Imperial College London

ProfessorStephenFranks

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Clinical Professor
 
 
 
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Contact

 

+44 (0)20 7594 2109s.franks

 
 
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Assistant

 

Miss Kiran Dosanjh +44 (0)20 7594 4217

 
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Location

 

5007Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

310 results found

Kristensen SG, Kumar A, Kalra B, Pors SE, Bøtkjær JA, Mamsen LS, Colmorn LB, Fedder J, Ernst E, Owens L, Hardy K, Franks S, Andersen CYet al., 2019, Quantitative differences in TGF-β family members measured in small antral follicle fluids from women with or without PCO., Journal of Clinical Endocrinology and Metabolism, ISSN: 0021-972X

CONTEXT: Members of the Transforming-Growth-Factor-β (TGF-β) family have been implicated in aberrant follicle development in women with polycystic ovaries (PCO). OBJECTIVE: Are there quantitative differences in the concentrations of TGF-β family members in fluid from small antral follicles (hSAF) from women with or without PCO? DESIGN SETTING: & Follicle fluids (FF) were collected from 4-11 mm hSAF obtained from women undergoing ovarian tissue cryopreservation for fertility preservation. PATIENTS: FFs from 16 women with PCO (FF=93) and 33 women without PCO (FF=92). MAIN OUTCOME MEASURES: Intrafollicular concentrations of Growth-Differentiation-Factor-9 (GDF9), Anti-Müllerian-Hormone (AMH), inhibin-A and -B, total inhibin, activin-A, -B and -AB, follistatin, follistatin-like-3, estradiol, and testosterone. RESULTS: Activin-B concentrations are reported for the first time in hSAF and concentrations were 10 times higher than activin-A and -AB. Activin-B showed significant associations to other growth factors. Concentrations of inhibin-A and -B were significantly lower in FF from women with PCO, especially in hSAF below 8 mm in diameter. AMH concentrations did not differ between the groups in hSAF below 8 mm, however, AMH remained high in hSAF above 8 mm in PCO but decreased in non-PCO women. Estradiol was significantly lower in FF from women with PCO and showed significant associations with AMH. Concentrations of GDF9 are reported for the first time showing significantly higher concentrations in PCO FF of follicles above 6 mm. CONCLUSIONS: Altered concentrations of TGF-β family members in hSAF from women with PCO highlight altered growth factor signaling as a potential mechanism for follicle growth arrest.

Journal article

Owens LA, Kristensen SG, Lerner A, Christopoulos G, Lavery S, Hanyaloglu AC, Hardy K, Yding Andersen C, Franks Set al., 2019, Gene expression in granulosa cells from small antral follicles from women with or without polycystic ovaries., Journal of Clinical Endocrinology and Metabolism, ISSN: 0021-972X

CONTEXT: Polycystic ovary syndrome (PCOS) is the commonest cause of anovulation. A key feature of PCOS is arrest of follicles at the small-medium sized antral stage. OBJECTIVE AND DESIGN: To provide further insight into the mechanism of follicle arrest in PCOS, we profiled; (1) gonadotropin receptors; (2) characteristics of aberrant steroidogenesis, and (3) expression of anti-Mullerian hormone (AMH) and its receptor in granulosa cells (GCs) from unstimulated, human small antral follicles (hSAFs) and from granulosa-lutein cells (GLCs). SETTING: GCs from hSAFs were collected at the time of cryopreservation of ovarian tissue for fertility preservation and GLCs collected during oocyte aspiration before IVF/ICSI. PARTICIPANTS: hSAF GCs were collected from 31 women (98 follicles), 10 with polycystic ovaries (PCO) and 21 without. GLCs were collected from 6 women with PCOS and 6 controls undergoing IVF. MAIN OUTCOME MEASURES: Expression of the following genes: LHCGR, FSHR, AR, INSR, HSD3B2, CYP11A1, CYP19, STAR, AMH, AMHR2, FST, INHBA, INHBB in GCs and GLCs were compared between women with PCO and controls. RESULTS: GCs in hSAFs from PCO women showed higher expression of LHCGR in a subset (20%) of follicles. Expression of FSHR (p<0.05), AR (p<0.05), CYP11A1 (P<0.05) was lower, and expression of CYP19A1 (p<0.05), STAR (p<0.05), HSD3B2 (ns), INHBA (p<0.05) higher in PCO GCs. Gene expression in GL cells differed between women with and without PCOS but also differed from that in GCs. CONCLUSIONS: Follicle arrest in PCO is characterised in GCs by differential regulation of key genes involved in follicle growth and function.

