Genetic construction between polycystic ovarian syndrome and type 2 diabetes

Polycystic ovarian syndrome (PCOS) in reproductive-aged women is identified to be one of the endocrine disorders. This heterogeneous disorder is categorized through oligo-anovulation and hyperandrogenemia. National institutes of health and Rotterdam criterions were used to diagnose PCOS women. Type 2 Diabetes (T2D) is one of the complications in PCOS which is connected through insulin resistance (IR), which is a condition in which liver, muscles and fat infrequently respond to the hormones, and this leads to extreme IR and consequently leads to T2D disease. PCOS is inherited by the autosomal dominant mode of inheritance and may also with the different intricate patterns. Till now, many studies have been performed in PCOS with the genes identified by T2D and till now no studies have shown the similar genetic association and pathophysiology between both the diseases. So, the current review aims to investigate the genetic relation between PCOS and T2D and why both the diseases cannot be reverted. In this review, published data were screened with the T2D related genes and single nucleotide polymorphisms in PCOS women. The case-control, hospital-based and meta-analysis molecular studies disclosed both positive and negative connotations. Genetically, no relationship has been established between PCOS and T2D. Maximum studies have shown as PCOS women had developed T2D later in life because as a risk-factor, but none of the studies documented T2D women having developed PCOS as a risk factor. Apart from this, the disease PCOS is developed in women with reproductive age and T2D develops in both the men and women during adulthood. This review concludes as there is a genetic relation only in between PCOS and T2D, but not with T2D to PCOS and further it cannot be explicitly reverted from T2D to PCOS.     

Genetic contribution between APE1 variants in polycystic ovarian syndrome

IntroductionPolycystic Ovarian Syndrome (PCOS) has been identified as a gynecological, hormonal, and metabolic condition in women of reproductive age. Genetic studies can contribute to understand the pathogenesis of PCOS; which can be beneficial in early diagnosis and long-term management of the disease. Apurinic/apyrimidinic endonuclease 1 (APE1) has been related in the literature to polycystic ovarian syndrome.AimThe purpose of this study was to investigate the effects of ?656 T > G and 1349 T > G single nucleotide polymorphisms (SNPs) in the APE1 gene in Saudi women with PCOS.MethodsThis study includes 100 PCOS women and 100 healthy controls were genotyped for ?656 T > G and 1349 T > G SNPs using PCR-RFLP method. Serum sample was used for FBG and lipid profile tests. The obtained biochemical and genotypes data were entered into Excel and utilized for statistical analysis.ResultsClinical data presented in Table 1 was used to calculate the t-tests between PCOS and control subjects and results indicate age, weight, BMI, TG, LDLC and PCOS family history was associated (p < 0.0001). Genotype and allele frequencies showed the negative association in ?656 T > G SNP (GG vs TT: OR-1.15 (0.61–2.17); p = 0.65 and GG + TG vs TT: OR-1.17 (0.67–2.04); p = 0.57) and positive association in 1349 T > G SNP (GG vs TT: OR-3.52 (1.48–8.36); p = 0.003 and GG + TG vs TT: OR-2.84 (1.27–6.31); p = 0.008) in APE1 gene. Anova analysis was not associated with any one of the involved parameters (p > 0.05).ConclusionThis study found that the 1349 T > G SNP was related with PCOS in Saudi women. However, the ?656SNP had no favorable effect on the APE1 gene.     

Insulin resistance and polycystic ovarian syndrome.

Insulin resistance (IR) and polycystic ovarian syndrome (PCOS) appear as linked phenomena, although this is not easy to obviate in common forms of PCOS while it is evident in the rare cases of extreme IR and hyperinsulinism (HI). Experimental data indicate that insulin could interfere with the local insulin-like growth factor systems in ovaries, and presumably in adrenals and in the hypothalamic pituitary system. The female puberty system offers a physiological model to explain the gonadotropic action of insulin. In patients with IR, HI could induce a state of hyperpuberty, leading to the constitution of PCOS during adolescence.     

