Publications
355 results found
Ernst EH, Franks S, Hardy K, et al., 2018, Granulosa cells from human primordial and primary follicles show differential global gene expression profiles, Human Reproduction, Vol: 33, Pages: 666-679, ISSN: 1460-2350
STUDY QUESTION: Can novel genetic candidates involved in follicle dormancy, activation and integrity be identified from transcriptomic profiles of isolated granulosa cells from human primordial and primary follicles? SUMMARY ANSWER: The granulosa cell compartment of the human primordial and primary follicle was extensively enriched in signal transducer and activator of transcription 3 (STAT3) and cAMP-response element binding protein (CREB) signalling, and several other putative signalling pathways that may also be mediators of follicle growth and development were identified. WHAT IS KNOWN ALREADY: Mechanistic target of rapamycin kinase (mTOR) signalling and the factors Forkhead Box L2 (FOXL2) and KIT proto-oncogene receptor tyrosine kinase (KITL) may be involved in defining the early steps of mammalian follicular recruitment through complex bidirectional signalling between the oocyte and granulosa cells. cAMP/protein kinase K (PKA)/CREB signalling is a feature of FSH-induced regulation of granulosa cell steroidogenesis that is essential to normal human fertility. STUDY DESIGN, SIZE, DURATION: A class comparison study was carried out on primordial follicles (n = 539 follicles) and primary follicles (n = 261) follicles) donated by three women having ovarian tissue cryopreserved before chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: RNA samples from isolates of laser capture micro-dissected oocytes and follicles from the primordial and primary stage, respectively, were sequenced on the HiSeq Illumina platform. Data mapping, quality control, filtering, FPKM (fragments per kilobase of exon per million) normalization and comparisons were performed. The granulosa cell contribution in whole follicle isolates was extracted in silico. Modelling of complex biological systems was performed using Ingenuity Pathway Analysis (IPA). For validation of transcriptomic findings, we performed quantitative RT-PCR of selected candidate genes. Furthermore, we interrogated the in s
Jonas KC, Chen S, Virta M, et al., 2018, Temporal reprogramming of calcium signalling via crosstalk of gonadotrophin receptors that associate as functionally asymmetric heteromers, Scientific Reports, Vol: 8, ISSN: 2045-2322
Signal crosstalk between distinct G protein-coupled receptors (GPCRs) is one mechanism that underlies pleiotropic signalling. Such crosstalk is also pertinent for GPCRs activated by gonadotrophic hormones; follicle-stimulating hormone (FSH) and luteinising hormone (LH), with specific relevance to female reproduction. Here, we demonstrate that gonadotrophin receptor crosstalk alters LH-induced Gαq/11-calcium profiles. LH-induced calcium signals in both heterologous and primary human granulosa cells were prolonged by FSHR coexpression via influx of extracellular calcium in a receptor specific manner. LHR/FSHR crosstalk involves Gαq/11 activation as a Gαq/11 inhibitor abolished calcium responses. Interestingly, the enhanced LH-mediated calcium signalling induced by FSHR co-expression was dependent on intracellular calcium store release and involved Gβγ. Biophysical analysis of receptor and Gαq interactions indicated that ligand-dependent association between LHR and Gαq was rearranged in the presence of FSHR, enabling FSHR to closely associate with Gαq following LHR activation. This suggests that crosstalk may occur via close associations as heteromers. Super-resolution imaging revealed that LHR and FSHR formed constitutive heteromers at the plasma membrane. Intriguingly, the ratio of LHR:FSHR in heterotetramers was specifically altered following LH treatment. We propose that functionally significant FSHR/LHR crosstalk reprograms LH-mediated calcium signalling at the interface of receptor-G protein via formation of asymmetric complexes.
