Publications by authors named "Juha S Tapanainen"

99 Publications

Low Expression of Stanniocalcin 1 (STC-1) Protein Is Associated With Poor Clinicopathologic Features of Endometrial Cancer.

Pathol Oncol Res 2021 28;27:1609936. Epub 2021 Sep 28.

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

Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors ( = 0.030), deep myometrial invasion ( = 0.003), lymphovascular space invasion ( = 0.050), and large tumor size ( = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women ( = 0.014) and in women with diabetes mellitus type 2 (DMT2; = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium ( = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.
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http://dx.doi.org/10.3389/pore.2021.1609936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505533PMC
September 2021

Parity, menopausal hormone therapy, and risk of ovarian granulosa cell tumor - A population-based case-control study.

Gynecol Oncol 2021 Dec 29;163(3):593-597. Epub 2021 Sep 29.

Faculty of Social Sciences, Tampere University, Tampere, Finland; Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.

Objective: Adult-type ovarian granulosa cell tumors (AGCTs) are hormonally active neoplasms with limited epidemiological data available. We evaluated the effect of parity and postmenopausal hormone therapy (HT) use on the risk of AGCT in a population-based case-control setting.

Methods: We identified all women diagnosed with AGCT during 1994-2015 (n = 505) from the Finnish Cancer Registry. For each case, five controls matched for age were selected from the National Population Registry, which also provided data on parity and ages at deliveries. Information on postmenopausal HT by different regimens (estradiol-only, sequential estrogen-progestin and continuous estrogen-progestin) was obtained from nationwide Prescription Register. The association between parity, ages at deliveries, HT use, and AGCT incidence was evaluated by odds ratios (ORs) using a conditional logistic regression model and stratified by age at index date (<55 years or ≥ 55 years).

Results: Parity and age at first or last delivery had no significant effect on AGCT risk. Systemic postmenopausal HT had been used by 20.4% of women who were later diagnosed with AGCT. The risk for subsequent AGCT was significantly decreased among users of estradiol-only therapy for at least five years (OR 0.28; 95% confidence interval 0.08-0.94) and continuous estradiol-progestin therapy for 6 months to 5 years (0.23; 0.08-0.71).

Conclusions: Unlike in epithelial ovarian cancer, AGCT development is not clearly associated with parity, and users of postmenopausal HT do not seem to carry an excess risk for AGCT formation.
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http://dx.doi.org/10.1016/j.ygyno.2021.09.013DOI Listing
December 2021

Outcomes of SARS-CoV-2 infected pregancies after medically assisted reproduction.

Hum Reprod 2021 10;36(11):2883-2890

Reproductive Medicine Service, Dexeus Mujer, Hospital Universitari Dexeus/Institut d'Investigació Biomedica de Bellvitge, IDIBELL, Barcelona Stem Cell Bank, Regenerative Medicine Programme, Barcelona, Spain.

Study Question: What is the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the outcome of a pregnancy after medically assisted reproduction (MAR)?

Summary Answer: Our results suggest that MAR pregnancies are not differentially affected by SARS-CoV-2 infection compared to spontaneous pregnancies.

What Is Known Already: Information on the effects of coronavirus disease 2019 (COVID-19) on pregnancy after MAR is scarce when women get infected during MAR or early pregnancy, even though such information is vital for informing women seeking pregnancy.

Study Design, Size, Duration: Data from SARS-CoV-2 affected MAR pregnancies were collected between May 2020 and June 2021 through a voluntary data collection, organised by the European Society of Human Reproduction and Embryology (ESHRE).

Participants/materials, Setting, Methods: All ESHRE members were invited to participate to an online data collection for SARS-CoV-2-infected MAR pregnancies.

Main Results And The Role Of Chance: The dataset includes 80 cases from 32 countries, including 67 live births, 10 miscarriages, 2 stillbirths and 1 maternal death. An additional 25pregnancies were ongoing at the time of writing.

Limitations, Reasons For Caution: An international data registry based on voluntary contribution can be subject to selective reporting with possible risks of over- or under-estimation.

