Publications
343 results found
Laru J, Ojaniemi M, Franks S, et al., 2022, An optimal growth pattern during pregnancy and early childhood associates with better fertility in men., Eur J Endocrinol, Vol: 187, Pages: 847-858
OBJECTIVE: This study aimed to evaluate the association between birth weight (BW), childhood and adolescent BMI, with reproductive capacity in men. DESIGN: A prospective, population-based cohort study (Northern Finland birth cohort 1966). METHODS: Around 6196 men born in 1966 were followed from birth to age 50 years. Weight and height were measured repeatedly by professionals. Reproductive capacity (infertility assessment, male factor infertility and infertility treatment by age 46 years) was evaluated by questionnaires at ages 31 and 46 years. The number of children by the age of 50 years was recovered from registers. After excluding the men who reported never having attempted to have children or not answering the question at age 31 or 46 years (n = 2041), 4128 men were included in the final study population. Results were adjusted for BW, BW for gestational age (GA), mother's smoking status, marital status, educational level and smoking status. RESULTS: Being small for GA (10.5% vs 8.2%, P = 0.012) or having a lower BW (3495 g vs 3548 g, P = 0.003) were associated with childlessness. The association was however no longer significant after adjusting for marital status. Being underweight in early childhood was associated with an increased risk of infertility assessment (adjusted, aOR: 2.04(1.07-3.81)) and childlessness (aOR: 1.47(1.01-2.17)) compared to the normal weight group. Conversely, overweight or obesity in early childhood was associated with a decreased risk of infertility assessment (aOR: 0.60 (0.41-0.87)), treatment (aOR: 0.42 (0.25-0.70)) and male factor infertility (aOR: 0.45 (0.21-0.97)). BMI in mid-childhood or puberty had no association with infertility or childlessness. CONCLUSION: In boys, an optimal growth trajectory during pregnancy and early childhood seems to be very important for life-long fertility.
Piltonen T, Morin-Papunen L, Ollila M-M, et al., 2022, Women self-reporting PCOS symptoms should not be overlooked, HUMAN REPRODUCTION, Vol: 38, Pages: 189-190, ISSN: 0268-1161
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Pölönen J, Pinola P, Ronkainen J, et al., 2022, Polycystic ovary syndrome and leukocyte telomere length: cross-sectional and longitudinal changes, European Journal of Endocrinology, Vol: 187, Pages: 651-661, ISSN: 0804-4643
Objective Telomeres are DNA-protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular ageing. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardio-metabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population. Design Population-based cohort study: women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (PCOS) (age 31:N=190; age 46:N=207) and referent women (age 31:N=1054; age 46:N=1324) with data on LTL. Methods The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age. Results Women with PCOS had similar mean LTL at ages 31 and 46 (P>0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P=0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P<0.001), but not in women with PCOS (P=0.96). Conclusions This finding may suggest a difference in LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms.
Joham AE, Norman RJ, Stener-Victorin E, et al., 2022, Polycystic ovary syndrome, LANCET DIABETES & ENDOCRINOLOGY, Vol: 10, Pages: 668-680, ISSN: 2213-8587
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Kujanpaa L, Arffman RK, Pesonen P, et al., 2022, Women with polycystic ovary syndrome are burdened with multimorbidity and medication use independent of body mass index at late fertile age: a population-based cohort study, Acta Obstetricia et Gynecologica Scandinavica, Vol: 101, Pages: 728-736, ISSN: 0001-6349
IntroductionThis population-based follow-up study investigated the comorbidities, medication use, and healthcare services among women with polycystic ovary syndrome (PCOS) at age 46 years.Material and methodsThe study population derived from the Northern Finland Birth Cohort 1966 and consisted of women reporting oligo/amenorrhea and hirsutism at age 31 years and/or a PCOS diagnosis by age 46 years (n = 246) and controls without PCOS symptoms or diagnosis (n = 1573), referred to as non-PCOS women. The main outcome measures were self-reported data on symptoms, diagnosed diseases, and medication and healthcare service use at the age of 46 years.ResultsOverall morbidity risk was increased by 35% (risk ratio [RR] 1.35, 95% confidence interval [CI] 1.16–1.57) and medication use by 27% [RR 1.27, 95% CI 1.08–1.50) compared with non-PCOS women, and the risk remained after adjusting for body mass index. Diagnoses with increased prevalence in women with PCOS were migraine, hypertension, tendinitis, osteoarthritis, fractures, and endometriosis. PCOS was also associated with autoimmune diseases and recurrent upper respiratory tract infections and symptoms. Interestingly, healthcare service use did not differ between the study groups after adjusting for body mass index.ConclusionsWomen with PCOS are burdened with multimorbidity and higher medication use, independent of body mass index.
