Chromosomal polymorphisms and susceptibility to menstrual disorders: a retrospective analysis of 24,578 women.

PURPOSE: To evaluate the association between the polymorphic variants of chromosomes and menstrual disorders. METHODS: The data from our previous retrospective, single-center cohort study were re-analyzed. Women with regular menstruation were included as controls. Women with menstrual cycle abnormalities were subgrouped according to reproductive causes. The frequency of chromosomal polymorphisms was compared between groups. Regression analysis was used to adjust for potential confounding variables. RESULT: A total of 24,578 women composed of 8062 women with regular cycles as the control group and 16,516 women as the menstrual cycle irregularity group were included. When compared with the control group, the incidence of chromosomal polymorphisms in the total menstrual cycle irregularity group, Polycystic ovary syndrome group, and Primary ovarian insufficiency group were significantly higher (4.49% versus 5.34%, P = 0.004, 4.49% versus 5.35%, P = 0.018 and 4.49% versus 5.94%, P = 0.002, respectively). The incidences of inv(9) in the Primary ovarian insufficiency group were significantly higher than that in the control individuals (1.0% versus 1.6%, P = 0.024). Logistic regression analysis showed an effect of chromosomal polymorphisms on menstrual cycle irregularity (OR: 1.62, 95% CI: 1.234-2.187, P = 0.007; adjusted OR: 1.46, 95% CI: 1.153-1.819, P < 0.001). The result demonstrated an effect of chromosomal polymorphisms on the Primary ovarian insufficiency group (OR: 2.52, 95% CI: 1.307-5.177, P < 0.001; adjusted OR: 2.61, 95% CI: 1.371-4.605, P < 0.001). CONCLUSION: The study suggests chromosomal polymorphisms adversely affect female menstrual cycle irregularity.

11-oxygenated androgens and their relation to hypothalamus-pituitary-gonadal-axis disturbances in adults with congenital adrenal hyperplasia.

CONTEXT: Hypothalamus-pituitary-gonadal (HPG)-axis disturbances are a common phenomenon in patients with classic congenital adrenal hyperplasia (CAH). 11-oxygenated androgens have been suggested to play a role in this context. DESIGN: Cross-sectional single center study including 89 patients (N = 42 men, N = 55 women) with classic CAH. MAIN OUTCOME MEASURES: Differences in steroid markers in men with hypogonadism and women with secondary amenorrhea with a special focus on 11-ketotestosterone (11KT) and 11ß-hydroxyandrostenedione (11OHA4). RESULTS: Hypogonadotropic hypogonadism was present in 23 % of men and 61 % of those women currently not on contraceptives suffered from irregular menstrual cycles or amenorrhea. Testicular adrenal rest tumor (TART) was documented in 28 % of men. 11KT (3.5x) and 11OHA4 (5.7x) among other adrenal steroids were significantly elevated in men with hypogonadism and in women with amenorrhea in comparison to those with a regular cycle (11KT: 5.2x; 11OHA4: 3.7x). 11-oxygenated androgens were not higher in men with TART than in those without. There was a negative association of 11KT and 11OHA4 with FSH but not with LH in men. As expected, all steroids were strongly correlated with each other and cases of disproportionally elevated 11-oxygenated androgens that could explain for HPG-disturbances or TART in otherwise controlled patients were rare and also found in eugonadal individuals. CONCLUSIONS: In CAH, 11-oxygenated androgens are elevated in women with menstrual disturbances and in men with hypogonadotropic hypogonadism. Due to the close correlation of 11-oxygenated androgens with other adrenal steroids it remains to be shown if their measurement is superior to conventional markers of androgen control.

Uncovering the pharmacological mechanism of motherwort (Leonurus japonicus Houtt.) for treating menstrual disorders: A systems pharmacology approach.

