Publications by authors named "Laure Morin-Papunen"

65 Publications

Markers of gastrointestinal permeability and dysbiosis in premenopausal women with PCOS: a case-control study.

BMJ Open 2021 07 5;11(7):e045324. Epub 2021 Jul 5.

Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland.

Objectives: Altered intestinal permeability and gut barrier dysfunction have been suggested to play a role in the pathogenetic mechanism of polycystic ovary syndrome (PCOS), the most common endocrine and metabolic condition in reproductive-aged women. However, data on intestinal permeability and dysbiosis of the gut microbiota in PCOS is still limited, with conflicting results. To this end, the concentrations of gastrointestinal permeability and gut dysbiosis markers were analysed in women with PCOS.

Design: Case-control study.

Setting: General community.

Participants: 104 women with PCOS and 203 body mass index (BMI) matched control women at age 46.

Primary And Secondary Outcome Measures: Serum levels of zonulin, fatty acid-binding protein 2 (FABP2), urinary levels of indican, and hormonal and metabolic parameters.

Results: Serum levels of zonulin (128.0±17.0 vs 130.9±14.0 ng/mL, p=0.13) and FABP2 (1.5±0.9 vs 1.5±0.7 ng/mL, p=0.63) and urinary levels of indican (9.5±5.5 vs 8.4±4.2 mg/dL, p=0.07) were comparable in women with PCOS and controls in the whole study population. Likewise, when the study population was divided into different BMI groups as normal weight, overweight and obese, the levels of the above markers were comparable between the study groups. After BMI adjustment, zonulin levels correlated with the levels of high-sensitivity C reactive protein and homoeostasis model assessment of insulin resistance (p<0.05) both in women with PCOS and controls.

Conclusions: Intestinal permeability markers zonulin and FABP2, and the dysbiosis marker indican do not seem to be altered in women with PCOS at age 46 compared with BMI-matched controls. Serum zonulin levels correlated with BMI, insulin resistance and inflammatory marker levels, but did not segregate women with PCOS and controls. This suggests that metabolic factors, but not PCOS per se, is the driving force of dysbiosis in premenopausal women with PCOS.
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http://dx.doi.org/10.1136/bmjopen-2020-045324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258572PMC
July 2021

Hyperandrogenemia in Early Adulthood Is an Independent Risk Factor for Abnormal Glucose Metabolism in Middle Age.

J Clin Endocrinol Metab 2021 Jun 21. Epub 2021 Jun 21.

Department of Obstetrics and Gynecology, University of Oulu and Oulu University Hospital, Medical Research Center, PEDEGO Research Unit, Oulu, Finland.

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.
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http://dx.doi.org/10.1210/clinem/dgab456DOI Listing
June 2021

Clinical and biochemical signs of polycystic ovary syndrome in young women born preterm.

Eur J Endocrinol 2021 Jul 1;185(2):279-288. Epub 2021 Jul 1.

Finnish Institute for Health and Welfare, Population Health Unit, Oulu and Helsinki, Finland.

Objective: It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term.

Design: The ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm (<34 gestational weeks, VMPT), 127 born late preterm (at 34-36 weeks, LPT), and 184 born full term (≥37 weeks, controls) were included in the analysis (mean age: 23.2 years).

Methods: We measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L).

Results: Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (-2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject's birth weight s.d. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70).

Conclusions: Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.
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http://dx.doi.org/10.1530/EJE-20-1462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284903PMC
July 2021

PCOS Features and Steroid Profiles Among Young Adult Women with a History of Premature Adrenarche.

J Clin Endocrinol Metab 2021 Jun 1. Epub 2021 Jun 1.

Kuopio Pediatric Research Unit, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

Context: Premature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS).

Objective: To study features of PCOS in young adult women with a history of PA.

Design And Participants: Thirty PA and forty-two control females were followed from prepuberty to young adulthood (median age 18.1 years).

Main Outcome Measures: Ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism.

Results: We found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone-binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/l, P < .001) resulting in higher free androgen index (3.94 vs 2.14, P < .001). The difference in SHBG levels persisted through BMI adjustment. SHBG correlated negatively with HOMA-IR (r -0.498, P = .003). Anti-Mullerian hormone concentrations were comparable between the groups (39.3 vs. 32.1 pmol/l, P = .619).

Conclusions: PA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens.
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http://dx.doi.org/10.1210/clinem/dgab385DOI Listing
June 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 2021 Mar 1;77(3):1010-1019. Epub 2021 Feb 1.

From the Department of Obstetrics and Gynecology, PEDEGO Research Unit (J.S.S.R., J.E.N., S.I.W., M.-M.E.O., A.H.B., J.S.T., T.T.P., M.S.V., L.C.M.-P.), Medical Research Center, Oulu University Hospital, University of Oulu, Finland.

