Relation between plasma prolactin and plasma homovanillic acid in normal subjects

The relation between fasting, a.m. plasma prolactin and plasma/homovanillic acid (HVA) was studied in 9 healthy males on one occasion and in 9 healthy females on two occasions (in the follicular and luteal phase of the menstrual cycle). There was a significant inverse correlation between plasma HVA and plasma prolactin in females in the follicular phase only. The correlation between these two measures, although also in the same direction, was not significant in females in the luteal phase or in males. The theoretical implications of these findings are discussed.     

Diurnal fluctuation of sleep propensity across the menstrual cycle

Most women experience sleep changes across the menstrual cycle. We applied the ultra-short sleep-wake schedule to healthy females to compare their 24-h sleep propensity rhythms in the follicular and luteal phases. The daytime (09.00-16.30 h) subjective sleepiness and the number of slow wave sleep-containing nap trials increased in the luteal phase compared to the follicular phase, but the mean sleep propensity did not change. During the periods of 17.00-00.30 h and 01.00-08.30 h there were no differences between the two phases. These results suggest that increased daytime sleepiness in the luteal phase may be related to brain mechanisms controlling slow wave sleep.     

Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study

BACKGROUND: There is increasing support for the hypothesis that gonadal steroids involved in the regulation of the human menstrual cycle modulate gamma-aminobutyric acid (GABA) neuronal function. This study tests the hypothesis that cortical GABA neuronal function, reflected in brain GABA concentrations, fluctuates across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder (PMDD) and that a menstrual cycle phase-dependent abnormality in brain GABA concentrations in women diagnosed as having PMDD would reflect altered central response to circulating gonadal and neuroactive steroids. METHODS: Fourteen healthy menstruating women and 9 women diagnosed as having PMDD were recruited from a women's behavioral health research program located at a university-based medical center. The women underwent serial proton magnetic resonance spectroscopic measurements of occipital cortex GABA levels across the menstrual cycle (primary outcome measure) and had blood drawn for gonadal hormone and neurosteroid levels determined on each scan day (secondary outcome measure). RESULTS: There was a significant group x phase interaction with most of the finding explained by the reduction in cortical GABA levels during the follicular phase in those with PMDD compared with healthy controls. Cortical GABA levels declined across the menstrual cycle in healthy women, whereas women with PMDD experienced an increase in cortical GABA levels from the follicular phase to the mid luteal and late luteal phases. Significant between-group differences in the relationship between hormones and GABA were observed for estradiol, progesterone, and allopregnanolone. CONCLUSIONS: These data strongly suggest that the GABAergic system is substantially modulated by menstrual cycle phase in healthy women and those with PMDD. Furthermore, they raise the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids as potentially important contributors to the pathogenesis of PMDD.     

Peak visual gamma frequency is modified across the healthy menstrual cycle

Fluctuations in gonadal hormones over the course of the menstrual cycle are known to cause functional brain changes and are thought to modulate changes in the balance of cortical excitation and inhibition. Animal research has shown this occurs primarily via the major metabolite of progesterone, allopregnanolone, and its action as a positive allosteric modulator of the GABA_A receptor. Our study used EEG to record gamma oscillations induced in the visual cortex using stationary and moving gratings. Recordings took place during twenty females’ mid‐luteal phase when progesterone and estradiol are highest, and early follicular phase when progesterone and estradiol are lowest. Significantly higher (～5 Hz) gamma frequency was recorded during the luteal compared to the follicular phase for both stimuli types. Using dynamic causal modeling, these changes were linked to stronger self‐inhibition of superficial pyramidal cells in the luteal compared to the follicular phase. In addition, the connection from inhibitory interneurons to deep pyramidal cells was found to be stronger in the follicular compared to the luteal phase. These findings show that complex functional changes in synaptic microcircuitry occur across the menstrual cycle and that menstrual cycle phase should be taken into consideration when including female participants in research into gamma‐band oscillations.     

Menstrual cycle, race and task effects on blood pressure recovery from acute stress.

This study examined cardiovascular recovery from two standardized laboratory stressors in 68 healthy black and white normotensive women and men (mean age 33 years). Women were studied in a randomized order at the same time of day on two separate occasions, once during the follicular phase (days 7 to 10 following menses) and once during the luteal phase (days 7 to 10 following the leutenizing-hormone surge) of the menstrual cycle. Men were studied twice approximately 6 weeks apart. There were differential effects of the tasks on blood pressure recovery (change scores) with a mirror star task yielding poorer diastolic blood pressure recovery (p = 0.004) and an interpersonal speaking task yielding poorer systolic blood pressure recovery (p = 0.003). Across both tasks, blacks evidenced greater diastolic blood pressure recovery as compared to whites (p = 0.02). Black women showed greater diastolic blood pressure recovery in the luteal as compared to the follicular phase (p = 0.01), whereas white women evidenced no such change across the menstrual cycle. Correlation analysis across testing sessions generally revealed comparable temporal stability values for recovery as compared to reactivity measures. The findings support prior studies indicating racial differences in recovery from acute stress and extend these findings by suggesting that the menstrual cycle may differentially affect recovery in black versus white women.     

Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (sIL-2R), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10-20 mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n=45; 19 males and 26 females). Our data indicated that a higher level of TNF-alpha might predict a non-response to treatment with escitalopram and that changes in concentrations of sIL-2R during the treatment were different in responders and non-responders.     

Increased tumor necrosis factor-alpha concentrations with interleukin-4 concentrations in exacerbations of schizophrenia

Several studies have indicated that cytokines may be involved in the pathophysiology of schizophrenia. Previous studies, however, have yielded contradictory results; in this study we assess the plasma levels of both T-helper-1 (Th1) and T-helper-2 (Th2) cytokines in patients with acute exacerbations of schizophrenia. Plasma concentrations of interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and soluble receptor of interleukin-6 (sIL-6R) were measured with high sensitivity, enzyme-linked immunosorbent assays (ELISA) in patients with acute exacerbations of schizophrenia as compared with healthy controls. Patients with an acute exacerbation of schizophrenia had significantly increased production of TNF-alpha and significantly reduced production of IL-4 as compared with healthy subjects. No significant difference was observed in IL-6, sIL-6R, IL-8 and IL-10. Acute exacerbations of schizophrenia are associated with increased TNF-alpha concentrations (Th1) with concomitantly reduced concentrations of IL-4 (Th2) and a resulting increased TNF-alpha/IL-4 ratio.     

Effects of menstrual cycle phase and oral contraceptives on alertness, cognitive performance, and circadian rhythms during sleep deprivation.

The influence of menstrual cycle phase and oral contraceptive use on neurobehavioral function and circadian rhythms were studied in healthy young women (n = 25) using a modified constant routine procedure during 24 h of sleep deprivation. Alertness and performance worsened across sleep deprivation and also varied with circadian phase. Entrained circadian rhythms of melatonin and body temperature were evident in women regardless of menstrual phase or oral contraceptive use. No significant difference in melatonin levels, duration, or phase was observed between women in the luteal and follicular phases, whereas oral contraceptives appeared to increase melatonin levels. Temperature levels were higher in the luteal phase and in oral contraceptive users compared to women in the follicular phase. Alertness on the maintenance of wakefulness test and some tests of cognitive performance were poorest for women in the follicular phase especially near the circadian trough of body temperature. These observations suggest that hormonal changes associated with the menstrual cycle and the use of oral contraceptives contribute to changes in nighttime waking neurobehavioral function and temperature level whereas these factors do not appear to affect circadian phase.     

Diurnal fluctuation of sleep propensity and hormonal secretion across the menstrual cycle.

BACKGROUND: The fact that most women experience sleep changes across the menstrual cycle is thought to be associated with changes in circadian rhythms; however, few studies have investigated this relationship. METHODS: We applied an ultrashort sleep-wake schedule to eight healthy women and studied diurnal fluctuations in sleep propensity, sleepiness, rectal temperature, and serum concentrations of melatonin, thyroid-stimulating hormone, and cortisol in the follicular and luteal phases. RESULTS: In the luteal phase, amplitude of core body temperature, total melatonin secretions, and amplitudes of TSH and cortisol rhythms were significantly decreased, whereas sleepiness and occurrence of slow-wave sleep during the daytime were significantly increased. Differences in the amount of daytime slow-wave sleep across the menstrual cycle were positively correlated with differences in the daily mean rectal temperature. CONCLUSIONS: The findings suggest that the amplitude of circadian oscillation may be dampened in the luteal phase. Increased daytime sleepiness in the luteal phase may be associated with increased daytime slow-wave sleep, due possibly to changes in thermoregulation in the luteal phase.     