Prolactin release in polycystic ovarian syndrome

To evaluate the prevalence of hyperprolactinemia in patients with polycystic ovarian syndrome (PCO), 72 patients with oligo- or anovulation were studied. All of the patients had persisting elevated LH (greater than 25 mIU/ml), normal FSH, high LH/FSH ratio (greater than 2.5), and exaggerated LH responses to LHRH. Mean testosterone and androstenedione concentrations were appreciably increased in these patients. Out of 171 samples for prolactin (PRL) determination from these 72 patients, only 5 patients had a PRL value above 30 ng/ml during the first sampling. The next sampling from these same 5 women disclosed that they were transiently hyperprolactinemic because the next samples showed a normal PRL value. To further investigate the PRL secretory capacity 500 micrograms of TRH and 10 mg of metoclopramide (MCP) were administered to these 72 and 44 patients, respectively. The PRL response to MCP was significantly blunted in these patients compared to normal women while the PRL response to TRH in these patients was not indistinguishable from that in normal women. These results indicate that the true prevalence rate of hyperprolactinemia in PCO may be low rather than high and the association of hyperprolactinemia with PCO may be coincidental rather than a pathogenically related phenomenon.     

Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome

Testosterone is a potent regulator of lipolysis by influencing catecholamine signal transduction in fat cells. Major species differences exist as regards the testosterone effect. In rodents testosterone increases beta-adrenergic receptor mediated signals to lipolysis at multiple steps in the lipolytic cascade. The sex hormone also increases alpha2-adrenoceptor antilipolytic signalling in hamster which unlike rat express this receptor in their fat cells. In humans the region of adipose tissue is critical. Visceral fat cell lipolysis is not responsive to testosterone but this sex hormone decreases catecholamine-induced lipolysis in subcutaneous fat cells due to inhibition of the expression of beta2-adrenoceptors and hormone sensitive lipase. In polycystic ovarian syndrome (PCOS), which is characterized as a hyperandrogenic state, the lipolytic effect of catecholamine is decreased in subcutaneous adipocytes due to low content of beta2-adrenoceptors and hormone sensitive lipase. It is possible that the increased testosterone levels are responsible for these abnormalities in catecholamine signal transduction in subcutaneous fat cells of PCOS women. However, in visceral fat cells of PCOS women catecholamine-induced lipolysis is enhanced which cannot be explained by testosterone.     

The metabolic aspects of polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is considered to be the main reason of hyperandrogenism in reproductive women. There are often metabolic disorders connected with carbohydrate and adipose metabolism in the patients with PCOS. However, presence of metabolic disorders does not influence the diagnosis of the syndrome. The investigations demonstrated that the changes in lifestyle and use of proper medications could normalize endocrine system and metabolism through insulin-sensitivity increase and in the result it could restore the menses and ovulations. This paper introduces present knowledge concerning metabolic disorders associated with PCOS.     

Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in reproductive-age women. It often presents during late adolescence but in some cases certain features are evident even before menarche. PCOS is a spectrum of disorders with any combination of oligo/anovulation, clinical and/or biochemical evidence of androgen excess, obesity, insulin resistance and polycystic ovaries on ultrasound. The pathogenesis is unknown; however, it is a complex multigenetic disorder where disordered gonadotropin release, dysregulation of steroidogenesis, hyperinsulinism and insulin resistance play a role. The diagnosis is based on a typical physical exam (acne, hirsutism, obesity, and acanthosis nigricans) and laboratory evidence of hyperandrogenism, such as elevated free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS), decreased sex hormone-binding globulin (SHBG) and increased luteinizing hormone (LH). An ovarian ultrasound may detect the multiple cysts. Secondary causes of PCOS need to be excluded. There are several classes of medications correcting different parameters of PCOS that can be used alone or in combination. Oral contraceptive therapy is used to reduce androgen and LH levels with resultant improvement in acne and hirsutism, and the induction of regular menses. Antiandrogens are usually required for a substantial improvement in hirsutism score. Insulin sensitizers such as metformin are a new class of drugs utilized in treatment of PCOS. By improving insulin sensitivity and decreasing insulin levels, they improve the unfavorable metabolic profile of patients with PCOS. Metformin also helps to increase SHBG, decrease androgen levels and induce ovulation. Despite all the available medications, life-style changes are the mainstay of therapy as weight loss and exercise improve all parameters of PCOS without the potential side effects of medication.     