The purpose of this prospective, population-based cohort study was to evaluate the roles of polycystic ovary syndrome (PCOS), obesity, weight gain, and hyperandrogenemia in the development of hypertensive disorders of pregnancy (HDP) through fertile age both in PCOS and in non-PCOS women. The study population-NFBC1966 (Northern Finland Birth Cohort 1966)-allowed a long-term follow-up of women from age 14 until 46 years who developed HDP (n=408) or did not (n=3373). HDP diagnosis was confirmed by combining hospital discharge records, data from Finnish Medical Birth Registers, and the questionnaire data at age 46. Women with self-reported PCOS (srPCOS; n=279), defined by both oligo-amenorrhea and hirsutism at age 31 or with PCOS diagnosis by age 46, were compared with women without reported PCOS (n=1577). Women with srPCOS had an increased HDP risk (odds ratio, 1.56 [95% CI, 1.03-2.37]), but the association disappeared after adjustment for body mass index. In women with srPCOS and HDP, body mass index increased from age 14 to 46 significantly more than in srPCOS women without HDP (median [interquartile range], 9.82 [6.23-14.6] and 7.21 [4.16-10.5] kg/m, respectively; <0.001). Also, in non-PCOS women, the increase was higher in women with (7.54 [5.32-11.62] kg/m; <0.001) than without HDP (6.33 [3.90-9.33] kg/m; <0.001). Increase in waist circumference between ages 31 and 46 years was associated with HDP but not with PCOS. Hyperandrogenemia at 31 or 46 years did not associate with HDP (1.44 [0.98-2.11]). In conclusion, obesity, especially abdominal obesity, and weight gain from adolescence to age 46, but not srPCOS or hyperandrogenemia, were associated with an increased risk of HDP.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15702DOI Listing
March 2021

Higher blood pressure in normal weight women with PCOS compared to controls.

Endocr Connect 2021 Feb;10(2):154-163

Department of Endocrinology, Odense University Hospital, Odense, Denmark.

Objective: Obesity is considered to be the strongest predictive factor for cardio-metabolic risk in women with polycystic ovary syndrome (PCOS). The aim of the study was to compare blood pressure (BP) in normal weight women with PCOS and controls matched for age and BMI.

Methods: From a Nordic cross-sectional base of 2615 individuals of Nordic ethnicity, we studied a sub cohort of 793 normal weight women with BMI < 25 kg/m2 (512 women with PCOS according to Rotterdam criteria and 281 age and BMI-matched controls). Participants underwent measurement of BP and body composition (BMI, waist-hip ratio), lipid status, and fasting BG. Data were presented as median (quartiles).

Results: The median age for women with PCOS were 28 (25, 32) years and median BMI was 22.2 (20.7, 23.4) kg/m2. Systolic BP was 118 (109, 128) mmHg in women with PCOS compared to 110 (105, 120) mmHg in controls and diastolic BP was 74 (67, 81) vs 70 (64, 75) mmHg, both P < 0.001. The prevalence of women with BP ≥ 140/90 mmHg was 11.1% (57/512) in women with PCOS vs 1.8% (5/281) in controls, P < 0.001. In women ≥ 35 years the prevalence of BP ≥ 140/90 mmHg was comparable in women with PCOS and controls (12.7% vs 9.8%, P = 0.6). Using multiple regression analyses, the strongest association with BP was found for age, waist circumference, and total cholesterol in women with PCOS.

Conclusions: Normal weight women with PCOS have higher BP than controls. BP and metabolic screening are relevant also in young normal weight women with PCOS.
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http://dx.doi.org/10.1530/EC-20-0527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983477PMC
February 2021

Obesity Represses CYP2R1, the Vitamin D 25-Hydroxylase, in the Liver and Extrahepatic Tissues.

JBMR Plus 2020 Nov 26;4(11):e10397. Epub 2020 Aug 26.

Research Unit of Biomedicine, Pharmacology and Toxicology University of Oulu Oulu Finland.

Low plasma level of 25-hydroxyvitamin D (25-OH-D), namely vitamin D deficiency, is associated with obesity and weight loss improves 25-OH-D status. However, the mechanism behind obesity-induced vitamin D deficiency remains unclear. Here, we report that obesity suppresses the expression of cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase, in both mice and humans. In humans, weight loss induced by gastric bypass surgery increased the expression of CYP2R1 in the s.c. adipose tissue suggesting recovery after the obesity-induced suppression. At the same time, CYP27B1, the vitamin D 1α-hydroxylase, was repressed by the weight loss. In a mouse (C57BL/6N) model of diet-induced obesity, the plasma 25-OH-D was decreased. In accordance, the CYP2R1 expression was strongly repressed in the liver. Moreover, obesity repressed the expression of CYP2R1 in several extrahepatic tissues, the kidney, brown adipose tissue, and testis, but not in the white adipose tissue. Obesity had a similar effect in both male and female mice. In mice, obesity repressed expression of the vitamin D receptor in brown adipose tissue. Obesity also upregulated the expression of the vitamin D receptor and CYP24A1 in the s.c. adipose tissue of a subset of mice; however, no effect was observed in the human s.c. adipose tissue. In summary, we show that obesity affects CYP2R1 expression both in the mouse and human tissues. We suggest that in mouse the CYP2R1 repression in the liver plays an important role in obesity-induced vitamin D deficiency. Currently, it is unclear whether the CYP2R1 downregulation in extrahepatic tissues could contribute to the obesity-induced low plasma 25-OH-D, however, this phenomenon may affect at least the local 25-OH-D concentrations. © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657391PMC
November 2020

The Gut Microbiome in Polycystic Ovary Syndrome and Its Association with Metabolic Traits.

J Clin Endocrinol Metab 2021 Mar;106(3):858-871

Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia.

Context: Despite the 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: A total of 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 = .979, unweighted UniFrac P = .175). Four genera whose balance helps to differentiate between PCOS and non-PCOS were identified. In the whole cohort, the abundance of 2 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 = .018) and markedly increased abundance of genus Dorea (false discovery rate = 0.03) compared with 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.
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http://dx.doi.org/10.1210/clinem/dgaa848DOI Listing
March 2021

Current use of combined hormonal contraception is associated with glucose metabolism disorders in perimenopausal women.

