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.     

Serotonin-1A receptors in frontotemporal dementia compared with controls

Using PET neuroimaging, we demonstrated that four frontotemporal lobar dementia (FTLD) patients had significantly decreased serotonin 5-HT_1A binding potential (BP) compared with controls in all 10 brain regions examined. These pilot data suggest that profound 5-HT_1A BP losses may be present and contribute to symptomatology and treatment response in FTLD.     

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.     

Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding

Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).     

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.     

Patients with premenstrual dysphoric disorder have increased startle modulation during anticipation in the late luteal phase period in comparison to control subjects

The acoustic startle response (ASR) is a withdrawal reflex to sudden or noxious auditory stimuli and, most importantly, an unbiased measure of emotional processing of appetitive and aversive stimuli. By exposing subjects to fearful situations, such as aversive pictures, the ASR may be enhanced, suggesting that amygdala modulates the startle circuit during threat situations. As one previous study, investigating affective modulation of the ASR in women with premenstrual dysphoric disorder (PMDD), discovered no difference during picture viewing it is possible that the mood changes observed in PMDD relate to anxious anticipation rather than to direct stimulus responding. Hence we sought to examine the effects of PMDD on picture anticipation and picture response. Sixteen PMDD patients and 16 controls watched slide shows containing pleasant and unpleasant pictures and positive and negative anticipation stimuli during the follicular and luteal phase of the menstrual cycle. Simultaneously, semi-randomized startle probes (105 dB) were delivered and the ASR was assessed with electromyography. Compared with control subjects, PMDD patients displayed an enhanced startle modulation by positive and negative anticipation stimuli in the luteal phase of the menstrual cycle. This finding was mainly driven by increased modulation in the luteal phase in comparison to the follicular phase among PMDD patients but also by an increased modulation in patients compared to controls during luteal phase. This suggests that the neural circuits underlying response to emotional anticipation are more sensitive during this period and emphasize the need of examining the neural correlates of anticipatory processes in women with PMDD.     

Heart rate variability in premenstrual dysphoric disorder

Measuring heart rate variability (HRV) is a way to assess the autonomic regulation of the heart. Decreased HRV, indicating reduced parasympathetic tone, has previously been found in depression and anxiety disorders. The objective of this study was to assess HRV in women with premenstrual dysphoric disorder (PMDD). To this end, time domain variables and frequency domain variables were assessed in 28 women with PMDD and in 11 symptom-free controls during both the symptomatic luteal phase and the non-symptomatic follicular phase of the menstrual cycle. Two variables reflecting vagal activity in the time domain, the root mean square of differences of successive normal RR intervals (rMSSD) and standard deviation of normal RR intervals (SDNN) were lower in PMDD patients, but this difference was statistically significant in the follicular phase only. The most important vagal measure in the frequency domain, supine high frequency (HF), also appeared lower in PMDD subjects during the follicular phase. It is suggested that PMDD may be associated with reduced vagal tone compared to controls and that this difference is most apparent in the non-symptomatic follicular phase of the menstrual cycle.     

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.     

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.     

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.     

Binding of [3H]paroxetine to serotonin uptake sites and of [3H]lysergic acid diethylamide to 5-HT2A receptors in platelets from women with premenstrual dysphoric disorder during gonadotropin releasing hormone treatment

Changes in serotonergic parameters have been reported in psychiatric conditions such as depression but also in the premenstrual dysphoric disorder (PMDD). In addition, hormonal effects on serotonergic activity have been established. In the present study, binding of [3H]paroxetine to platelet serotonin uptake sites and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors were studied in patients with PMDD treated with a low dose of a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and compared to controls. The PMDD patients were relieved of premenstrual symptoms like depression and irritability during buserelin treatment. The number of [3H]paroxetine binding sites (Bmax) were significantly higher in the follicular phase in untreated PMDD patients compared to controls. When treated with buserelin the difference disappeared. No differences in [3H]LSD binding between the three groups were shown. The present study demonstrated altered platelet [3H]paroxetine binding characteristics in women with PMDD compared to controls. Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low dose of buserelin. The results are consistent with the hypothesis that changes in serotonergic transmission could be a trait in the premenstrual dysphoric disorder.     

Multiple high-affinity [H]serotonin binding sites in human frontal cortex

High-affinity [³H]serotonin (5-hydroxytryptamine, 5-HT) binding sites from human frontal cortex can be divided into at least 3 pharmacological subtypes (5-HT_1A, 5-HT_1B and 5-HT₃) based on affinity for [³H]serotonin and spiperone. All 3 sites are solubilized by 3% Triton X-100, 1% Tween-80 and can be enriched by serotonin-linked-Sepharose 4B affinity chromatography. However, 5-HT₃ sites are more sensitive to heat inactivation, long-term storage, and sulfhydrylalkylation. The pharmacological profiles are distinct for the spiperone-insensitive 5-HT_1B and 5-HT₃ sites in both human and bovine cortex. In addition, evidence is presented for the existence of a novel, low concentration [³H]serotonin binding site in human cortex.     