Leonurus japonicus (motherwort) is a traditional Chinese medicine that is widely used to treat menstrual disorders (MDs). However, the pharmacological mechanisms that underlie its clinical application remain unclear. In this study, a network pharmacology-based approach was used that integrated drug-likeness evaluation, oral bioavailability prediction, target exploration, network construction, bioinformatic annotation and molecular docking to investigate the mechanisms that underlie motherwort treatment for MDs. In total, 29 bioactive compounds were collected from 51 compounds in motherwort, which shared 17 common MDs-related targets. Network analysis indicated that motherwort played a therapeutic role in MDs treatment through multiple components that acted on multiple targets. Pathway enrichment analysis showed that the putative targets of motherwort were primarily involved in various pathways associated with the endocrine system, cancers, vascular system, and anti-inflammation process. Notably, five targets (i.e., AKT1, PTGS2, ESR1, AR and PPARG) were screened as hub genes based on a degree algorithm. Moreover, most of the bioactive components in motherwort had good binding ability with these genes, implying that motherwort could regulate their biological function. Collectively, this study elucidated the molecular mechanisms that underlay the efficiency of motherwort against MDs and demonstrated the potential of network pharmacology as an approach to uncover the action mechanism of herbal medicines.

Genetic and epigenetic characteristics in ovarian tissues from polycystic ovary syndrome patients with irregular menstruation resemble those of ovarian cancer.

BACKGROUND: Irregular menstruation is clinically associated with an increased risk for ovarian cancer and disease-related mortality. This relationship remains poorly understood, and a mechanism explaining it has yet to be described. METHODS: Ovarian tissues from women with polycystic ovary syndrome (PCOS) and regular menstruation (n = 10) or irregular menstruation (n = 10) were subjected to DNA methylation sequencing, real-time PCR array, whole-exome sequencing, and bioinformatics analysis. RESULTS: We demonstrated that ovarian tissue from PCOS patients with irregular menstruation displayed global DNA hypomethylation, as well as hypomethylation at several functionally and oncologically significant regions. Furthermore, we showed that several cancer-related genes were aberrantly expressed in ovarian tissue from patients with irregular menstruation, and that their mRNA and microRNA profiles shared appreciable levels of coincidence with those from ovarian cancer tissue. We identified multiple point mutations in both the BRCA1 and MLH1 genes in patients with irregular menstruation, and predicted the potential pathogenicity of these mutations using bioinformatics analyses. CONCLUSIONS: Due to the nature of ovarian cancer, it is important to broaden our understanding of the pathogenesis and risk factors of the disease. Herein, we provide the first description of a genetic and epigenetic basis for the clinical relationship between irregular menstruation and an increased risk for ovarian cancer.

Long-term follow-up of a female patient with non-classical 11ß-hydroxylase deficiency and two novel mutations in CYP11B1.

11ß-Hydroxylase deficiency is the second most common enzyme disorder after 21-hydroxylase deficiency causing congenital adrenal hyperplasia (CAH11ß). In females, the clinical phenotype of CAH11ß classic forms is associated with ambiguous genitalia, virilization and hypertension, while most common complaints in milder non-classic forms include hirsutism, acne, menstrual disturbances, and infertility. Herein, we present clinical and genetic characteristics of an adult woman with 11ß-hydroxylase deficiency, hypertension and infertility; she has been followed up from her first pregnancy to her early menopause. Genetic analyses of the patient revealed a compound-heterozygosity due to two variants in the CYP11B1 gene p.Val316Met and p.Asp480ThrfsTer2. Both mutations have not been previously reported as pathogenic in the literature. Emerging questions concerning the clinical management, fertility potential, mineral corticoid abnormalities and perimenopausal transition in patients with non-classic CAH11ß have also been briefly discussed. The presented case of an adult woman with CAH11ß shows that the proper diagnosis and close monitoring of patients with different CAH forms might ensure good therapy adherence and successful fertility.

The NRP1 migraine risk variant shows evidence of association with menstrual migraine.

BACKGROUND: In 2016, a large meta-analysis brought the number of susceptibility loci for migraine to 38. While sub-type analysis for migraine without aura (MO) and migraine with aura (MA) found some loci showed specificity to MO, the study did not test the loci with respect to other subtypes of migraine. This study aimed to test the hypothesis that single nucleotide polymorphisms (SNPs) robustly associated with migraine are individually or collectively associated with menstrual migraine (MM). METHODS: Genotyping of migraine susceptibility SNPs was conducted using the Agena MassARRAY platform on DNA samples from 235 women diagnosed with menstrual migraine as per International Classification for Headache Disorders II (ICHD-II) criteria and 140 controls. Alternative genotyping methods including restriction fragment length polymorphism, pyrosequencing and Sanger sequencing were used for validation. Statistical analysis was performed using PLINK and SPSS. RESULTS: Genotypes of 34 SNPs were obtained and investigated for their potential association with menstrual migraine. Of these SNPs, rs2506142 located near the neuropilin 1 gene (NRP1), was found to be significantly associated with menstrual migraine (p = 0.003). Genomic risk scores were calculated for all 34 SNPs as well as a subset of 7 SNPs that were nearing individual significance. Overall, this analysis suggested these SNPs to be weakly predictive of MM, but of no prognostic or diagnostic value. CONCLUSIONS: Our results suggest that NRP1 may be important in the etiology of MM. It also suggests some genetic commonality between common migraine subtypes (MA and MO) and MM. The identification of associated SNPs may be the starting point to a better understanding of how genetic factors may contribute to the menstrual migraine sub-type.