Journal article

Teede H, Misso M, Tassone EC, Dewailly D, Ng EH, Azziz R, Norman RJ, Andersen M, Franks S, Hoeger K, Hutchison S, Oberfield S, Shah D, Hohmann F, Ottey S, Dabadghao P, Laven JSEet al., 2019, Anti-mullerian hormone in PCOS: A review informing international guidelines, Trends in Endocrinology and Metabolism, Vol: 30, Pages: 467-478, ISSN: 1879-3061

Polycystic ovary syndrome (PCOS) affects 8–13% of women. The Rotterdam diagnostic criteria include polycystic ovarian morphology (PCOM) on ultrasound, but given recognized challenges, serum anti-Müllerian hormone (AMH) is proposed as an alternative. To inform international PCOS guidelines, a systematic review was completed. Key identified gaps include large international studies in well-defined populations across the lifespan, clustering of AMH with PCOS features, relationships to long-term health outcomes, and improved quality, assay standardization, and sample handling, all needed to determine cut offs. Here we identify research priorities to address these gaps and enhance AMH utility in PCOS. Once issues are addressed, AMH levels could replace more costly and less accessible ultrasound in PCOS diagnosis.

Journal article

Bond TOM, Coin LJM, Loh M, Franks S, Elliott PAUL, Prokopenko I, Sebert S, Jarvelin MRet al., GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child and adult BMI, Science Advances, ISSN: 2375-2548

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here we combine genome-wide association studies with modelling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score and co-localization analyses to determine how developmental timings, molecular pathways and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult BMI, with variants associated with adult BMI acting as early as 4-6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Journal article

Granados-Aparici S, Hardy K, Franks S, Sharum IB, Waite SL, Fenwick MAet al., 2019, SMAD3 directly regulates cell cycle genes to maintain arrest in granulosa cells of mouse primordial follicles, Scientific Reports, Vol: 9, ISSN: 2045-2322

Primordial follicles, consisting of granulosa cell (GC)-enveloped oocytes are maintained in a state of developmental arrest until activated to grow. The mechanism that operates to maintain this arrested state in GCs is currently unknown. Here, we show the TGFβ-activated transcription factor SMAD3 is expressed in primordial GC nuclei alongside the cell cycle proteins, cyclin D2 (CCND2) and P27. Using neonatal C57/Bl6 mouse ovaries densely populated with primordial follicles, CCND2 protein co-localised and was detected in complex with P27 by immunofluorescence and co-immunoprecipitation, respectively. In the same tissue, SMAD3 co-precipitated with DNA sequences upstream of Ccnd2 and Myc transcription start sites implicating both as direct SMAD3 targets. In older ovaries follicle growth was associated with nuclear exclusion of SMAD3 and reduced P27 and CCND2 in GCs, alongside elevated Myc expression. Brief (2 H) exposure of neonatal ovaries to TGFβ1 (10 ng/ml) in vitro led to immediate dissociation of SMAD3 from the Ccnd2 and Myc promoters. This coincided with elevated Myc and phospho-S6, an indicator of mTOR signalling, followed by a small increase in mean primordial GC number after 48 H. These findings highlight a concentration-dependent role for TGFβ signalling in the maintenance and activation of primordial follicles, through SMAD-dependent and independent signalling pathways, respectively.

Journal article

Lerner A, Owens LA, Coates M, Simpson C, Poole G, Velupillai J, Liyanage M, Christopoulos G, Lavery S, Hardy K, Franks Set al., 2019, Expression of genes controlling steroid metabolism and action in granulosalutein cells of women with polycystic ovaries, Molecular and Cellular Endocrinology, Vol: 486, Pages: 47-54, ISSN: 0303-7207

