Treatment of premenstrual tension with lithium carbonate – A PILOT STUDY

Some previous reports have suggested that lithium treatment is of benefit to women with the premenstrual tension syndrome (PMTS). In this study 15 women carefully selected for severe PMTS were given lithium carbonate (600–900 mg/day) continuously for three menstrual cycles. Lithium did not affect physical premenstrual symptoms and was ineffective in most women against behavioral premenstrual symptoms. Despite the low dosage most women also experienced significant drug-related side effects. Although a statistically significant improvement was recorded by several symptom rating instruments, this benefit was of no practical clinical value. The three women who responded best to lithium, and who requested continued treatment beyond 3 months, met diagnostic criteria for subsyndromal affective (cyclothymic) disorder. Lithium is not recommended for the average woman with PMTS.     

Menstrual cycle-related brain metabolite changes using 1H magnetic resonance spectroscopy in premenopausal women: a pilot study

Proton magnetic resonance spectroscopy (1H-MRS) was used to assess neurochemical brain changes across the menstrual cycle in five women with premenstrual dysphoric disorder (PMDD) and six control subjects. Women with PMDD and control subjects were scanned on days 8 and 26 within one menstrual cycle (i.e. at times of complete absence and height of PMDD symptoms, respectively). The point resolved spectroscopic sequence (PRESS) was used to localize a voxel of 8 ml in the medial frontal gray matter and in the occipito-parietal white matter. The ratio of N-acetyl-aspartate to creatine in the region of the medial prefrontal cortex and the cingulate gyrus declined significantly from the follicular to the luteal phase in both groups of subjects. The menstrual phase-dependent significant increase in the ratio of choline to creatine was observed in the parietal white matter. The myo-inositol/creatine ratio exhibited a trend toward higher levels in the PMDD patients in the luteal phase of the menstrual cycle. Differences between PMDD and control subjects were not statistically significant. Menstrual cycle phase-dependent changes in ovarian hormonal concentrations may influence the neurochemistry of brain activity in premenopausal women.     

Urinary 6-sulphatoxy melatonin levels within the menstrual cycle and in patients with premenstrual syndrome

The present investigation examined the production of urinary 6-sulphatoxy melatonin (aMT.6S) during the early follicular and late luteal (premenstrual) phases in healthy, normal women and in patients with premenstrual syndrome (PMS). There was no significant difference in levels of aMT.6S on either day 6 or 26 of the menstrual cycle between control subjects and those with PMS. There also was no significant change in urinary aMT.6S levels within the menstrual cycle. These findings do not support an involvement of melatonin in the development of PMS symptomatology and are not supportive of the proposed role of melatonin in regulating ovulation in humans. However, our analysis of 12-hr urine samples may have been insensitive to small, yet possibly biologically significant, changes in the amplitude and period of melatonin excretion during the early hours of the morning.     

Ovarian morphology in premenstrual dysphoria

Ovarian cyclicity is a prerequisite for premenstrual dysphoria (PMD), as illustrated by the fact that this condition is effectively eliminated by ovariectomy or by treatment with a GnRH agonist. Despite the possibility of differences in ovarian function between women with and without PMD, no study comparing ovarian morphology in these two groups has ever been published. Fifty-two women were recruited for this study; 26 had premenstrual dysphoria, fulfilling criteria slightly modified from those of the premenstrual dysphoric disorder, and 26 were asymptomatic age-matched controls. Ovarian morphology was assessed using transvaginal 7 MHz ultrasonography on day 5 after the start of menses, and venous blood was sampled for hormone analysis on days 3 and 8, the expected day of ovulation, and day -4 of the menstrual cycle. There were no significant differences between the groups with respect to the prevalence of polycystic ovaries (PCO), the total number of follicles, the total ovarian volume or serum levels of androgen hormones. In addition, serum free testosterone levels in late premenstrual phase showed an inverse association to premenstrual symptoms of irritability and a similar inverse association trend to symptoms of depressed mood. Unexpectedly, the prevalence of ovaries with fewer than five antral or growing follicles was significantly higher in women with PMD than in controls (p=0.016). While the results do not support a role for PCO or androgen hormones in eliciting late luteal phase irritability, the possible relationship between oligofollicular ovaries and PMD deserves further study.     