Eur J Endocrinol 2020 Dec;183(6):619-626

Department of Obstetrics and Gynecology, Oulu University Hospital, University of Oulu and Medical Research Center, and PEDEGO Research Unit (Research Unit for Pediatrics, Dermatology, Clinical Genetics, Obstetrics and Gynecology), Oulu, Finland.

Objective: The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial.

Design: The study is a prospective longitudinal population-based cohort study.

Methods: The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884).

Results: In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3-3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1-9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status.

Conclusions: CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.
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http://dx.doi.org/10.1530/EJE-20-0406DOI Listing
December 2020

Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis.

BMJ Open 2020 05 21;10(5):e036981. Epub 2020 May 21.

Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, Victoria, Australia.

Introduction: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps.

Methods And Analysis: MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD.

Ethics And Dissemination: All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.
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http://dx.doi.org/10.1136/bmjopen-2020-036981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247411PMC
May 2020

Overweight, obesity and hyperandrogenemia are associated with gestational diabetes mellitus: A follow-up cohort study.

Acta Obstet Gynecol Scand 2020 10 1;99(10):1311-1319. Epub 2020 Jun 1.

Department of Obstetrics and Gynecology, Medical Research Center Oulu and PEDEGO Research Unit (Research Unit for Pediatrics, Dermatology, Clinical Genetics, Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, Oulu, Finland.

Introduction: The 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 Methods: A 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.

Results: Self-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.

Conclusions: The 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.
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http://dx.doi.org/10.1111/aogs.13883DOI Listing
October 2020

Population-based Data at Ages 31 and 46 Show Decreased HRQoL and Life Satisfaction in Women with PCOS Symptoms.

J Clin Endocrinol Metab 2020 06;105(6)

Department of Obstetrics and Gynecology, PEDEGO Research Unit and Medical Research Centre Oulu and PEDEGO Research Unit, Oulu, University Hospital of Oulu, University of Oulu, Oulu, Finland.

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 the 15D questionnaire, life satisfaction, and self-reported health status in women with PCOS symptoms at ages 31 and 46 years.

Design: A longitudinal assessment using the Northern Finland Birth Cohort 1966.

Setting: General community.

Participants: The 15D data were available for women reporting isolated oligo-amenorrhea (OA; at age 31 years, 214; and 46 years, 211), isolated hirsutism (H; 31 years, 211; and 46 years, 216), OA + H (PCOS; 31 years, 74; and 46 years, 75), or no PCOS symptoms (controls; 31 years, 1382; and 46 years, 1412). Data for life satisfaction and current health status were available for OA (31 years, 329; and 46 years, 247), H (31 years, 323; and 46 years, 238), PCOS (31 years, 125; and 46 years, 86), control (31 years, 2182; and 46 years, 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 than in the controls. PCOS was an independent risk factor for low HRQoL, and the decrease in HRQoL in PCOS was similar to that of women with other chronic conditions, such as asthma, migraine, rheumatoid arthritis, and depression. The risk for low HRQoL in PCOS remained significant after adjusting for body mass index, 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 the fertile age.
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http://dx.doi.org/10.1210/clinem/dgz256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150615PMC
June 2020

Awareness of polycystic ovary syndrome among obstetrician-gynecologists and endocrinologists in Northern Europe.

PLoS One 2019 26;14(12):e0226074. Epub 2019 Dec 26.

Department of Obstetrics and Gynaecology, University of Oulu and Oulu University Hospital, Medical Research Centre, PEDEGO Research Unit, Oulu, Finland.

Objective: To date, little is known about differences in the knowledge, diagnosis making and treatment strategies of health care providers regarding polycystic ovary syndrome (PCOS) across different disciplines in countries with similar health care systems. To inform guideline translation, we aimed to study physician reported awareness, diagnosis and management of PCOS and to explore differences between medical disciplines in the Nordic countries and Estonia.

Methods: This cross-sectional survey was conducted among 382 endocrinologists and obstetrician-gynaecologists in the Nordic countries and Estonia in 2015-2016. Of the participating physicians, 43% resided in Finland, 18% in Denmark, 16% in Norway, 13% in Estonia, and 10% in Sweden or Iceland, and 75% were obstetrician-gynaecologists. Multivariable logistic regression models were run to identify health care provider characteristics for awareness, diagnosis and treatment of PCOS.

Results: Clinical features, lifestyle management and comorbidity were commonly recognized in women with PCOS, while impairment in psychosocial wellbeing was not well acknowledged. Over two-thirds of the physicians used the Rotterdam diagnostic criteria for PCOS. Medical endocrinologists more often recommended lifestyle management (OR = 3.6, CI 1.6-8.1) or metformin (OR = 5.0, CI 2.5-10.2), but less frequently OCP (OR = 0.5, CI 0.2-0.9) for non-fertility concerns than general obstetrician-gynaecologists. The physicians aged <35 years were 2.2 times (95% CI 1.1-4.3) more likely than older physicians to recommend lifestyle management for patients with PCOS for fertility concerns. Physicians aged 46-55 years were less likely to recommend oral contraceptive pills (OCP) for patients with PCOS than physicians aged >56 (adjusted odds ratio (OR) = 0.4, 95% CI 0.2-0.8).

Conclusion: Despite well-organized healthcare, awareness, diagnosis and management of PCOS is suboptimal, especially in relation to psychosocial comorbidities, among physicians in the Nordic countries and Estonia. Physicians need more education on PCOS and evidence-based information on Rotterdam diagnostic criteria, psychosocial features and treatment of PCOS, with the recently published international PCOS guideline well needed and welcomed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226074PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932801PMC
April 2020

Effect of polycystic ovary syndrome on cardiac autonomic function at a late fertile age: a prospective Northern Finland Birth Cohort 1966 study.

