Polycystic Ovarian Syndrome: Role of Genes and Genetics (original) (raw)
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Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology
Genetics research international, 2018
Polycystic ovary syndrome is a multifactorial endocrine disorder whose pathophysiology baffles many researchers till today. This syndrome is typically characterized by anovulatory cycles and infertility, altered gonadotropin levels, obesity, and bulky multifollicular ovaries on ultrasound. Hyperandrogenism and insulin resistance are hallmark features of its complex pathophysiology. Hyperandrogenemia is a salient feature of PCOS and a major contributor to cosmetic anomalies including hirsutism, acne, and male pattern alopecia in affected women. Increased androgen levels may be intrinsic or aggravated by preexisting insulin resistance in women with PCOS. Studies have reported augmented ovarian steroidogenesis patterns attributed mainly to theca cell hypertrophy and altered expression of key enzymes in the steroidogenic pathway. Candidate gene studies have been performed in order to delineate the association of polymorphisms in genes, which encode enzymes in the intricate cascade of st...
Journal of Ovarian Research
Polycystic ovary syndrome (PCOS) is the most common endocrinopathies affecting the early reproductive age in women, whose pathophysiology perplexes many researchers till today. This syndrome is classically categorized by hyperandrogenism and/or hyperandrogenemia, menstrual and ovulatory dysfunction, bulky multi follicular ovaries on Ultrasonography (USG), and metabolic abnormalities such as hyperinsulinemia, dyslipidemia, obesity. The etiopathogenesis of PCOS is not fully elucidated, but it seems that the hypothalamus-pituitary-ovarian axis, ovarian, and/or adrenal androgen secretion may contribute to developing the syndrome. Infertility and poor reproductive health in women’s lives are highly associated with elevated levels of androgens. Studies with ovarian theca cells taken from PCOS women have demonstrated increased androgen production due to augmented ovarian steroidogenesis attributed to mainly altered expression of critical enzymes (Cytochrome P450 enzymes: CYP17, CYP21, CYP1...
Genetics of polycystic ovarian syndrome
Reproductive Biomedicine Online, 2005
Polycystic ovarian syndrome (PCOS) is a reproductive system disorder characterized by irregular menses, anovulation, clinical and/or biochemical signs of hyperandrogenism (hirsutism and/or acne), ovarian micropolycystic appearance and metabolic abnormalities, such as hyperinsulinaemia and obesity. The aetiopathogenesis of this syndrome is not well known. Several pathogenetic hypotheses have been proposed to explain the full array of symptoms and signs, but with elusive results. A genetic abnormality causing PCOS is supported by the observation that different members of the same family are often affected, and about half of the sisters of PCOS women have elevated serum testosterone concentrations. Therefore, the presence of gene abnormalities in women with PCOS has been widely explored in the attempt to establish whether their mutations or polymorphisms may cause PCOS. The main genes evaluated are those involved in steroidogenesis, steroid hormone effects, gonadotrophin release regulation and action, insulin secretion and action, and adipose tissue metabolism. Despite the vast body of literature produced, none of the genes evaluated seems to play a key role in PCOS pathogenesis. It is likely that PCOS may represent the final outcome of different, deeply inter-related genetic abnormalities that influence each other and perpetuate the syndrome.
Genetics of Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mechanisms that result in the expression of chronic anovulation and hyperandrogenism. This syndrome has been for many years one of the most controversial entities in gynecological endocrinology. Polycystic ovary syndrome has been proven to be a familial condition. Although the role of genetic factors in PCOS is strongly supported, the genes that are involved in the etiology of the syndrome have not been fully investigated until now, as well as the environmental contribution in their expression. The heterogeneity of the syndrome entertains the mystery around this condition which concerns thousands of infertile women worldwide. Some genes have shown altered expression suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling steroidogenesis, steroid hormones action, gonadotrophin action and regulation, insulin action and secretion, energy homeostasis, chronic inflammation and others. The present review of the contemporary literature constitutes an effort to present all the trends in the current research for the etiology of polycystic ovary syndrome. Hippokratia 2009; 13 (4): 216-223
An investigation of steroid biosynthesis pathway genes in women with polycystic ovary syndrome
Journal of Human Reproductive Sciences, 2022
Background: Polycystic ovary syndrome (PCOS) is a common endocrinopathy whose heterogeneous genetic basis results in a variable clinical presentation. One of the main clinical features of PCOS is hyperandrogenism which occurs due to dysregulation of ovarian and adrenal steroidogenesis. Aims: This study aimed to investigate potentially pathogenic variants in steroidogenic genes associated with PCOS. Settings and Design: This was a hospital‑based observational study. Materials and Methods: We recruited 51 women who presented with PCOS. Fasting blood samples were drawn from the participants and their whole‑exome sequencing analysis was carried out to look for pathogenic variants involved in steroidogenic pathways. The variants were predicted for their probable deleterious effects on proteins through in silico prediction tools. We evaluated the variants with respect to the hormonal characteristics and clinical outcomes of the patients. Statistical Analysis Used: All variables were analysed using GraphPad Prism 8. Kruskal–Wallis t‑test and Fisher’s exact test were used to compare clinical parameters and frequency differences among PCOS patients with and without variants. Results: The data presented here reveal eight heterozygous exonic variants, namely CYP21A2 (p.Ala392Thr, p.Gln319Ter and p.I143N), steroidogenic acute regulatory (p.Arg53 Leu), AKR1C3 (p.Phe205Val), P450 oxidoreductase (p.Val334Ile and p.Val251Met) and HSD17B6 (p.Gly40Ser), of which three were pathogenic, and four variants of uncertain significance in 8 out of 51 patients (15.68%). The identified variants were predicted to cause protein destabilisation, thus likely contributing to the pathogenesis of PCOS. Some of the variants showed significant differences between PCOS patients and population database (P < 0.05). Conclusion: The results of this study add to the mutational spectrum of steroidogenic genes and their association with PCOS.
