Effects of gonadal steroids on reward circuitry function and anhedonia in women with a history of postpartum depression.

BACKGROUND: Reward system dysfunction is evident across neuropsychiatric conditions. Here we present data from a double-blinded pharmaco-fMRI study investigating the triggering of anhedonia and reward circuit activity in women. METHODS: The hormonal states of pregnancy and parturition were simulated in euthymic women with a history of postpartum depression (PPD+; n = 15) and those without such a history (PPD-; n = 15) by inducing hypogonadism, adding back estradiol and progesterone for 8 weeks ("addback"), and then withdrawing both steroids ("withdrawal"). Anhedonia was assessed using the Inventory of Depression and Anxiety Symptoms (IDAS) during each hormone phase. Those who reported a 30 % or greater increase in IDAS anhedonia, dysphoria, or ill temper during addback or withdrawal, compared with pre-treatment, were identified as hormone sensitive (HS+) and all others were identified as non-hormone sensitive (HS-). The monetary incentive delay (MID) task was administered during fMRI sessions at pre-treatment and during hormone withdrawal to assess brain activation during reward anticipation and feedback. RESULTS: On average, anhedonia increased during addback and withdrawal in PPD+ but not PPD-. During reward feedback, both HS+ (n = 10) and HS- (n = 18) showed decreased activation in clusters in the right putamen (p < .031, FWE-corrected) and left postcentral and supramarginal gyri (p < .014, FWE-corrected) at the withdrawal scans, relative to pre-treatment scans. LIMITATIONS: A modest sample size, stringent exclusion criteria, and relative lack of diversity in study participants limit the generalizability of results. CONCLUSION: Although results do not explain differential hormone sensitivity in depression, they demonstrate significant effects of reproductive hormones on reward-related brain function in women.

Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study.

Preclinical evidence suggests that the actions of ovarian steroid hormones and brain-derived neurotrophic factor (BDNF) are highly convergent on brain function. Studies in humanized mice document an interaction between estrus cycle-related changes in estradiol secretion and BDNF Val66Met genotype on measures of hippocampal function and anxiety-like behavior. We believe our multimodal imaging data provide the first demonstration in women that the effects of the BDNF Val/Met polymorphism on hippocampal function are selectively modulated by estradiol. In a 6-month pharmacological hormone manipulation protocol, healthy, regularly menstruating, asymptomatic women completed positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans while performing the n-back working memory task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist, leuprolide acetate; leuprolide plus estradiol; and leuprolide plus progesterone. For each of the three hormone conditions, a discovery data set was obtained with oxygen-15 water regional cerebral blood flow PET in 39 healthy women genotyped for BDNF Val66Met, and a confirmatory data set was obtained with fMRI in 27 women. Our results, in close agreement across the two imaging platforms, demonstrate an ovarian hormone-by-BDNF interaction on working memory-related hippocampal function (PET: F2,37=9.11, P=0.00026 uncorrected, P=0.05, familywise error corrected with small volume correction; fMRI: F2,25=5.43, P=0.01, uncorrected) that reflects differential hippocampal recruitment in Met carriers but only in the presence of estradiol. These findings have clinical relevance for understanding the neurobiological basis of individual differences in the cognitive and behavioral effects of ovarian steroids in women, and may provide a neurogenetic framework for understanding neuropsychiatric disorders related to reproductive hormones as well as illnesses with sex differences in disease expression and course.

Adverse life events, psychiatric history, and biological predictors of postpartum depression in an ethnically diverse sample of postpartum women.