IntroductionAberrant function of granulosa cells has been implicated in the pathophysiology of PCOS.Materials & methodsGranulosa lutein (GL) cells were collected during oocyte retrieval for IVF/ICSI. RT-qPCR was used to compare gene expression between 12 control women, 12 with ovulatory PCO and 12 with anovulatory PCOS. To examine which genes are directly regulated by androgens, GL cells from an additional 12 control women were treated in-vitro with 10 nM dihydrotestosterone (DHT).ResultsGL cells from women with PCOS showed reduced expression of CYP11A1 3-fold (p = 0.005), HSD17B1 1.8-fold (p = 0.02) and increased expression of SULT1E1 7-fold (p = 0.0003). Similar results were seen in ovulatory women with PCO. GL cells treated with 10 nM DHT showed a 4-fold (p = 0.03) increase in expression of SULT1E1 and a 5-fold reduction in SRD5A1 (p = 0.03).ConclusionsThese findings support the notion that aberrant regulation of steroid metabolism or action play a part in ovarian dysfunction in PCOS.

Journal article

Koivuaho E, Laru J, Ojaniemi M, Puukka K, Kettunen J, Tapanainen JS, Franks S, Järvelin M-R, Morin-Papunen L, Sebert S, Piltonen TTet al., 2019, Age at adiposity rebound in childhood is associated with PCOS diagnosis and obesity in adulthood-longitudinal analysis of BMI data from birth to age 46 in cases of PCOS, International Journal of Obesity, ISSN: 0307-0565

BACKGROUND: Adiposity rebound (AR), the second BMI rise in childhood at around the age of 6 years, is associated with obesity and metabolic alteration in later life. Given that polycystic ovary syndrome (PCOS) has a strong metabolic component, early life growth patterns could reveal a risk of PCOS. Thus, we aimed to investigate the associations between age at AR and PCOS diagnosis and BMI later in life. MATERIALS AND METHODS: This study is part of a prospective, population-based longitudinal study, where women with PCOS diagnosis by age 46 (n = 280) were compared with asymptomatic women (CTRLs, n = 1573). Weight and height data from birth to age 13 years, at age at menarche, and at ages 31 and 46 years were analyzed RESULTS: Women with PCOS had lower birth weight (3357 ± 477 vs. 3 445 ± 505 g, p < 0.001), earlier age at AR (5.2 ± 1.0 vs. 5.6 ± 0.90 years, p < 0.001) and higher BMI from AR onwards compared with controls. Early timing of AR was associated with PCOS diagnosis independently of BMI (OR 1.62, 95% Cl 1.37-1.92). Women with PCOS and early AR had higher BMI at 31 and 46 years when compared to controls with early AR. The age at AR did not associate with T levels at ages 31 or 46 years. CONCLUSIONS: Early AR was associated with PCOS diagnosis and high BMI in adulthood. Adolescent girls with early AR and persisting obesity should be screened for PCOS symptoms, such as persistent irregular cycles and hirsutism.

Journal article

Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, Kraft P, Lin N, Huang H, Broer L, Magi R, Saxena R, Laisk T, Urbanek M, Hayes MG, Thorleifsson G, Fernandez-Tajes J, Mahajan A, Mullin BH, Stuckey BGA, Spector TD, Wilson SG, Goodarzi MO, Davis L, Obermayer-Pietsch B, Uitterlinden AG, Anttila V, Neale BM, Jarvelin M-R, Fauser B, Kowalska I, Visser JA, Andersen M, Ong K, Stener-Victorin E, Ehrmann D, Legro RS, Salumets A, McCarthy MI, Morin-Papunen L, Thorsteinsdottir U, Stefansson K, Styrkarsdottir U, Perry JRB, Dunaif A, Laven J, Franks S, Lindgren CM, Welt CKet al., 2018, Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria, PLoS Genetics, Vol: 14, ISSN: 1553-7390

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comp

Journal article

Jayasena CN, Alkaabi FM, Liebers CS, Handley T, Franks S, Dhillo WSet al., 2018, A systematic review of randomised controlled trials investigating the efficacy and safety of testosterone therapy for female sexual dysfunction in postmenopausal women, Clinical Endocrinology, ISSN: 1365-2265

The clinical sequelae of oestrogen deficiency during menopause are undoubted. However, the pathophysiological role of testosterone during the menopause is less clear. Several randomised, placebo-controlled clinical trials suggest that testosterone therapy improves sexual function in post-menopausal women. Some studies suggest that testosterone therapy has additional effects which include increased bone mineral density and decreased serum high density lipoprotein (HDL) cholesterol. Furthermore, the long-term safety profile of testosterone therapy in post-menopausal women is not clear. This article will provide a concise and critical summary of the literature, to guide clinicians treating post-menopausal women. This article is protected by copyright. All rights reserved.

