view this significant influence of ovarian hormone level on emotion processing and an important neural correlate, the amygdala, may enable a higher social sensitivity in females during their follicular phase, thus facilitating socio-emotional behavior (and social interaction) which may possibly facilitate mating behavior as well.     

Association between sleep duration and menstrual cycle irregularity in Korean female adolescents

ObjectiveThe association between sleep and the menstrual cycle in the adolescent population has been scarcely studied. This study aimed to investigate the association between sleep duration and menstrual cycle irregularity among female adolescents using nationwide representative data from the South Korean population.MethodsThis population-based, cross-sectional study used the data collected from Korea National Health and Nutrition Examination Survey 2010–2012, and the data from 801 female adolescents were analyzed. Hierarchical multivariable logistic regression analysis was performed to assess the risk of menstrual cycle irregularity in relation to sleep duration.ResultsSubjects with menstrual cycle irregularity accounted for 15% (N = 120). The mean sleep duration in subjects with menstrual cycle irregularity was significantly shorter than that in those without (p = 0.003). Menstrual cycle irregularity prevalence tended to decrease as sleep duration increased (p for trend = 0.004), which was significantly different based on sleep duration and presence of depressive mood (p = 0.011). Sleep duration ≤5 h per day was significantly associated with increased risk of menstrual cycle irregularity compared with that in the subjects whose sleep duration is ≥8 h per day even after adjusting for confounding variables. The odds ratios of menstrual cycle irregularity tended to increase for shorter sleep duration in all adjusted models.ConclusionThis study found a significant inverse association between sleep duration and menstrual cycle irregularity among Korean female adolescents. Increasing sleep duration is required to improve the reproductive health of female adolescents.     

Neuroendocrinological aspects of epilepsy: important issues and trends in future research

Neuroendocrine research in epilepsy focuses on the interface among neurology, endocrinology, gynecology/andrology and psychiatry as it pertains to epilepsy. There are clinically important reciprocal interactions between hormones and the brain such that neuroactive hormones can modulate neuronal excitability and seizure occurrence while epileptiform discharges can disrupt hormonal secretion and promote the development of reproductive disorders. An understanding of these interactions and their mechanisms is important to the comprehensive management of individuals with epilepsy. The interactions are relevant not only to the management of seizure disorder but also epilepsy comorbidities such as reproductive dysfunction, hyposexuality and emotional disorders. This review focuses on some of the established biological underpinnings of the relationship and their clinical relevance. It identifies gaps in our knowledge and areas of promising research. The research has led to ongoing clinical trials to develop hormonal therapies for the treatment of epilepsy. The review also focuses on complications of epilepsy treatment with antiepileptic drugs. Although antiepileptic drugs have been the mainstay of epilepsy treatment, they can also have some adverse effects on sexual and reproductive function as well as bone density. As longevity increases, the prevention, diagnosis and treatment of osteoporosis becomes an increasingly more important topic, especially for individuals with epilepsy. The differential effects of antiepileptic drugs on bone density and their various mechanisms of action are reviewed and some guidelines and future directions for prevention of osteoporosis and treatment are presented.     

How Common Is Catamenial Epilepsy?

Forty women of childbearing age with refractory epilepsy were asked to record their seizures, the first and last days of their menstrual periods, and symptoms of premenstrual tension for 3 consecutive months. By defining catamenial epilepsy as the occurrence of at least 75% of seizures each month in the 10-day time frame, which included the 4 days preceding menstruation and the 6 days after its onset, only 5 women (12.5%) were identified who fulfilled the criterion. Nevertheless, after the study was completed, 31 (78%) of these patients claimed that most of their seizures occurred near the time of and were exacerbated by menstruation. The patients with catamenial epilepsy reported no more symptoms of premenstrual tension than did the rest of the group. Clustering outside the menstrual cycle was noted in 4 other patients. Catamenial epilepsy is an uncommon condition. Patient claims about frequency of seizures in relation to menstruation are not always accurate. A standard definition should be adopted because the diagnosis has implications for management.     