Owens LA, Abbara A, Lerner A, et al., 2018, The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function, Human Reproduction, Vol: 33, Pages: 292-302, ISSN: 1460-2350
STUDY QUESTIONWhat are the in vivo and in vitro actions of kisspeptin-54 on the expression of genes involved in ovarian reproductive function, steroidogenesis and ovarian hyperstimulation syndrome (OHSS) in granulosa lutein (GL) cells when compared with traditional triggers of oocyte maturation?SUMMARY ANSWERThe use of kisspeptin-54 as an oocyte maturation trigger augmented expression of genes involved in ovarian steroidogenesis in human GL cells including, FSH receptor (FSHR), LH/hCG receptor (LHCGR), steroid acute regulatory protein (STAR), aromatase, estrogen receptors alpha and beta (ESR1, ESR2), 3-beta-hydroxysteroid dehydrogenase type 2 (3BHSD2) and inhibin A (INHBA), when compared to traditional maturation triggers, but did not alter markers of OHSS.WHAT IS KNOWN ALREADYhCG is the most widely used trigger of oocyte maturation, but is associated with an increased risk of OHSS. The use of GnRH agonists to trigger oocyte maturation is a safer alternative to hCG. More recently, kisspeptin-54 has emerged as a novel therapeutic option that safely triggers oocyte maturation even in women at high risk of OHSS. Kisspeptin indirectly stimulates gonadotropin secretion by acting on hypothalamic GnRH neurons. Kisspeptin and its receptor are also expressed in the human ovary, but there is limited data on the direct action of kisspeptin on the ovary.STUDY DESIGN SIZE, DURATIONForty-eight women undergoing IVF treatment for infertility consented to kisspeptin-54 triggering and/or granulosa cell collection and were included in the study. Twelve women received hCG, 12 received GnRH agonist and 24 received kisspeptin-54 to trigger oocyte maturation. In the kisspeptin-54 group, 12 received one injection of kisseptin-54 (9.6 nmol/kg) and 12 received two injections of kisspeptin-54 at a 10 h interval (9.6 nmol/kg × 2).PARTICIPANTS/MATERIALS, SETTING, METHODSFollicular fluid was aspirated and pooled from follicles during the retrieval of oocytes for IVF/ICSI. GL cells were iso
Schierding W, Antony J, Karhunen V, et al., 2017, GWAS on prolonged gestation (post-term birth): analysis of successive Finnish birth cohorts., Journal of Medical Genetics, Vol: 55, Pages: 55-63, ISSN: 1468-6244
Background Gestation is a crucial timepoint in human development. Deviation from a term gestational age correlates with both acute and long-term adverse health effects for the child. Both being born preterm and post-term, that is, having short and long gestational ages, are heritable and influenced by the prenatal and perinatal environment. Despite the obvious heritable component, specific genetic influences underlying differences in gestational age are poorly understood.Methods We investigated the genetic architecture of gestational age in 9141 individuals, including 1167 born post-term, across two Northern Finland cohorts born in 1966 or 1986.Results Here we identify one globally significant intronic genetic variant within the ADAMTS13 gene that is associated with prolonged gestation (p=4.85×10−8). Additional variants that reached suggestive levels of significance were identified within introns at the ARGHAP42 and TKT genes, and in the upstream (5’) intergenic regions of the B3GALT5 and SSBP2 genes. The variants near the ADAMTS13, B3GALT5, SSBP2 and TKT loci are linked to alterations in gene expression levels (cis-eQTLs). Luciferase assays confirmed the allele specific enhancer activity for the BGALT5 and TKT loci.Conclusions Our findings provide the first evidence of a specific genetic influence associated with prolonged gestation. This study forms a foundation for a better understanding of the genetic and long-term health risks faced by induced and post-term individuals. The long-term risks for induced individuals who have a previously overlooked post-term potential may be a major issue for current health providers.
Franks S, 2017, Dormancy and activation of human oocytes from primordial and primary follicles: molecular clues to oocyte regulation, Human Reproduction, ISSN: 0268-1161
Karjula S, Morin-Papunen L, Auvinen J, et al., 2017, Psychological distress is more prevalent in fertile age and premenopausal women with PCOS symptoms: 15-year follow-up, Journal of Clinical Endocrinology & Metabolism, Vol: 102, Pages: 1861-1869, ISSN: 1945-7197
Context:Polycystic ovary syndrome (PCOS) is associated with increased psychological distress, obesity and hyperandrogenism being suggested as key promoters.Objectives:To investigate the prevalence of anxiety/depression and their coexistence in women with PCOS/PCOS-related symptoms at ages 31 and 46. The roles of obesity, hyperandrogenism, and awareness of PCOS on psychological distress were also assessed.Design:Population-based follow-up.Setting:Northern Finland Birth Cohort 1966 with 15-year follow-up.Participants:At age 31, a questionnaire-based screening for oligoamenorrhea (OA) and hirsutism (H): 2188 asymptomatic (controls), 331 OA, 323 H, and 125 OA plus H (PCOS). Follow-up at age 46: 1576 controls, 239 OA, 231 H, and 85 PCOS.Interventions:Questionnaire-based screening for anxiety and depression symptoms (Hopkins Symptom Checklist-25) and previously diagnosed/treated depression at ages 31 and 46. Body mass index (BMI), serum testosterone/free androgen index, and awareness of polycystic ovaries/PCOS on psychological distress were also assessed.Main Outcomes:Population-based prevalence of anxiety and/or depression in women with PCOS/PCOS-related symptoms at ages 31 and 46.Results:Anxiety and/or depression symptoms, their coexistence, and rate of depression were increased at ages 31 and 46 in women with PCOS or isolated H compared with controls. High BMI or hyperandrogenism did not associate with increased anxiety or depression symptoms. The awareness of PCOS was associated with increased anxiety.Conclusions:Women with PCOS or isolated H present more often with anxiety and/or depression symptoms and their coexistence compared with controls. High BMI or hyperandrogenism did not provoke psychological distress in PCOS. The awareness of PCOS increased anxiety but did not associate with severe anxiety or depression.