Wider Implications Of The Findings: The current data can be used to guide clinical decisions in the care of women pregnant after MAR, in the context of the COVID-19 pandemic.

Study Funding/competing Interest(s): The authors acknowledge the support of ESHRE for the data registry and meetings. J.S.T. reports grants or contracts from Sigrid Juselius Foundation, EU and Helsinki University Hospital Funds, outside the scope of the current work. The other authors declare that they have no conflict of interest.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523208PMC
October 2021

Small RNA expression and miRNA modification dynamics in human oocytes and early embryos.

Genome Res 2021 Aug;31(8):1474-1485

University of Helsinki, Department of Obstetrics and Gynecology, 00014, Helsinki, Finland.

Small noncoding RNAs (sRNAs) play important roles during the oocyte-to-embryo transition (OET), when the maternal phenotype is reprogrammed and the embryo genome is gradually activated. The transcriptional program driving early human development has been studied with the focus mainly on protein-coding RNAs, and expression dynamics of sRNAs remain largely unexplored. We profiled sRNAs in human oocytes and early embryos using an RNA-sequencing (RNA-seq) method suitable for low inputs of material. We show that OET in humans is temporally coupled with the transition from predominant expression of oocyte short piRNAs (os-piRNAs) in oocytes, to activation of microRNA (miRNA) expression in cleavage stage embryos. Additionally, 3' mono- and oligoadenylation of miRNAs is markedly increased in zygotes. We hypothesize that this may modulate the function or stability of maternal miRNAs, some of which are retained throughout the first cell divisions in embryos. This study is the first of its kind elucidating the dynamics of sRNA expression and miRNA modification along a continuous trajectory of early human development and provides a valuable data set for in-depth interpretative analyses.
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http://dx.doi.org/10.1101/gr.268193.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327922PMC
August 2021

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 Oct;106(11):e4621-e4633

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 years is associated with insulin resistance, insulin secretion and AGM by age 46.

Design: Prospective study including 5889 females followed at ages 31 and 46 years.

Setting: General community.

Participants: Women with HA were compared with normoandrogenic women at ages 31 and 46 years.

Intervention: None.

Main Outcome Measurements: AGM, including prediabetes and type 2 diabetes mellitus, homeostatic model assessments of insulin resistance (HOMA-IR) and of pancreatic β-cell function (HOMA-B).

Results: At age 31 years, HA women displayed increased HOMA-IR (P = 0.002), HOMA-B (P = 0.007), and higher fasting insulin (P = 0.03) than normoandrogenic women after adjusting for body mass index (BMI). At age 46 years, there was a nonsignificant trend toward higher fasting glucose (P = 0.07) and glycated hemoglobin A1 (P = 0.07) levels in HA women. Women in the highest T quartile (odds ratio [OR] = 1.80; 95%CI, 1.15-2.82) at age 31 years and in the 2 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) years had increased risk for AGM, independently of BMI, when compared with women in Q1. SHBG was inversely associated with AGM (at age 31 years: Q4: OR = 0.37; 95% CI, 0.23-0.60, at age 46 years: 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530724PMC
October 2021

Impact of parity on the incidence of ovarian cancer subtypes: a population-based case-control study.

Acta Oncol 2021 Jul 17;60(7):850-855. Epub 2021 May 17.

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

Background: Parity is known to have a protective effect as regards ovarian cancer, but its effect on the different histological subtypes of ovarian cancer is not well known. The impact of parity on the incidence of ovarian cancer subtypes was studied.

Material And Methods: All Finnish women diagnosed 1994-2013 with ovarian cancer for the first time were included. Altogether, 5412 cases of ovarian cancer were identified in the Finnish Cancer Registry and stratified according to morphology into serous, mucinous, endometrioid, clear cell and others. Five age-matched controls were randomly selected for each case from the Finnish National Population Registry. Data on postmenopausal hormonal therapy were derived from the Registry of Prescribed drugs and used as cofactors. Multivariate conditional logistic regression for matched case-control data was used to examine the associations between parity parameters and ovarian cancer risk.

