Towards understanding the biology of premenstrual dysphoric disorder: From genes to GABA.

Premenstrual dysphoric disorder (PMDD) is a severe mood disorder, with affective symptoms that rise and fall in concert with the hormonal fluctuations of the menstrual cycle. PMDD's pathophysiology is poorly understood. This review describes recent research on potential biological contributors to PMDD, with a focus on neuroactive steroids, genetics, neuroimaging and cellular studies. Studies suggest that a key contributor is abnormal central nervous system (CNS) response to fluctuations in neuroactive steroid hormones. Imaging studies are limited but support alterations in serotonergic and GABA transmission. Genetic studies suggest heritability, yet specific genetic contributors have not been characterized. Finally, recent cutting-edge cellular studies indicate an underlying vulnerability to the effect of sex hormones at a cellular level. Overall the findings across studies do not yet fit together into a complete description of the underlying biology of PMDD. It is possible that PMDD consists of biological subtypes, and future research may benefit from a subtyping approach.

A Japanese herbal medicine attenuates anxiety-like behavior through GABAA receptor and brain-derived neurotrophic factor expression in a rat model of premenstrual syndrome.

Inochinohaha White (IHW) is a Japanese herbal medicine for treating women with anxiety associated with premenstrual syndrome (PMS). In this study, we examined the effects of IHW on anxiety-like behavior in rats undergoing progesterone withdrawal (PWD), a model for PMS. Female rats were injected daily with progesterone for 21 days. Water and ethanol extracts of IHW (WE-IHW and EE-IHW, respectively) were administered orally 15 days after the initiation of progesterone injections. Anxiety-like behavior in an elevated plus maze was evaluated 48 h after the final injection of progesterone. PWD induced anxiety-like behavior, and EE-IHW (300 mg/kg), but not WE-IHW, significantly attenuated this behavior. Administration of the GABA agonists, diazepam or muscimol, significantly attenuated PWD-induced anxiety-like behavior. To investigate the underlying mechanisms of IHW action, we analyzed GABAA receptor expression in the amygdala of these rats. EE-IHW ameliorated the PWD-induced decrease in GABAA receptor ß2-subunit mRNA, although ß2-subunit protein was unchanged. Brain-derived neurotrophic factor (BDNF) has been reported to have anxiolytic effects and enhance GABAergic synaptic transmission. We found that EE-IHW increased BDNF levels in a dose-dependent manner. Our results suggest that EE-IHW attenuates PWD-induced anxiety-like behavior by increasing GABAA receptor-mediated signaling via increases in ß2-subunit and BDNF in the amygdala.

ESTRADIOL BLOOD LEVEL AND ESR1 GENE POLYMORPHISM IN WOMEN WITH PREMENSTRUAL SYNDROME.

OBJECTIVE: The aim: To evaluate the association between estrogen receptor (ESR1) α- Xbal polymorphism with estradiol serum blood level in the patients with premenstrual syndrome. PATIENTS AND METHODS: Materials and methods: 50 women with premenstrual syndrome and 20 controls were examined. The level of estradiol was measured in the blood serum in both phases of the menstrual cycle by ELISA method. Polymerase chain reaction was used to study ESR1 gene polymorphism (A-351G variant). RESULTS: Results: The estradiol concentration was similar in two phases of the menstrual cycle between healthy women and patients with premenstrual syndrome. But the more growth of estradiol in the luteal phase was determined in the persons with premenstrual syndrome. The rate of GG genotype was the largest in women with severe premenstrual syndrome (χ2=3.52, p=0.06). Also, in the persons with severe premenstrual syndrome who had G allele (GG+AG genotype) the estradiol concentration in the luteal phase of the menstrual cycle was on 50.00 % (p=0.02) higher compared to carriers of AA genotype. There was no difference in estradiol level between healthy women with GG+AG genotype and AA genotype. CONCLUSION: Conclusions: AG polymorphism of ESR1 gene may be the marker of development of premenstrual syndrome.

ASSOCIATION OF ACE GENE POLYMORPHISM WITH THE DEVELOPMENT OF PREMENSTRUAL SYNDROME.