Pathogenetic role of vitamin D deficiency in the development of menstrual dysfunction in pubertal girls: a literature review.

In the literature review, 50 scientific sources surrounding the problem of vitamin D deficiency, 80% of which amounted to the issuance of the last 5 years, have been analyzed. Despite the impact of vitamin D deficiency on the health of children and adolescents has been studied for a long time, the information on the role of vitamin D in the formation of menstrual function in pubertal girls is scant and ambiguous. Among the hypotheses of menstrual dysfunction with vitamin D deficiency, neurohumoral regulation of the hypothalamic-pituitary-ovarian system is considered to be essential due to the localization of vitamin D receptors (VDR), unlike other vitamins, in the nuclei of various tissues and organs. However, in the last 10 years, data on the role of genetic polymorphism of the VDR gene in the pathogenesis of various manifestations of menstrual dysfunction have been accumulated. Some studies indicated a beneficial effect of cholecalciferol on such menstrual dysfunctions as oligomenorrhea and dysmenorrhea. Regarding numerous data on the role of vitamin D, both traditional and recently published, there is a strong correlation between vitamin D deficiency and other various factors, determining a wide range of polymorphic clinical manifestations where menstrual dysfunction is essential in girls at the age of puberty.

Reduced Transforming Growth Factor-ß Activity in the Endometrium of Women With Heavy Menstrual Bleeding.

Context: Heavy menstrual bleeding (HMB) is common and incapacitating. Aberrant menstrual endometrial repair may result in HMB. The transforming growth factor (TGF)-ß superfamily contributes to tissue repair, but its role in HMB is unknown. Objective: We hypothesized that TGF-ß1 is important for endometrial repair, and women with HMB have aberrant TGF-ß1 activity at menses. Participants/Setting: Endometrial biopsies were collected from women, and menstrual blood loss objectively measured [HMB >80 mL/cycle; normal menstrual bleeding (NMB) <80 mL]. Design: Immunohistochemistry and reverse transcription polymerase chain reaction examined endometrial TGF-ß1 ligand, receptors, and downstream SMADs in women with NMB and HMB. The function and regulation of TGF-ß1 were examined using cell culture. Results: TGFB1 mRNA was maximal immediately prior to menses, but no differences detected between women with NMB and HMB at any cycle stage. Histoscoring of TGFB1 revealed reduced staining in the stroma during menses in women with HMB (P < 0.05). There were no significant differences in TGFBR1/2 or TGFBR1/2 immunostaining. Cortisol increased activation of TGFB1 in the supernatant of human endometrial stromal cells (HES; P < 0.05) via thrombospondin-1. Endometrial SMAD2 and SMAD3 were lower in women with HMB during menstruation (P < 0.05), and decreased phosphorylated SMAD2/3 immunostaining was seen in glandular epithelial cells during the late secretory phase (P < 0.05). Wound scratch assays revealed increased repair in HES cells treated with TGF-ß1 versus control (P < 0.05). Conclusions: Women with HMB had decreased TGF-ß1 and SMADs perimenstrually. Cortisol activated latent TGF-ß1 to enhance endometrial stromal cell repair. Decreased TGF-ß1 activity may hinder repair of the denuded menstrual endometrium, resulting in HMB.

Case-control study of glucocorticoid receptor and corticotrophin-releasing hormone receptor gene variants and risk of perinatal depression.

