Melinda Morgan

Progesterone metabolite allopregnanolone in women with premenstrual syndrome

Objective To evaluate the anxiolytic 3α-5α-reduced progesterone metabolite allopregnanolone in the luteal phase of the menstrual cycle in women with premenstrual syndrome (PMS) and controls. Methods Thirty-five women with prospectively documented PMS and 36 controls were evaluated. Serum progesterone and allopregnanolone levels were measured on days 19 and 26 of the cycle as determined by urinary LH detection kits. Analysis of variance and Student t tests were used to analyze the data. Results Allopregnanolone levels were significantly lower on day 26 in the PMS group than in controls (3.6 ± 0.8 versus 7.5 ± 1.3 ng/mL; P <.04). Significant differences in the ratio of the metabolite to progesterone also were noted, with a smaller ratio in the PMS subjects (0.9 ± 0.3 versus 3.2 ± 1.3 ng/mL; P <.05). There were no significant differences between the PMS and control groups with respect to serum progesterone levels. Conclusion Subjects with PMS manifested lower levels of the anxiolytic metabolite allopregnanolone in the luteal phase when compared with controls. Diminished concentrations of allopregnanolone in women with PMS may lead to an inability to enhance gamma aminobutyric acid-mediated inhibition during states of altered central nervous system excitability, such as ovulation or physiologic or psychological stress. The lowered metabolite levels could contribute to the genesis of various mood symptoms of the disorder, such as anxiety, tension, and depression.

Early changes in prefrontal activity characterize clinical responders to antidepressants.

Previous studies have shown that changes in brain function precede clinical response to antidepressant medications. Here we examined quantitative EEG (QEEG) absolute and relative power and a new measure, cordance, for detecting regional changes associated with treatment response. Fifty-one adults with unipolar depression completed treatment trials using either fluoxetine or venlafaxine vs. placebo. Data were recorded at baseline and after 48 h and 1 week on drug or placebo. Baseline and change from baseline values were examined for specific brain regions in four subject groups (medication and placebo responders and nonresponders). No regional baseline QEEG differences were found among the groups; there also were no significant changes in theta power over time. In contrast, medication responders uniquely showed significant decreases in prefrontal cordance at 48 h and 1 week. Clinical differences did not emerge until after four weeks. Subjects with greater changes in cordance had the most complete 8-week responses. These findings implicate the prefrontal region in mediating response to antidepressant medications. Cordance may have clinical applicability as a leading indicator of individual response.

Neuroimaging Evidence of Cerebellar Involvement in Premenstrual Dysphoric Disorder

BACKGROUND Premenstrual dysphoric disorder (PMDD) is a debilitating cyclic disorder that is characterized by affective symptoms, including irritability, depression, and anxiety, which arise in the luteal phase of the menstrual cycle and resolve soon after the onset of menses. Despite a prevalence of up to 8% in women of reproductive age, few studies have investigated the brain mechanisms that underlie this disorder. METHODS We used positron emission tomography with [(18)F] fluorodeoxyglucose and self-report questionnaires to assess cerebral glucose metabolism and mood in 12 women with PMDD and 12 healthy comparison subjects in the follicular and late luteal phases of the menstrual cycle. The primary biological end point was incorporated regional cerebral radioactivity (scaled to the global mean) as an index of glucose metabolism. Relationships between regional brain activity and mood ratings were assessed. Blood samples were taken before each session for assay of plasma estradiol and progesterone concentrations. RESULTS There were no group differences in hormone levels in either the follicular or late luteal phase, but the groups differed in the effect of menstrual phase on cerebellar activity. Women with PMDD but not comparison subjects showed an increase in cerebellar activity (particularly in the right cerebellar vermis) from the follicular phase to the late luteal phase (p = .003). In the PMDD group, this increase in cerebellar activity was correlated with worsening of mood (p = .018). CONCLUSIONS These findings suggest that the midline cerebellar nuclei, which have been implicated in other mood disorders, also contribute to negative mood in PMDD.