Vitamin D and calcium dysregulation in the polycystic ovarian syndrome.

Over the past 30 years, numerous studies in invertebrates and vertebrates have established a role of calcium in oocyte maturation as well as in the resumption and progression of follicular development. Polycystic ovarian syndrome (PCO) is characterized by hyperandrogenic chronic anovulation, theca cell hyperplasia, and arrested follicular development. The aim of this observational study was to determine whether vitamin D and calcium dysregulation contribute to the development of follicular arrest in women with PCO, resulting in reproductive and menstrual dysfunction. Thirteen premenopausal women (mean age 31 +/- 7.9 years) with documented chronic anovulation and hyperandrogenism were evaluated. Four women were amenorrheic and nine had a history oligomenorrhea, two of whom had dysfunctional bleeding. Nine had abnormal pelvic sonograms with multiple ovarian follicular cysts. All were hirsute, two had alopecia, and five had acanthosis nigricans. The mean 25 hydrovitamin D was 11.2 +/- 6.9 ng/ml [normal (nl): 9-52], and the mean 1,25 dihydroxyvitamin D was 45.8 +/- 18 pg/ml. with one woman with a 1,25 dihydroxyvitamin D <5 pg/ml (nl: 15-60). The mean intact parathyroid hormone level was 47 +/- 19 pg/ml (nl: 10-65), with five women with abnormally elevated parathyroid hormone levels. All were normocalcemic (9.3 +/- 0.4 mg/dl). Vitamin D repletion with calcium therapy resulted in normalized menstrual cycles within 2 months for seven women, with two experiencing resolution of their dysfunctional bleeding. Two became pregnant, and the other four patients maintained normal menstrual cycles. These data suggest that abnormalities in calcium homeostasis may be responsible, in part, for the arrested follicular development in women with PCO and may contribute to the pathogenesis of PCO.     

Dehydroepiandrosterone stimulates inflammation and impairs ovarian functions of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in child-bearing-age women. It is characterized by ovulation dysfunction, polycystic ovaries, and hyperandrogenism. Inflammation is likely to be a crucial contributor to the pathogenesis of PCOS. However, the association between the inflammatory cytokines and the development of PCOS has not been reported. To explore the relationship between the inflammatory cytokines and PCOS, alterations of serum proteins in dehydroepiandrosterone (DHEA)-induced PCOS rats were screened by protein array, and the concentration of IFN-γ was further measured by using enzyme-linked immunosorbent assay (ELISA). DHEA-induced PCOS rats had a decreased level of IFN-γ compared with the control rats, which was restored partly in flutamide (an androgen receptor antagonist)-treated rats. Moreover, the level of IFN-γ in serum of patients with PCOS was also lower than that in healthy women. Using the ovarian granulosa cells (KGN), we demonstrated that DHEA downregulated the expression and secretion of IFN-γ in dose- and time-dependent manners, which could be restored to some extent by treating with flutamide. Furthermore, flutamide ameliorated the inhibitory effect on cell proliferation and promotive effect on cell apoptosis by DHEA. The results also revealed that IFN-γ promoted the proliferation but inhibited the apoptosis of KGN cells, which was suppressed by DHEA via activating the downstream PI3K/AKT signaling pathway. Taken together, these results showed that DHEA inhibited the proliferation and promoted the apoptosis of ovarian granulosa cells through downregulating the expression of IFN-γ which could be restored by flutamide, and IFN-γ may serve as a potential inflammatory biomarker for PCOS detection.     