BACKGROUND: Depression during pregnancy or after childbirth is the most frequent perinatal illness affecting women of reproductive age. It could result in unfavourable outcomes for both women and their newborns. The incidence of perinatal depression is higher for those with family history of depression and other mental illness, suggesting the contribution of genetic factors. There is postulation that disruption or fluctuation of reproductive hormones could play a part in women who are sensitive to such changes. METHODS: This is a case-control study comparing the frequencies of candidate gene variants in patients with perinatal depression with controls. Patients of Chinese descent (N = 725) were recruited from the outpatient clinics of the hospital between 2010 and 2013. Controls were patients who came for postnatal consultations at the obstetrics clinics and scored ≤ 7 on the Edinburgh Postnatal Depression Scale (EPDS) at the postnatal screening programme of the hospital. Cases with confirmed diagnosis of clinical (major) depression related to pregnancy/postpartum were recruited from the hospital's outpatient clinic. Genomic DNA was extracted from saliva samples and genotyped for the polymorphisms of interest. Differences between groups were assessed by chi-square analysis. RESULTS: CRHR1 rs242939 and rs1876828 were not polymorphic in the study population. There was no statistically significant association of perinatal depression for CRHR1 rs242941 and GR rs41423247 (BclI). When all subjects were grouped based on family history of mental illness, there was a statistically significant association of CRHR1 rs242941 with family history regardless of depression status (P = 0.043). There was also a statistically significant difference for GR rs41423247 and regularity of menstrual periods (P < 0.000). Although not statistically significant, women with perinatal depression showed a trend towards higher frequency of self-reported menstrual irregularity. CONCLUSIONS: No evidence was found for the association of any of the genetic markers with perinatal depression in this study cohort. Instead, the possible genetic links were found in women with positive family history of mental illness and menstrual irregularity, suggesting these could be identifying risk markers for women.

Association between the CLOCK gene 3111 T > C polymorphism and an irregular menstrual cycle in Korean adolescents.

The menstrual cycle is an example of a human infradian rhythm, but an altered sleep-wake cycle or a disrupted circadian rhythm can change the regularity of the menstrual cycle. In this study, we investigated whether an irregular menstrual cycle is associated with polymorphisms in the CLOCK (3111T > C) and/or PER3 (variable number tandem repeat, VNTR) genes, which are known to have an impact on the circadian rhythm. One hundred ninety-seven postmenarchal, adolescent girls from two girls' high schools in Seoul, Korea, were studied. All participants were requested to complete the Perceived Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI) to assess the emotional distress that might cause menstrual irregularity. Every participant donated a blood sample from which DNA was extracted and genotyped for the CLOCK 3111T > C and PER3 VNTR polymorphisms. A significant association was found between the CLOCK 3111T > C genotype and irregular menstrual cycles. Subjects with the 3111T > C genotype had a high risk of an irregular menstrual cycle compared with 3111T/T homozygous subjects (odds ratio [OR] = 2.88; 95% confidence interval [CI]: 1.26-6.55). When multivariate logistic regression analysis was performed to adjust for age, PSS, STAI, BDI and BMI, subjects with the 3111T > C polymorphism showed a significantly increased OR for irregular menstrual cycles (OR = 3.09; 95% CI: 1.32-7.21). There was no significant association between the PER3 VNTR polymorphism and the irregularity of the menstrual cycle (p > 0.05). The results of this study suggest that the CLOCK 3111T > C polymorphism could be an independent risk factor for irregular menstrual cycles, irrespective of psychological distress and endocrine or metabolic conditions, and could be used as a molecular marker for gynecological studies on this aspect.

A novel mutation of the hGR gene causing Chrousos syndrome.

BACKGROUND: Natural mutations in the human glucocorticoid receptor (hGR, NR3C1) gene cause Chrousos syndrome, a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. OBJECTIVE: To present a new case of Chrousos syndrome caused by a novel mutation in the hGR gene, and to elucidate the molecular mechanisms through which the natural mutant receptor affects glucocorticoid signal transduction. DESIGN AND RESULTS: The index case presented with hirsutism, acne, alopecia, anxiety, fatigue and irregular menstrual cycles, but no clinical manifestations suggestive of Cushing's syndrome. Endocrinologic evaluation revealed elevated 08:00 h plasma adrenocorticotropic hormone, serum cortisol and androstenedione concentrations and increased urinary free cortisol excretion. The patient harbored a novel A > G transition at nucleotide position 2177, which resulted in histidine (H) to arginine (R) substitution at amino acid position 726 of the receptor (c.2177A > G, p.H726R). Compared with the wild-type receptor, the mutant receptor hGRαH726R demonstrated decreased ability to transactivate glucocorticoid-responsive genes and to transrepress the nuclear factor-κB signalling pathway, displayed 55% lower affinity for the ligand and a four-fold delay in nuclear translocation, and interacted with the glucocorticoid receptor-interacting protein 1 coactivator mostly through its activation function-1 domain. Finally, a 3-dimensional molecular modelling study of the H726R mutation revealed a significant structural shift in the rigidity of helix 10 of the receptor, which resulted in reduced flexibility and decreased affinity of the mutant receptor for binding to the ligand. CONCLUSIONS: The natural mutant receptor hGRαH726R impairs multiple steps of glucocorticoid signal transduction, thereby decreasing tissue sensitivity to glucocorticoids.