Luteal serum BDNF and HSP70 levels in women with premenstrual dysphoric disorder

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome characterized by psychological and somatic symptoms commencing in the luteal phase of the menstrual cycle and concludes with menstrual bleeding. PMDD affects 3–8 % of premenopausal women and represents a significant public health problem especially in young women. Decreased brain-derived neurotrophic factor (BDNF) levels are associated with several mental disorders. Heat-shock protein-70 (HSP70) is an important member of the molecular chaperone system, which provides a molecular defense against proteotoxic stress. We hypothesized that there would be changed levels of BDNF and HSP70 in women with PMDD compared with non-symptomatic women, reflecting impaired and/or activated stress-related responses involved in the underlying pathogenesis of PMDD. Female medical students were screened, and 24 women without premenstrual symptoms and 25 women with PMDD were enrolled in the study. Psychiatric evaluation and the Daily Record of Severity of Problems-Short Form were used for two consecutive menstrual cycles to diagnose PMDD. Serum BDNF and HSP70 levels were assessed in the third luteal phase. Participants with PMDD had significantly higher serum BDNF and HSP70 levels compared with controls, and there was a significant positive correlation between serum BDNF and HSP70 levels. Increased HSP70 levels may reflect cellular distress in PMDD. Increased serum BDNF levels in the luteal phase in subjects with PMDD may reflect a compensation process, which results in subsequent improvement of PMDD-associated depressive symptoms in the follicular phase. Thus, increased serum BDNF levels may be indicative of a compensating capacity in PMDD.     

Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression

The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.     

Late luteal phase dysphoric disorder in young women

The authors determined the prevalence of late luteal phase dysphoric disorder in 217 university women aged 17-29 years. Unaware of the focus on premenstrual syndrome (PMS), the participants rated DSM-III-R symptoms of late luteal phase dysphoric disorder over 90 days. Using a 30% or greater premenstrual change as an index of luteal variation, the authors found that 10 women (4.6%) met the symptom criteria during two menstrual cycles. Compared to 25 young women seeking treatment for PMS who met the same diagnostic criteria, the 10 women from the university sample reported significantly less fatigue and impaired concentration and somewhat less severe depression and overall symptoms.     

Sympathetic skin response in premenstrual syndrome

Abstract Premenstrual syndrome is a term which includes a broad group of emotional, behavioral and physical symptoms that occur for several days before menses and subside following the menstrual period. Many women experience premenstrual syndrome symptoms, particularly physical ones such as breast tenderness and swelling. Approximately 5–10% women suffer from severe premenstrual syndrome and another 30–40% have moderate symptoms. Premenstrual syndrome continues to be an unsolved problem.In this study, we evaluated 24 premenstrual syndrome patients and 20 healthy women in the control group. The ages of the women were 22–34 years (mean ± SD: 25±3) for the premenstrual syndrome group and 23–34 (25±3) for the control group. The sympathetic skin response was recorded from the palms, soles and genital regions by using electrical stimuli to the median nerve at the wrist.The sympathetic skin response was recorded twice, in the follicular and late luteal phases of menstruation.The follicular and late luteal phase sympathetic skin response of the two groups were compared. The amplitudes and latency values of the late luteal and follicular phase sympathetic skin response from the premenstrual syndrome group and control group women were statistically similar. We also did not find any latency or amplitude difference in the sympathetic skin response obtained from the three regions of the premenstrual syndrome patients and the control group.We checked sympathetic skin response in the symptomatic (late luteal phase) and asymptomatic (follicular phase) periods of patients with premenstrual syndrome, a disorder known to have many autonomic symptoms, to determine whether there was sudomotor sympathetic involvement.The results of our PMS patients indicate at the very least that there is no difference with the control subjects as regards peripheral sudomotor functions.     