The influence of endogenous estrogen on transcranial direct current stimulation: A preliminary study

Transcranial direct current stimulation (tDCS) is a non‐invasive neuromodulatory technique. Responses to tDCS differ substantially between individuals. Sex hormones that modulate cortical excitability, such as estrogen, may contribute to this inter‐individual variability. The influence of estrogen on tDCS after‐effects has not yet been researched. This study aimed to investigate whether endogenous estrogen levels influence cortical response to tDCS. Data from 15 male and 14 female healthy adults were analyzed. Males completed one experimental session. Females completed two, one during the early follicular phase of the menstrual cycle when estrogen was low, one during the mid‐luteal phase when estrogen was high. Each session comprised 15‐min of anodal tDCS delivered to the left dorsolateral prefrontal cortex (DLPFC). Response to stimulation was assessed using electroencephalography with DLPFC transcranial magnetic stimulation (TMS) administered before, immediately after, and 20‐min after tDCS. Changes in amplitudes of N120 and P200 components of TMS‐evoked potentials over time were compared between males, women with low estrogen and women with high estrogen. Blood assays verified estrogen levels. Women with high estrogen demonstrated a significant increase in P200 amplitude at both time points and change over time was greater for the high estrogen group compared with males. No significant differences were observed between males and women with low estrogen, or between women with low and high estrogen. These preliminary results indicate that greater neuroplastic response to DLPFC tDCS is seen in highest compared with lowest estrogen states, suggesting that endogenous estrogen levels contribute to inter‐individual variability of tDCS outcomes.     

Working memory for emotional facial expressions: role of the estrogen in young women

Physiological hormonal fluctuations during the menstrual cycle, postpartum, and menopause have been implicated in the modulation of mood, cognition, and affective disorders. Taking into account that women's performance in memory tasks can also fluctuate with circulating hormones levels across the menstrual cycle, the cognitive performance in a working memory task for emotional facial expressions, using the six basic emotions as stimuli in the delayed matching-to-sample, was evaluated in young women in different phases of the menstrual cycle. Our findings suggest that high levels of estradiol in the follicular phase could have a negative effect on delayed matching-to-sample working memory task, using stimuli with emotional valence. Moreover, in the follicular phase, compared to the menstrual phase, the percent of errors was significantly higher for the emotional facial expressions of sadness and disgust. The evaluation of the response times (time employed to answer) for each facial expression with emotional valence showed a significant difference between follicular and luteal in reference to the emotional facial expression of sadness. Our results show that high levels of estradiol in the follicular phase could impair the performance of working memory. However, this effect is specific to selective facial expressions suggesting that, across the phases of the menstrual cycle, in which conception risk is high, women could give less importance to the recognition of the emotional facial expressions of sadness and disgust. This study is in agreement with research conducted on non-human primates, showing that fluctuations of ovarian hormones across the menstrual cycle influence a variety of social and cognitive behaviors. Moreover, our data could also represent a useful tool for investigating emotional disturbances linked to menstrual cycle phases and menopause in women.     

Menstrual cycle influences on pain and emotion in women with fibromyalgia

OBJECTIVE: This study examined the influence of the menstrual cycle on pain and emotion in women with fibromyalgia (FM) as compared with women with rheumatoid arthritis (RA) and to healthy controls. METHODS: One hundred and twenty-five premenopausal women (21-45 years old) participated in this study (57 with FM, 20 with RA, and 48 controls). Pain and emotion assessments were conducted during the follicular and the luteal phases of the menstrual cycle. RESULTS: Women with FM experienced more pain, menstrual symptoms, and negative affect than did women with RA and the controls. All women reported less positive affect during the luteal phase, although this pattern was more pronounced in women with FM and RA than in controls. CONCLUSION: Although FM pain did not vary across the menstrual cycle, these results point to the importance of considering the lower level and cyclical nature of positive affect when studying women with chronic pain.     

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.     

Circadian rhythms, sleep, and the menstrual cycle

Women with ovulatory menstrual cycles have a circadian rhythm superimposed on the menstrual-associated rhythm; in turn, menstrual events affect the circadian rhythm. In this paper, we review circadian rhythms in temperature, selected hormone profiles, and sleep-wake behavior in healthy women at different phases of the menstrual cycle. The effects on menstrual cycle rhythmicity of disrupted circadian rhythms, for example, with shiftwork and altered circadian rhythms in women with menstrual-related mood disturbances, are discussed. Compared to the follicular phase, in the post-ovulation luteal phase, body temperature is elevated, but the amplitude of the temperature rhythm is reduced. Evidence indicates that the amplitude of other rhythms, such as melatonin and cortisol, may also be blunted in the luteal phase. Subjective sleep quality is lowest around menses, but the timing and composition of sleep remains relatively stable across the menstrual cycle in healthy women, apart from an increase in spindle frequency activity and a minor decrease in rapid eye movement (REM) sleep during the luteal phase. Disruption of circadian rhythms is associated with disturbances in menstrual function. Female shiftworkers compared to non-shiftworkers are more likely to report menstrual irregularity and longer menstrual cycles. There also is accumulating evidence that circadian disruption increases the risk of breast cancer in women, possibly due to altered light exposure and reduced melatonin secretion. Further investigations into the biological consequences of circadian disruption in women will offer insight into some menstrual-associated disorders, including mood changes, as well as reproductive function and possible links with breast cancer.     

