A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria

The cause of premenstrual dysphoric disorder (PMDD) is largely unknown. It has been hypothesized that normal ovarian function triggers PMDD-related biochemical events within the brain and that serotonin plays an important role. In the present study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to examine serotonin 5-HT(1A) receptors in a control group of women and in a group of women with PMDD. Two PET examinations were performed in each subject, one before (follicular phase) and one after ovulation (luteal phase). Each subject's menstrual cycle was confirmed by ultrasonography of the ovaries as well as with hormone levels in blood and urine. The 5-HT(1A) binding potential was measured in six regions of interest and calculated according to the simplified reference tissue model. In the raphe nuclei, the 5-HT(1A) binding potential changed from the follicular to the luteal phase of the menstrual cycle in asymptomatic controls. In women with PMDD, the observed change between phases was significantly smaller. The results are in concordance with previously reported challenge studies of 5-HT(1A) receptor-mediated effects indicating different serotonergic responses between women with PMDD and controls. The study principally provides new support, in vivo, for a serotonergic dysregulation in women with PMDD.     

Treatment of premenstrual dysphoria with alprazolam. A controlled study

Thirty women who met DSM-III-R criteria for late luteal phase dysphoric disorder completed a double-blind, randomly assigned crossover treatment study comparing alprazolam with placebo. Alprazolam was found to be superior to placebo. The outcome measures included physicians' global ratings as well as patients' prospective (daily) ratings and retrospective assessments. Improved study design, which addressed methodologic flaws of most previous studies of treatment outcome of "premenstrual syndrome" may account, in part, for our ability to demonstrate significant drug/placebo differences. This includes extensive screening to eliminate women who had premenstrual exacerbations of a more persistent mental illness rather than a discrete premenstrual disorder, use of prospective ratings to confirm retrospective reports of symptom patterns, placebo washout before randomization, and use of patients as their own controls.     

Longitudinal sleep EEG, temperature, and activity measurements across the menstrual cycle in patients with premenstrual depression and in age-matched controls

After a 2-month evaluation period, eight women with moderate to severe premenstrual depression and eight age- and sex-matched controls underwent sleep electroencephalographic (EEG) and temperature recordings 2 nights a week over the course of one menstrual cycle. Overall, patients had more Stage 2 (%) sleep and less rapid eye movement (REM) sleep (% and minutes) than normal controls. Stage 3 sleep and number of intermittent awakenings varied with phases of the menstrual cycle. Temperature minima were earlier in patients compared with controls, but this difference was not statistically significant, and there was no significant effect of menstrual cycle phase on the timing of temperature minima. Wrist motor activity did not change during the menstrual cycle in patients or controls. Thus, in this sample of women with premenstrual depression, we did not find sleep EEG alterations similar to those reported in some patients with major depressive disorder. In light of the small number of subjects and the large individual variability, the absence of marked changes with the menstrual cycle may be a function of a Type II error.     

A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria

The cause of premenstrual dysphoric disorder (PMDD) is largely unknown. It has been hypothesized that normal ovarian function triggers PMDD-related biochemical events within the brain and that serotonin plays an important role. In the present study, positron emission tomography (PET) and [carbonyl-¹¹C]WAY-100635 were used to examine serotonin 5-HT_1A receptors in a control group of women and in a group of women with PMDD. Two PET examinations were performed in each subject, one before (follicular phase) and one after ovulation (luteal phase). Each subject's menstrual cycle was confirmed by ultrasonography of the ovaries as well as with hormone levels in blood and urine. The 5-HT_1A binding potential was measured in six regions of interest and calculated according to the simplified reference tissue model. In the raphe nuclei, the 5-HT_1A binding potential changed from the follicular to the luteal phase of the menstrual cycle in asymptomatic controls. In women with PMDD, the observed change between phases was significantly smaller. The results are in concordance with previously reported challenge studies of 5-HT_1A receptor-mediated effects indicating different serotonergic responses between women with PMDD and controls. The study principally provides new support, in vivo, for a serotonergic dysregulation in women with PMDD.     

Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles

BACKGROUND: Few studies have determined the impact of a lifetime history of major depression on an early transition to menopause. METHODS: Reproductive and psychiatric interviews and early follicular-phase blood specimens were obtained at study enrollment and every 6 months during 36 months of follow-up from 332 women with and 644 women without a history of major depression, 36 to 45 years of age. We used menstrual cycle markers to determine inception of perimenopause, defined as time from study enrollment to a follow-up interview with: (1) 7-day or more change in menstrual cycle length; (2) a change in menstrual flow amount or duration; or (3) amenorrhea lasting at least 3 months. RESULTS: Women with a history of depression had 1.2 times the rate of perimenopause of women with no such history (95% confidence interval, 0.9-1.6). Compared with nondepressed women, depressed women with more pronounced depressive symptoms at study enrollment (Hamilton Rating Scale for Depression scores >8) had twice the risk of an earlier perimenopausal transition. Among the women with greater depressive symptoms (Hamilton scores >8), those who also reported use of antidepressants had nearly 3 times the risk of an earlier perimenopausal transition (hazard ratio, 2.7; 95% confidence interval, 1.5-4.8) of nondepressed women. Women with a lifetime history of depression also had higher follicle-stimulating hormone and luteinizing hormone levels and lower estradiol levels at study enrollment and during the follow-up period after adjustment for covariates. CONCLUSION: A lifetime history of major depression may be associated with an early decline in ovarian function.     

Panic disorder and the menstrual cycle: panic disorder patients, healthy control subjects, and patients with premenstrual syndrome

The authors prospectively evaluated 20 normally menstruating women with panic disorder across a minimum of two drug-free menstrual cycles. There were no significant effects of menstrual cycle phase on anxiety ratings in the panic disorder patients or in 20 healthy control subjects; this contrasted with a robust increase in premenstrual anxiety in 20 subjects with premenstrual syndrome. These findings suggest that the symptoms of panic disorder are not commonly exacerbated by the premenstrual phase of the menstrual cycle and highlight the need for prospective evaluation in the attempt to document an association between psychiatric symptoms and the menstrual cycle.     

Hashimoto's encephalopathy: exacerbations associated with menstrual cycle

The authors report a patient who had five relapses of encephalopathy with seizures and aseptic meningitis that coincided with the end of the menstrual cycle. High titers of antithyroid antibodies and the patient's response to corticosteroids suggested Hashimoto's encephalopathy. Pharmacologic suppression of the menstrual cycle made it possible to withdraw corticosteroids.     

Treatment of premenstrual depression with nortriptyline: a pilot study

There are no reports on treatment of premenstrual syndrome with antidepressants, although depression is a common symptom of the syndrome. Eleven women who met DSM-III-R criteria for late luteal phase dysphoric disorder were treated with nortriptyline in an open pilot study after they failed to respond to placebo or another medication. Eight of 11 patients had a good therapeutic response. The efficacy of antidepressants in the treatment of premenstrual depression needs confirmation with double-blind studies.     

Nocturnal polysomnographic sleep across the menstrual cycle in premenstrual dysphoric disorder

ObjectivesWomen with premenstrual dysphoric disorder (PMDD) experience disturbed mood, altered melatonin circadian rhythms, and frequent reports of insomnia during the luteal phase (LP) of their menstrual cycle. In this study we aimed to investigate nocturnal polysomnographic (PSG) sleep across the menstrual cycle in PMDD women and controls.MethodsSeven PMDD women who indicated insomnia during LP, and five controls, spent every third night throughout a complete menstrual cycle sleeping in the laboratory.ResultsIn PMDD and controls progesterone and core body temperature (BT_core) were elevated during LP compared to the follicular phase (FP). Stage 2 sleep showed a significant main effect of menstrual phase and was significantly increased during mid-LP compared to early-FP in both groups. Rapid eye movement (REM) sleep for both groups was decreased during early-LP compared to early-FP. Slow wave sleep (SWS) was significantly increased, and melatonin significantly decreased, in PMDD women compared to controls.ConclusionsPMDD women who experience insomnia during LP had decreased melatonin secretion and increased SWS compared to controls. The sleep and melatonin findings in PMDD women may be functionally linked. Results also suggest an altered homeostatic regulation of the sleep–wake cycle in PMDD, perhaps implicating melatonin in the homeostatic process of sleep–wake regulation.     

