Study On The Susceptibility Gene And Psychological Factors In Polycystic Ovary Syndrome

Background. Polycystic ovary syndrome (PCOS) is a common complex and heterogenous endocrine disorder affecting women in their reproductive years that is characterized by oligomenorrhea or amenorrhea, hyperandrogenism, multiple small subcapsular cystic follicles in the ovary on ultrasonography, insulin resistance/hyperinsulinemia, and hyperlipidemia. Its complexity stems from the syndrome's typical heterogeneity and its unknown etiology. There is an increasing evidence to support a major genetic basis for PCOS, since the syndrome is strongly familial. The complex biochemical characteristics may have their respective genetic susceptibility or common genetic link. It is clear that more than one gene (and probably several) contributes to the heterogeneous phenotype, and the clinical and biochemical presentation is undoubtedly influenced by additional environmental factors, such as nutrition, mental and psychological factors. Meanwhile Several previous studies indicate that the psychological factors were closely associated with PCOS, and maybe the important incentive of PCOS and lead to the long-term complications. So this study was designed to explore the susceptibility gene of PCOS, to analysis the psychological characteristics of PCOS patients, and toevaluate its role in the PCOS pathophysiology.(1). It is generally recognized that insulin resistance is a key component in the pathogenesis of the disorder, and several reports have documented the association of PCOS with genes influencing insulin action. Multiple organs in insulin synthesis, transport, storage and degradation were involved in insulin resistance. Its mechanisms may be involved in pancreaticβ-cell dysfunction, lower insulin clearance, insulin receptor reduction and insulin receptor mutation or defects.Insulin clearance is a process involving all tissues, not only insulin sensitive ones. Insulin degrading enzyme is considered to be the major degradative insulin system, although other systems, like protein disulfide isomerase and lysosomal cathepsin D, are involved in insulin metabolism. Many studies have shown that the dysfunction of IDE caused by gene mutation could lead to insulin clearance and degradation reduced, and several studies in human have demonstrated that decreased insulin clearance and degradation were associated with insulin resistance. Possibly, a decreased intracellular degradation of insulin bound to its receptor would inhibit receptor-mediated signal transduction, by lowering the number of available receptors on the cell membrane and/or compromising the down-stream signaling from the receptor. In addition to an effect on insulin receptor recycling and signaling, reduced IDE activity may also have a diabetogenic effect through its ability to degrade peptides, this notion may also be important for the susceptibility to insulin resistance. So this study was designed to analysis the distribution of IDE gene variants in PCOS women and controls since the association between IDE gene and PCOS have never been reported in the literature.(2). Ghrelin, acts as the endogenous ligand for growth hormone secretagogues receptor (GHS-R), is a novel growth hormone (GH) releasing peptide with several functions which stimulates food intake and controls energy balance. It is known to play a role in glucose metabolism and in beta-cell function. Different polymorphisms of this gene have been described, including the single base substitutions G152A, with Gln replacing Arg at position 51 of mature Ghrelin, and C214A with Met replacing Leu at position 72 in the repro-Ghrelin C-terminal tail since their important function. Many researches demonstrated that, the polymorphism of the Ghrelin gene was associated with obese, diabetes, metabolism syndrome and the insulin resistance. Moreover, Ghrelin was associated with adipnection, resistin closely which participates in the obese physiopathologic process together. More recent years, several studies reported that Low Ghrelin plasma concentrations were asociated with PCOS. As far as we know, this is the first study exploring the distribution of the two polymorphism Arg-51-Gln and Leu-72-Met in PCOS and healthy controls, and the association of polymorphism in Ghrelin gene with the different phenotype of PCOS.(3). The majority of researches in PCOS focused on its pathophysiology and treatment. However, the psychological problems of PCOS patients were often ignored. Many aspects of PCOS could lead to emotional stress. Infertility, menstrual disorders, hirsutism and obesity might cause psychological diseases. Moreover the psychological factors maybe the important incentive of PCOS and lead to the long-term complications. So this study was designed to evaluate the psychological characteristics of PCOS patients and its role in the PCOS pathophysiology.Objectives. (1) To analyze the clinical, endocrine and metabolism characteristics of PCOS and to find the factors associated with insulin resistance. (2) To investigate the distribution of the four single nucleotide polymorphism of IDE gene in PCOS patients and controls in a Chinese population and to analysis the association of four single nucleotide polymorphisms of IDE gene with the clinical, the hormonal and metabolic characteristics of PCOS. (3) To investigate the distribution of the two single nucleotide polymorphism of Ghrelin gene in PCOS patients and controls in a Chinese population and to analysis the association of two single nucleotide polymorphisms in Ghrelin gene with the clinical, the hormonal and metabolic characteristics of PCOS. (4) To evaluate the psychological characteristics in PCOS patients and healthy controls, and to explore the role of psychological factors in the PCOS pathophysiology.Methods. (1) 315 Patients with PCOS were recruited according to the revised diagnostic criteria, announced in the 2003 American Society for Reproductive Medicine/European Society for Human Reproduction and Embryology (ASRM/ESHRE) Rotterdam consensus. 