Journal article

Ollila M-ME, Kaikkonen K, Järvelin M-R, Huikuri HV, Tapanainen JS, Franks S, Piltonen TT, Morin-Papunen Let al., 2018, Self-reported polycystic ovary syndrome is associated with hypertension: a Northern Finland Birth Cohort 1966 Study, Journal of Clinical Endocrinology and Metabolism, ISSN: 0021-972X

Context: PCOS is associated with many traditional cardiovascular disease risk factors, but it is unclear whether PCOS is an independent risk factor for hypertension. Objective: To investigate in a population-based set-up whether PCOS associates with the risk of hypertension independently of body-mass-index (BMI), and with cardiovascular manifestations. Design: Cross-sectional assessments in the Northern Finland Birth Cohort 1966 at ages 31 and 46. Setting: General community. Participants: Women who reported both oligo/amenorrhea and hirsutism at age 31 and/or diagnosis of PCOS by age 46 (self-reported PCOS [srPCOS], n=279) and women without PCOS symptoms or diagnosis (n=1577). Intervention: None. Main Outcome Measures: Blood pressure (BP), BMI, cardiovascular manifestations. Results: Use of antihypertensive medication was significantly more common in women with srPCOS. At age 31, women with srPCOS had significantly higher systolic (SBP) and diastolic BP (DBP) than control women (SBP: normal-weight: 119.9±13.2 vs. 116.9±11.4mmHg, P=0.017; overweight/obese: 126.1±14.3 vs. 123.0±11.9mmHg, P=0.031; and DBP: normal-weight: 75.5±10.0 vs. 72.4±9.6mmHg, P=0.003; overweight/obese: 80.7±11.8 vs. 78.0±10.6mmHg, P=0.031). At age 46, srPCOS was significantly associated with hypertension (AOR=1.56 [1.14-2.13]) independently of BMI, and with higher cardiovascular morbidity (6.8% vs. 3.4%, P=0.011). Hypertensive srPCOS displayed consistent, unfavorable changes in cardiac structure and function compared with controls. Conclusion: Women with srPCOS displayed higher BP compared with controls already at early age and srPCOS was associated with hypertension independently of overweight/obesity. srPCOS was associated with increased cardiovascular morbidity in premenopausal women, suggesting that cardiovascular disease risk factors should be screened and efficiently managed early enough in women with PCOS.

Journal article

Hardy K, Mora JM, Dunlop C, Carzaniga R, Franks S, Fenwick MAet al., 2018, Nuclear exclusion of SMAD2/3 in granulosa cells is associated with primordial follicle activation in the mouse ovary, Journal of Cell Science, Vol: 131, ISSN: 0021-9533

Maintenance and activation of the limited supply of primordial follicles in the ovary are important determinants of reproductive lifespan. Currently, the molecular programme that maintains the primordial phenotype and the early events associated with follicle activation are not well defined. Here, we have systematically analysed these events using microscopy and detailed image analysis. Using the immature mouse ovary as a model, we demonstrate that the onset of granulosa cell (GC) proliferation results in increased packing density on the oocyte surface and consequent GC cuboidalization. These events precede oocyte growth and nuclear translocation of FOXO3a, a transcription factor important in follicle activation. Immunolabelling of the TGFβ signalling mediators and transcription factors SMAD2/3 revealed a striking expression pattern specific to GCs of small follicles. SMAD2/3 were expressed in the nuclei of primordial GCs but were mostly excluded in early growing follicles. In activated follicles, GC nuclei lacking SMAD2/3 generally expressed Ki67. These findings suggest that the first phenotypic changes during follicle activation are observed in GCs, and that TGFβ signalling is fundamental for regulating GC arrest and the onset of proliferation.