BMJ Open 2019 12 15;9(12):e033780. Epub 2019 Dec 15.

Department of Obstetrics and Gynaecology, University of Oulu and Oulu University Hospital, Medical Research Centre, PEDEGO Research Unit, Oulu, Finland

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) ms, 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 function, the findings underline the importance of screening and treating metabolic abnormalities early on in women with PCOS.
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http://dx.doi.org/10.1136/bmjopen-2019-033780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924836PMC
December 2019

Recommendations for epidemiologic and phenotypic research in polycystic ovary syndrome: an androgen excess and PCOS society resource.

Hum Reprod 2019 11;34(11):2254-2265

Division of Endocrinology and Metabolism, Department of Internal Medicine, Hacettepe University School of Medicine, Hacettepe, Ankara, Turkey.

Study Question: What are the best practices for undertaking epidemiologic and phenotypic studies in polycystic ovary syndrome (PCOS)?

Summary Answer: Best practices for the undertaking of epidemiologic and phenotypic studies in PCOS are outlined.

What Is Known Already: Currently methodologies used for studies of PCOS epidemiology and phenotypes vary widely, and the comparability of studies is low, reducing the ability to harmonize studies.

Study Design, Size, Duration: The Androgen Excess and PCOS (AE-PCOS) Society established a Task Force to draft a research resource for epidemiologic and phenotypic studies in PCOS, with the aim of providing guidelines on study design and execution, insights into the limitations and alternatives and protocols to be used, taking into consideration a global perspective.

Participants/materials, Setting, Methods: A targeted review of the literature was carried out as necessary.

Main Results And The Role Of Chance: High level recommendations include the following: (i) Before initiating the study, a number of critical factors should be addressed including selecting the population and diagnostic criteria (which should ideally align with the recommendations of the International Guidelines), the type of observational study to be undertaken and the primary and secondary endpoint(s) of the study.(ii) To assess the 'natural' or true phenotype and epidemiology of PCOS, the least medically biased, broadest and most generalizable population, and the broadest definition of PCOS, should be used.(iii) Four PCOS phenotypes (Phenotypes A through D), based on the presence or absence of three general features (oligo-anovulation, hyperandrogenism and polycystic ovarian morphology), should be ascertained.(iv) In epidemiologic and phenotypic studies, the detection of PCOS rests on the accuracy and sensitivity of the methods used for assessing the individual features of the disorder, and how 'normal' is defined.(v) Although an assessment algorithm that minimizes the use of certain measures (e.g. androgen levels and/or ovarian ultrasonography) can be devised, when possible it is preferable to uniformly assess all subjects for all parameters of interest.

(vi) The inclusion of subjects in epidemiologic studies who do not appear to have PCOS (i.e. 'non-PCOS') will provide the necessary cohort to establish population-specific normative ranges for the various features of PCOS. (vii) Epidemiologic studies of PCOS in unselected populations will yield relatively limited numbers of PCOS subjects available for genetic study; alternatively, large population-based epidemiologic studies of PCOS will potentially generate large numbers of unaffected individuals that may serve as genetic controls. (viii) Epidemiologic studies of PCOS will benefit from a clear governance structure and should begin by informing, educating and engaging both the formal and informal leaders of the populations targeted for study. (ix) In designing their study investigators should, in advance, establish statistical power and recognize, manage and account for inherent biases. (x) Subjects suspected of having PCOS but who do not/cannot complete their evaluation (i.e. have 'possible PCOS') can be included by imputation, assigning them a 'diagnostic weight' based on those subjects of similar clinical phenotype that have completed the study. (xi) In obtaining, storing and retrieving subject data, subjects should be assessed consecutively using a uniform data collection form; providing as complete and in depth data as possible. (xii) Maintenance of both paper and electronic medical records should focus on ensuring data quality, accuracy and institutional ethical compliance, and familiarity with country-dependent laws, including biobanking-specific laws, tissue laws and research laws. (xiii) In obtaining and biobanking study samples, these should be ideally collected at the time of the first assessment. (xiv) Access to stored data sets should ideally be granted to other bona fide researchers conducting research in the public interest. (xv) SOPs detailing the exact method of each of the activities for handling the data and the samples are necessary to ensure that all methods are performed uniformly. (xvi) Epidemiologic studies of PCOS must be resourced adequately.

Limitations, Reasons For Caution: As with all reports involving expert interpretation of experiential and published data, inherent individual biases are possible. This risk is minimized in the present study by including experts from varying fields of study, aligning with recent international evidence-based guidelines and obtaining consensus approval of the recommendations from the Task Force and the board of the AE-PCOS.

Wider Implications Of The Findings: These guidelines should encourage investigators worldwide to undertake much needed epidemiologic studies of PCOS, increasing the validity, integrity and comparability of the data.

Study Funding/competing Interest(s): The study received no funding. R.A. serves as consultant for Medtronic, Spruce Biosciences and Ansh Labs; has received research funding from Ferring Pharmaceuticals; and is on the advisory board of Martin Imaging; R.L. has received research funding from MSD Pharmaceuticals; J.L. has received fees and/or grant support from the Dutch Heart Association, The Netherlands Organisation for Health Research and Development (ZonMw), Ferring Pharmaceuticals, Danone, Euroscreen/Ogeda and Titus Health Care; H.T. receives grant funding from the National Health and Medical Research Council; K.K., L.M.-P., S.S.M. and B.O.Y. have no potential conflicts of interest.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/dez185DOI Listing
November 2019

First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis.