Premenstrual syndrome (PMS) is a common problem of women in reproductive age. Genetic aspects of this pathology are not completely clear. The aim of the article is devoted to the study of the frequency of ID polymorphism of angiotensin-converting enzyme gene ACE in patients with premenstrual syndrome. The object of the study were 50 women in reproductive age with the diagnosis of PMS, 25 of them had mild form of the disease, 25 - severe one. 25 persons without PMS were controls. Polymerase chain reaction was used to study ACE gene polymorphism. We determined an equal distribution of ACE gene genotypes between women with PMS and without this pathology (DD genotype was established in 24% of controls and 30% women with PMS, ID genotype - 60% and 46% respectively, II genotype - 16% and 24%). However, DD genotype was found in 2.17 times more often in patients with severe form of the disease (52%) compared to healthy persons. Thus, women with DD genotype of ACE gene have the tendency to the development of severe PMS (χ2=3.06, p=0.08; OR=3.43, 95% CI 1.02-11.47, p=0.045).

Premenstrual syndrome in Turkish medical students and their quality of life.

This study aimed to analyse the frequency and symptoms of premenstrual syndrome (PMS) and its effect on quality of life in medical students. Sociodemographic data, a symptom calendar for the following consecutive two menstrual periods and SF-36 quality of life questionnaire were collected. A total of 228 students joined the survey. The average age of the students was 20.77 ± 1.90. The frequency of PMS was 91.8%. The most frequent symptoms were abdominal bloating (89.5%), irritability (88.3%) and breast tenderness (82.6%). Quality of life scores ranged from 17.00 to 97.00 and were lowest in the severe PMS group. Alcohol consumption, stress events and fat rich diets increased the severity of PMS. Family history significantly affected the severity of PMS and quality of life scores. Premenstrual syndrome was found to be a frequent entity among medical students and seemed to affect quality of life in a moderate way.

Effect of estrogen receptor gene ESR1 polymorphism on development of premenstrual syndrome.

To identify risks of development of any disease is a priority of modern medicine. The aim of this study was to investigate the frequency of polymorphic variants of A-351G gene estrogen receptor ESR1 in patients with various forms of PMS. Molecular genetic analysis of ESR1 gene polymorphism in 50 women with PMS (25 women of them had edematous form of disease, 25 - neuropsychical, 25 - mild, 25 - severe form) was carried out. 25 women without diagnosis of PMS were examined as controls. The study A-351G polymorphism estrogen gene ESR1 showed no statistically significant differences in the frequency of distribution of genotypes and alleles between women with PMS and without this pathology. However, the frequency of GG genotype in women with severe PMS was significantly higher in 8.0 times compared with healthy women (χ2=4.87, p=0.03) and in women with edematous form of PMS - in 7.0 times (χ2=3.72, p=0.05). Thus, a polymorphic variant of A-351G gene ESR1 estrogen can be considered as a marker of PMS. Pathological variant GG genotype was significantly associated with the presence of edematous and severe forms of the disease.

Premenstrual syndrome, body fat and bitter taste receptor gene TAS2R38 among adult Kullu females of Himachal Pradesh, India.

OBJECTIVE: Premenstrual syndrome (PMS) is still a poorly understood and accepted condition. We evaluate the phenotypic variations at TAS2R38 gene locus in relation to PMS severity and adiposity measures among adult women. This is the first ever report describing association of PTC taste genetic locus with the PMS susceptibility. METHODS: The study was based on a cross-sectional sample of 105 adult rural women from the Kullu district, Himachal Pradesh. Retrospective approach was used to assess PMS. PTC tasting ability was assessed after Harris & Kalmus (1949). Each subject was measured for height, weight and body fat measures. RESULTS: 19.05% of the females were PTC non-tasters and 80.95% were tasters. Prevalence of PMS was 45.71%. Prevalence of severe type of PMS was very low, varying from 0-6%. Severity was highest in PMS-A type characterized by anxiety/irritability, tension, clumsiness, mood swings, nervousness, and insomnia. Females who tasted PTC bitter at lower concentrations had lowest PMS prevalence, while those who tasted PTC at higher concentration had highest PMS prevalence. Stature and body weight decreased with increase in PTC taste sensitivity. However, one-way ANOVA revealed that all the F-ratios were insignificant between the three discrete categories of low, medium and high PTC thresholds. CONCLUSION: Our results are compatible with the hypothesis that the bitter receptor gene TAS2R38 could not serve as a significant predictor of anthropometric measurements though some indirect pathways may not be ruled out, but the gene is significantly correlated with PMS susceptibility and severity.

SRD5A1 genotype frequency differences in women with mild versus severe premenstrual symptoms.