Couto Alves A, Valcarcel B, Makinen V, et al., 2017, Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity, International Journal of Obesity, Vol: 41, Pages: 1331-1340, ISSN: 1476-5497
Background: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance, and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels.Design and Methods: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3,127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. On each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls.Results: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (≥98 cm) had significantly lower high density lipoprotein (HDL) levels, ApoA1 and albumin values compared to the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, adversely associated with insulin levels and HOMA IR in cases but not in the controls.Conclusions: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long term health of women with PCOS.
Ollila MM, West S, Keinanen-Kiukaaniemi S, et al., 2017, Correction: Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus-a prospective population-based cohort study, Human Reproduction, Vol: 32, Pages: 968-968, ISSN: 1460-2350
This is a correction to:Human Reproduction, Volume 32, Issue 2, 1 February 2017, Pages 423–431, https://doi.org/10.1093/humrep/dew329
Vimalesvaran S, Narayanaswamy S, Yang L, et al., 2017, Using kisspeptin to assess GnRH function in an unusual case of primary amenorrhoea, Endocrinology, Diabetes & Metabolism, Vol: 16, ISSN: 2052-0573
SUMMARY: Primary amenorrhoea is defined as the failure to commence menstruation by the age of 15 years, in the presence of normal secondary sexual development. The potential causes of primary amenorrhoea extend from structural to chromosomal abnormalities. Polycystic ovarian syndrome (PCOS) is a common cause of secondary amenorrhoea but an uncommon cause of primary amenorrhoea. An early and prompt diagnosis of PCOS is important, as up to 30% of these women are predisposed to glucose intolerance and obesity, with the subgroup of women presenting with primary amenorrhoea and PCOS displaying a higher incidence of metabolic dysfunction. We describe a case of an 18-year-old female presenting with primary amenorrhoea of unknown aetiology. Although initial investigations did not demonstrate clinical or biochemical hyperandrogenism or any radiological evidence of polycystic ovaries, a raised luteinising hormone (LH) suggested a diagnosis of PCOS. If PCOS was the correct diagnosis, then one would expect intact hypothalamic GnRH and pituitary gonadotropin release. We used the novel hormone kisspeptin to confirm intact hypothalamic GnRH release and a GnRH stimulation test to confirm intact pituitary gonadotroph function. This case highlights that kisspeptin is a potential unique tool to test GnRH function in patients presenting with reproductive disorders. LEARNING POINTS: Polycystic ovarian syndrome (PCOS) can present with primary amenorrhoea, and therefore, should be considered in the differential diagnosis.PCOS is a heterogeneous condition that may present in lean women with few or absent signs of hyperandrogenism.GnRH stimulation tests are useful in evaluating pituitary function; however, to date, we do not have a viable test of GnRH function. Kisspeptin has the potential to form a novel diagnostic tool for assessing hypothalamic GnRH function by monitoring gonadotropin response as a surrogate marker of GnRH release.Confirmation of intact GnRH function helps consolidate a
Ollila M-ME, West S, Keinanen-Kiukaanniemi S, et al., 2017, Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus-a prospective, population-based cohort study, Human Reproduction, Vol: 32, Pages: 423-431, ISSN: 1460-2350
STUDY QUESTIONWhat are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years?SUMMARY ANSWERThe risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM.WHAT IS KNOWN ALREADYPCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear.STUDY DESIGN, SIZE, DURATIONIn a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers.MAIN RESULTS AND THE ROLE OF CHANCEPCOS per se significantly increased the risk of T2DM in overweight/obese (BMI ≥ 25.0 kg/m2) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28–4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was signi
Laird M, Thomson K, Fenwick M, et al., 2017, Androgen stimulates growth of mouse preantral follicles in vitro: interaction with follicle stimulating hormone and with growth factors of the TGFβ superfamily., Endocrinology, Vol: 158, Pages: 920-935, ISSN: 0013-7227
Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the commonest cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aims of investigating interaction with FSH, the steroidogenic pathway and with growth factors of the TGFβ superfamily that are known to have a role in early follicle development.Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72h in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor (Fshr) expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was downregulated. The key androgen-induced changes in the TGFβ signaling pathway were downregulation of Amh, Bmp15 and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin, resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression.Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis and, importantly, implicate the intra-follicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS.