Kristensen SG, Kumar A, Mamsen LS, et al., 2022, Intrafollicular concentrations of the oocyte-secreted factors GDF9 and BMP15 vary inversely in polycystic ovaries, Journal of Clinical Endocrinology and Metabolism, Vol: 107, Pages: E3374-E3383, ISSN: 0021-972X
ContextThe oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome.ObjectiveAre there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)?Design and SettingFollicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation.PatientsTwenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size.Main outcome measuresIntrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays.ResultsThe detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL [mean ± SEM], n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO.ConclusionsIntrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new
Karjula S, Arffman RK, Morin-Papunen L, et al., 2022, A population-based follow-up study shows high psychosis risk in women with PCOS, Archives of Womens Mental Health, Vol: 25, Pages: 301-311, ISSN: 1434-1816
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 18% of women. Besides metabolic and fertility aspects, attention has lately been directed towards the detrimental effect of PCOS on psychological health. The objective of the study was to investigate whether women with PCOS are at higher risk for psychotic disorders. The study population derives from the Northern Finland Birth Cohort 1966 (N = 5889 women). The women with PCOS were identified by two simple questions on oligo-amenorrhea and hirsutism at age 31. Women reporting both symptoms were considered PCOS (N = 124) and asymptomatic women as controls (N = 2145). The diagnosis of psychosis was traced using multiple national registers up to the year 2016. Symptoms of psychopathology were identified using validated questionnaires at age 31. Women with PCOS showed an increased risk for any psychosis by age 50 (HR [95% CI] 2.99, [1.52–5.82]). Also, the risk for psychosis after age 31 was increased (HR 2.68 [1.21–5.92]). The results did not change after adjusting for parental history of psychosis, nor were they explained by body mass index or hyperandrogenism at adulthood. The scales of psychopathology differed between women with PCOS and non-PCOS controls showing more psychopathologies among the affected women. PCOS cases were found to be at a three-fold risk for psychosis, and they had increased psychopathological symptoms. PCOS should be taken into consideration when treating women in psychiatric care. More studies are required to further assess the relationship between PCOS and psychotic diseases.
Sayers S, Anujan P, Yu H, et al., 2022, Follicle-stimulating hormone induces lipid droplets via Gαi/o and β- arrestin in an endometrial cancer cell line, Frontiers in Endocrinology, Vol: 12, Pages: 1-15, ISSN: 1664-2392
Follicle-stimulating hormone (FSH) and its G protein-coupled receptor, FSHR, represents a paradigm for receptor signaling systems that activate multiple and complex pathways. Classically, FSHR activates Gαs to increase intracellular levels of cAMP, but its ability to activate other G proteins, and β-arrestin-mediated signaling is well documented in many different cell systems. The pleiotropic signal capacity of FSHR offers a mechanism for how FSH drives multiple and dynamic downstream functions in both gonadal and non-gonadal cell types, including distinct diseases, and how signal bias may be achieved at a pharmacological and cell system-specific manner. In this study, we identify an additional mechanism of FSH-mediated signaling and downstream function in the endometrial adenocarcinoma Ishikawa cell line. While FSH did not induce increases in cAMP levels, this hormone potently activated pertussis toxin sensitive Gαi/o signaling. A selective allosteric FSHR ligand, B3, also activated Gαi/o signaling in these cells, supporting a role for receptor-mediated activation despite the low levels of FSHR mRNA. The low expression levels may attribute to the lack of Gαs/cAMP signaling as increasing FSHR expression resulted in FSH-mediated activation of the Gαs pathway. Unlike prior reports for FSH-mediated Gαs/cAMP signaling, FSH-mediated Gαi/o signaling was not affected by inhibition of dynamin-dependent receptor internalization. While chronic FSH did not alter cell viability, FSH was able to increase lipid droplet size. The β-arrestins are key adaptor proteins known to regulate FSHR signaling. Indeed, a rapid, FSH-dependent increase in interactions between β-arrestin1 and Gαi1 was observed via NanoBiT complementation in Ishikawa cells. Furthermore, both inhibition of Gαi/o signaling and siRNA knockdown of β-arrestin 1/2 significantly reduced FSH-induced lipid droplet accumulation, implying a role for a