Premenstrual tension syndrome: The development of research diagnostic criteria and new rating scales

Research diagnostic criteria for premenstrual tension syndrome (PMTS) are developed using data collected from a study of 42 women who were suffering from severe PMTS but were well at other times. Two specific scales are also devised for rating the severity of PMTS, a 36-item self-report questionnaire and a 10-item scale for use by therapist/researcher. It is proposed that after further evaluation and validation, these instruments may permit more useful comparisons of data on the etiology and treatment of this disorder.     

Serotonergic dysfunction in women with pure premenstrual dysphoric disorder: is the fenfluramine challenge test still relevant?

The fenfluramine (FEN) neuroendocrine challenge paradigm, which involves measuring the response of prolactin (PRL) release to an oral challenge dose of FEN, provides a means of assessing serotonin (5-HT) function. The purpose of this study was to ascertain the role of 5-HT in premenstrual dysphoric disorder (PMDD) by measuring: (1) PRL and cortisol (CORT) responses to FEN; and (2) platelet 3H-imipramine binding levels, in females with pure PMDD (without a past or present comorbid mood disorder) in comparison to healthy controls. FEN challenge tests were administered to nine female patients with pure PMDD and nine healthy female controls during the follicular and late luteal phases of a menstrual cycle. There were no differences in the PRL response to FEN for women with PMDD compared to healthy controls. However, the trend toward a delayed response to FEN and a significant negative correlation between delta(max) PRL and basal CORT in patients but not in controls during both phases of the menstrual cycle suggest an underlying 5-HT dysfunction in patients as compared to controls. This is further supported by the finding of significantly lower Bmax 3H-imipramine binding levels in the patients during the late luteal phase.     

A comparison of the Tridimensional Personality Questionnaire in premenstrual dysphoric disorder and major depressive disorder

OBJECTIVE: Numerous symptoms of premenstrual dysphoric disorder (PMDD) overlap with those of major depressive disorder (MDD). This study investigates differences in novelty seeking, harm avoidance, and reward dependence between patients with PMDD, MDD without premenstrual symptoms or premenstrual exacerbation, and normal control subjects. METHOD: The Chinese version of the Tridimensional Personality Questionnaire was administered to 51 PMDD, 39 MDD, and 52 normal control women during the luteal phase (between the menstrual cycle days 23 and 28). RESULTS: Harm avoidance score was significantly higher in women with MDD and PMDD than in controls, whereas reward dependence score was lower in women with MDD than in controls. However, Tridimensional Personality Questionnaire (except for the subscale of impulsiveness) did not distinguish between PMDD and MDD during the luteal phase. CONCLUSION: The similarities between PMDD and MDD during luteal phase suggest a similar psychopathology.     

High nocturnal body temperature in premenstrual syndrome and late luteal phase dysphoric disorder

OBJECTIVE: Because women with late luteal phase dysphoric disorder (LLPDD) experience symptomatic affective states predictably, they can be studied to determine whether there are biological findings related solely to the clinically symptomatic state. The authors sought to answer the question, Does body temperature change with affective state? METHOD: The core body temperature and motor activity patterns of 10 women with premenstrual syndrome (PMS), six of whom also met criteria for LLPDD, and no other psychological or medical illness were compared to those of six women with chronic, noncyclic dysphoria and six asymptomatic comparison women at four phases of the menstrual cycle. RESULTS: The nocturnal temperatures of the women with PMS/LLPDD were significantly higher than those of the comparison subjects across the entire menstrual cycle, but there were no differences in nocturnal activity levels. The women with noncyclic dysphoria had a mean nocturnal temperature in the follicular phase as high as that of the women with PMS/LLPDD. The temperatures of all women were higher in the luteal phase than in the follicular phase. CONCLUSIONS: These findings suggest that in the future investigators should document menstrual cycle phase in all female subjects and, when studying body temperature, should carefully monitor symptomatic state in comparison subjects.     