Hum Reprod Update 2019 11;25(6):717-732

Robinson Research Institute and Adelaide Medical School, University of Adelaide, North Adelaide, SA, Australia.

Background: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine.

Objective And Rationale: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics.

Search Methods: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs.

Outcomes: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06).

Wider Implications: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.
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http://dx.doi.org/10.1093/humupd/dmz029DOI Listing
November 2019

Metformin decreases bone turnover markers in polycystic ovary syndrome: a post hoc study.

Fertil Steril 2019 08 18;112(2):362-370. Epub 2019 Jun 18.

Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address:

Objective: To study the effects of metformin treatment on bone turnover in women with polycystic ovary syndrome (PCOS), as measured by serum concentrations of bone turnover markers.

Design: Post hoc study of a previously conducted prospective multicenter, placebo-controlled, randomized study.

Setting: University clinic.

Patient(s): The study cohort consisted of 74 non-obese women (body mass index < 27 kg/m) and 44 obese women (body mass index ≥ 27 kg/m) diagnosed with PCOS, with a mean age of 27.6 ± 4.0 (SD) years.

Intervention(s): Randomization to receive metformin or placebo for 3 months.

Main Outcome Measure(s): Serum levels of bone formation marker procollagen type I amino-terminal propeptide (PINP) and bone resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX) at baseline and after metformin/placebo treatment.

Result(s): Serum levels of PINP and CTX were similar between the metformin and placebo groups at baseline in the whole study population. Obese women, when compared with non-obese, had lower baseline levels of PINP and CTX. Levels of PINP and CTX were significantly reduced in the whole study population, as well as in both non-obese and obese women after 3 months of metformin treatment, whereas no significant changes were observed in the placebo group.

Conclusion(s): Metformin treatment, when compared with placebo, was associated with reduced bone turnover, as suggested by reductions in markers of bone formation and resorption, leading to slower bone remodeling in premenopausal women with PCOS.

Clinical Trial Registration Number: NCT00994812.
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http://dx.doi.org/10.1016/j.fertnstert.2019.04.013DOI Listing
August 2019

Serum retinol-binding protein 4 levels in polycystic ovary syndrome.

Endocr Connect 2019 Jun;8(6):709-717

Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, University of Oulu and Oulu University Hospital, Oulu, Finland.

Objective: Serum levels of retinol-binding protein 4 (RBP4), an adipokine thought to affect systemic insulin sensitivity, were compared between women with polycystic ovary syndrome (PCOS) and non-PCOS controls to evaluate the association of RBP4 with clinical, hormonal and metabolic parameters of PCOS.

Subjects And Methods: Serum RBP4 levels were analysed in 278 women with PCOS (age range 18-57 years) and 191 non-PCOS controls (age 20-53 years) by enzyme-linked immunosorbent assay.

Results: Serum levels of RBP4 were increased in women with PCOS compared with control women in the whole population (45.1 ± 24.0 (s.d.) vs 33.5 ± 18.3 mg/L, P < 0.001). Age-stratified analysis showed that serum RBP4 levels were increased in women with PCOS aged ≤30 years compared with controls (47.7 ± 23.5 vs 27.1 ± 10.4 mg/L, P < 0.001), whereas no significant differences were seen in the other age groups. No significant correlations of RBP4 were seen with either steroids or indices of insulin resistance.

Conclusions: Although serum RBP4 levels were increased in younger women with PCOS compared with age-matched non-PCOS controls, RBP4 does not seem to be a good marker of insulin resistance or other metabolic derangements in women with PCOS.
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http://dx.doi.org/10.1530/EC-19-0116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547302PMC
June 2019

Hormone profiling, including anti-Müllerian hormone (AMH), for the diagnosis of polycystic ovary syndrome (PCOS) and characterization of PCOS phenotypes.

Gynecol Endocrinol 2019 Jul 22;35(7):595-600. Epub 2019 Jan 22.

a Department of Obstetrics and Gynaecology , University of Oulu and Oulu University Hospital, Medical Research Centre, PEDEGO Research Unit , Oulu , Finland.

Objective was to evaluate serum anti-Müllerian hormone (AMH) levels in polycystic ovary syndrome (PCOS) and in its different phenotypes in relation to clinical, endocrine and metabolic parameters using a new automated VIDAS method and to compare it with the Gen II method. Study design was multi-center study including 319 PCOS women and 109 healthy controls. Serum AMH levels measured using VIDAS were significantly higher in PCOS women than controls ( < .001), and they correlated with those measured using the AMH Gen II method. An AMH cutoff value of 42.1 pmol/L distinguished PCOS women from controls with 67% sensitivity and 83% specificity. The PCOS women with three Rotterdam criteria or hyperandrogenism displayed significantly higher AMH levels compared with those with two Rotterdam criteria or normoandrogenism. In PCOS, AMH levels correlated positively with luteinizing hormone (LH), androgen and sex hormone-binding globulin (SHBG) levels and negatively with BMI, abdominal obesity, follicle-stimulating hormone (FSH), fasting glucose and insulin, and insulin resistance. In conclusion, AMH evaluated using the VIDAS method distinguished PCOS patients from healthy controls relatively well, especially in those with more severe phenotypes. Further studies are needed to establish whether AMH measurements can distinguish PCOS patients with different metabolic risk factors.
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http://dx.doi.org/10.1080/09513590.2018.1559807DOI Listing
July 2019

Circulating antimüllerian hormone and steroid hormone levels remain high in pregnant women with polycystic ovary syndrome at term.

Fertil Steril 2019 03 7;111(3):588-596.e1. Epub 2019 Jan 7.

Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.

Objective: To investigate plasma antimüllerian hormone (AMH) concentration and its relation to steroid hormone levels in pregnant women with polycystic ovary syndrome (PCOS) and controls at term.

Design: Case-control study.

Setting: University-affiliated hospital.

Patient(s): A total of 74 pregnant women at term: 25 women with PCOS (aged 31.6 ± 3.9 years [mean ± standard deviation], body mass index 24.0 ± 3.9 kg/m2, mean gestational length 279 ± 9 days) and 49 controls (aged 31.7 ± 3.3 years, body mass index 24.0 ± 3.3 kg/m2, mean gestational length 281 ± 9 days).

Intervention(s): None.

Main Outcome Measure(s): Plasma AMH and steroid hormone levels.

Result(s): Antimüllerian hormone, T, and androstenedione levels were higher in women with PCOS at term compared with controls, whereas estrogen and P levels were similar. The differences were pronounced in women carrying a female fetus. Testosterone and AMH levels correlated positively in both groups, but E levels only in women with PCOS.

Conclusion(s): Pregnant women with PCOS present with elevated AMH and androgen levels even at term, suggesting a hormonal imbalance during PCOS pregnancy. Differences were detected especially in pregnancies with a female fetus, raising the question of whether female pregnancies are more susceptible to AMH and steroid hormone actions.
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http://dx.doi.org/10.1016/j.fertnstert.2018.11.028DOI Listing
March 2019

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

PLoS Genet 2018 12 19;14(12):e1007813. Epub 2018 Dec 19.

Department of Reproductive Medicine and Gynaecology, University Medical Center, Utrecht, The Netherlands.

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 comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.
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http://dx.doi.org/10.1371/journal.pgen.1007813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300389PMC
December 2018

Self-Reported Polycystic Ovary Syndrome Is Associated With Hypertension: A Northern Finland Birth Cohort 1966 Study.

J Clin Endocrinol Metab 2019 04;104(4):1221-1231

Department of Obstetrics and Gynecology, University of Oulu and Oulu University Hospital, Medical Research Center, PEDEGO Research Unit, Oulu, Finland.

Context: Polycystic ovary syndrome (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 setup 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 years.

Setting: General community.

Participants: Women who reported both oligo/amenorrhea and hirsutism at age 31 years and/or a diagnosis of PCOS by age 46 years [self-reported PCOS (srPCOS), n = 279] and women without PCOS symptoms or diagnosis (n = 1577).

Intervention: None.

Main Outcome Measures: Blood pressure (BP), BMI, and cardiovascular manifestations.

Results: Use of antihypertensive medication was significantly more common in women with srPCOS. At age 31 years, women with srPCOS had significantly higher systolic BP (SBP) and diastolic BP (DBP) than control women (SBP: normal weight: 119.9 ± 13.2 vs 116.9 ± 11.4 mm Hg, P = 0.017; overweight/obese: 126.1 ± 14.3 vs 123.0 ± 11.9 mm Hg, P = 0.031; and DBP: normal weight: 75.5 ± 10.0 vs 72.4 ± 9.6 mm Hg, P = 0.003; overweight/obese: 80.7 ± 11.8 vs 78.0 ± 10.6 mm Hg, P = 0.031). At age 46 years, srPCOS was significantly associated with hypertension (adjusted odds ratio = 1.56; 95% CI, 1.14 to 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.
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http://dx.doi.org/10.1210/jc.2018-00570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296204PMC
April 2019

Polycystic ovary syndrome and risk factors for gestational diabetes.

Endocr Connect 2018 Jul 1;7(7):859-869. Epub 2018 Jun 1.

PEDEGO Research UnitMRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

Objective: To study the roles of self-reported symptoms and/or prior diagnosis of polycystic ovary syndrome (PCOS) and other potential risk factors for gestational diabetes mellitus (GDM) and to clarify whether the screening of GDM in early pregnancy is beneficial for all women with PCOS.

Design: The FinnGeDi multicentre case-control study including 1146 women with singleton pregnancies diagnosed with GDM and 1066 non-diabetic pregnant women. There were 174 women with PCOS (symptoms and/or diagnosis self-reported by a questionnaire) and 1767 women without PCOS (data missing for 271).

Methods: The study population ( = 1941) was divided into four subgroups: GDM + PCOS ( = 105), GDM + non-PCOS ( = 909), non-GDM + PCOS ( = 69), and controls ( = 858). The participants' characteristics and their parents' medical histories were compared.

Results: The prevalence of PCOS was 10.4% among GDM women and 7.4% among non-diabetics (odds ratios (OR) 1.44, 95% CI: 1.05-1.97), but PCOS was not an independent risk for GDM after adjustments for participants' age and pre-pregnancy BMI (OR 1.07, 95% CI: 0.74-1.54). In a multivariate logistic regression analysis, the most significant parameters associated with GDM were overweight, obesity, age ≥35 years, participant's mother's history of GDM, either parent's history of type 2 diabetes (T2D) and participant's own preterm birth.

Conclusions: The increased risk of GDM in women with PCOS was related to obesity and increased maternal age rather than to PCOS itself, suggesting that routine early screening of GDM in PCOS women without other risk factors should be reconsidered. Instead, family history of GDM/T2D and own preterm birth were independent risk factors for GDM.
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http://dx.doi.org/10.1530/EC-18-0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026881PMC
July 2018

The Long-Term Footprint of Endometriosis: Population-Based Cohort Analysis Reveals Increased Pain Symptoms and Decreased Pain Tolerance at Age 46 Years.