Laru J, Nedelec R, Koivuaho E, et al., 2021, BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years, Human Reproduction, Vol: 36, Pages: 2948-2961, ISSN: 0268-1161
STUDY QUESTION: What is the association between childhood and adolescent BMI and reproductive capacity in women? SUMMARY ANSWER: Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). WHAT IS KNOWN ALREADY: Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. STUDY DESIGN, SIZE, DURATION: A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth registe
Tuorila K, Ollila M-M, Järvelin M-R, et al., 2021, Hyperandrogenemia in early adulthood is an independent risk factor for abnormal glucose metabolism in middle age, Journal of Clinical Endocrinology and Metabolism, Vol: 106, Pages: e4621-e4633, ISSN: 0021-972X
CONTEXT: The role of androgen excess as a contributing factor to abnormal glucose metabolism (AGM) and insulin resistance in women remains controversial. OBJECTIVE: To investigate whether hyperandrogenemia (HA) estimated by serum testosterone (T) level and free androgen index (FAI) at ages 31 and 46 is associated with insulin resistance, insulin secretion and AGM by age 46. DESIGN: Prospective study including 5,889 females followed at ages 31 and 46. SETTING: General community. PARTICIPANTS: Women with HA were compared with normoandrogenic women at ages 31 and 46. INTERVENTION: None. MAIN OUTCOME MEASUREMENTS: AGM, including pre-diabetes and T2DM, homeostatic model assessments of insulin resistance (HOMA-IR) and of pancreatic β-cell function (HOMA-B). RESULTS: At age 31, HA women displayed increased HOMA-IR P=0.05), HOMA-B (P=0.006), and higher fasting insulin (P=0.034) than normoandrogenic women after adjusting for body mass index (BMI). At age 46, there was a nonsignificant trend towards higher fasting glucose (P=0.07) and glycated hemoglobin A1 (P=0.067) levels in HA women. Women in the highest T quartile (odds ratio [OR]= 1.80;95%CI, 1.15-2.82) at age 31 and in the two highest FAI quartiles at ages 31 (Q4:OR=3.76;95%CI, 2.24-6.32) and 46 (Q4:OR=2.79;95%CI, 1.74-4.46) had increased risk for AGM, independently of BMI, when compared with women in Q1. Sex hormone-binding globulin (SHBG) was inversely associated with AGM (at age 31:Q4:OR=0.37;95%CI, 0.23-0.60, at age 46:Q4:OR=0.28;95%CI, 0.17-0.44). CONCLUSION: Hyperandrogenemia and low SHBG in early and middle age associates with AGM independently of BMI.
Barber TM, Franks S, 2021, Obesity and polycystic ovary syndrome, Clinical Endocrinology, Vol: 95, Pages: 531-541, ISSN: 0300-0664
The increased global prevalence of obesity over the last 40‐years has driven a rise in prevalence of obesity‐related co‐morbidities, including polycystic ovary syndrome (PCOS). On a background of genetic susceptibility, PCOS often becomes clinically manifest following weight gain, commonly during adolescence. A common endocrinopathy affecting between 6%‐10% of reproductive‐age women, PCOS presents with the cardinal features of hyperandrogenism, reproductive and metabolic dysfunction. PCOS associates with insulin resistance, independently of (but amplified by) obesity. Insulin resistance in PCOS is characterized by abnormal post‐receptor signalling within the phosphatidylinositol‐kinase (PI3‐K) pathway. Multiple factors (including most notably, weight gain) contribute towards the severity of insulin resistance in PCOS. Compensatory hyperinsulinaemia ensues, resulting in over‐stimulation of the (intact) post‐receptor mitogen‐activated protein kinase (MAP‐K) insulin pathway, with consequent implications for steroidogenesis and ovarian function. In this concise review, we explore the effects of weight gain and obesity on the pathogenesis of PCOS from the perspective of its three cardinal features of hyperandrogenism, reproductive and metabolic dysfunction, with a focus on the central mediating role of the insulin pathway. We also consider key lifestyle strategies for the effective management of obese and overweight women with PCOS.