327 women were selected as healthy controls. After undergoing a physical examination, including measurement of abdominal and hip circumferences, testing for the measurement of hormone, an oral glucose tolerance test (OGTT) was performed in PCOS patients. DNA was extracted from human leukocyte nuclei isolated from whole blood. IDE genotyping was performed using polymerase chain reaction (PCR) amplification on regions covering each particular polymorphism. PCR products were then digested with the corresponding restriction enzyme, and then visualized on a 2% ethidium bromide stained agarose gels. (2) 77 PCOS patients, 200 non-PCOS infertility women and 100 healthy controls were recruited for this psychological study. All of them filled in the SCL-90 and a standardized questionnaire including demographic and clinical characteristics after having a general physical examination and an ultrasound examination.Results. (1) In PCOS group, the ratio of patients with BM≥25kg/m~2 were 47%. Patients with hyperandrogenism were 61 %. Patients with LH/FSH≥2 were 22.8%, Patients with abnormal fasting insulin level were 13.6%. Patients with abnormal fasting glucose level were 7.9%. Patients with abnormal CHO level were 17.7%, Patients with abnormal TG level were 6.8%. Patients with borderline hypertension were 18.6%. Patients with hypertension were 11.1%. (2) There were significant differences in level of BMI, WHR, and TG between IR group and non-IR group. But the LH level in non-IR the group was significantly higher than that of the IR group. The level of plasma glucose, plasma insulin, HOMA-IR and TG were significantly higher than that of the non-obese group. However, the LH level in non-obese group was significantly higher than that of the obese group. The blood cholesterol and LDL level of hyperandrogenism group were significantly higher than that of the non- hyperandrogenism group. (3) The HOMA-IR of PCOS patients was demonstrated to be significantly positive correlated with BMI, waist and the TG level. There were no correlation between HOMA-IR and the level of T and LH. (4) There was no significant difference in age between the PCOS patient and the control groups. However, the level of T, LH, BMI, and WHR was significantly higher in the PCOS group than that in control group. (5) No significant differences between the distributions of these polymorphisms were observed when PCOS group and the control group were compared. But the frequency of C allele of rs2209972 was significantly higher in PCOS group than that in control group. The SNP rs4646953, rs1887922 and rs1544210 had no impact on clinical and biochemical characteristics of PCOS women. There were significant differences in BMI and insulin level in different rs2209972 genotype of PCOS women. Both the PCOS women with CC and CT genotype of rs2209972 had statistically significantly higher fasting insulin level and HOMA-IR than that of the PCOS women with TT genotype. (6) The polymorphism Arg-51 -Gln was not found in Chinese population. (7) The distribution of Leu-72-Met was similar in PCOS group and in healthy controls. It is also similar in IR group and non-IR group, in obese group and non-obese group, in hyperandrogenism group and non- hyperandrogenism group. There was no significant difference of age, BMI, WHR, the level of FSH, LH, E2, and PRL in different genotype PCOS patients. But the level of T in PCOS women with CC and CA genotype was significantly higher than that of PCOS women with AA genotype. Although the level of plasma glucose and insulin was similar, the HOMA-IR in CC genotype patients is significantly higher than that of AA genotype patients. (8) PCOS women scored significantly higher on all subscales of the SCL-90 than did controls. In addition, women in the PCOS group had significantly higher scores on somatization, obsessive compulsive, interpersonal sensitivity, depression, anger and hostility, and total scores than those in the non-PCOS infertile women. There was statistically significant difference between the women in non-PCOS infertility group and controls on the scales of obsessive compulsive, interpersonal sensitivity, depression, anxiety, phobic anxiety and total scores. Further more, women in the IVF subgroup had significantly higher scores on depression scale than those in the ICSI subgroup. (9) The regression analysis indicates that the variance in SCL-90 outcome measures could be partly accounted for by duration of marriage and infertility, residential district, education and yearly income, especially clinical symptoms, such as hirsutism, menstrual disorders and obesity.Conclusions. (1) There are many phenotypes of metabolism syndrome in PCOS patients, including obese, IR and dyslipidemia. Obese, particular the abdomen obese might aggravate IR. There were no association of hyperandrogenism and elevated luteinizing hormone levels with IR. The association of IR and dyslipidemia was coadjustment. (2) It is the first research to investigate the distribution of IDE gene rs2209972, rs1887922, rs4646953, rs1544210 in PCOS group and in health controls. There were no association of SNP rs1887922 rs4646953 rs1544210 with IR. But SNP rs2209972 was found to be associated with IR in PCOS group. The linkage disequilibrium was not found in SNP rs2209972 and rs1887922. (3) The Arg51Gln in the ghrelin gene wasn't found in Chinese population. (4) The Leu72Met in the ghrelin gene was found to be significantly associated with T level. Leu72Met was related with IR in some degree. However, there is no association between BMI and Leu72Met. (5) The psychological health status was significantly declined in infertile women, especially PCOS women. Duration of infertility, residential district, education and yearly income, especially clinical symptoms, such as hirsutism, menstrual disorders and obesity had negative impact on their psychological health status.