J Pain 2018 07 2;19(7):754-763. Epub 2018 Mar 2.

Department of Obstetrics and Gynecology, Oulu University Hospital, University of Oulu and PEDEGO Research Unit, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. Electronic address:

Previous studies have shown increased pain sensitivity in fertile-aged women with endometriosis in response to mechanical stimuli. As yet, population-based studies on the association of endometriosis with pain sensation and pain symptoms in late fertile age are lacking. The main objective of this population-based cohort study was to investigate whether a history of endometriosis is associated with altered pain sensation and musculoskeletal pain symptoms at age 46 years. Our data are derived from the Northern Finland Birth Cohort 1966, which contains postal questionnaire data (72% response rate) as well as clinical data assessing pressure-pain threshold and maximal pain tolerance. The study population consisted of 284 women with endometriosis and 3,390 controls. Our results showed that at age 46 women with a history of endometriosis had a 5.3% lower pressure-pain threshold and 5.1% lower maximal pain tolerance compared with controls. The most significant contributors besides endometriosis were anxiety, depression, and current smoking status. Women with endometriosis also reported an increased number of pain sites (0 pain sites, 9.6 vs 17.9%; 5-8 pain sites, 24.8 vs 19.1%, endometriosis vs controls respectively; P < .001), and their pain was more troublesome and intense. The results were adjusted for body mass index, smoking, depressive/anxiety symptoms, education, and use of hormonal contraceptives. These unique data revealed an altered pain sensation and a greater likelihood of reporting musculoskeletal pain at age 46 years among women with a history of endometriosis. The results imply that endometriosis has a long-term footprint on affected women, thus underlying the need for psychological support and medical treatment beyond fertile age.

Perspective: This population-based cohort study showed decreased pain threshold and maximal pain tolerance in women with endometriosis in the late fertile age of 46 years. The pain was also found to be more bothersome and intense compared with controls.
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http://dx.doi.org/10.1016/j.jpain.2018.02.005DOI Listing
July 2018

The prevalence of Type 2 diabetes is not increased in normal-weight women with PCOS.

Hum Reprod 2017 11;32(11):2279-2286

Department of Endocrinology, Odense University Hospital, Kløvervænget 6, 6th floor, DK-5000 Odense C, Odense, Denmark.

Study Question: Is oral glucose tolerance test (OGTT) needed in all women with polycystic ovary syndrome (PCOS)?

Summary Qnswer: OGTT is not routinely needed in women with PCOS and BMI < 25 kg/m2.

What Is Known Already: PCOS is associated with insulin resistance and increased prevalence of prediabetes and Type 2 diabetes (T2D) which is closely linked to obesity and possibly age, ethnicity and PCOS phenotype. Several guidelines recommend OGTT upon diagnosis of PCOS and during follow-up.

Study Design, Size, Duration: A Nordic cross-sectional study including 876 women.

Participants/materials, Setting, Methods: The 876 Nordic women with PCOS, aged 14-57 years, were examined for T2D and prediabetes (impaired glucose tolerance [IGT] or impaired fasting glucose (IFG) by OGTT.

Main Result And The Role Of Chance: Of all study subjects 3% (23/876) had T2D, 23% (204/876) prediabetes and 74% (649/876) had normal glucose tolerance (NGT). Increased BMI and waist circumference were significantly (P < 0.001) associated with prevalence of prediabetes and T2D. No normal-weight woman (BMI < 25 kg/m2) was diagnosed with T2D. The prevalence of BMI ≥ 25 kg/m2 was 66% (578/ 876). 91% of women (21/23) with T2D had BMI ≥ 30 kg/m2. Testosterone levels and PCOS phenotype did not predict 2-h glucose levels during OGTT after adjustment for BMI and age.

Limitations, Reasons For Caution: The present study included cross-sectional data and prospective studies are needed to confirm our results. These results may not apply to populations of other ethnic origin.

Wider Implications Of The Findings: Routine OGTT may not be indicated in normal-weight women with PCOS.

Study Funding/competing Interest(s): None.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/dex294DOI Listing
November 2017

Bone markers in polycystic ovary syndrome: A multicentre study.

Clin Endocrinol (Oxf) 2017 Dec 21;87(6):673-679. Epub 2017 Sep 21.

Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland.

Objective: Hyperandrogenism, hyperinsulinaemia and obesity, known characteristics of polycystic ovary syndrome (PCOS), may influence bone mineral density and biochemical markers of bone turnover (BTMs) can provide a noninvasive assessment of bone turnover. To this end, the serum concentrations of BTMs and 25-hydroxyvitamin D (25OHD) were analysed in women with PCOS, and their possible associations with metabolic parameters of PCOS were determined.

Subjects And Methods: Bone formation markers procollagen type I amino-terminal propeptide (PINP) and osteocalcin (OC), and bone resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX), along with 25OHD, were measured in 298 women with PCOS and 194 healthy controls.

Results: Serum levels of PINP (47.0 ± 20.2 vs 58.1 ± 28.6 μg/L, P < .001) and OC (18.2 ± 7.5 vs 20.6 ± 9.8 μg/L, P < .001) were decreased in women with PCOS compared with controls, whereas no significant differences were found in CTX and 25OHD levels. Age-stratified analyses suggested that PINP (50.5 ± 21.7 vs 68.2 ± 26.6 μg/L, P < .001) and OC levels (20.4 ± 7.6 vs 25.5 ± 9.6 μg/L, P < .001) were decreased only in the younger age group (≤30 years) women with PCOS compared with controls. The formation markers and resorption marker decreased with age in both study groups.