The aims of this small pilot study were to explore the association between premenstrual symptom severity and two genes from the gamma-aminobutyric acid (GABA) pathway: steroid-5-alpha-reductase, alpha polypeptide 1 (SRD5A1) and gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4). Saliva samples were obtained from a convenience sample of 19 Caucasian females ages 18-25 years, ten cases and nine controls. Deoxyribonucleic acid (DNA) was isolated, and genotyping performed on ten single nucleotide polymorphisms (SNPs). Ten percent of cases and 44% of controls had the cytosine/cytosine (C/C) genotype for the SRD5A1 SNP, rs501999 indicating that this genotype may protect women against severe premenstrual symptoms. Replication of this study using an adequately powered sample size is warranted.

The heritability of premenstrual syndrome.

We aimed to determine (1) the prevalence of premenstrual syndrome in a sample of twins and (2) the relative contribution of genes and environment in premenstrual syndrome. A group of 193 subjects inclusive of same gender twins (n = 176) and females from opposite sex twin sets (n = 17) entered the study. Heritability analysis used same gender twin data only. The probandwise concordance rate for the presence or absence of premenstrual syndrome was calculated and the heritability of premenstrual syndrome was assessed by a quantitative genetic model fitting approach using MX software. The prevalence of premenstrual syndrome was 43.0% and 46.8% in monozygotic and dizygotic twins, respectively. The probandwise concordance for premenstrual syndrome was higher in monozygotic (0.81) than in dizygotic twins (0.67), indicating a strong genetic effect. Quantitative genetic modeling found that a model comprising of additive genetic (A) and unique environment (E) factors provided the best fit (A: 95%, E: 5%). No association was found between premenstrual symptom and the following variables: belonging to the opposite gender twin set, birth weight, being breast fed and vaccination. These results established a clear genetic influence in premenstrual syndrome.

[Role of GABA receptors in pathological processes].

The review presents data indicative that both qualitative and quantitative changes in the structure of GABA--receptor complexes can lead to neurologic, mental, vegetotropic, somatic, hormonal and other disorders. The knowledge of structure of GABA receptors, their functions, and participation in the development of pathological states can promote the search for new selective synthetic substances capable of affecting receptor target, which opens ways to creating new highly effective and safe preparations for the treatment of various diseases.

[Effects of Baixiangdan capsule on location and expression levels of GABA(A) receptor beta2 subunit in hippocampus of PMS model rats with liver-qi invasion].

OBJECTIVE: To explore the effects of Baixiangdan capsule(BXD), a Chinese herbal compound, on the location and expression levels of GABA(A) receptor beta2 subunit (GABA(A)Rbeta2) in hippocampus of PMS model rats with liver-qi invasion. METHOD: After vaginal smear examination and open field test, the selected SD rats were randomly divided into 3 groups Normal group, PMS model group with liver-qi invasion and PMS BXD-administration group with liver-qi invasion (BXD was administered with oral dosage of 10 g x kg(-1) body weight every day for 5 days). PMS model rats with liver-qi invasion were induced by electric stimulating, and evaluated by macro-behavior observation and open-field test. The location and expression of GABA(A) receptor in hippocampus were measured by fluorescence microscopy and western blot respectively. RESULT: Compared with the normal group, the open field scores and GABA(A) Rbeta2 expression of PMS model rats with liver-qi invasion were increased significantly, and the distribution of GABA(A) receptor is more concentrated. However, the scores and GABA(A) beta2 expression of PMS BXD-administration group with liver-qi invasion were decreased markedly. Compared with the PMS model group the location had no significant change. CONCLUSION: One of micro-mechanisms of PMS model rats with liver-qi invasion may be related with the high expression of GABA(A) Receptor beta2 subunit in hippocampus, and the Chinese medicinal formula, BXD granule, had an adjust on the above abnormal changes.

Genetics of menstrual migraine: the epidemiological evidence.

Approximately one of every three to five women with migraine without aura experience migraine attacks in relation to menstruation. The International Classification of Headache Disorders, 2nd Edition provides appendix diagnoses for pure and menstrually related migraine without aura that need further validation. Probands with menstrual migraine might have more affected relatives than probands with nonmenstrual migraine. However, precise epidemiological, family, and twin data still are lacking.

Genetics of menstrual migraine: the molecular evidence.