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.     

Troubles dysphoriques prémenstruels : diagnostic et traitements médicamenteux

Premenstrual dysphoric disorder is a form of mood disorder causing a significant reduction in the quality of life and in the daily function for about 3 % to 5 % of women of fertile age. Premenstrual dysphoric disorder (PMDD) includes various symptoms regularly present during the luteal phase of menstrual cycles, with principally depressive mood, anxiety, emotional lability and decrease of interest. The serotoninergic system is in close reciprocal relation with the gonadal hormones and has been identified as the most plausible target for interventions. The selective serotonin reuptake inhibitors are increasingly used as first-line therapy for severe PMDD. The response rate reported are better than responses to treatment of depression, obsessive-compulsive disorder or panic disorder. The doses used are variable, between 20 and 60 mg/day for fluoxétine, 50 and 150 mg/day for sertraline and 10-30 mg/day for paroxetine. The administration may be continuous every day in the menstrual cycle or intermittent (premenstrual only) or semi-intermittent (low doses during follicular phase and higher doses during luteal phase). Several studies indicate that intermittent treatment is more efficient in these women and thus, may offer an attractive treatment option because with reduced side-effects.     

Involvement of 5-HT1A receptor mechanisms in the inhibitory effects of methamphetamine on photic responses in the rodent suprachiasmatic nucleus

We examined the role of serotonin 1A (5-HT_1A) receptors in the inhibitory effects of methamphetamine (MA) on photic entrainment to the circadian pacemaker in the suprachiasmatic nucleus (SCN) of rodents. MA inhibited optic nerve stimulation-evoked field potential in the SCN, light-induced Fos expression in the SCN and light-induced phase shift of hamster wheel-running rhythm. NAN-190, a 5-HT_1A receptor antagonist, eliminated the inhibitory effects of MA. NAN-190 has also been reported to antagonize ₁ adrenergic receptors. However, prazosin, which selectively antagonizes ₁ adrenergic receptors, did not affect the inhibitory action of MA on light-induced Fos expression. In addition, parachloroamphetamine, which is known to be a 5-HT releaser, dose-dependently inhibited light-induced phase shift of wheel-running rhythm. These findings suggest that elevation of endogenous 5-HT levels by MA inhibits the photic entraining responses of the circadian pacemaker in the SCN via 5-HT_1A receptor stimulation of the 5-HT released by MA.     

Inhibitory effects of tandospirone, a 5-HT1A agonist, on medial vestibular nucleus neurons responding to lateral roll tilt stimulation in rats

An electrophysiological study was performed using chloral hydrate-anesthetized rats to determine whether tandospirone, a 5-HT_1A agonist, affects neuronal activities of the medial vestibular nucleus (MVN), since serotonergic innervation and 5-HT_1A receptors are present in this nucleus. Tandospirone applied microiontophoretically at a current of 20–60 nA caused an inhibition of tilt-induced firing of -type neurons, which showed increased and decreased firing with lateral tilt ipsilateral and contralateral to the recording site, respectively, along with that of β-type neurons which exhibited the reverse responses to ipsilateral and contralateral tilt stimulation. The inhibition was antagonized during simultaneous, iontophoretic application of WAY-100635 (20–60 nA), a 5-HT_1A receptor antagonist, although WAY-100635 alone rarely affected spontaneous or tilt-induced firing in either type of neurons. These results suggest that tandospirone acts on a 5-HT_1A receptor to inhibit transmission of otolith information to - and β-type MVN neurons.     

Effects of serotonergic drugs in experimental brain ischemia: evidence for a protective role of serotonin in cerebral ischemia