The effect of a low dose of alcohol on allopregnanolone serum concentrations across the menstrual cycle in women with severe premenstrual syndrome and controls

BACKGROUND: Neurosteroids have been proposed to play an important role in the interaction between alcohol and GABA(A) receptors and for the symptomatology of premenstrual dysphoric disorder (PMDD). The primary aim of this study was to investigate possible alcohol-induced changes in allopregnanolone serum concentrations across different menstrual cycle phases in women with severe premenstrual syndrome (PMS) and controls. METHODS: The allopregnanolone and cortisol responses to a low-dose of alcohol were evaluated in 14 women with and 12 women without severe premenstrual syndrome in the follicular and late luteal phases. The effect of a 30-min intravenous alcohol infusion (0.2 g/kg) on allopregnanolone and cortisol serum concentrations was compared to placebo, and compared between cycle phases and groups. Blood samples for measuring allopregnanolone were taken at baseline 25, 55, and 75 min after the start of the alcohol infusion. RESULTS: In the late luteal phase, the alcohol infusion decreased allopregnanolone levels, compared to baseline levels as well as to placebo. The difference in allopregnanolone levels between alcohol and placebo was evident 25 min (P < 0.01), 55 min (P < 0.01), and 75 min (P < 0.05) after start of the infusion. There was no change in allopregnanolone levels during the alcohol infusion in the follicular phase. Also, no difference in alcohol-induced allopregnanolone response between PMS patients and control subjects was detected. Cortisol levels declined during both the placebo and alcohol infusion, but did not differ with respect to which infusion had been given. CONCLUSION: During the late luteal phase, independent of PMS diagnosis, the low-dose alcohol infusion resulted in decreasing peripheral allopregnanolone levels.     

Serum levels of androgens are higher in women with premenstrual irritability and dysphoria than in controls.

Serum levels of progesterone, total testosterone, free testosterone, androstenedione (A2), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), 17-OH-progesterone (17-OHP), and sex hormone binding globulin (SHBG) were measured in the follicular phase, around ovulation, and in the luteal phase of 11 women with severe premenstrual irritability and dysphoria and in 11 age-matched controls with no premenstrual complaints. Serum levels of free testosterone were significantly higher in the subjects with premenstrual syndrome (PMS) than in the controls in the luteal phase (p < 0.01), the follicular phase (p < 0.05), and around ovulation (p < 0.01). DHEA levels were significantly higher in the PMS subjects, as compared to controls, around ovulation (p < 0.05), while 17-OHP levels were higher in the PMS women in the luteal phase (p < 0.05). With respect to the other steroids measured, as well as SHBG, no differences between PMS subjects and controls were found. These results indicate a possible involvement of androgens in the pathophysiology of premenstrual irritability and dysphoria.     

Response to flumazenil in women with premenstrual dysphoric disorder

OBJECTIVE: The authors sought to determine whether the administration of flumazenil would induce marked panic symptoms in women suffering from premenstrual dysphoric disorder. METHOD: Ten women with premenstrual dysphoric disorder and 11 comparison subjects were injected with flumazenil or placebo in a double-blind, randomized, balanced crossover design in a single session in the luteal phase of their menstrual cycles. RESULTS: Flumazenil induced a much greater panic response in the women with premenstrual dysphoric disorder than in the comparison subjects. CONCLUSIONS: These preliminary results are consistent with a dysregulation of the g-aminobutyric acid A/benzodiazepine receptor complex during the premenstruum of women suffering from premenstrual dysphoric disorder.     

A preliminary study of luteal phase versus symptom-onset dosing with escitalopram for premenstrual dysphoric disorder