Hopkins T, Bemmer V, Franks S, et al., 2021, Micromechanical mapping of the intact ovary interior reveals contrasting mechanical roles for follicles and stroma, Biomaterials, Vol: 277, Pages: 1-9, ISSN: 0142-9612
Follicle development in the ovary must be tightly regulated to ensure cyclical release of oocytes (ovulation). Disruption of this process is a common cause of infertility, for example via polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). Recent ex vivo studies suggest that follicle growth is mechanically regulated, however, crucially, the actual mechanical properties of the follicle microenvironment have remained unknown. Here we use atomic force microscopy (AFM) spherical probe indentation to map and quantify the mechanical microenvironment in the mouse ovary, at high resolution and across the entire width of the intact (bisected) ovarian interior. Averaging over the entire organ, we find the ovary to be a fairly soft tissue comparable to fat or kidney (mean Young’s Modulus 3.3 +/-2.5 kPa). This average, however, conceals substantial spatial variations, with the overall range of tissue stiffnesses from c. 0.5 –10 kPa, challenging the concept that a single Young’s Modulus can effectively summarize this complex organ. Considering the internal architecture of the ovary, we find that stiffness is low at the edge and centre which are dominated by stromal tissue, and highest in an intermediate zone that is dominated by large developmentally-advanced follicles, confirmed by comparison with immunohistology images. These results suggest that largefollicles are mechanically dominant structures in the ovary, contrasting with previous expectations that collagen-rich stroma would dominate. Extending our study to the highest resolutions (c. 5 μm) showed substantial mechanical variations within the larger zones, even over very short (sub-100 μm) lengths, and especially within the stiffer regions of the ovary. Taken together, our results provide a new, physiologically accurate, framework for ovaria
Abou Sherif S, Newman R, Haboosh S, et al., 2021, Investigating the potential of clinical and biochemical markers to differentiate between functional hypothalamic amenorrhoea and polycystic ovarian syndrome: A retrospective observational study, CLINICAL ENDOCRINOLOGY, Vol: 95, Pages: 618-627, ISSN: 0300-0664
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Surendran P, Feofanova EV, Lahrouchi N, et al., 2021, Publisher Correction: Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals, Nature Genetics, Vol: 53, Pages: 1-2, ISSN: 1061-4036
Rantakallio JSS, Nevalainen JE, West S, et al., 2021, Association of Self-Reported Polycystic Ovary Syndrome, Obesity, and Weight Gain From Adolescence to Adulthood With Hypertensive Disorders of Pregnancy A Community-Based Approach, HYPERTENSION, Vol: 77, Pages: 1010-1019, ISSN: 0194-911X
Al Wattar BH, Bueno A, Martin MG, et al., 2021, Harmonizing research outcomes for polycystic ovary syndrome (HARP), a marathon not a sprint: current challenges and future research need, Human Reproduction, Vol: 36, Pages: 523-528, ISSN: 0268-1161
Investing in clinical research and evidence-based medicine has helped to improve the care for women with polycystic ovary syndrome (PCOS). However, several important questions remain unanswered on the optimal prevention and management strategies for PCOS. Addressing this uncertainty is often hindered by suboptimal research conduct leading to inefficient evidence synthesis and research wastage. PCOS research is often practised by varied specialized teams in silo leading to disharmonious and fragmented efforts neglecting the lifelong impact of PCOS on women's wellbeing. Poor engagement among key stakeholders and lay consumers continues to limit the impact and benefits of research to society. Selective reporting on surrogate outcomes with a 'significant' P-value is a common malpractice in PCOS outputs. Effective adoption of the harmonizing research outcomes for PCOS (HARP) core outcome set is needed to minimize heterogeneity in reporting and promote research excellence. Small single-centre studies offer limited value to assess the varied PCOS phenotypes. Efficient large scale data-sharing is needed to address complex research questions and glean the benefits of big data research. We propose a roadmap to address these challenges and remedy future research need by promoting patient and public involvement in PCOS research to guide research efforts and address real patients' needs; engaging all key stakeholder groups to promote a multi-disciplinary lifelong approach to new research; continuously refining research needs and priorities to revise the knowledge gap and allocate resources judiciously; standardizing outcomes definitions and measurement tools to harmonize reporting and promote excellence in research; and by investing in large data-sharing infrastructure to facilitate big data research and govern ethical data sharing.