Conclusions: Bone formation markers were decreased in younger women with PCOS when compared with healthy women, which may affect bone mass in these women.
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http://dx.doi.org/10.1111/cen.13456DOI Listing
December 2017

Testosterone is associated with insulin resistance index independently of adiposity in women with polycystic ovary syndrome.

Gynecol Endocrinol 2018 Jan 5;34(1):40-44. Epub 2017 Jul 5.

a Department of Obstetrics and Gynecology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.

Objective: To study the associations between androgens, glucose homeostasis, inflammation and statin treatment in women with polycystic ovary syndrome (PCOS).

Design And Methods: Oral glucose tolerance tests, androgens, hs-CRP and interleukin-1 receptor antagonist (IL-1Ra) were analyzed at baseline and after 6 months of atorvastatin (20 mg/d) or placebo treatment in 27 women with PCOS.

Results: Testosterone associated with insulin resistance measured with ISI independently of BMI, age and SHBG concentrations and the full model, including IL-1Ra, hs-CRP and HDL-C, also showed independency of BMI and waist circumference (p ≤ .042). Free androgen index (FAI) associated with ISI independently of adiposity (p ≤ .025) but in the full model with waist circumference the association was insignificant. ISI decreased with testosterone >1.2 nmol/l compared with lower levels at baseline (p = .043) and at six months (p = .003). Accordingly, 30-minute insulin levels were increased with moderately elevated testosterone independently of adiposity (p ≤ .046). Increased fasting glucose and AUC insulin associated with statin treatment independently of adiposity and the associations attenuated after adjusting for testosterone.

Conclusions: Moderately elevated testosterone concentrations together with obesity-related inflammatory factors modify glucose homeostasis by increasing insulin resistance and early insulin secretion.
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http://dx.doi.org/10.1080/09513590.2017.1342793DOI Listing
January 2018

Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome: a regional cross-sectional study.

Am J Obstet Gynecol 2017 08 8;217(2):189.e1-189.e8. Epub 2017 Apr 8.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Pennsylvania, Philadelphia, PA. Electronic address:

Background: Polycystic ovary syndrome is a heterogeneous disorder and its presentation varies with race and ethnicity. Reproductive-age women with polycystic ovary syndrome are at increased risk of metabolic syndrome; however, it is not clear if prevalence of metabolic syndrome and clustering of its components differs based on race and ethnicity. Moreover, the majority of these women do not undergo routine screening for metabolic syndrome.

Objective: We sought to compare the prevalence of metabolic syndrome and clustering of its components in women with polycystic ovary syndrome in the United States with women in India, Brazil, Finland, and Norway.

Study Design: This is a cross-sectional study performed in 1089 women with polycystic ovary syndrome from 1999 through 2016 in 5 outpatient clinics in the United States, India, Brazil, Finland, and Norway. Polycystic ovary syndrome was defined by the Rotterdam criteria. Main outcome measures were: metabolic syndrome prevalence, blood pressure, body mass index, fasting high-density lipoprotein cholesterol, fasting triglycerides, and fasting glucose. Data from all sites were reevaluated for appropriate application of diagnostic criteria for polycystic ovary syndrome, identification of polycystic ovary syndrome phenotype, and complete metabolic workup. The US White women with polycystic ovary syndrome were used as the referent group. Logistic regression models were used to evaluate associations between race and metabolic syndrome prevalence and its components and to adjust for potential confounders, including age and body mass index.

Results: The median age of the entire cohort was 28 years. Women from India had the highest mean Ferriman-Gallwey score for clinical hyperandrogenism (15.6 ± 6.5, P < .001). The age-adjusted odds ratio for metabolic syndrome was highest in US Black women at 4.52 (95% confidence interval, 2.46-8.35) compared with US White women. When adjusted for age and body mass index, the prevalence was similar in the 2 groups. Significantly more Black women met body mass index and blood pressure criteria (P < .001), and fewer met fasting triglycerides criteria (P < .05). The age- and body mass index-adjusted prevalence of metabolic syndrome was highest in Indian women (odds ratio, 6.53; 95% confidence interval, 3.47-12.30) with abnormalities in glucose and fasting high-density lipoprotein cholesterol criterion and in Norwegian women (odds ratio, 2.16; 95% confidence interval, 1.17-3.98) with abnormalities in blood pressure, glucose, and fasting high-density lipoprotein cholesterol criterion. The Brazilian and Finnish cohorts had similar prevalence of metabolic syndrome and its components compared to US White women.

Conclusion: Despite a unifying diagnosis of polycystic ovary syndrome, there are significant differences in the prevalence of metabolic syndrome and clustering of its components based on race and ethnicity, which may reflect contributions from both racial and environmental factors. Our findings indicate the prevalence of metabolic syndrome components varies in women with polycystic ovary syndrome, such that compared to White women from the United States, Black US women had the highest prevalence, whereas women from India and Norway had a higher prevalence of metabolic syndrome independent of obesity. The differences in clustering of components of metabolic syndrome based on ethnicity highlight the need to routinely perform complete metabolic screening to identify specific targets for cardiovascular risk reduction strategies in these reproductive-age women.
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http://dx.doi.org/10.1016/j.ajog.2017.04.007DOI Listing
August 2017

Psychological Distress Is More Prevalent in Fertile Age and Premenopausal Women With PCOS Symptoms: 15-Year Follow-Up.

J Clin Endocrinol Metab 2017 06;102(6):1861-1869

Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, FI-90014 Oulu, Finland.

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.
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http://dx.doi.org/10.1210/jc.2016-3863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470769PMC
June 2017
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