Results: Parous women had lower risk than nulliparous women in getting ovarian cancer of any type under age of 55 years. The odds ratio (OR) for serous cancer was 0.65 (95% confidence interval 0.56-0.77), for mucinous cancer 0.66 (0.52-0.83), for endometrioid cancer 0.52 (0.40-0.68), for clear-cell cancer 0.30 (0.19-0.46) and for other types 0.59 (0.43-0.80). In women aged 55 or older, the respective ORs were 0.86 (0.75-0.99), 0.78 (0.57-1.07), 0.61 (0.47-0.79), 0.44 (0.29-0.66) and 0.74 (0.57-0.95), adjusted for hormone therapy. Number of childbirths was associated with a trend toward reduction of risk, especially in serous and clear-cell cancers. Higher age at first birth was associated with higher risk of clear-cell cancer but otherwise age at first or last birth did not have an impact on the incidence of cancer subtypes.

Conclusions: Childbirths decrease the risk of all histologic subtypes of epithelial ovarian cancer in women in premenopausal and postmenopausal age.
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http://dx.doi.org/10.1080/0284186X.2021.1919754DOI Listing
July 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 03 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

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

J Clin Endocrinol Metab 2021 03;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

Ethinyl estradiol vs estradiol valerate in combined oral contraceptives - Effect on glucose tolerance: A randomized, controlled clinical trial.

Contraception 2021 01 21;103(1):53-59. Epub 2020 Oct 21.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, PO 140, 00029 Helsinki, Finland; Department of Obstetrics and Gynecology, University of Oulu, Oulu University Hospital and Medical Research Centre PEDEGO Research Unit, Kajaanintie 50, PO 5000, 90014 Oulu, Finland. Electronic address:

Objective: To compare the effects of two formulations of combined oral contraceptives (COCs), estradiol valerate (EV) and ethinyl estradiol (EE) combined with dienogest (DNG), and DNG-only, on glucose tolerance.

Study Design: We performed a randomized, controlled 9-week clinical trial. Inclusion criteria were: age 18-35 years, regular menstrual cycle (28 ± 7 days), no polycystic ovaries, non-smoking, no contraindications for COC use and a 2-month wash-out from hormonal contraceptive use. The women were randomized to EV + DNG (n = 20), EE + DNG (n = 20), and DNG-only (n = 19), and evaluated at baseline, at 4-5 weeks and 8-9 weeks of treatment. Study medications were used continuously for 63 days. Primary outcome measure was change in the whole-body insulin sensitivity index (Matsuda index) derived from the oral glucose tolerance test (OGTT) over the treatment period. Secondary outcome measures were area under curves (AUC) of glucose and insulin, homeostatic model assessment - insulin resistance (HOMA-IR) and Insulin Sensitivity Index (ISI).

Results: Fifty-nine women enrolled, and 56 women completed the study. The Matsuda index changed from baseline as follows (mean percentage change, mean change [95%CI]): DNG-only -12%, -1.45 [95%CI -3.22-0.325] P = 0.10; EV + DNG + 2.7%, -0.10 [-1.34 to 1.14] P = 0.86; EE + DNG -5.5%, -1.02 [-2.51 to 0.46] P = 0.16, comparing the groups P = 0.27. There were no clinically significant differences in glucose tolerance between the COC groups, but the DNG-only group showed an improvement in the 2-h glucose levels (5.5 [95%CI 5.0-6.0] to 4.7 mmol/l [4.2-5.2], P = 0.001).

Conclusion: We found no clinically significant differences between EV and EE combined with DNG and DNG-only on glucose tolerance in healthy, young, normal-weight women, indicating that these preparations appear close to neutral regarding glucose metabolism when used continuously for nine weeks.

Implications: Combinations of both ethinyl estradiol and natural estradiol (estradiol valerate) with dienogest (DNG), as well as DNG-only, seem metabolically safe in young and healthy women in short-term continuous use.
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http://dx.doi.org/10.1016/j.contraception.2020.10.014DOI Listing
January 2021

The calm after the storm: re-starting ART treatments safely in the wake of the COVID-19 pandemic.

Hum Reprod 2021 01;36(2):275-282

Rotunda Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.