Lüll K, Arffman RK, Sola-Leyva A, et al., 2021, The Gut microbiome in polycystic ovary syndrome and its association with metabolic traits, Journal of Clinical Endocrinology and Metabolism, Vol: 106, Pages: 858-871, ISSN: 0021-972X
CONTEXT: Despite gut microbiome being widely studied in metabolic diseases, its role in polycystic ovary syndrome (PCOS) has been scarcely investigated. OBJECTIVE: Compare the gut microbiome in late fertile age women with and without PCOS and investigate whether changes in the gut microbiome correlate with PCOS-related metabolic parameters. DESIGN: Prospective, case-control study using the Northern Finland Birth Cohort 1966. SETTING: General community. PARTICIPANTS: 102 PCOS women and 201 age- and body mass index (BMI)-matched non-PCOS control women. Clinical and biochemical characteristics of the participants were assessed at ages 31 and 46 and analyzed in the context of gut microbiome data at the age of 46. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Bacterial diversity, relative abundance, and correlations with PCOS-related metabolic measures. RESULTS: Bacterial diversity indices did not differ significantly between PCOS and controls (Shannon diversity p = 0.979, unweighted UniFrac p = 0.175). Four genera whose balance helps to differentiate between PCOS and non-PCOS were identified. In the whole cohort, the abundance of two genera from Clostridiales, Ruminococcaceae UCG-002 and Clostridiales Family XIII AD3011 group, were correlated with several PCOS-related markers. Prediabetic PCOS women had significantly lower alpha diversity (Shannon diversity p = 0.018) and markedly increased abundance of genus Dorea (FDR = 0.03) compared to women with normal glucose tolerance. CONCLUSION: PCOS and non-PCOS women at late fertile age with similar BMI do not significantly differ in their gut microbial profiles. However, there are significant microbial changes in PCOS individuals depending on their metabolic health.
Hopkins T, Bemmer V, Franks S, et al., 2021, Mapping the mechanical microenvironment in the ovary, Publisher: Bioarxiv
Follicle development in the human ovary must be tightly regulated to ensure cyclical release of oocytes (ovulation), and disruption of this process is a common cause of infertility. Recent ex vivo studies suggest that follicle growth may be mechanically regulated, however the actual mechanical properties of the follicle microenvironment have remained unknown. Here we map and quantify the mechanical microenvironment in mouse ovaries using colloidal probe atomic force microscope (AFM) indentation, finding an overall mean Young's Modulus 3.3 ± 2.5 kPa. Spatially, stiffness is low at the ovarian edge and centre, which are dominated by extra-follicular ECM, and highest in an intermediate zone dominated by large follicles. This suggests that large follicles should be considered as mechanically dominant structures in the ovary, in contrast to previous expectations. Our results provide a new, physiologically accurate framework for investigating how mechanics impacts follicle development and will underpin future tissue engineering of the ovary.
Lerner A, Kewada D, Ahmed A, et al., 2021, Androgen reduces mitochondrial respiration in mouse brown adipocytes: a model for disordered energy balance in polycystic ovary syndrome, International Journal of Molecular Sciences, Vol: 22, ISSN: 1422-0067
Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including reduced postprandial thermogenesis. Although abnormalities in adipose tissue function have been widely reported in women with PCOS, less is known about direct effects of androgen on white and, particularly, brown adipocytes. The purpose of this study was to investigate the effect of the nonaromatizable androgen dihydrotestosterone (DHT) on (1) lipid accumulation and expression of adipogenic markers in immortalized mouse brown adipose cell lines (IMBATs), (2) mitochondrial respiration in IMBATs, (3) mitochondrial DNA content and gene expression, (4) expression of brown adipose tissue (BAT) markers and thermogenic activation. In addition, we profiled the relative levels of 38 adipokines secreted from BAT explants and looked at androgen effects on adipokine gene expression in both IMBATs and immortalized mouse white adipose (IMWATs) cell lines. Androgen treatment inhibited IMBAT differentiation in a dose-dependent manner, reduced markers of adipogenesis, and attenuated the β-adrenoceptor-stimulated increase in uncoupling protein-1 (UCP1) expression. In explants of mouse interscapular BAT, androgen reduced expression of UCP1, peroxisome proliferator-activated receptor-γ coactivator-1 (PCG-1) and Cidea. Significantly, as well as affecting genes involved in thermogenesis in BAT, androgen treatment reduced mitochondrial respiration in IMBATs, as measured by the Seahorse XF method. The results of this study suggest a role for excess androgen in inhibiting brown adipogenesis, attenuating the activation of thermogenesis and reducing mitochondrial respiration in BAT. Together, these data provide a plausible molecular mechanism that may contribute to reduced postprandial thermogenesis and the tendency to obesity in women with PCOS.