The genetic basis of polycystic ovary syndrome
European Journal of Endocrinology, 2002
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The disorder is characterized by clinical features of hyperandrogenism, menstrual irregularities and often central obesity and hyperinsulinaemia. PCOS may increase the risk for infertility, type 2 diabetes mellitus, dyslipidaemia, cardiovascular disease and endometrial cancer, emphasizing the need for early diagnosis of the syndrome.
Human Reproduction, 2008
BACKGROUND: Polycystic ovary syndrome (PCOS) may be programmed in utero by androgen excess. Our aim was to examine the role of the sex hormone-binding globulin (SHBG) and androgen receptor (AR) gene polymorphisms, in the phenotypic expression of PCOS. METHODS: A cohort of 180 women with PCOS and 168 healthy women of reproductive age were investigated. BMI was recorded and the hormonal profile was determined on Day 3-5 of menstrual cycle. DNA was extracted from peripheral blood leucocytes and the SHBG(TAAAA)n and AR(CAG)n polymorphisms were genotyped by PCR. RESULTS: Genotype analysis revealed six SHBG(TAAAA)n alleles with 6-11 repeats and 19 AR(CAG)n alleles with 6-32 repeats, present in both PCOS and control women. Long SHBG(TAAAA)n alleles (>8 repeats) were at greater frequency in PCOS than normal women (P 5 0.001), whereas short AR(CAG)n alleles ( 20 repeats) tended to be more frequent in PCOS women than controls. When categorized into subgroups, PCOS women also tended to have at greater frequency the combination of long SHBG-short AR alleles (8.3%) than normal women (6.5%). Furthermore, PCOS women with combined long SHBG-short AR alleles had significantly lower serum SHBG levels (P 5 0.001) and higher serum androgens (P 5 0.03) compared with those with other genotype combinations. This difference was independent of BMI or insulin resistance. CONCLUSIONS: The presence of long SHBG(TAAAA)n alleles is associated with increased risk for PCOS and in combination with short AR(CAG)n alleles may influence the hyperandrogenic phenotype of PCOS. This combined genotype may contribute to 'fetal programming' of PCOS.
PCOS Forum: research in polycystic ovary syndrome today and tomorrow
Clinical Endocrinology, 2011
Objective To summarize promising areas of investigation into polycystic ovary syndrome (PCOS) and to stimulate further research in this area. Design Summary of a conference held by international researchers in the field of polycystic ovary syndrome. Results Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and lifestyle. The concept that androgen excess may contribute to insulin resistance needs to be re-examined from a developmental perspective, since animal studies have supported the hypothesis that early exposure to modest androgen excess is associated with insulin resistance. Defining alterations of steroidogenesis in PCOS should quantify ovarian, adrenal and extraglandular contribution, as well as clearly define blood reference levels by some universal standard. Intraovarian regulation of follicle development and mechanisms of follicle arrest should be further elucidated. Finally, PCOS status is expected to have longterm consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals through genomic and proteomic approaches would help to individualize therapy and prevention. Conclusions There are several intriguing areas for future research in PCOS. A potential limitation of our review is that we focused selectively on areas we viewed as the most controversial.
Exploration of the role of androgens and adipokines in the development of polycystic ovary syndrome
2011
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women being characterized by reproductive and metabolic abnormalities. Our hypothesis is that overproduction of ovarian androgens during early development is a key factor in the development of PCOS. The objective of the work in this thesis was to explore, using both an animal model of PCOS and human ovarian tissue, the role of androgens in the development of the ovarian abnormalities in PCOS and how these relate to disorders in fat metabolism. The expression of the key steroidogenic enzymes in androgen biosynthesis was determined in histological sections of polycystic and normal ovaries. Results supported the concept of intrinsic up-regulation of P450c17 enzyme in theca cells. In ovaries from ewes exposed prenatally to excess androgen, a similar disruption of P450c17 was observed along with increased androgen receptor expression and increased granulosa cell proliferation in preantral follicles. The interaction o...
Archives of Gynecology and Obstetrics, 2010
Purpose The aim of the present study was to determine the prevalence and association of the G972S polymorphism of the insulin receptor substrate-1 gene (IRS-1 G972S SNP) with polycystic ovary syndrome (PCOS) and insulin resistance-related traits in a distinct phenotypic group of lean PCOS women with biochemical hyperandrogenemia, excluding obesity, which is considered to be an aggravating parameter of insulin resistance. Methods The study included 162 women with PCOS and 122 regularly menstruating, ovulatory women as controls. Physical measurements included weight, height, fat-free mass, fat mass, systolic and diastolic blood pressure and resting heart rate. Biochemical parameters included the serum testosterone, free testosterone, androstenedione, total cholesterol, triglycerides, HDL and LDL cholesterol and glucose levels. Insulin resistance was assessed by determining fasting insulin levels, fasting glucose levels, the fasting glucose/insulin ratio, as well as the HOMA and QUICKI indexes. All DNA samples were genotyped by a PCR–restriction fragment length polymorphism (RLFP) assay. Results No association of the genotype frequencies of the G972S polymorphism in insulin receptor substrate-1 gene (IRS-1 G972S SNP) with PCOS phenotype and insulin resistance was detected. Conclusion The G972S polymorphism of the IRS-1 gene should not be viewed as major contributor to the development of PCOS or as a causative variant for insulin resistance.