Journal article

Franks S, Hardy K, 2018, Androgen action in the ovary, Frontiers in Endocrinology, Vol: 9, ISSN: 1664-2392

Androgen production by the ovary is an essential requirement for normal cyclical secretion of estradiol but its physiological role extends to important actions on both preantral and antral follicle development, including promotion of granulosa cell proliferation. It is likely only in mature antral follicles that androgens encourage apoptosis and consequent follicle atresia, and this may be an important mechanism to ensure mono-follicular ovulation in primates, including humans. Recent studies have provided new insight into the mechanism of androgen signaling in the ovary which involves both genomic and non-genomic effects that are complementary in effecting a cellular response. In polycystic ovary syndrome, a condition characterized by intra-ovarian androgen excess, aberrant development of both preantral and antral follicles is a salient feature. We present evidence that local action of androgens plays a part in such abnormalities. Finally, we review the role of androgens in follicle atresia and conclude that the effects are part of the normal physiology of follicle maturation.

Journal article

Karjula S, Morin-Papunen L, Auvinen J, Franks S, Jarvelin MR, Tapanainen J, Jokelainen J, Miettunen J, Piltonen Tet al., 2018, Long-term health related quality of life (HRQoL), life satisfaction and health status in women with PCOS-a population-based follow-up analysis at ages 31 and 46, 34th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 444-445, ISSN: 0268-1161

Conference paper

White D, Hardy K, Lovelock S, Franks Set al., 2018, Low-dose gonadotropin induction of ovulation in anovulatory women - still needed in the age of IVF, Reproduction, Vol: 156, Pages: F1-F10, ISSN: 1470-1626

Low-dose, step-up gonadotropin is the treatment of choice for women with PCOS who have not conceived after anti-estrogen treatment, and as an effective alternative to pulsatile GnRH in women with hypogonadotropic hypogonadism (HH). There has been, however, no large-scale, comparative study between the two groups using low-dose gonadotropins. Here we performed a retrospective, comparative analysis, in a single clinic database, of efficacy and safety of induction of ovulation using low-dose gonadotropins in 364 Women with PCOS and 80 women with HH. The rate of ovulation was high in both PCOS (83%) and HH (84%) but mono-follicular, ovulatory cycles were more prevalent in PCOS than in HH (77% vs 53%, p<0.0001) and the proportion of cycles that were abandoned was higher in HH than in PCOS (25% vs 15%, p<0.0001). The median threshold dose of gonadotropin required to induce ovulation was 75iu/day in PCOS and 113iu/day in HH (p<0.001) and the range of doses was greater in HH women. Forty-nine percent of women with PCOS and 65% of those with HH conceived (more than 90% within 6 cycles of treatment) and had a least one pregnancy. Multiple pregnancies (all twins) occurred in only 4% of women with PCOS and 5% of those with HH. These findings emphasise the efficacy and safety of low-dose gonadotropin treatment for both clomiphene-resistant women with PCOS and those with HH. These results highlight the importance of choosing the more physiological approach of gonadotropin induction of ovulation in both groups as the most appropriate treatment, in preference to IVF.

Journal article

Laru J, Nedelec R, Ojaniemi M, Jarvelin MR, Tapanainen JS, Franks S, Sebert S, Piltonen TT, Morin-Papunen Let al., 2018, Childhood and adolescence body mass index associates with impaired reproductive function - a prospective, population-based cohort study, 34th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 448-449, ISSN: 0268-1161

Conference paper

Owens L, Abbara A, Lerner A, O'Floinn S, Christopoulos G, Khanjani S, Islam R, Liyanage M, Hardy K, Lavery S, Hanyaloglu A, Dhillo W, Franks Set al., 2018, The in vivo and in vitro effects of kisspeptin on human ovarian function, Publisher: SPRINGER LONDON LTD, Pages: S181-S182, ISSN: 0021-1265

Conference paper

Ernst EH, Franks S, Hardy K, Villesen P, Lykke-Hartmann Ket 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

Journal article

Jonas KC, Chen S, Virta M, Mora J, Franks S, Huhtaniemi I, Hanyaloglu ACet 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.

Journal article

Owens LA, Abbara A, Lerner A, O'floinn S, Christopoulos G, Khanjani S, Islam R, Hardy K, Hanyaloglu AC, Lavery SA, Dhillo WS, Franks Set 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

Journal article

Schierding W, Antony J, Karhunen V, Vaarasmaki M, Franks S, Elliott P, Kajantie E, Sebert S, Blakemore A, Horsfield JA, Jarvelin MR, O'Sullivan J, Cutfield WSet 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.

Journal article

Karjula S, Morin-Papunen L, Auvinen J, Ruokonen A, Puukka K, Franks S, Jarvelin M-R, Tapanainen JS, Jokelainen J, Miettunen J, Piltonen TTet 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.