Correlation analysis of the PNPLA7 gene polymorphism and susceptibility to menstrual disorder.

We examined the correlation between PNPLA7 gene polymorphisms at the rs61754920 and rs11137410 loci and menstrual disorder in women of reproductive age in the Central Plain. Genomic DNA was extracted from peripheral blood; polymerase chain reaction-ligase detection reaction and SNaPshot genotyping were used to detect polymorphisms in the rs61754920 and rs11137410 gene loci, respectively. The results for the 2 loci in individuals of different blood types were statistically analyzed. The proportion of the AA homozygote at the rs61754920 locus in the PNPLA7 gene was the lowest, while the proportion of the CC homozygote at the rs11137410 locus in the PNPLA7 gene was the highest. There were no statistical differences in the frequency distribution of genotypes and alleles at the 2 loci between control and test groups. The frequency of the TT genotype at the rs11137410 locus in women with type O blood was significantly lower in the test group than in the control group. Frequencies of the C and T alleles were significantly different between the 2 groups. There may be an association between the PNPLA7 gene and type O blood or a combined effect of the 2 genes.

Genetic association and gene expression studies suggest that genetic variants in the SYNE1 and TNF genes are related to menstrual migraine.

BACKGROUND: Menstrual migraine (MM) encompasses pure menstrual migraine (PMM) and menstrually-related migraine (MRM). This study was aimed at investigating genetic variants that are potentially related to MM, specifically undertaking genotyping and mRNA expression analysis of the ESR1, PGR, SYNE1 and TNF genes in MM cases and non-migraine controls. METHODS: A total of 37 variants distributed across 14 genes were genotyped in 437 DNA samples (282 cases and 155 controls). In addition levels of gene expression were determined in 74 cDNA samples (41 cases and 33 controls). Association and correlation analysis were performed using Plink and RStudio. RESULTS: SNPs rs3093664 and rs9371601 in TNF and SYNE1 genes respectively, were significantly associated with migraine in the MM population (p = 0.008; p = 0.009 respectively). Analysis of qPCR results found no significant difference in levels of gene expression between cases and controls. However, we found a significant correlation between the expression of ESR1 and SYNE1, ESR1 and PGR and TNF and SYNE1 in samples taken during the follicular phase of the menstrual cycle. CONCLUSIONS: Our results show that SNPs rs9371601 and rs3093664 in the SYNE1 and TNF genes respectively, are associated with MM. The present study also provides strong evidence to support the correlation of ESR1, PGR, SYNE1 and TNF gene expression in MM.

Family background of Diabetes Mellitus, obesity and hypertension affects the phenotype and first symptom of patients with PCOS.

BACKGROUND: The phenotypic variability among PCOS could be due to differences in insulin patterns. Hyperinsulinemia commonly accompanies Diabetes Mellitus (DM), obesity, hypertension and CAD, though, to a variable degree. We speculate that a family history of these diseases could differentially affect the phenotype of PCOS. AIM: To study the effect of DM/CAD/HT and obesity on the phenotype of PCOS. METHODS: PCOS patients and age matched controls were enquired for a family background of DM, hypertension, CAD and obesity among parents and grandparents. Regression modelling was employed to examine predictors of obesity and first symptom in PCOS patients. RESULTS: There were 88 PCOS women and 77 age-matched controls (46 lean, 31 obese). A high prevalence of DM, CAD, obesity and hypertension was observed among parents and grandparents of women with PCOS compared to controls. Hypertension and CAD manifested more in father's side of family. BMI of PCOS subjects was significantly related to parental DM and obesity after correcting for age. First symptom of weight gain was significantly associated with number of parents with DM (p = 0.02) and first symptom of irregular periods was associated with number of parents with hypertension (p = 0.06). CONCLUSION: A family background of DM/HT and obesity diseases affects the phenotype of PCOS.