The coronavirus disease 2019 (COVID-19) pandemic created a significant impact on medically assisted reproduction (MAR) services. ESHRE decided to mobilize resources in order to collect, analyse, monitor, prepare and disseminate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) knowledge specifically related to ART and early pregnancy. This article presents the impact of the SARS-CoV-2 pandemic focusing on reproductive healthcare. It details the rationale behind the guidance prepared to support MAR services in organizing and managing the re-start of treatments or in case of any future wave of COVID-19 disease. The guidance includes information on patient selection and informed consent, staff and patient triage and testing, adaptation of ART services, treatment planning and code of conduct. The initiatives detailed in this article are not necessarily COVID-specific and such action plans could be applied effectively to manage similar emergency situations in different areas of medicine, in the future.
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http://dx.doi.org/10.1093/humrep/deaa285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665491PMC
January 2021

A picture of medically assisted reproduction activities during the COVID-19 pandemic in Europe.

Hum Reprod Open 2020 17;2020(3):hoaa035. Epub 2020 Aug 17.

Reproductive Medicine Service, Dexeus Mujer, Hospital Universitari Dexeus/Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, Barcelona Stem Cell Bank, Regenerative Medicine Programme, Barcelona, Spain.

Study Question: How did coronavirus disease 2019 (COVID-19) impact on medically assisted reproduction (MAR) services in Europe during the COVID-19 pandemic (March to May 2020)?

Summary Answer: MAR services, and hence treatments for infertile couples, were stopped in most European countries for a mean of 7 weeks.

What Is Known Already: With the outbreak of COVID-19 in Europe, non-urgent medical care was reduced by local authorities to preserve health resources and maintain social distancing. Furthermore, ESHRE and other societies recommended to postpone ART pregnancies as of 14 March 2020.

Study Design Size Duration: A structured questionnaire was distributed in April among the ESHRE Committee of National Representatives, followed by further information collection through email.

Participants/materials Setting Methods: The information was collected through the questionnaire and afterwards summarised and aligned with data from the European Centre for Disease Control on the number of COVID-19 cases per country.

Main Results And The Role Of Chance: By aligning the data for each country with respective epidemiological data, we show a large variation in the time and the phase in the epidemic in the curve when MAR/ART treatments were suspended and restarted. Similarly, the duration of interruption varied. Fertility preservation treatments and patient supportive care for patients remained available during the pandemic.

Large Scale Data: N/A.

Limitations Reasons For Caution: Data collection was prone to misinterpretation of the questions and replies, and required further follow-up to check the accuracy. Some representatives reported that they, themselves, were not always aware of the situation throughout the country or reported difficulties with providing single generalised replies, for instance when there were regional differences within their country.

Wider Implications Of The Findings: The current article provides a basis for further research of the different strategies developed in response to the COVID-19 crisis. Such conclusions will be invaluable for health authorities and healthcare professionals with respect to future similar situations.

Study Funding/competing Interests: There was no funding for the study, apart from technical support from ESHRE. The authors had no COI to disclose.
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http://dx.doi.org/10.1093/hropen/hoaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430925PMC
August 2020

Type 1 and type 2 diabetes after gestational diabetes: a 23 year cohort study.

Diabetologia 2020 10 29;63(10):2123-2128. Epub 2020 Jul 29.

Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.

Aims/hypothesis: The aim of this work was to examine the progression to type 1 and type 2 diabetes after gestational diabetes mellitus (GDM) in a 23 year follow-up study.

Methods: We carried out a cohort study of 391 women with GDM diagnosed by an OGTT or the use of insulin treatment during pregnancy, and 391 age- and parity-matched control participants, who delivered in 1984-1994 at the Oulu University Hospital, Finland. Diagnostic cut-off levels for glucose were as follows: fasting, ≥4.8 mmol/l; 1 h, ≥10.0 mmol/l; and 2 h, ≥8.7 mmol/l. Two follow-up questionnaires were sent (in 1995-1996 and 2012-2013) to assess the progression to type 1 and type 2 diabetes. Mean follow-up time was 23.1 (range 18.7-28.8) years.