Hardy K, Fenwick M, Mora J, et al., 2016, Onset and heterogeneity of responsiveness to FSH in mouse preantral follicles in culture, Endocrinology, Vol: 158, Pages: 134-147, ISSN: 1945-7170
The obligatory role of follicle stimulating hormone (FSH) in normal development and function of antral follicles in the mammalian ovary is well recognized but its function in preantral growth is less clear. The specific objective of this study was to investigate the response, in culture, to FSH of mouse preantral follicles of increasing size, focusing particularly on growth rate and gene expression. Preantral follicles were mechanically isolated from ovaries of C57BL/6 mice, 12-16 days post partum and single follicles cultured for up to 96h in medium alone (n=511) or with rhFSH 10ng/ml (n=546). Data were grouped according to initial follicle diameter in 6 strata ranging from <100 to >140 μ m. Follicles of all sizes grew in the absence of FSH (p<0.01, paired t-test). All follicles grew at a faster rate (p<0.0001) in the presence of 10 ng/ml FSH but larger follicles showed the greatest change in response to FSH. Even the smallest follicles expressed FSH receptor mRNA. FSH-induced growth was inhibited by KT5720, an inhibitor of protein kinase A (PKA), implicating the PKA pathway in FSH-induced follicle growth. In response to FSH in vitro, FSH receptor mRNA (measured by qPCR) was reduced (p<0.01) as was Amh (p<0.01) whereas expression of StAR (p<0.0001) and the steroidogenic enzymes Cyp11a1 (p<0.01) and Cyp19 (p<0.0001) was increased. These results show heterogeneous responses to FSH according to initial follicle size, smaller follicles being less FSH-dependent than larger preantral follicles. These findings strongly suggest that FSH has a physiological role in preantral follicle growth and function.
Surendran P, Drenos F, Young R, et al., 2016, Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension, Nature Genetics, Vol: 48, Pages: 1151-1161, ISSN: 1546-1718
High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
Kanoni S, Masca NG, Stirrups KE, et al., 2016, Analysis with the exome array identifies multiple new independent variants in lipid loci., Human Molecular Genetics, Vol: 25, Pages: 4094-4106, ISSN: 1460-2083
It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.
Ollila MM, Keinanen-Kiukaanniemi S, Piltonen T, et al., 2016, Polycystic ovary syndrome (PCOS), hyperandrogenism and overweight/obesity, independently and interactively, increase the risk of metabolic syndrome, Publisher: OXFORD UNIV PRESS, Pages: 129-129, ISSN: 0268-1161
Huang-Doran I, Franks S, 2016, Genetic Rodent Models of Obesity-Associated Ovarian Dysfunction and Subfertility: Insights into Polycystic Ovary Syndrome, Frontiers in Endocrinology, Vol: 7, ISSN: 1664-2392
Barber TM, Dimitriadis GK, Andreou A, et al., 2016, Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance, Clinical Medicine, Vol: 16, Pages: 262-266, ISSN: 1470-2118
Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue.