BACKGROUND: Race, psychiatric history, and adverse life events have all been independently associated with postpartum depression (PPD). However, the role these play together in Black and Latina women remains inadequately studied. Therefore, we performed a case-control study of PPD, including comprehensive assessments of symptoms and biomarkers, while examining the effects of genetic ancestry. METHODS: We recruited our sample (549 cases, 968 controls) at 6 weeks postpartum from obstetrical clinics in North Carolina. PPD status was determined using the MINI-plus. Psychiatric history was extracted from medical records. Participants were administered self-report instruments to assess depression (Edinburgh Postnatal Depression Scale) and adverse life events. Levels of estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanalone were assayed. Principal components from genotype data were used to estimate genetic ancestry and logistic regression was used to identify predictors of PPD. RESULTS: This population was racially diverse (68% Black, 13% Latina, 18% European). Genetic ancestry was not a predictor of PPD. Case status was predicted by a history of major depression (p = 4.01E-14), lifetime anxiety disorder diagnosis (p = 1.25E-34), and adverse life events (p = 6.06E-06). There were no significant differences between groups in any hormones or neurosteroids. CONCLUSIONS: Psychiatric history and multiple exposures to adverse life events were significant predictors of PPD in a population of minority and low-income women. Genetic ancestry and hormone levels were not predictive of case status. Increased genetic vulnerability in conjunction with risk factors may predict the onset of PPD, whereas genetic ancestry does not appear predictive.

The steroid metabolome in women with premenstrual dysphoric disorder during GnRH agonist-induced ovarian suppression: effects of estradiol and progesterone addback.

Clinical evidence suggests that symptoms in premenstrual dysphoric disorder (PMDD) reflect abnormal responsivity to ovarian steroids. This differential steroid sensitivity could be underpinned by abnormal processing of the steroid signal. We used a pharmacometabolomics approach in women with prospectively confirmed PMDD (n=15) and controls without menstrual cycle-related affective symptoms (n=15). All were medication-free with normal menstrual cycle lengths. Notably, women with PMDD were required to show hormone sensitivity in an ovarian suppression protocol. Ovarian suppression was induced for 6 months with gonadotropin-releasing hormone (GnRH)-agonist (Lupron); after 3 months all were randomized to 4 weeks of estradiol (E2) or progesterone (P4). After a 2-week washout, a crossover was performed. Liquid chromatography/tandem mass spectrometry measured 49 steroid metabolites in serum. Values were excluded if >40% were below the limit of detectability (n=21). Analyses were performed with Wilcoxon rank-sum tests using false-discovery rate (q<0.2) for multiple comparisons. PMDD and controls had similar basal levels of metabolites during Lupron and P4-derived neurosteroids during Lupron or E2/P4 conditions. Both groups had significant increases in several steroid metabolites compared with the Lupron alone condition after treatment with E2 (that is, estrone-SO4 (q=0.039 and q=0.002, respectively) and estradiol-3-SO4 (q=0.166 and q=0.001, respectively)) and after treatment with P4 (that is, allopregnanolone (q=0.001 for both PMDD and controls), pregnanediol (q=0.077 and q=0.030, respectively) and cortexone (q=0.118 and q=0.157, respectively). Only sulfated steroid metabolites showed significant diagnosis-related differences. During Lupron plus E2 treatment, women with PMDD had a significantly attenuated increase in E2-3-sulfate (q=0.035) compared with control women, and during Lupron plus P4 treatment a decrease in DHEA-sulfate (q=0.07) compared with an increase in controls. Significant effects of E2 addback compared with Lupron were observed in women with PMDD who had significant decreases in DHEA-sulfate (q=0.065) and pregnenolone sulfate (q=0.076), whereas controls had nonsignificant increases (however, these differences did not meet statistical significance for a between diagnosis effect). Alterations of sulfotransferase activity could contribute to the differential steroid sensitivity in PMDD. Importantly, no differences in the formation of P4-derived neurosteroids were observed in this otherwise highly selected sample of women studied under controlled hormone exposures.

Predictors of premenstrual impairment among women undergoing prospective assessment for premenstrual dysphoric disorder: a cycle-level analysis.