Results: Type 1 diabetes developed (5.7%) during the first 7 years after GDM pregnancy and was predictable at a 2 h OGTT value of 11.9 mmol/l during pregnancy (receiver operating characteristic analysis: AUC 0.91, sensitivity 76.5%, specificity 96.0%). Type 2 diabetes increased linearly to 50.4% by the end of the follow-up period and was moderately predictable with fasting glucose (AUC 0.69, sensitivity 63.5%, specificity 68.2%) at a level of 5.1 mmol/l (identical to the fasting glucose cut-off recommended by the International Association of Diabetes and Pregnancy Study Groups [IADPSG) and WHO]).

Conclusions/interpretation: All women with GDM should be intensively monitored for a decade, after which the risk for type 1 diabetes is minimal. However, the incidence of type 2 diabetes remains linear, and therefore individualised lifelong follow-up is recommended.
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http://dx.doi.org/10.1007/s00125-020-05215-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476985PMC
October 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

Estradiol Valerate in COC Has More Favorable Inflammatory Profile Than Synthetic Ethinyl Estradiol: A Randomized Trial.

J Clin Endocrinol Metab 2020 07;105(7)

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

Context: Combined oral contraceptives (COCs) alter inflammatory status and lipid metabolism. Whether different estrogens have different effects is poorly understood.

Objective: We compared the effects of COCs containing ethinyl estradiol (EE) or estradiol valerate (EV) and dienogest (DNG) with those containing DNG only on inflammation and lipid metabolism.

Design: Randomized, controlled, open-label clinical trial.

Setting: Two-center study in Helsinki and Oulu University Hospitals.

Participants: Fifty-nine healthy, young, nonsmoking women with regular menstrual cycles. Age, body mass index, and waist-to-hip ratio were comparable in all study groups at the beginning. Fifty-six women completed the study (EV + DNG, n = 20; EE + DNG, n = 19; DNG only, n = 17).

Interventions: Nine-week continuous use of COCs containing either EV + DNG or EE + DNG, or DNG only as control.

Main Outcome Measures: Parameters of chronic inflammation (high-sensitivity C-reactive protein [hs-CRP], and pentraxin 3 [PTX-3]) and lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol).

Results: Serum hs-CRP increased after 9-week use of EE + DNG (mean change ± standard deviation 1.10 ± 2.11 mg/L) compared with EV + DNG (-0.06 ± 0.97 mg/L, P = 0.001) or DNG only (0.13 ± 0.68 mg/L, P = 0.021). Also, PTX-3 increased in the EE + DNG group compared with EV + DNG and DNG-only groups (P = 0.017 and P = 0.003, respectively). In the EE + DNG group, HDL and triglycerides increased compared with other groups (HDL: EE + DNG 0.20 ± 0.24 mmol/L vs EV + DNG 0.02 ± 0.20 mmol/L [P = 0.002] vs DNG 0.02 ± 0.18 mmol/L [P = 0.002]; triglycerides: EE + DNG 0.45 ± 0.21 mmol/L vs EV + DNG 0.18 ± 0.36 mmol/L [P = 0.003] vs DNG 0.06 ± 0.18 mmol/L [P < 0.001]).

Conclusions: EV + DNG and DNG only had a neutral effect on inflammation and lipids, while EE + DNG increased both hs-CRP and PTX-3 levels as well as triglycerides and HDL.

Trial Registration: ClinicalTrials.gov NCT02352090.
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http://dx.doi.org/10.1210/clinem/dgaa186DOI Listing
July 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

Complement in Human Pre-implantation Embryos: Attack and Defense.

Front Immunol 2019 18;10:2234. Epub 2019 Sep 18.