Cognitive functioning in premenstrual syndrome

Objective To evaluate cognitive functioning in women with premenstrual syndrome (PMS) and controls during the follicular and luteal phases of the menstrual cycle. Methods Thirty women with PMS and 31 controls were selected on the basis of psychiatric interview and prospective daily diary recordings. Subjects were tested on two occasions, follicular (days 8–10) and luteal (days 24–26), using complex tasks consisting of measures validated previously for the assessment of “executive” frontal-lobe functions. Tests were counterbalanced for order across subjects. Results The Beck Depression Inventory scores were significantly different between the groups and across time (P < .001). Women with PMS had a mean luteal phase Beck score of 13.3 consistent with mild-to-moderate premenstrual depression. There were no statistically significant score differences in tests for attention, memory, cognitive flexibility, and overall mental agility. The evaluation of our preliminary data with 30 PMS subjects and 31 controls indicated a very small effect size (.02). To detect an effect size this small (if in fact one exists) with a power of .8 would require a sample of more than 1000 subjects per group. Conclusion Our sample of women with PMS failed to demonstrate objective evidence of diminished cognitive performance, despite subjective feelings of inadequacy.

Clitoral and vulvar vestibular sensation in women taking 20 mcg ethinyl estradiol combined oral contraceptives: a preliminary study.

INTRODUCTION Many women taking low-dose (20 mcg) oral contraceptive pills (OCPs) complain of decreased libido and arousal and some develop vulvar vestibular pain and dyspareunia. Free testosterone concentrations are decreased by the OCP. Genital sensation has not been objectively measured in women taking OCPs. AIM We assessed whether the 20 mcg ethinyl estradiol combined OCP and associated decrease in free testosterone levels affected genital sensation in a pilot study of a group of asymptomatic OCP users and controls. METHODS Clitoral thermal, vibratory, and vestibular pain thresholds, sexual functioning, and free testosterone levels were measured in 24 women taking 20 mcg ethinyl estradiol combined OCPs and 28 comparison women not using hormonal contraception. MAIN OUTCOME MEASURES Female Sexual Functioning Index (FSFI), free testosterone, and clitoral heat, cold, and vibratory thresholds for sensation and vestibular pain thresholds. RESULTS Free testosterone levels were lower in OCP users. There were no differences in FSFI scores, clitoral thermal or vibratory thresholds, or vestibular pain thresholds between groups. CONCLUSIONS Low-dose (20 mcg) oral contraceptives decrease free testosterone but are not associated with alterations in clitoral or vestibular sensation. Further studies of genital sensation in women with OCP-related sexual dysfunction are warranted.

Neurophysiologic Correlates of Side Effects in Normal Subjects Randomized to Venlafaxine or Placebo

Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n=15) or venlafaxine IR (n=17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r=−0.67, p<0.003), at 2 weeks (r=−0.77, p<0.002), and at 4 weeks (r=−0.77, p<0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-in—prior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.

Peritoneal fluid interleukin-6 in women with chronic pelvic pain

OBJECTIVE To determine the relationship between peritoneal fluid concentrations of interleukin-6 (IL-6) and chronic pelvic pain symptomatology in women with adhesions, endometriosis, or no obvious intraperitoneal pathology. DESIGN Clinical research study. SETTING Healthy volunteers in an academic research environment. PATIENT(S) Reproductive-aged women undergoing laparoscopy for the diagnosis of pelvic pain, infertility, or sterilization were selected. INTERVENTION(S) Peritoneal fluid was collected at the time of the laparoscopy and later assayed for IL-6. Subjects completed a pelvic pain questionnaire, and operative reports were used to obtain the underlying diagnosis. MAIN OUTCOME MEASURE(S) Interleukin-6 concentrations. RESULT(S) No correlation between the presence or absence of pelvic pain, findings of adhesions or endometriosis, and the concentration of peritoneal fluid IL-6 was observed. CONCLUSION(S) The cytokine IL-6 does not seem to play a role in the genesis of chronic pelvic pain in women with adhesions or endometriosis.