Siemienowicz KJ, Coukan F, Franks S, et al., 2021, Aberrant subcutaneous adipogenesis precedes adult metabolic dysfunction in an ovine model of polycystic ovary syndrome (PCOS), Molecular and Cellular Endocrinology, Vol: 519, ISSN: 0303-7207
Polycystic ovary syndrome (PCOS) affects over 10% of women. Insulin resistance, elevated free fatty acids (FFAs) and increased adiposity are key factors contributing to metabolic dysfunction in PCOS. We hypothesised that aberrant adipogenesis during adolescence, and downstream metabolic perturbations, contributes to the metabolic phenotype of adult PCOS. We used prenatally androgenised (PA) sheep as a clinically realistic model of PCOS. During adolescence, but not during fetal or early life of PA sheep, adipogenesis was decreased in subcutaneous adipose tissue (SAT) accompanied by decreased leptin, adiponectin, and increased FFAs. In adulthood, PA sheep developed adipocyte hypertrophy in SAT paralleled by increased expression of inflammatory markers, elevated FFAs and increased expression of genes linked to fat accumulation in visceral adipose tissue. This study provides better understanding into the pathophysiology of PCOS from puberty to adulthood and identifies opportunity for early clinical intervention to normalise adipogenesis and ameliorate the metabolic phenotype.
Surendran P, Gao H, Zhang W, et al., 2020, Discovery of rare variants associated with blood pressure regulation trhough meta-analaysis of 1.3 million individuals, Nature Genetics, Vol: 52, Pages: 1314-1332, ISSN: 1061-4036
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (e.g.GATA5, PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
West S, Ollila M-M, Franks S, et al., 2020, Overweight, obesity and hyperandrogenemia are associated with gestational diabetes mellitus: A follow-up cohort study, Acta Obstetricia et Gynecologica Scandinavica, Vol: 99, Pages: 1311-1319, ISSN: 0001-6349
IntroductionThe aim of the study was to determine the association of body mass index (BMI), self‐reported symptoms or diagnosis of polycystic ovary syndrome (PCOS), and hyperandrogenemia with the occurrence of gestational diabetes mellitus (GDM) through reproductive life.Material and methodsA cohort of women born in 1966 were investigated at ages 14, 31 and 46. Women with self‐reported PCOS symptoms (presence of both oligo‐amenorrhea and hirsutism) at age 31 or with formally diagnosed polycystic ovaries (PCO)/PCOS by age 46 formed the group of self‐reported PCOS (srPCOS, n = 222) and were compared with women without self‐reported PCOS symptoms or diagnosis (n = 1357). We investigated also the association of hyperandrogenism (hirsutism or biochemical hyperandrogenism) at age 31 with the occurrence of GDM throughout reproductive life.ResultsSelf‐reported PCOS alone was not a risk factor for GDM, but combined with overweight at age 31 (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.22‐4.86) or 46 (OR 3.04, 95% CI 1.58‐5.83) srPCOS was associated with GDM when compared with normal weight controls. The association disappeared when comparing overweight srPCOS women with overweight controls. However, hyperandrogenemia at age 31, but not hirsutism, was associated with GDM even after adjustment for BMI.ConclusionsThe increased risk of GDM in women with srPCOS was mostly attributed to overweight or obesity. Importantly, normal weight women with srPCOS did not seem to be at increased risk for developing GDM. However, hyperandrogenemia was associated with GDM even after adjustment for BMI. These findings strengthen the importance of weight management in reproductive‐age women and suggest a noteworthy role of hyperandrogenemia in the pathophysiology of GDM.