Menopausal complaints in Slovak midlife women and the impact of CYP1B1 polymorphism on their incidence.

A wide variety of symptoms have been attributed to menopause, negatively influencing women's physical and psychological health. In addition to lifestyle parameters and personal history, genetic factors are considered to be the main source of this variation. This study aims to investigate the incidence of menopausal symptoms among midlife women according to their menopausal status, and to evaluate the contribution to their manifestation from CYP1B1 Leu432Val polymorphism as a predisposing factor for menopausal symptoms. The studied cohort consisted of 299 women ranging from 39 to 59 years of age. Women were recruited from the western and middle parts of Slovakia, and all participants completed a menopause-specific questionnaire and provided blood or saliva samples for genotyping. Our results indicated that all women are at risk of typical menopausal symptoms, but there is a higher number of postmenopausal women affected than premenopausal ones. Regression analysis showed that the CYP1B1 Leu/Leu genotype can increase the experience of bloated stomach and facial hair increase in all the sampled women, while the Leu/Leu genotype may increase experience of palpitations and involuntary urination in the premenopausal women. The Leu/Leu genotype may increase the experience of nausea, bloated stomach, and vaginal dryness in peri- and postmenopausal women. We determined that women with the Leu/Leu, or Leu/Val genotypes were approximately five times more likely to suffer from vaginal dryness than the Val/Val women (OR = 4.948; 95% CI, 1.259-19.447). We therefore suggest that CYP1B1 Leu432Val polymorphism could be involved in individual susceptibility to menopausal symptoms in Slovak midlife women.

A postgenomic integrated view of prostaglandins in reproduction: implications for other body systems.

Prostaglandins are primary mediators of pain and are involved in pathological conditions such as hypertension, cancer and inflammation but are also needed for normal function of the female reproductive system. This may hold true for other systems because long term use of selective COX-2 inhibitors such as VIOXX and BEXTRA was associated with heart failure, leading to their withdrawal. A thorough study of the contribution of prostaglandins in the regulation of normal body function is clearly needed. A major drawback of the current therapeutic strategies aiming at controlling PGs is that they aim at early steps of biosynthesis thus blocking all PGs, good and bad. However, PGs often work as opposing dyads such as PGI2-TXA2 in the vascular system and PGF2alpha-PGE2 in the female reproductive system. The paradigm thus appears as effecting selective synthesis, transport and action of individual PG isoforms. In this respect, the female reproductive system appears as an ideal study model. Data from human and animal genome projects allowed identifying the corresponding members of the biosynthetic and signal transduction components of the PG system in different animal species. Of particular interest was that PG terminal synthase shared similarities or identity with enzymes previously known for steroid or sugar metabolism and free radical detoxification. We present here an integrated view of PG action based on observations in the female reproductive system, but with potential strategic implications for cardiovascular and metabolic complications.

[Polymorphism of estrogen receptor alpha genes Pvu I, Xba I and TA repeat sequence and hypomenorrhea with unknown aetiology].

OBJECTIVE: To study the roles of the polymorphism of the estrogen receptor genes in hypomenorrhea with unknown aetiology. METHODS: A case control study was carried out in south west of China, with 100 patients with hypomenorrhea in the case group and 100 eumenorrhea women in the control group. Molecular biology test was undertaken to test the restriction fragment length polymorphism (RFLP) of the first intron incision enzyme Pvu II, Xba I in ERa gene. Depuration, clone and sequence analysis was performed to the TA repeated sequence in the hypervariable region of estrogen receptor gene. The genotype distribution of ERa gene polymorphism was compard between the case and control groups. RESULTS: The patients with hypomennorrhea had higher P genotypic frequency (47.5%) than the control (30.5%), with an OR of 1. 810 (95% CI = 1.113-2.765, P = 0.012). The patients with hypomennorrhea had lower X genotypic frequency (20.5%) than the control (32.0%), with an OR of 0.641 (95% CI = 0.361-0. 898, P = 0.036). The patients with hypomennorrhea had higher frequency of TA13 allele (P = 0.006) and lower Frequency of TA15 allele frequency (P = 0.033) than the control. CONCLUSION: ERa gene polymorphism is associated with hypomenorrhea with unknown aetiology. P allele and TA13 allele may be risk factors, while X allele and TA15 allele may be protective factors.