Sex differences in cardiovascular stress responses: Modulation as a function of menstrual cycle phases

An experiment was conducted to study the effects of two laboratory stresses (unsignalled shock-avoidance reaction time and cold pressor tasks) on cardiovascular responses of young adult women during the follicular or the luteal phases of the menstrual cycle. A comparison group of male subjects, matched for family history of hypertension and for time between stress and rest sessions, was also tested. Results showed reduced cardiovascular responsiveness to the reaction time task (heart rate and blood pressure) for the women in the follicular phase of their cycle as compared with those in the luteal phase or with the males. Cardiovascular hyperresponsivity to this task has been previously related to familial history of hypertension. No differential changes were observed during the cold pressor test. These results are discussed in terms of possible hormonal effects on blood pressure regulation, and with respect to methodological considerations for assessing stress reactivity among women.     

Language lateralization and cognitive control across the menstrual cycle assessed with a dichotic-listening paradigm

Lateralization has been shown to vary across the menstrual cycle, however, the underlying mechanisms are not fully understood, and results are inconsistent. Additionally, it has been suggested that estradiol enhances cognitive control. By modulating attention in a consonant-vowel dichotic listening test, the current study aims to investigate the effects of cycle-related changes on language lateralization (non-forced condition), as well as the effects of estradiol-modulated cognitive control (forced left condition) on the ear advantage. Fifteen women and fifteen men tested three times on the dichotic listening test, women once in menstrual, follicular, and luteal phase (verified by hormone assays). Whereas the results from the non-forced and forced-right condition remained stable, results from the forced left condition changed across the cycle, where women in the follicular phase compared to both menstrual and luteal phases showed a stronger left ear advantage, i.e. better cognitive control performance. The increase in performance from menstrual to follicular phase correlated negatively with increase in estradiol levels, indicating a shift from a stimulus-driven right ear advantage (indicating a left hemispheric asymmetry for language) when estradiol levels were low toward a cognitively controlled left ear advantage when estradiol levels were high. This finding strongly suggests an active role of estradiol on cognitive control. The study further suggests that the degree of cognitive control demands of a given task is important to consider when investigating lateralization across the menstrual cycle.     

S-Citalopram in neuroendocrine challenge-tests: serotonergic responsivity in healthy male and female human participants

The aim of the present study was to assess the usefulness of the selective serotonin-reuptake-inhibitor S-Citalopram as a serotonergic challenge probe in 24 healthy male and 24 healthy female participants. The participants received a single oral dose of 10 and 20 mg of S-Citalopram in a placebo-controlled double blind crossover design. In female subjects phases of the menstrual cycle were controlled. Changes in concentrations of cortisol in saliva were used to indicate serotonergic reactivity. S-Citalopram induced a reliable dose dependent rise in cortisol concentrations. Results reveal a clear dose–response relationship in both sexes. However, in contrast to the 10 mg condition the dosage of 20 mg led to significantly higher cortisol levels in females, whereas no differences could be observed with respect to different phases of the menstrual cycle (follicular vs. luteal). Adverse side effects were reported only after 20 mg. The results clearly indicate that the dosage of 10 mg should be preferred when challenging males and females. Results will be discussed with regard to the further use of S-Citalopram in neuroendocrine challenge tests.     

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer''s disease

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.     

Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy

OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.     

Serum and CSF levels of IL-2, sIL-2R, TNF-alpha, and IL-1 beta in chronic progressive multiple sclerosis: expected lack of clinical utility

We measured interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) by ELISA in paired sera and CSF from 50 chronic progressive multiple sclerosis (CPMS) patients during worsening disability, 19 patients with other neurologic diseases (OND), and in sera from 40 healthy volunteers. In the CPMS patients, 28% (14/50), 10% (5/50), 16% (8/50), and 6% (3/50) had elevated serum levels of IL-2, sIL-2R, TNF-alpha and IL-1 beta, respectively, compared with healthy controls. The only analyte we detected in the CSF was IL-2 in 1 CPMS patient (1/50, 2%). We also saw elevated serum sIL-2R in 16% (3/19) of OND patients. We found no significant difference in mean levels of serum sIL-2R between the 3 groups. Our study, the largest to date of CPMS patients, shows that serum and CSF levels of IL-2, sIL-2R, TNF-alpha, or IL-1 beta are not sensitive for, and the serum sIL-2R level is not specific for, CPMS. Therefore, measurement of these analytes will not be clinically useful for therapeutic or prognostic purposes in the majority of CPMS patients.