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

It is essential for early human life that mucosal immunological responses to developing embryos are tightly regulated. An imbalance of the complement system is a common feature of pregnancy complications. We hereby present the first full analysis of the expression and deposition of complement molecules in human pre-implantation embryos. Thus, far, immunological imbalance has been considered in stages of pregnancy following implantation. We here show that complement activation against developing human embryos takes place already at the pre-implantation stage. Using confocal microscopy, we observed deposition of activation products on healthy developing embryos, which highlights the need for strict complement regulation. We show that embryos express complement membrane inhibitors and bind soluble regulators. These findings show that mucosal complement targets human embryos, and indicate potential adverse pregnancy outcomes, if regulation of activation fails. In addition, single-cell RNA sequencing revealed cellular expression of complement activators. This shows that the embryonic cells themselves have the capacity to express and activate C3 and C5. The specific local embryonic expression of complement components, regulators, and deposition of activation products on the surface of embryos suggests that complement has immunoregulatory functions and furthermore may impact cellular homeostasis and differentiation at the earliest stages of life.
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http://dx.doi.org/10.3389/fimmu.2019.02234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759579PMC
November 2020

Long-term health of women with genetic POI due to FSH-resistant ovaries.

Endocr Connect 2019 Oct;8(10):1354-1362

Department of Obstetrics and Gynecology, Reproductive Medicine Unit, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Objective: To study the use of hormone therapy (HT), morbidity and reproductive outcomes of women with primary ovarian insufficiency (POI) due to FSH-resistant ovaries (FSHRO).

Design: A prospective follow-up study in a university-based tertiary clinic setting.

Methods: Twenty-six women with an inactivating A189V FSH receptor mutation were investigated by means of a health questionnaire and clinical examination. Twenty-two returned the health questionnaire and 14 were clinically examined. Main outcome measures in the health questionnaire were reported as HT, morbidity, medication and infertility treatment outcomes. In the clinical study, risk factors for cardiovascular disease (CVD) and metabolic syndrome (MetS) were compared to age-matched controls from a national population survey (FINRISK). Average number of controls was 326 per FSHRO subject (range 178-430). Bone mineral density and whole-body composition were analyzed with DXA. Psychological and sexual well-being was assessed with Beck Depression Inventory (BDI21), Generalized Anxiety Disorder 7 (GAD-7) and Female Sexual Function Index (FSFI) questionnaires.

Results: HT was initiated late (median 18 years of age) compared with normal puberty and the median time of use was shorter (20-22 years) than the normal fertile period. Osteopenia was detected in 9/14 of the FSHRO women despite HT. No major risk factors for CVD or diabetes were found.

Conclusions: HT of 20 years seems to be associated with a similar cardiovascular and metabolic risk factor profile as in the population control group. However, optimal bone health may require an early-onset and longer period of HT, which would better correspond to the natural fertile period.
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http://dx.doi.org/10.1530/EC-19-0244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790899PMC
October 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

The effect of length of birth interval on the risk of breast cancer by subtype in grand multiparous women.

BMC Cancer 2019 Mar 4;19(1):199. Epub 2019 Mar 4.

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

Background: The length of interval between successive childbirths (birth interval) might influence the incidence of breast cancer, either by stimulating or by inhibiting the factors that are responsible for the initiation of breast cancer or its early development.

Methods: This is a case-control study nested in a cohort of 47,479 Finnish grand-multiparous (GM) women born after 1934, and registered as having had at least five births before 2013. The 1354 women with breast cancer diagnosis were compared with controls (1:5) matched by parity and date of birth of the mother. Conditional logistic regression was used to estimate odds ratios of the risk of ductal and lobular breast cancer subtypes associated with each of the intervals between the 1st and 5th birth, stratified by age at diagnosis. Age at first and last birth before index date were used as covariates.

Results: Increased intervals between the 1st and 5th births were associated with an increased risk of lobular breast cancer. In contrast, regarding ductal cancer, premenopausal women with shorter length of interval (< 2 years) between the 1st and 2nd birth had greater risk and longer intervals (3+ years) were associated with reduced risk. Spacing between the 2nd and 5th birth did not influence the risk of ductal breast cancer.

Conclusion: The findings of our study suggest that the effect of the length of birth interval on breast cancer depends on the age and histology. The protective effect of shorter birth intervals on lobular breast among postmenopausal women and the opposite effect on ductal cancer in premenopausal women may reflect distinct differentiation and functional roles of lobular and ductal cells, and possibly also different response to hormonal exposure.
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http://dx.doi.org/10.1186/s12885-019-5404-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399864PMC
March 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

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

Demographic and evolutionary trends in ovarian function and aging.