OBJECTIVE: This preliminary study compared the efficacy and tolerability of escitalopram administered at symptom onset or throughout the luteal phase in premenstrual dysphoric disorder (PMDD). METHOD: Twenty-seven women meeting DSM-IV criteria for PMDD were randomly assigned in a double-blind manner to luteal phase (N = 13) or symptom-onset (N = 14) dosing of escitalopram (10-20 mg/day) for 3 consecutive menstrual cycles. Participants were enrolled from November 2002 to July 2003, and data collection was completed in December 2003. Symptoms were assessed using the 17-item Penn Daily Symptom Report (DSR), the Clinical Global Impressions-Improvement scale, the Hamilton Rating Scale for Depression, and the Sheehan Disability Scale. Scores were compared using repeated measures analysis of covariance and t statistics. RESULTS: Luteal phase and symptom-onset groups received escitalopram for a mean of 13.5 and 6.0 days, respectively (mean +/- SD dose = 15.2 +/- 5.1 mg/day at the third treatment cycle). Total premenstrual DSR scores significantly improved from baseline (p = .003), with a 57% decrease in the luteal phase group and a 51% decrease in the symptom-onset group. Clinical improvement (DSR score decrease > or = 50% from baseline) was reported by 11 of 13 patients in the luteal phase group and 9 of 14 patients in the symptom-onset group. Symptom severity differentiated the response in the symptom-onset group, with those having more severe symptoms less likely to respond. Symptom severity did not differentiate treatment response to luteal phase dosing. Escitalopram was well tolerated. Adverse events were mild and transient, with only 2 patients discontinuing due to adverse events related to the medication. CONCLUSION: Premenstrual dysphoric disorder improved significantly with either luteal phase or symptom-onset dosing of escitalopram. Women with more severe PMDD may respond better to luteal phase dosing than symptom-onset dosing.     

Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

BACKGROUND: In this study we extended previous work by examining whether disturbances in the circadian rhythms of cortisol during the menstrual cycle distinguish patients with premenstrual dysphoric disorder (PMDD) from normal control (NC) subjects. In addition, we tested the differential response to the effects of early and late partial sleep deprivation on cortisol rhythms. METHODS: In 15 PMDD and 15 NC subjects we measured cortisol levels every 30 min from 6:00 PM to 9:00 AM during midfollicular (MF) and late luteal (LL) menstrual cycle phases and also during a randomized crossover trial of early (sleep 3:00 AM-7:00 AM) versus late (sleep 9:00 PM-1:00 AM) partial sleep deprivation administered in two subsequent and separate luteal phases. RESULTS: In follicular versus luteal menstrual cycle phases we observed altered timing but not quantitative measures of cortisol secretion in PMDD subjects, compared with NC subjects: in the LL versus MF phase the cortisol acrophase was a mean of 1 hour earlier in NC subjects, but not in PMDD subjects. The effect of sleep deprivation on cortisol timing measures also differed for PMDD versus NC subjects: during late partial sleep deprivation (when subjects' sleep was earlier), the cortisol acrophase was almost 2 hours earlier in PMDD subjects. CONCLUSIONS: Timing rather than quantitative measures of cortisol secretion differentiated PMDD subjects from NC subjects both during the menstrual cycle and in response to early versus late sleep deprivation interventions.     

Estrogen affects cognition in women with psychosis

Estrogen has been reported to affect aspects of cognition and psychopathology in women, both normal and with psychosis. This study aimed to replicate and extend this research by investigating the effect of estrogen on cognition over the menstrual cycle in a group of normal women and women with psychosis. The sample consisted of 31 premenstrual normal control subjects, and 29 women with psychosis. Subjects were tested twice, 2 weeks apart on a number of cognitive tests. There was no difference in Positive and Negative Symptom Scale scores between the follicular and luteal phases of the menstrual cycle. Both groups of women performed better on the Revised Mental Rotation Test and Trails A during the follicular phase when estrogen levels were low. Contrary to expectation, during the luteal phase, when estrogen was high, the control subjects showed no significant improvement in performance on verbal articulatory-motor tasks, and the women with psychosis performed significantly worse on the Purdue Pegboard. The unexpected adverse effect of high levels of estrogen on motor performance in the psychotic women was hypothesized to be related to their disease process.     

Prolactin responses to haloperidol in normal young women

The prolactin (PRL) responses to intramuscular haloperidol (HPD) (0.5, 1.0, and 1.5 mg) were evaluated in six normal premenopausal women during the follicular and luteal phases of their menstrual cycles. These were compared to the PRL responses to these doses of HPD in normal young men. PRL responses to HPD did not differ between the follicular and luteal phases. The mean log-transformed PRL response to the lowest HPD dose (0.5 mg) in women was less than that in the men, but the women had greater PRL responses than the men to the higher haloperidol doses (1.0 mg and 1.5 mg).     

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.