Pinola P, Polonen J, Ronkainen J, et al., 2020, Polycystic ovary syndrome and leukocyte telomere length: results of cross-sectional and longitudinal analyses in a birth cohort study, 36th Virtual Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 85-85, ISSN: 0268-1161
Siemienowicz K, Rae MT, Howells F, et al., 2020, Insights into manipulating postprandial energy expenditure to manage weight gain in polycystic ovary syndrome., iScience, Vol: 23, Pages: 1-22, ISSN: 2589-0042
Women with polycystic ovary syndrome (PCOS) are more likely to be obese and have difficulty in losing weight. They demonstrate an obesity-independent deficit in adaptive energy expenditure. We used a clinically realistic preclinical model to investigate the molecular basis for the reduced postprandial thermogenesis (PPT) and develop a therapeutic strategy to normalize this deficit. Sheep exposed to increased androgens before birth develop the clinical features of PCOS. In adulthood they develop obesity and demonstrate an obesity-independent reduction in PPT. This is associated with reduced adipose tissue uncoupling protein expression and adipose tissue noradrenaline concentrations. These sheep are insulin resistant with reduced insulin signaling in the brain. Increasing brain insulin concentrations using intranasal insulin administration increased PPT in PCOS sheep without any effects on blood glucose concentrations. Intranasal insulin administration with food is a potential novel strategy to improve adaptive energy expenditure and normalize the responses to weight loss strategies in women with PCOS.
Hayes MG, Urbanek M, Ehrmann DA, et al., 2020, Publisher correction: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations., Nature Communications, Vol: 11, Pages: 1-1, ISSN: 2041-1723
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Al Wattar BH, Teede H, Garad R, et al., 2020, Harmonising research outcomes for polycystic ovary syndrome: an international multi-stakeholder core outcome set, Human Reproduction, Vol: 35, Pages: 404-412, ISSN: 0268-1161
STUDY QUESTION: What are the key core outcomes to be reported in studies on polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We identified 3 generic and 30 specific core outcomes in 6 specialist domains: metabolic (8), reproductive (7), pregnancy (10), oncological (1), psychological (1) and long-term outcomes (1). WHAT IS KNOWN ALREADY: Research reporting PCOS is heterogeneous with high variation in outcome selection, definition and quality. STUDY DESIGN, SIZE, DURATION: Evidence synthesis and a modified Delphi method with e-surveys were used as well as a consultation meeting. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 71 health professionals and 123 lay consumers (women with lived experience of PCOS and members of advocacy and peer support groups) from 17 high-, middle- and low-income countries were involved in this analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The final core outcome set included 3 generic outcomes (BMI, quality of life, treatment satisfaction) that are applicable to all studies on women with PCOS and 30 specific outcomes that were categorised into six specialist domains: 8 metabolic outcomes (waist circumference, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypertension, coronary heart disease, lipid profile, venous thromboembolic disease); 7 reproductive outcomes [viable pregnancy (confirmed by ultrasound including singleton, twins and higher multiples), clinical and biochemical hyperandrogenism, menstrual regularity, reproductive hormonal profile, chronic anovulation, ovulation stimulation success including the number of stimulated follicles ≥ 12 mm, incidence and severity of ovarian hyperstimulation syndrome]; 10 pregnancy outcomes (live birth, miscarriage, stillbirth, neonatal mortality, gestational weight gain, gestational diabetes, preterm birth, hypertensive disease in pregnancy, baby birth weight, major congenital abnormalities); 3 psychological outcomes (depression, anxiety, eating disor
Karjula S, Morin-Papunen L, Franks S, et al., 2020, Population-based data at ages 31 and 46 show decreased HRQoL and life satisfaction in women with PCOS symptoms., Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: 1-13, ISSN: 0021-972X