Ollila MM, Piltonen T, Puukka K, et al., 2016, Weight gain and dyslipidemia in early adulthood associate with polycystic ovary syndrome: prospective cohort study, Journal of Clinical Endocrinology and Metabolism, Vol: 101, Pages: 739-747, ISSN: 0021-972X
CONTEXT: Obesity affects the majority of women with polycystic ovary syndrome (PCOS), but previous studies are inconsistent about the prevalence of obesity and the importance of weight gain in the development of the syndrome. OBJECTIVE: Our objective was to explore the association between weight, weight gain, hyperandrogenism, and PCOS from adolescence to late adulthood. DESIGN: The study includes a prospective Northern Finland Birth Cohort 1966 study including 5889 females born in 1966 and followed at the ages of 14, 31, and 46 years. SETTING: The setting was the general community. PARTICIPANTS: Women presenting both oligo/amenorrhea (OA) and hirsutism (H) at age 31 (N = 125) or with formally diagnosed PCOS by age 46 (N = 181) were compared with women without PCOS symptoms or diagnosis (n = 1577). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Body mass index (BMI), weight change through life, waist circumference, Free Androgen Index, lipids, glucose, insulin, high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance, and PCOS. RESULTS: Women with OA+H at age 31 or diagnosis of PCOS by age 46 had the highest BMI at all ages compared with the controls. Increase of BMI between ages 14 and 31, but not between 31 and 46, was greater in women with isolated OA (P = .006), OA+H (P = .001), and diagnosis of PCOS (P = .001) compared with controls. In the multivariate analysis, PCOS was significantly associated with BMI at all ages (BMI at age 31: odds ratio [OR] = 1.05 [95% confidence interval (CI), 1.00-1.10], Free Androgen Index (OR = 1.08 [95% CI, 1.03-1.14]), serum levels of insulin (OR = 1.05 [95% CI, 1.00-1.09]), and triglycerides (OR = 1.48 [95% CI, 1.08-2.03]). CONCLUSIONS: Symptoms or diagnosis of PCOS are associated with dyslipidemia, hyperandrogenemia, and significantly increased weight gain, especially in early adulthood. This observation is important because it may identify a sensitive time period when weight gain plays a crucial rol
Barber TM, Dimitriadis GK, Andreou A, et al., 2015, Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance., Clinical Medicine, Vol: 15, Pages: s72-s76, ISSN: 1473-4893
Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue.
Felix JF, Bradfield JP, Monnereau C, et al., 2015, Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index., Human Molecular Genetics, Vol: 25, Pages: 389-403, ISSN: 1460-2083
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
Kato N, Loh M, Takeuchi F, et al., 2015, Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation, Nature Genetics, Vol: 47, Pages: 1282-1293, ISSN: 1546-1718
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
Hayes MG, Urbanek M, Ehrmann DA, et al., 2015, Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations, Nature Communications, Vol: 6, ISSN: 2041-1723
Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder ofunknown aetiology characterized by hyperandrogenism, chronic anovulation and defects inglucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormonesecretion, insulin resistance and developmental exposure to androgens are hypothesized toplay a causal role in PCOS. Here we map common genetic susceptibility loci in Europeanancestry women for the National Institutes of Health PCOS phenotype, which confers thehighest risk for metabolic morbidities, as well as reproductive hormone levels. Three locireach genome-wide significance in the case–control meta-analysis, two novel loci mapping tochr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. Thesame chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide(FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels.These findings implicate neuroendocrine changes in disease pathogenesis.
Franks S, 2015, Polycystic ovary syndrome: not just a fertility problem., Womens Health, Vol: 11, Pages: 433-436, ISSN: 1745-5057
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women which typically presents itself during adolescence and is estimated to affect up to one in five of the female population of reproductive age [1]. As its name implies, ovarian dysfunction is a prominent feature of the syndrome. PCOS is the most prevalent cause of infertility due to infrequent or absent ovulation. Another important characteristic of PCOS is excessive secretion of ovarian androgens leading to distressing cutaneous symptoms of hirsutism, chronic acne and in some cases, alopecia. But PCOS is not just a disorder that affects ovarian function, it also has consequences for long-term health and it is the established (and potential) impact of these nonreproductive effects of PCOS on metabolic and cardiovascular health that has been the focus of a considerable interest and research in the recent years.
Franks S, 2015, Can Animal Models of PCOS Help Point the Way Towards Early and Effective Therapeutic Intervention in Women With the Syndrome?, ENDOCRINOLOGY, Vol: 156, Pages: 2371-2373, ISSN: 0013-7227
Ollila M, Piltonen T, Puukka K, et al., 2015, Body-mass-index and weight gain in early adulthood are associated with polycystic ovary syndrome (PCOS): prospective population-based cohort study, 31st Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 405-405, ISSN: 0268-1161
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