BACKGROUND: Women who experience significant premenstrual symptoms differ in the extent to which these symptoms cause cyclical impairment. This study clarifies the type and number of symptoms that best predict premenstrual impairment in a sample of women undergoing prospective assessment for premenstrual dysphoric disorder (PMDD) in a research setting. Central research goals were to determine (1) which emotional, psychological, and physical symptoms of PMDD are uniquely associated with premenstrual impairment, and (2) how many cyclical symptoms optimally predict the presence of a clinically significant premenstrual elevation of impairment. METHOD: A total of 267 naturally cycling women recruited for retrospective report of premenstrual emotional symptoms completed daily symptom reports using the Daily Record of Severity of Problems (DRSP) and occupational, recreational, and relational impairment for 1-4 menstrual cycles (N = 563 cycles). RESULTS: Multilevel regression revealed that emotional, psychological, and physical symptoms differ in their associations with impairment. The core emotional symptoms of PMDD were predictors of impairment, but not after accounting for secondary psychological symptoms, which were the most robust predictors. The optimal number of premenstrual symptoms for predicting clinically significant premenstrual impairment was four. CONCLUSION: Results enhance our understanding of the type and number of premenstrual symptoms associated with premenstrual impairment among women being evaluated for PMDD in research contexts. Additional work is needed to determine whether cognitive symptoms should receive greater attention in the study of PMDD, and to revisit the usefulness of the five-symptom diagnostic threshold.

The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder.

Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and addback clinical trial, and controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (for example, gene transcription) and protein (for example, RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared with the controls, and with significant effects for MTF2, PHF19 and SIRT1 (P<0.05). RNA and protein expression of the 13 ESC/E(Z) complex genes were individually quantitated. This pattern of increased ESC/E(Z) mRNA expression was confirmed in a larger cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs with MTF2, PHF19 and SIRT1 all significantly decreased (P<0.05). Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in controls only, and decreased by estradiol in PMDD LCLs. These findings demonstrate that LCLs from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated condition and in response to ovarian hormones. Dysregulation of ESC/E(Z) complex function could contribute to PMDD.

The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale.

BACKGROUND: Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset. METHOD: Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA. RESULTS: Education, but not ethnicity/race, influenced the reporting of postpartum depression [difference between robust comparative fit indexes (∆*CFI) 0.01), but not between European countries (∆*CFI < 0.01). CONCLUSIONS: Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.

Oestrogen receptor alpha localisation in the prefrontal cortex of three mammalian species.

Oestrogen modulates cognitive function and affective behaviours subserved by the prefrontal cortex (PFC). Identifying and localising oestrogen receptor (ER)alpha, in human PFC will contribute to our understanding of the molecular mechanism of oestrogen action in this region. Inferences about the site of action of oestrogen in human brain are derived largely from studies performed in nonhuman mammalian species; however, the congruence of findings across species has not been demonstrated. Furthermore, the laminar, cellular, and subcellular localisation of ERalpha in the cortex is debated. Therefore, we compared the distribution of ERalpha in human dorsolateral prefrontal cortex (DLPFC) with that of monkey DLPFC and rat medial PFC. Immunohistochemistry performed on frontal cortex from the three species demonstrated ERalpha positive cells throughout all layers of the PFC, in pyramidal and nonpyramidal neurones, with both nuclear and cytoplasmic immunoreactivity. Western blot analyses and preabsorption studies confirmed that the antibody used recognised ERalpha and not ERbeta. A strong ERalpha immunoreactive band corresponding to the full-length ERalpha protein (65-67 kDa) in the frontal cortex of all three species matched the size of the predominant immunoreactive band detected in breast cancer cell lines known to express ERalpha. Additionally, other ERalpha immunoreactive proteins of varying molecular weight in breast cancer cells, rat ovary and mammalian brain were detected, suggesting that ERalpha may exist in more than one form in the mammalian frontal cortex. The present study provides evidence that ERalpha protein exists in neurones in mammalian PFC and that ERalpha is anatomically well-positioned to directly mediate oestrogen action in these neurones.