Migraine is considered to be a multifactorial disorder in which genetic, environmental, and, in the case of menstrual and menstrually related migraine, hormonal events influence the phenotype. Certainly, the role of female sex hormones in migraine has been well established, yet the mechanism behind this well-known relationship remains unclear. This review focuses on the potential role of hormonally related genes in migraine, summarizes results of candidate gene studies to date, and discusses challenges and issues involved in interpreting hormone-related gene results. In light of the molecular evidence presented, we discuss future approaches for analysis with the view to elucidate the complex genetic architecture that underlies the disorder.

[Effects of jingqianshu granule on expression of estrogen receptor alpha and beta mRNA in hypothalamus and hippocampus of PMS rats with liver-qi depression].

OBJECTIVE: To investigate the effects of Jingqianshu granule (JQS), a Chinese medicinal formula on the expression levels of ERa and ERbeta mRNA in hypothalamus and hippocampus of PMS model rats with liver-qi depression. METHOD: The female SD rats were divided randomly into three groups: control, model and model plus Jingqianshu granule. We make the model rats of PMS with liver-qi depression using the method of emotional stimulation multiple factors. Then we applied semi-quantitative RT-PCR gene amplification technology to detect the expression levels of ERalpha and ERbeta mRNA in the brain regions of all rats. RESULT: Compared with the control group, the expression levels of ERalpha and ERbeta mRNA in hypothalamus and hippocampus of model rats were higher significantly (P < 0.05), while in the JQS-administration group, the expression levels of ERalpha and ERbeta mRNA were lower than model group (P < 0.05), and were no difference with the control group. CONCLUSION: The JQS granule can down-regulate the expression levels of ERalpha and ERbeta mRNA in hypothalamus and hippocampus, which maybe one of the mechanism to treat PMS with Liver-qi depression.

Analysis of the serotonin transporter promoter rs25531 polymorphism in premenstrual dysphoric disorder.

OBJECTIVE: The objective of this study was to investigate whether the functional rs25531 promoter polymorphism in the serotonin transporter gene is associated with premenstrual dysphoric disorder. STUDY DESIGN: The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range, 27-46 years; mean, 37.7 years) and 52 healthy control subjects (age range, 22-48 years; mean, 36.2 years). The rs25531 polymorphism was genotyped in both groups. Because of its close proximity to rs25531, the 5-HTTLPR promoter polymorphism was also genotyped. Genotype and allele frequencies for rs25531 and for the composite 5-HTTLPR/rs25531 marker were analyzed by chi(2) test. RESULTS: There was no significant association between any genotype and clinical category and no significant allele distribution profiles for rs25531 or 5-HTTLPR/rs25531 in either the premenstrual dysphoric disorder or the control groups. CONCLUSION: These findings do not support a major role for rs25531, either in isolation or combined with 5-HTTLPR, in contributing to susceptibility to premenstrual dysphoria.

Neuroticism-related personality traits are related to symptom severity in patients with premenstrual dysphoric disorder and to the serotonin transporter gene-linked polymorphism 5-HTTPLPR.

Neuroticism has been linked to a functional polymorphism in the serotonin transporter gene (5-HTTLPR), with short-allele carriers being overrepresented among high-scorers on neuroticism. Studies evaluating neuroticism-related personality traits in relation to the 5-HTTLPR polymorphism among patients with premenstrual dysphoric disorder (PMDD) and are lacking. The primary aim of this study was to evaluate the relationship between PMDD and neuroticism-related personality traits, and secondly, to relate the personality trait scores of PMDD patients to experienced symptom severity and to the 5-HTTLPR short allele. Thirty PMDD patients and 55 asymptomatic healthy controls were included in the study. The Swedish Universities Scale of Personality was used to evaluate personality traits. Genotype analyses were available in 27 PMDD patients and 18 healthy controls. Women with PMDD displayed higher levels of neuroticism-related personality traits (psychic trait anxiety, somatic trait anxiety, embitterment, stress susceptibility and mistrust) than healthy controls, and these effects were most prominent in women with more severe luteal phase symptoms. Furthermore, PMDD patients with at least one copy of the short allele of the 5-HTTLPR polymorphism scored higher on psychic trait anxiety and lack of assertiveness than PMDD patients who were homozygous for the long allele. PMDD patients who suffer from more severe luteal phase symptoms also display increased scores of neuroticism-related personality traits in comparison with healthy controls. Within the group of PMDD patients, differences in certain personality trait scores are associated with the short allele of the 5-HTTLPR polymorphism.

Estrogen receptor alpha (ESR-1) associations with psychological traits in women with PMDD and controls.