The psychobiology of premenstrual dysphoria: the role of prolactin

(1) The evidence for a role of prolactin in the premenstrual syndrome is discussed in this review. (2) The timing of the onset and offset of both physical and psychological dysphoric symptoms corresponds with the luteal elevation and menstrual decrease of serum prolactin levels. (3) Women with premenstrual symptoms have been shown to have high prolactin levels throughout the menstrual cycle and especially in the premenstruum. (4) Suppression of prolactin secretion with bromocriptine is reported to be effective in preventing both physical and psychological premenstrual symptoms. (5) The mode of action of bromocriptine requires further study to exclude possible direct central nervous system effects of the drug, independent of its prolactin-suppressing action. (6) Indirect evidence for a role of prolactin in the premenstrual syndrome comes from (a) the actions of prolactin in causing renal retention of water, sodium and potassium; (b) the interactions of prolactin with lithium (which is reported to relieve premenstrual symptoms in some patients); some of the other reported treatments also may suppress prolactin secretion or antagonize its peripheral effects. (7) Prolactin may interact with the ovarian hormones to cause specific types of dysphoric symptoms. High prolactin levels associated with low estrogen levels may cause depressive symptoms. High prolactin levels associated with low progesterone levels may cause symptoms of anxiety or irritable hostility. (8) Interactions of prolactin with the ovarian hormones may also help to account for some related clinical states—mid-cycle mood elevations, elation in late pregnancy, postpartum depression and dysphoric menopausal symptoms.     

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.     

The psychobiology of premenstrual dysphoria: review of theories and treatments

(1) Premenstrual mood changes such as depression, elation, anxiety, hostility and irritability are a common cause of disability in women. (2) The nature of the disorder, the clinical dimensions, the incidence, the psychological and psychosocial theories are reviewed. (3) A long list of treatments recommended over the years is also reviewed and discussed, illustrating the ambiguity and uncertainty in this area. (4) The relationship to other periodic functional conditions, especially manic-depressive illness is discussed with particular emphasis on predictive studies. (5) The psychoneuroendocrine mechanisms possibly involved in these premenstrual conditions are reexamined. A specific role for prolactin in the etiology of these premenstrual dysphoric states is suggested.     

Autonomic arousal and pain sensitivity in women with premenstrual syndrome at different phases of the menstrual cycle

Eleven women with a clinical diagnosis of premenstrual syndrome (PMS) and ten non-PMS control women were compared on physiological measures in the intermenstrual and premenstrual phases of their menstrual cycle. Heart rate (HR) and skin conductance level (SCL) were monitored during baseline conditions and in response to a stressful laboratory procedure. Analyses for HR revealed a three-way interaction (groups X phase X tests) which approached significance indicating that the PMS group was generally lower during the intermenstrual testing but was higher in the premenstrual phase. No significant differences were observed on behavioral measures (pain threshold, pain tolerance) between the groups. Pain intensity ratings were found to be overall higher in the PMS group irrespective of menstrual cycle phase. The role of cognitive-perceptual processes is discussed in the context of the acquisition and maintenance of PMS symptomatology.     

Effects of the menstrual cycle on measures of personality in women with premenstrual syndrome: a preliminary study.