Expression of estrogen receptor alpha exon-deleted mRNA variants in the human and non-human primate frontal cortex.

Although estrogen receptor alpha (ERalpha) mRNA has been detected in the primate frontal cortex, the types of ERalpha transcripts expressed, including exon-deleted variants (Delta), have not been determined in the monkey or human frontal cortex. Because the types of ERalpha mRNA expressed in brain could define neuronal responses to estrogens, we examined the transcript pool of ERalpha mRNAs expressed in normal adult and developing human and macaque frontal cortex. We reverse transcribed total RNA from the postmortem frontal cortex of 29 normal adult humans, 12 rhesus macaques, and 19 people ranging from infants to adults and employed two rounds of nested polymerase chain reaction (PCR) to generate ERalpha products spanning the coding domain. In a third nested PCR, we used primers specific for novel sequences of exon-exon junctions created when whole exons are missing. By sequencing PCR products, we detected 60 instances of 12 distinct DeltaERalpha mRNAs in adult humans and 94 instances of 13 distinct DeltaERalpha mRNAs in monkeys in differing patterns from one individual to another. In adult humans, 83% of individuals expressed at least 1 DeltaERalpha mRNA variant, and 100% of the monkeys expressed at least 1 DeltaERalpha mRNA variant. The single Delta2, Delta5, and Delta7 variants were frequently expressed in both human and monkey frontal cortex, Delta3 variants were rare in both species, and Delta6 variants were more frequently expressed in monkeys. In both species, we detected double, triple and quadruple Deltas, but these were less common than single Deltas. The pattern of human variant expression did not appear to change dramatically as a function of age. These findings imply the potential to produce different ERalpha proteins in frontal cortex, possibly with altered structure and function which may have physiological relevance for gene transcription by virtue of altered functional interactions with each other, other steroid hormone receptors, and genomic DNA.

Reproductive steroids in context.

The effects of reproductive steroids on the brain are highly context-dependent, a concept necessary to understand disorders of mood related to the reproductive endocrine system.

Direct binding of estradiol enhances Slack (sequence like a calcium-activated potassium channel) channels' activity.

17Beta-estradiol (E2) is a major neuroregulator, exerting both genomic and non-genomic actions. E2 regulation of Slack (sequence like a calcium-activated potassium channel) potassium channels has not been identified in the CNS. We demonstrate E2-induced activation of Slack channels, which display a unitary conductance of about 60 pS, are inhibited by intracellular calcium, and are abundantly expressed in the nervous system. In lipid bilayers derived from rat cortical neuronal membranes, E2 increases Slack open probability and appears to decrease channel inactivation. Additionally, E2 binds to the Slack channel and activates outward currents in human embryonic kidney-293 cells that express Slack channels but not classical estrogen receptors (i.e. ERalpha or ERbeta). Neither E2-induced activation nor the binding intensity of E2 to the Slack channel is blocked by tamoxifen, an ER antagonist/agonist. Thus, E2 activates a potassium channel, Slack, through a non-traditional membrane binding site, adding to known non-genomic mechanisms by which E2 exerts pharmacological and toxicological effects in the CNS.

Stressful life events, personal losses, and perimenopause-related depression.

We compared the number and quality of life events reported by depressed perimenopausal women and a non-depressed comparison group. Additionally, we examined the effects of the presence of hot flushes on life event reports. All women were 44-55 years old, had irregular menses and elevated plasma gonadotropin levels. The Psychiatric Epidemiology Research Interview recorded both the frequency of occurrence and the desirability of life events experienced by the women during the six months prior to the interview. Depressed perimenopausal women (n=50) reported significantly more undesirable events [Student's t-test (unpaired) with Bonferroni correction, t(98)=3.9, p=0.001] but not more exit events (e.g., divorce, last child leaving home or death in family) (t(98)=0.9, p=NS) compared to the non-depressed women (n=50). There were no effects of hot flushes on these diagnostic differences. The "empty nest" syndrome does not appear to be relevant in the development of perimenopausal depression. Nevertheless, independent of the presence of hot flushes, perimenopausal depressed women are more likely to report both negative life events and diminished self esteem.