Impact of adrenal versus ovarian androgen ratio on signs and symptoms of polycystic ovarian syndrome

The aim of this study was to examine the effect of adrenal versus ovarian androgen (dehydroepiandrosterone sulfate/total testosterone [DHEAS/TT]) on clinical presentation and related metabolic disturbances in Turkish women with polycystic ovarian syndrome (PCOS). Two hundred eighty PCOS cases were taken into the study. For all cases, the DHEAS/TT ratio was calculated. The median value of this ratio was 4.40. Patients with an androgen ratio lower than 4.40 were included in Group 1 and cases with a ratio higher than 4.40 were Group 2. The two groups were compared in terms of hormonal, biochemical and clinical parameters. Body mass index and waist circumference were lower, the Ferriman-Gallwey score was higher and the cycle length was shorter in Group 2. High DHEAS level was associated with better lipid profiles and lower levels of inflammatory markers, meaning good metabolic control in these women, in spite of increased hirsutism rates. In patients with PCOS, both androgens are usually high in proportion to each other. Therefore, it would be more meaningful to use the DHEAS/TT ratio for an assessment of the metabolic and phenotypic effects of PCOS.     

HOXA10基因在多囊卵巢综合症患者卵巢中的表达

目的 探讨HOXA10基因在卵巢中颗粒细胞的表达及其与多囊卵巢综合征的关系.方法 采用逆转录聚合酶链反应及免疫印迹法分别测定25例多囊卵巢综合征(PCOS)妇女和32例卵巢功能正常(Non-PCOS)妇女卵巢黄素化颗粒细胞中HOXA10 mRNA和蛋白的表达水平.结果 PCOS妇女黄素化颗粒细胞中HOXA10 mRNA的表达和蛋白的表达均低于Non PCOS妇女(P＜0.01,P＜0.05).结论 HOXA10基因在卵巢中有表达,PCOS妇女卵巢黄素化颗粒细胞HOXA10 mRNA和蛋白表达水平明显低于Non-PCOS妇女,提示该基因可能参与了PCOS的发生及发展过程.     

Relationship between leptin receptor and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, which is involved in the multi-system disease, and its etiology is still not clearly understood. It is currently considered that not only the genetic factors but also the environment factors play a crucial role in the pathogenesis of PCOS. Obesity plays an important role through the insulin, leptin and endocannabinoid system in the pathological process of PCOS, leading to more severe clinical manifestations. The aim of our present study is to investigate whether there is association between single nucleotide polymorphisms (SNPs) of Gln223Arg and Pro1019Pro in the leptin receptor gene (LEPR) and PCOS in a Korean population. Interestingly, a significant association was found between the Pro1019Pro in LEPR gene and PCOS, and a highly significant association was found between the Gln223Arg in LEPR gene and PCOS (P = 0.033, OR = 1.523, 95% confidence interval and P < 0.0001, OR = 0.446, 95% confidence interval). Moreover, genotype combination and haplotype analyses indicate that Gln223Arg and Pro1019Pro polymorphisms of LEPR are significantly associated with the risk of PCOS.     

Testosterone levels and cognitive functioning in women with polycystic ovary syndrome and in healthy young women

We investigated the possible influence of testosterone (T) on cognitive functioning in women with polycystic ovary syndrome (PCOS), an endocrine disorder associated with elevated levels of free testosterone (free T). Performance on a battery of neuropsychological tests in 29 women with elevated free T levels due to PCOS was compared to the performance of 22 age- and education-matched, healthy control women with free T levels in the normal female range. Women with PCOS had significantly higher levels of free T (estimated by the free androgen index) and demonstrated significantly worse performance on tests of verbal fluency, verbal memory, manual dexterity, and visuospatial working memory than the healthy control women. No differences between the groups were found on tests of mental rotation, spatial visualization, spatial perception, or perceptual speed. These results suggest that, in women, elevations in free T may be associated with poorer performance on cognitive tasks that tend to show a female advantage.