BACKGROUND: Previous studies suggest that women with premenstrual syndrome (PMS) differ from those without PMS in measures of personality. The purpose of this study was to measure the effect of menstrual cycle phase on personality variables in women with and without PMS. METHOD: The Personality Diagnostic Questionnaire-Revised (PDQ-R) was administered in both the follicular and luteal phases to women with PMS (according to National Institute of Mental Health PMS Workshop Diagnostic Guidelines) (N = 40). An asymptomatic control group (N = 20) as well as a symptomatic group of women with DSM-IV-diagnosed recurrent, non-menstrual-cycle-related brief depression (N = 20) also completed the questionnaire in both phases. RESULTS: Only women with PMS demonstrated a significant increase in total PDQ-R score (reflecting overall personality disorder) from the follicular to the luteal phase (p < .01). Women with PMS had significantly higher total PDQ-R scores than the asymptomatic controls during both the follicular (p < .05) and luteal (p < .01) phases, whereas there was no significant difference between women with PMS and symptomatic controls during either phase. Subscale scores fit similar patterns, as did the number of women in each group meeting a cutoff score indicative of the presence of personality dysfunction. CONCLUSION: In this preliminary study, women with PMS were unique in demonstrating a menstrual cycle phase effect on PDQ-R score, while their scores in both phases were closer to symptomatic controls than asymptomatic controls. These findings suggest that personality disorder in women with PMS may have both state- and trait-related components.     

Provocation of panic with carbon dioxide inhalation in patients with premenstrual dysphoria

The effects of double breath inhalation of a 35% CO2 mixture in oxygen and placebo air inhalation were compared in 14 women seeking treatment for marked premenstrual dysphoric changes who did not have panic disorder and 12 control women. The first exposure to CO2 inhalation induced a panic attack reaction (severe subjective anxiety with autonomic symptoms) in 9 of 14 women with premenstrual dysphoria but none of the controls. Neither patients nor controls panicked in response to the air inhalation. Control subjects experienced mild anxiety and/or somatic symptoms after CO2 inhalation, but these did not resemble panic attacks and were clearly different from the response of the patient group.     

Brain-derived neurotrophic factor plasma variation during the different phases of the menstrual cycle in women with premenstrual syndrome

Premenstrual syndrome (PMS) is characterized by a cluster of psychological and somatic symptoms that begin during the late luteal phase of the menstrual cycle and disappear after the onset of menses. Since PMS might be caused by an alteration in the cyclical hormonal modifications and ovarian steroids are directly involved in the regulation of mood, affective and cognitive functions and influence neurotrophins expression, in particular the brain-derived neurotrophic factor (BDNF), we aimed to evaluate whether plasma BDNF levels in women with PMS differ from those of normally menstruating women without PMS. Sixty-two women were divided into two groups: one group of women (n=35) with PMS and one group (n=27) composed by normally menstruating women. Plasma samples were collected at day 7 (follicular phase) and day 21 (luteal phase) of the menstrual cycle. Plasma BDNF of the control group significantly increased (p<0.001) from the follicular phase (402.90±74.41pg/ml) to the luteal phase (1098.79±146.49pg/ml). On the other hand, in the PMS group plasma BDNF levels significantly decreased (p<0.001) from the follicular phase (412.45±78.35pg/ml) to the luteal phase (233.03±75.46pg/ml) Luteal BDNF levels of the PMS women were significantly lower than those of the control group (p<0.001). In women with PMS, plasma BDNF followed a decreasing trend during the ovarian cycle, in opposition to the increasing trend observed in women without PMS. The lower luteal BDNF levels of the PMS women might be a consequence of an altered hormonal response and might play a role in the onset of the symptoms PMS related.     

The menstrual cycle in context, I: Affective syndromes associated with reproductive hormonal changes

In some women, mood and behavioral changes appear to be linked to the menstrual cycle. New basic science data on steroid-brain interactions have renewed interest in the menstrual cycle as a naturalistic model for assessing gonadal steroid-induced mental and behavioral changes. The authors investigate similarities and differences in affective symptoms associated with reproductive-related gonadal steroid changes that span the life cycle of women, including the menstrual cycle, oral contraceptive use, pregnancy, the postpartum period, and perimenopause. Recommendations for reporting of symptoms and implications for future research are discussed.