Changes in Brain Function during Administration of Venlafaxine or Placebo to Normal Subjects

Previous research has demonstrated neurophysiologic effects of antidepressants in depressed subjects. We evaluated neurophysiologic effects of venlafaxine in normal subjects. Healthy adults (n=32) received a 1-week placebo lead-in followed by 4 weeks randomized double-blind treatment with venlafaxine IR 150 mg. (n = 17) or placebo (n = 15). Brain function was examined using quantitative electroencephalographic (QEEG) power and theta cordance. Normal subjects receiving venlafaxine showed a decrease in theta-band cordance in the midline-and-right-frontal (MRF) region at 48 hours and at 1 week after randomization. Decreases in relative power also were seen in the MRF region; there were no significant changes in absolute power. These changes were significantly different from those in subjects receiving placebo. Changes in MRF cordance accurately identified treatment condition at 48 hours in 81.3% of subjects, and relative power from this region identified 60.7% of subjects. In conclusion, cordance may detect the pharmacological effects of antidepressant medication in normal subjects. Future studies should examine other classes of medication, as well as antidepressants with other mechanisms of action, to determine if cordance detects antidepressant medication effects in general in normal subjects.

Influence of Age, Gender, Health Status, and Depression on Quantitative EEG

Quantitative electroencephalography (QEEG) has shown increasing utility in assessing brain function in clinical research studies of depression. QEEG findings may be influenced by a variety of factors other than the presence of depression, including age, gender, depression severity, and physical health status. Many of these factors have not been systematically evaluated. We therefore examined QEEG measures in 104 subjects with depression and normal controls to determine the influence of these factors. We examined QEEG power as well as cordance, a QEEG measure that has a stronger association with cerebral perfusion than conventional QEEG measures. Prefrontal cordance in the theta band has been associated with the pathophysiology of depression and response to treatment. We found that prefrontal cordance and relative power in the theta band were unaffected by age, gender, severity of depression, and health status, while prefrontal absolute power was higher in women than men. All of these measures were different from global measures of absolute and relative power, which were influenced by age, gender, and health status. These findings suggest that prefrontal cordance in depressed patients is not significantly affected by factors of age, gender, severity of depression, or physical illness. Global measures of power, and to a lesser extent prefrontal absolute power, must be interpreted with regard to confounding factors of age, gender, physical illness, and severity of depression.

Elevated gray matter volume of the emotional cerebellum in women with premenstrual dysphoric disorder.

OBJECTIVE Premenstrual dysphoric disorder (PMDD) is characterized by severe, negative mood symptoms during the luteal phase of each menstrual cycle. We recently reported that women with PMDD show a greater increase in relative glucose metabolism in the posterior cerebellum from the follicular to the luteal phase, as compared with healthy women, and that the phase-related increase is proportional to PMDD symptom severity. We extended this work with a study of brain structure in PMDD. METHODS High-resolution magnetic resonance imaging (MRI) scans were obtained from 12 women with PMDD and 13 healthy control subjects (whole-brain volume-corrected p<.05). Voxel-based morphometry was used to assess group differences in cerebral grey-matter volume (GMV), using a statistical criterion of p<.05, correcting for multiple comparisons in the whole-brain volume. RESULTS PMDD subjects had greater GMV than controls in the posterior cerebellum but not in any other brain area. Age was negatively correlated with GMV within this region in healthy women, but not in women with PMDD. The group difference in GMV was significant for women over age 30(p=.0002) but not younger participants (p>.1). CONCLUSIONS PMDD appears to be associated with reduced age-related loss in posterior cerebellar GMV. Although the mechanism underlying this finding is unclear, cumulative effects of symptom-related cerebellar activity may be involved.