We have examined the significance of the serotonergic system in the pathophysiology of ischemic brain damage. Permanent occlusion of the middle cerebral artery (MCA) was performed in male NMRI mice. After 48 h, the animals received a transcardiac injection of carbon black. The area of ischemia was restricted to the neocortex and its size was determined planimetrically by means of an image analyzing system. In control experiments, the NMDA antagonist dizocilpine (MK-801), the AMPA/kainate antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline) and the L-type calcium channel blocker nimodipine all produced a significant reduction in ischemic injury of the mouse neocortex. Interestingly, all of the 5-HT_1A agonists tested (ipsapirone, CM 57493 [4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridine] and urapidil) were equally efficacious in reducing ischemic injury. On the other hand, the 5-HT₂ antagonist naftidrofuryl failed to protect the brain tissue significantly against ischemic brain damage. Roxindole, a 5-HT_1A agonist and 5-HT uptake inhibitor, was the most potent serotonergic compound tested. In order to examine the effects of 5-HT_1A receptor activation in a different context, 10 min of forebrain ischemia was induced in male Wistar rats by a bilateral occlusion of the common carotid arteries combined with systemic hypotension. Administration of the 5-HT_1A agonist CM 57493 reduced the neuronal damage within the ventral hippocampus and the entorhinal cortex as assessed histologically 7 days after ischemia. Finally, we found that 5-HT_1A agonists are capable of reducing neuronal damage of cultured neocortical and hippocampal neurons subjected to a chemical hypoxia or glutamate in a dose dependent manner. These data suggest that 5-HT, released during ischemia, may have protective effects in the pathophysiology of ischemic brain damage through a direct action on neurons mediated via the inhibitory 5-HT_1A receptor subtype. The results obtained from different in vivo and in vitro models indicate that 5-HT_1A agonists are promising agents for the treatment of ischemic brain disorders.     

Long-term fluoxetine, but not desipramine, inhibits the ACTH and oxytocin responses to the 5-HT1A agonist, 8-OH-DPAT, in male rats

The present studies determined whether serotonin 5-HT_1A receptor-mediated function is modified by chronic exposure to antidepressants. Hormone responses to the 5-HT_1A agonist, 8-OH-DPAT, were evaluated after long-term exposure to two antidepressants, the 5-HT uptake blocker, fluoxetine, and the norepinephrine uptake blocker, desipramine (DMI). In addition, the density and affinity of 5-HT_1A receptors in the hypothalamus and cerebral cortex were measured. Male rats received fluoxetine (10 mg/kg i.p.), DMI (5 mg/kg i.p) or saline injections once daily for 21 days. 8-OH-DPAT (0–500 μg/kg s.c.) was administered 18 h after the final antidepressant injection and 15 min before sacrifice. 8-OH-DPAT significantly increased plasma ACTH, corticosterone, oxytocin and prolactin, but not renin or vasopressin concentrations. Chronic injections of fluoxetine inhibited the ACTH, corticosterone and oxytocin responses to 8-OH-DPAT. suggesting reduced 5-HT_1A receptor function. In contrast, chronic DMI did not alter the hormone responses to 8-OH-DPAT. The density and affinity of 5-HT_1A receptors in the frontal cortex or hypothalamus were not altered by either fluoxetine or DMI. To verify that the observed effects require prolonged exposure to fluoxetine, rats received a single injection of fluoxetin (10 mg/kg, i.p.), 3 h before 8-OH-DPAT (0–500 μg/kg s.c.). Acute fluoxetine did not reduce any of the hormone responses to 8-OH-DPAT. In conclusion, the results suggest that chronic, but not acute, exposure to fluoxetine decreases 5-HT_1A receptor function. This effects is not seen in rats chronically exposed to DMI. The mechanism of the effects of chronic fluoxetine on 5-HT_1A receptor-mediated hormone responses is not likely due to reduced density of 5-HT_1A receptors, because no changes were observed in [³H]8-OH-DPAT binding in hypothalamus and cortex, but could be due to changes in signal transduction.     

Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder

BACKGROUND: Affective disorders, and possibly also premenstrual dysphoric disorder (PMDD) are risk factors for alcohol abuse in women. Although the majority of prior studies have indicated that alcohol sensitivity does not differ between menstrual cycle phases, patients with PMDD have thus far not been studied. METHODS: We have evaluated the functional sensitivity to a low dose of alcohol in 12 women with and 12 women without PMDD in the mid-follicular and late luteal phases of the menstrual cycle, by comparing the effects of an intravenous alcohol infusion on a number of saccadic eye movement measures, including saccadic eye velocity (SEV), saccade deceleration, and self-rated levels of intoxication. RESULTS: PMDD patients displayed blunted SEV (p<0.01) and saccade deceleration responses (p<0.01) to alcohol infusion in the late luteal phase compared to the mid-follicular phase. Control subjects, on the other hand, did not change their SEV or saccade deceleration responses to alcohol between cycle phases. CONCLUSION: These findings are compatible with altered saccadic eye movement sensitivity in response to alcohol among PMDD patients, particularly in the late luteal phase of the menstrual cycle.     

Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder.

BACKGROUND: This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels. METHODS: Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed. RESULTS: During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls. CONCLUSIONS: These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.