Gonadotropin-releasing hormone-stimulated gonadotropin levels in women with premenstrual dysphoria.

Despite consistent evidence that premenstrual dysphoria (PMD) is not characterized by abnormalities in basal ovarian hormone secretion, the possibility remains that PMD is associated with an abnormality in the regulation of the hypothalamic-pituitary-ovarian (HPO) axis. We studied HPO axis regulation in 11 women with prospectively confirmed PMD and 20 asymptomatic controls, during both the follicular and luteal phases of the menstrual cycle. Plasma levels of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were obtained before and after stimulation with gonadotropin-releasing hormone (GnRH) (100 microg intravenously). Potential diagnostic- and menstrual cycle phase-related diferences in basal and plasma hormone levels were analyzed by repeated-measures analysis of variance. No significant differences were observed between women with PMD and controls in either basal or stimulated levels of FSH and LH. Stimulated FSH was significantly increased and stimulated LH was significantly decreased during the follicular compared with the luteal phase in both women with PMD and controls. These data are consistent with prior findings of normal basal reproductive hormone levels in women with PMD. Our data suggest the absence in women with PMD of an abnormality of dynamic ovarian function as measured by GnRH stimulation.

Neuroendocrine and behavioral effects of high-dose anabolic steroid administration in male normal volunteers.

OBJECTIVE: Despite widespread abuse of anabolic-androgenic steroids (AAS), the endocrine effects of supraphysiologic doses of these compounds remain unclear. We administered the AAS methyltestosterone (MT) to 20 normal volunteers in an in-patient setting, examined its effects on levels of pituitary-gonadal, -thyroid, and -adrenal hormones, and examined potential relationships between endocrine changes and MT-induced psychological symptoms. METHOD: Subjects received MT (three days of 40 mg/day, then three days of 240 mg/day) or placebo in a fixed sequence with neither subjects nor raters aware of order. Samples were obtained at the ends of the baseline, high-dose MT and withdrawal phases. Potential relationships between hormonal changes and visual analog scale measured mood changes were examined. RESULTS: Significant decreases in plasma levels of gonadotropins, gonadal steroids, sex hormone binding globulin, free T3 and T4, and thyroid binding globulin (Bonferroni t, p<0.01 for each) were seen during high-dose MT; free thyroxine and TSH increased during high-dose MT, with TSH increases reaching significance during withdrawal. No significant changes in pituitary-adrenal hormones were observed. Changes in free thyroxine significantly correlated with changes in aggressiveness (anger, violent feelings, irritability) (r=0.5,p=0.02) and changes in total testosterone correlated significantly with changes in cognitive cluster symptoms (forgetfulness, distractibility) (r=0.52,p=0.02). Hormonal changes did not correlate with plasma MT levels. CONCLUSIONS: Acute high-dose MT administration acutely suppresses the reproductive axis and significantly impacts thyroid axis balance without a consistent effect on pituitary-adrenal hormones. Mood and behavioral effects observed during AAS use may in part reflect secondary hormonal changes.

A curriculum for teaching psychiatric research bioethics.

Psychiatric research has received intense ethical scrutiny during the past decade. Changes in how studies are designed, reviewed by ethics boards, conducted, and reported in the literature have created a need for a systematic approach to teaching psychiatric research ethics to clinical researchers in training. The purpose of this article is to describe a model curriculum and comprehensive background reading list for training in psychiatric research bioethics. The curriculum was designed as an interactive seminar in a research fellowship program but can be adapted and incorporated into existing medical school and psychiatry residency training curricula. Participants in the seminar provide formal and informal evaluations of each session and the seminar as a whole. The seminar, now in it's third year, has been regularly attended and highly regarded by the NIMH research fellows who have participated. In response to recommendations by the participants, the content and organization of the seminar has been modified. Clinical research is both scientifically and ethically complex. Our initial experience with a formal curriculum in psychiatric research bioethics suggests that this educational activity has been both meaningful and relevant for psychiatrists training to be clinical investigators.

Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway.

Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides contributes to the aetiology of Alzheimer's disease (AD) by stimulating formation of free radicals. Thus, the antioxidant alpha-lipoate, which is able to cross the blood-brain barrier, would seem an ideal substance in the treatment of AD. We have investigated the potential effectiveness of alpha-lipoic acid (LA) against cytotoxicity induced by Abeta peptide (31-35) (30 microM) and hydrogen peroxide (H(2)O(2)) (100 microM) with the cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction and fluorescence dye propidium iodide assays in primary neurons of rat cerebral cortex. We found that treatment with LA protected cortical neurons against cytotoxicity induced by Abeta or H(2)O(2). In addition, LA-induced increase in the level of Akt in the neurons was observed by Western blot. The LA-induced neuroprotection and Akt increase were attenuated by pre-treatment with the phosphatidylinositol 3-kinase inhibitor, LY294002 (50 microM). Our data suggest that the neuroprotective effects of the antioxidant LA are partly mediated through activation of the PKB/Akt signaling pathway.

Estrogen protects against beta-amyloid-induced neurotoxicity in rat hippocampal neurons by activation of Akt.

The cellular mechanisms underlying the neuroprotective effects of estrogen are only beginning to be elucidated. Here we examined the role of protein kinase B (Akt) activation in 17beta-estradiol (E2) inhibition of beta-amyloid peptide (31-35) (Abeta31-35)-induced neurotoxicity in cultured rat hippocampal neurons. Abeta31-35 (25-30 betaM) significantly decreased the total number of microtubule associated protein-2 positive cells (MAP2+). This decrease was significantly reversed by pre-treatment with 100 nM E2. Further, 100 nM E2 alone significantly increased the total number of protein kinase B and microtubule associated protein-2 positive cells compared with controls. Such E2-induced increases were inhibited by LY294002 (20 microM), a specific PI3-K inhibitor, as well as by tamoxifen, an estrogen receptor antagonist/selective estrogen receptor modulator. These results indicate that the neuroprotective effects of E2 may be mediated at least in part via estrogen receptor-mediated protein kinase B activation.

Effects of gonadal steroids on peripheral benzodiazepine receptor density in women with PMS and controls.

BACKGROUND: GABA receptor-modifying neurosteroids may play a role in premenstrual syndrome (PMS). The peripheral benzodiazepine receptor (PBR) both regulates the formation of neurosteroids and is, in animals, regulated by ovarian steroids. Alterations in PBR density have been observed in association with several psychiatric disorders. METHODS: We examined the effects of gonadal steroids on lymphocytic PBR density in nine women with prospectively confirmed PMS and nine controls. PBR densities were measured during three pharmacologically controlled conditions: gonadotropin releasing hormone agonist (Lupron)-induced hypogonadism, Lupron plus estradiol, and Lupron plus progesterone replacement. Blood samples were obtained after six weeks of Lupron alone and after 3-4 weeks of estradiol and progesterone replacement. RESULTS: No significant hormone state-related changes in PBR density were observed (ANOVA-R: phase-F(2,32)=1.5, P=0.2). Despite mood symptom development in the subjects with PMS, PBR density did not differ in women with PMS compared to controls across hormonal states (ANOVA-R: F(1,16)=0.6, P=0.4). CONCLUSIONS: PBR densities are not altered in women with PMS and are not changed significantly by selective gonadal steroid administration. Changes in PBR density would not appear to underlie the differential sensitivity to the mood destabilizing effects of ovarian steroids in PMS.

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.