Journal article

Couto Alves A, Valcarcel B, Makinen V, Morin-Papunen L, Sebert S, Kangas AJ, Sioninen P, Das S, De Iorio M, Coin L, Ala-Korpela M, Jarvelin MR, Franks Set 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.

Journal article

Ollila MM, West S, Keinanen-Kiukaaniemi S, Jokelainen J, Auvinen J, Puukka K, Ruokonen A, Jarvelin M-R, Tapanainen JS, Franks S, Piltonen TT, Morin-Papunen LCet 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

Journal article

Vimalesvaran S, Narayanaswamy S, Yang L, Prague JK, Buckley A, Miras AD, Franks S, Meeran K, Dhillo WSet 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

Journal article

Ollila M-ME, West S, Keinanen-Kiukaanniemi S, Jokelainen J, Auvinen J, Puukka K, Ruokonen A, Jarvelin M-R, Tapanainen JS, Franks S, Piltonen TT, Morin-Papunen LCet 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

Journal article

Laird M, Thomson K, Fenwick M, Mora J, Franks S, Hardy Ket 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.

Journal article

Hardy K, Fenwick M, Mora J, Laird M, Thomson K, Franks Set 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.

Journal article

Surendran P, Drenos F, Young R, Warren H, Cook JP, Manning AK, Grarup N, Sim X, Barnes DR, Witkowska K, Staley JR, Tragante V, Tukiainen T, Yaghootkar H, Masca N, Freitag DF, Ferreira T, Giannakopoulou O, Tinker A, Harakalova M, Mihailov E, Liu C, Kraja AT, Nielsen SF, Rasheed A, Samuel M, Zhao W, Bonnycastle LL, Jackson AU, Narisu N, Swift AJ, Southam L, Marten J, Huyghe JR, Stančáková A, Fava C, Ohlsson T, Matchan A, Stirrups KE, Bork-Jensen J, Gjesing AP, Kontto J, Perola M, Shaw-Hawkins S, Havulinna AS, Zhang H, Donnelly LA, Groves CJ, Rayner NW, Neville MJ, Robertson NR, Yiorkas AM, Herzig KH, Kajantie E, Zhang W, Willems SM, Lannfelt L, Malerba G, Soranzo N, Trabetti E, Verweij N, Evangelou E, Moayyeri A, Vergnaud AC, Nelson CP, Poveda A, Varga TV, Caslake M, de Craen AJ, Trompet S, Luan J, Scott RA, Harris SE, Liewald DC, Marioni R, Menni C, Farmaki AE, Hallmans G, Renström F, Huffman JE, Hassinen M, Burgess S, Vasan RS, Felix JF, CHARGE-Heart Failure Consortium, Uria-Nickelsen M, Malarstig A, Reilly DF, Hoek M, Vogt TF, Lin H, Lieb W, EchoGen Consortium, Traylor M, Markus HS, METASTROKE Consortium, Highland HM, Justice AE, Marouli E, GIANT Consortium, Lindström J, Uusitupa M, Komulainen P, Lakka TA, Rauramaa R, Polasek O, Rudan I, Rolandsson O, Franks PW, Dedoussis G, Spector TD, EPIC-InterAct Consortium, Jousilahti P, Männistö S, Deary IJ, Starr JM, Langenberg C, Wareham NJ, Brown MJ, Dominiczak AF, Connell JM, Jukema JW, Sattar N, Ford I, Packard CJ, Esko T, Mägi R, Metspalu A, de Boer RA, van der Meer P, van der Harst P, Lifelines Cohort Study, Gambaro G, Ingelsson E, Lind L, de Bakker PI, Numans ME, Brandslund I, Christensen C, Petersen ER, Korpi-Hyövälti E, Oksa H, Chambers JC, Kooner JS, Blakemore AI, Franks S, Jarvelin MR, Husemoen LL, Linneberg A, Skaaby T, Thuesen B, Karpe F, Tuomilehto J, Doney AS, Morris AD, Palmer CN, Holmen OL, Hveem K, Willer CJ, Tuomi T, Groop L, Käräjämäki A, Palotie A, Ripatti S, Salomaa V, Alam DS, Majumder AA, Di Anget 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.

Journal article

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