Does the seizure frequency increase in Ramadan?

During Ramadan, the ninth month of the Islamic lunar calendar, adult Muslims are required to refrain from taking any food, beverages, or oral drugs, as well as from sexual intercourse between dawn and sunset. In this study, we aimed at discovering alterations in drug regimens and the seizure frequency of epileptic patients during Ramadan (15 October 2004–13 November 2004). In the 3 months following Ramadan in the year 2004, 114 patients with epilepsy who were fasting during Ramadan were examined at our Epilepsy Department. Of the 114 patients who were included in the study, 38 patients had seizures and one of these patients developed status epilepticus during Ramadan. When the seizure frequency of these patients during Ramadan was compared to that in the last 1 year and last 3 months period just prior to Ramadan, a statistically significant increase was observed (p < 0.001). Moreover, there was an important increase in the risk of having seizures in the patients who changed their drug regimens compared with those who did not (p < 0.05). In the patients who received monotherapy or polytherapy, no difference in the frequency of seizures during Ramadan was seen (p > 0.05).During Ramadan, an increase in the seizure frequency of patients with epilepsy was observed. The most important reason for this situation was the alteration in the pharmacokinetics and pharmacodynamics of drugs, and consequently, in their efficacy. We believe that in the patients who received monotherapy and who did not change their drug regimes, the increase in seizure frequency may have been related to the changes in their daily rhythms, emotional stress, tiredness and their day-long fasting.     

Assessing the assessment measures for menstrual cycle symptoms: a guide for researchers and clinicians

A review of measures of menstrual cycle symptoms is provided. This will enable researchers and clinicians to make the appropriate choice of method for their study requirements. In recent years, these measures have taken the form of retrospective questionnaires (rating severity of symptoms from memory) and prospective diaries (daily checklists of symptoms). Many of these draw on aspects of the well-known retrospective questionnaires, the Menstrual Distress Questionnaire and Premenstrual Assessment Form, in their development and validation. Each measure will be briefly described, followed by comments on its development, psychometric properties and finally an evaluation of its strengths and weaknesses. It concludes with an examination of the implications arising from the review, and some recommendations that menstrual cycle researchers and clinicians may wish to consider, as they decide upon the most appropriate measure for their needs.     

Acute psychiatric admission related to the menstrual cycle

A study of menstrual cycle phase on the day of acute admission to a psychiatric hospital for 121 women aged 20-39 showed an unequal distribution of admissions. More admissions than expected took place in the menstrual period, and correspondingly fewer intermenstrually. The difference was significant, and points to a certain degree of cyclicity in female psychiatric disturbance. This cyclicity was not significantly influenced by age, diagnosis, oral contraceptives or tendency for premenstrual symptoms. In the age group 20-39 one and a half times as many men as women are admitted to Danish psychiatric departments. Thus, in view of a common baseline, the most conspicuous feature is, that remarkably few women were admitted intermenstrually.     

Self-reported sleep across the menstrual cycle in young, healthy women

OBJECTIVE: To establish the association between subjective sleep and phase of the menstrual cycle in healthy, young, ovulating women. METHODS: Twenty-six women (mean age: 21 years) who did not suffer from any menstrual-associated disorders, and in whom we had detected ovulation, completed daily questionnaires about their sleep over 1 month. RESULTS: The women reported a lower sleep quality over the 3 premenstrual days and 4 days during menstruation, compared to the mid-follicular and early/mid luteal phases. Total sleep time, sleep onset latency, number and duration of awakenings, and morning vigilance were not affected by the menstrual cycle. CONCLUSION: The normal, ovulatory cycle is associated with changes in the perception of sleep quality but not sleep continuity in healthy, young women. The temporal relationship of sleep complaints with menstrual phase should be considered in the evaluation of sleep disorders, particularly insomnia, in women.