Premenstrual Dysphoric Disorder (PMDD) is a mood disorder affecting about 5% of women and is associated with substantial morbidity. Albeit inconsistently, PMDD is described as being characterized by heritable personality traits. Although PMDD is a heritable disorder, it is unclear whether any of the heritable susceptibility to PMDD resides in heritable personality traits. In groups of carefully characterized women with PMDD (n=68) and controls (n=56), we attempted to determine whether diagnosis-related traits could be confirmed, as well as to determine whether such traits were associated with SNPs in estrogen receptor alpha (ESR-1) that we previously demonstrated were associated with PMDD. We observed 7/25 traits to be significantly different in patients and controls and further showed that 11/12 significant associations observed between these 7 traits and 16 ESR-1 SNPs involved the intron 4 SNPs previously shown to be the locus of the association with PMDD. While several interactions between genotype and diagnosis were observed, the effect of genotype in most instances was in the same direction in patients and controls. These data demonstrate affective state-independent personality traits that distinguish patients with PMDD from controls and further support the relevance of ESR-1 polymorphic variants in the regulation of non-reproductive behaviors.

Premenstrual mood symptoms: study of familiality and personality correlates in mood disorder pedigrees.

We sought to determine whether premenstrual mood symptoms exhibit familial aggregation in bipolar disorder or major depression pedigrees. Two thousand eight hundred seventy-six women were interviewed with the Diagnostic Interview for Genetic Studies as part of either the NIMH Genetics Initiative Bipolar Disorder Collaborative study or the Genetics of Early Onset Major Depression (GenRED) study and asked whether they had experienced severe mood symptoms premenstrually. In families with two or more female siblings with bipolar disorder (BP) or major depressive disorder (MDD), we examined the odds of having premenstrual mood symptoms given one or more siblings with these symptoms. For the GenRED MDD sample we also assessed the impact of personality as measured by the NEO-FFI. Premenstrual mood symptoms did not exhibit familial aggregation in families with BP or MDD. We unexpectedly found an association between high NEO openness scores and premenstrual mood symptoms, but neither this factor, nor NEO neuroticism influenced evidence for familial aggregation of symptoms. Limitations include the retrospective interview, the lack of data on premenstrual dysphoric disorder, and the inability to control for factors such as medication use.

Premenstrual dysphoric disorder: neuroendocrine interferences.

Premenstrual dysphoric disorder (PMDD) consists in severe cognitive and mood changes, more aggressive as seen in premenstrual syndrome (PMS). These two syndromes are situated at the border between gynecology and psychiatry but the link between the two domains remains the neuroendocrine underlying mechanisms. In present, there are some molecular systems certainly proved as being involved, like estrogens. The hormonal pattern consists not in different levels of the hormones but different response to normal hormonal levels. The cyclical biochemical triggers are related to neurotransmitters as serotonin, endorphin and gamma-amino butyric acid (GABA). The heritability of the syndrome is sustained by genetic polymorphism in ESR1 gene. Thus, the PMDD is the result of multiple disturbances regarding neuroendocrine systems.

FKBP5, SERT and COMT mRNA expressions in the peripheral leukocytes during menstruation cycle in healthy reproductive females.

There have been several evidences that the mRNA expressions in the peripheral leukocytes may indicate not only physical but also psychological states. The purpose of this study is whether the mRNA expressional changes in the leukocytes are related to the mental states across the menstrual cycle in reproductive healthy female subjects. Thirty-eight female subjects (22.4+/-1.4 year-old) were participated in this study at three menstruation cycle periods (menstrual, follicular and luteal phase). The FKBP5 (FK506-binding protein gene), SERT (serotonin transporter gene) and COMT (catechol-o-methyltransferase gene) mRNA expressions in the leukocytes were determined with hormonal data. The psychological changes were assessed with self-rating hospital anxiety and depression scale (HADS). Only one thirds of subjects (n=12) had regular menstrual cycles during the experiment. So we analyzed the data from these 12 subjects. The anxiety score of each subject was changed across the menstrual cycle (Friedman test: P<0.05). The FKBP5 mRNA expression was significantly lower in the follicular phase than in the other phases but no changes were seen in either SERT or COMT mRNA expressions among the phases. In conclusion, there are differences of HADS anxiety score and FKBP5 mRNA expression in the leukocytes across the menstrual cycle but there is no correlation between anxiety scores and FKBP5 mRNA.