Hum Reprod Update 2019 01;25(1):34-50

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, Helsinki, Finland.

Background: The human female reproductive lifespan is regulated by the dynamics of ovarian function, which in turn is influenced by several factors: from the basic molecular biological mechanisms governing folliculogenesis, to environmental and lifestyle factors affecting the ovarian reserve between conception and menopause. From a broader point of view, global and regional demographic trends play an additional important role in shaping the female reproductive lifespan, and finally, influences on an evolutionary scale have led to the reproductive senescence that precedes somatic senescence in humans.

Objective And Rationale: The narrative review covers reproductive medicine, by integrating the molecular mechanisms of ovarian function and aging with short-term demographic and long-term evolutionary trends.

Search Methods: PubMed and Google Scholar searches were performed with relevant keywords (menopause, folliculogenesis, reproductive aging, reproductive lifespan and life history theory). The reviewed articles and their references were restricted to those written in English.

Outcomes: We discuss and summarize the rapidly accumulating information from large-scale population-based and single-reproductive-cell genomic studies, their constraints and advantages in the context of female reproductive aging as well as their possible evolutionary significance on the life history trajectory from foetal-stage folliculogenesis until cessation of ovarian function in menopause. The relevant environmental and lifestyle factors and demographic trends are also discussed in the framework of predominant evolutionary hypotheses explaining the origin and maintenance of menopause.

Wider Implications: The high speed at which new data are generated has so far raised more questions than it has provided solid answers and has been paralleled by a lack of satisfactory interpretations of the findings in the context of human life history theory. Therefore, the recent flood of data could offer an unprecedented tool for future research to possibly confirm or rewrite human evolutionary reproductive history, at the same time providing novel grounds for patient counselling and family planning strategies.
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http://dx.doi.org/10.1093/humupd/dmy031DOI Listing
January 2019

Hyperglycosylated hCG activates LH/hCG-receptor with lower activity than hCG.

Mol Cell Endocrinol 2019 01 2;479:103-109. Epub 2018 Oct 2.

Competence Centre on Health Technologies, Tartu, Estonia; Institute of Chemistry, University of Tartu, Tartu, Estonia.

While human chorionic gonadotropin (hCG) appears to have an essential role in early pregnancy, it is controversial whether the hyperglycosylated form of hCG (hCG-h), which is the major hCG isoform during the first 4-5 weeks of pregnancy, is able to activate LH/hCG receptor (LHCGR). To address this, we utilized different extensively characterized hCG and hCGβ reference reagents, cell culture- and urine-derived hCG-h preparations, and an in vitro reporter system for LHCGR activation. The WHO hCG reference reagent (99/688) was found to activate LHCGR with an EC-value of 3.3 ± 0.6 pmol/L (n = 9). All three studied hCG-h preparations were also able to activate LHCGR, but with a lower potency (EC-values between 7.1 ± 0.5 and 14 ± 3 pmol/L, n = 5-11, for all P < 0.05 as compared to the hCG reference). The activities of commercial urinary hCG (Pregnyl) and recombinant hCG (Ovitrelle) preparations were intermediate between those of the hCG reference and the hCG-h. These results strongly suggest that the hCG-h is functionally similar to hCG, although it has lower potency for LHCGR activation. Whether this explains the reduced proportion of hCG-h to hCG reported in patients developing early onset pre-eclampsia or those having early pregnancy loss remains to be determined.
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http://dx.doi.org/10.1016/j.mce.2018.09.006DOI Listing
January 2019

Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency.

Trends Endocrinol Metab 2018 06 26;29(6):400-419. Epub 2018 Apr 26.

Medical Faculty, Univ. Paris Sud and Paris Saclay, Bicetre Hospital 94275, Le Kremlin Bicêtre, France. Electronic address:

Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.
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http://dx.doi.org/10.1016/j.tem.2018.03.010DOI Listing
June 2018
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