CONTEXT: Polycystic ovary syndrome (PCOS) is associated with decreased health-related quality of life (HRQoL), but longitudinal data beyond the reproductive years are lacking, and the impact of isolated PCOS symptoms is unclear. OBJECTIVE: To study generic HRQoL using 15D, life satisfaction, and self-reported health status in women with PCOS symptoms at ages 31 and 46yr. DESIGN: A longitudinal assessment using the Northern Finland Birth Cohort 1966. SETTING: General community. PARTICIPANTS: The 15D data were available for women reporting isolated oligomenorrhea (OA;at age 31yr:214 and 46yr: 211), isolated hirsutism (H; 31yr:211 and 46yr:216), OA+H (PCOS; 31yr:74 and 46yr:75), or no PCOS symptoms (controls; 31yr:1382 and 46yr:1412). Data for life satisfaction and current health status were available for OA (31yr:329 and 46yr:247), H (31yr:323 and 46yr:238), PCOS (31yr:125 and 46yr:86), control (31yr:2182 and 46yr:1613) groups. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): 15D HRQoL, questionnaires on life satisfaction, and self-reported health status. RESULTS: HRQoL was lower at ages 31 and 46 in women with PCOS or H compared with the controls. PCOS was an independent risk factor for low HRQoL, and the decrease in HRQoL in PCOS was comparable to that of women with other chronic conditions, like asthma, migraine, rheumatoid arthritis, and depression. The risk for low HRQoL in PCOS remained significant after adjusting for BMI, hyperandrogenism, and socioeconomic status. Mental distress was the strongest contributing factor to HRQoL. PCOS was also associated with a risk for low life satisfaction and a 4-fold risk for reporting a poor health status. CONCLUSIONS: Women with PCOS present with low HRQoL, decreased life satisfaction, and a poorer self-reported health status up to their late reproductive years. Assessments and interventions aiming to improve HRQoL in PCOS should be targeted beyond fertile age.
Ollila M-M, Kiviniemi A, Stener-Victorin E, et al., 2019, Effect of polycystic ovary syndrome on cardiac autonomic function at a late fertile age: a prospective Northern Finland Birth Cohort 1966 study, BMJ Open, Vol: 9, Pages: e033780-e033780, ISSN: 2044-6055
OBJECTIVES: Previous studies of women in their 20s and 30s have reported impaired autonomic function in women with polycystic ovary syndrome (PCOS). We aimed to study, for the first time, whether PCOS is associated with impaired cardiac autonomic function independent of metabolic and hormonal status in their late reproductive years. DESIGN: A prospective Northern Finland Birth Cohort 1966 (NFBC1966) study including 5889 women born in 1966 and followed through the age of 46. At that age, n=3706/5123 women (72%) answered the postal questionnaires and n=3280/5123 women (64%) participated in the clinical examination. SETTING: General community. PARTICIPANTS: The sample included women presenting both irregular menses (oligomenorrhoea or amenorrhoea) and hirsutism at age 31 (n=125) or with formally diagnosed PCOS by age 46 (n=181) and women without PCOS symptoms or diagnosis (n=1577). PRIMARY AND SECONDARY OUTCOME MEASURES: Heart rate variability parameters: the root mean square of successive R-R differences (rMSSD), spectral power densities (LF: low frequency and HF: high frequency) and baroreflex sensitivity (BRS). RESULTS: We found that parasympathetic activity (assessed by rMSSD: 19.5 (12.4; 31.9) vs 24.3 (16.1; 34.8) ms, p=0.004 and HF: 172 (75; 399) vs 261 (112; 565) ms2, p=0.002) and BRS (6.13±3.12 vs 6.99±3.52 ms/mm Hg, p=0.036) were lower in women with PCOS compared with the controls. However, in the multivariate regression analysis, PCOS, body mass index and the free androgen index did not significantly associate with rMSSD, whereas blood pressure, insulin resistance and triglycerides did. CONCLUSIONS: We report here for the first time that late reproductive-aged women with PCOS display impaired cardiac autonomic function manifested as decreased vagal activity. Metabolic status, rather than hyperandrogenaemia and PCOS per se, was the strongest contributing factor. Given the link between cardiac morbidity and impaired autonomic functio
Kristensen SG, Kumar A, Kalra B, et 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, Vol: 104, Pages: 6371-6384, 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.
Owens LA, Kristensen SG, Lerner A, et al., 2019, Gene expression in granulosa cells from small antral follicles from women with or without polycystic ovaries, Journal of Clinical Endocrinology and Metabolism, Vol: 104, Pages: 6182-6192, 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.
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