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

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(2)) 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. ((C) 2019 by American Society for Reproductive Medicine.)Peer reviewe

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

BackgroundThe 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.MethodsThis 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.ResultsIncreased 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 (Peer reviewe

Determination of biological activity of gonadotropins hCG and FSH by Forster resonance energy transfer based biosensors

Determination of biological activity of gonadotropin hormones is essential in reproductive medicine and pharmaceutical manufacturing of the hormonal preparations. The aim of the study was to adopt a G-protein coupled receptor (GPCR)-mediated signal transduction pathway based assay for quantification of biological activity of gonadotropins. We focussed on studying human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH), as these hormones are widely used in clinical practice. Receptor-specific changes in cellular cyclic adenosine monophosphate (cAMP, second messenger in GPCR signalling) were monitored by a Forster resonance energy transfer (FRET) biosensor protein (T)Epac(VV) in living cells upon activation of the relevant gonadotropin receptor. The BacMam gene delivery system was used for biosensor protein expression in target cells. In the developed assay only biologically active hormones initiated GPCR-mediated cellular signalling. High assay sensitivities were achieved for detection of hCG (limit of detection, LOD: 5 pM) and FSH (LOD: 100 pM). Even the smallscale conformational changes caused by thermal inactivation and reducing the biological activity of the hormones were registered. In conclusion, the proposed assay is suitable for quantification of biological activity of gonadotropins and is a good alternative to antibody- and animal-testing-based assays used in pharmaceutical industry and clinical research.Peer reviewe

Incidence of cancer among grand multiparous women in Finland with special focus on non-gynaecological cancers : A population-based cohort study

Background. Many studies have previously revealed evidence of an association between grand multiparity (five or more deliveries) and gynaecological cancer. Oestrogen has an impact on cancer formation and the amount of circulating oestrogen is significantly higher during pregnancy. Also the lifestyle of grand multiparous women differs somewhat from the average population. Considering these factors it is plausible that also non-gynaecological cancers are associated with multiparity. The aim of our study was to determine cancer incidence among grand multiparous women, with special attention to non-gynaecological cancers. Material and methods. All 102 541 women alive in 1974-2011 and having had at least five deliveries were identified in the Finnish Population Register and followed up for cancer incidence through the Finnish Cancer Registry to the end of 2011. Standardised incidence ratios (SIRs) were defined as ratios between observed and expected numbers of cases, the latter ones based on incidence in the entire Finnish female population. Results. The overall incidence of non-gynaecological cancers was the same as in the reference population (SIR 0.98, 95% confidence interval 0.90-1.06). The incidence of cancers of the gall-bladder (SIR 1.42, 1.26-1.58), biliary tract (1.19, 1.04-1.35) and kidney (1.22, 1.14-1.31) was increased. There were significantly fewer cases than expected of urinary bladder cancer (SIR 0.70, 0.61-0.78), lung cancer (0.87, 0.81-0.92), colon cancer (0.94, 0.89-0.99) and all types of skin cancers. As a consequence of the decreased incidence of gynaecological cancers (SIR 0.74, 0.71-0.77) and breast cancer (0.60, 0.58-0.61), the SIR for cancer overall was 0.84 (0.83-0.85). Conclusion. The study demonstrated that grand multiparous women have a similar overall risk of non-gynaecological cancers as other women, despite significant differences in some specific forms of cancer.Peer reviewe

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

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.Peer reviewe

Ageing women with PCOS: Menstrual cycles, metabolic health and health related quality of life (HRQoL)

Women with polycystic ovary syndrome (PCOS) in their reproductive years age present with metabolic dysfunction and thus increased likelihood of long-term health consequences and diminished well-being in later life. Due to their larger ovarian reserve, however, they may experience menopause at later age and protection from metabolic and cardiovascular diseases. Moreover, previous studies have indicated that late reproductive aged, normal-weight women with PCOS do not seem to have the expected high risk for type 2 diabetes (T2D), as previously thought. Health related quality of life (HRQoL), nevertheless, is decreased in women with PCOS up until late fertile age, warranting attention and actions from the health care personnel. Given conflicting reports regarding the risk of cardiovascular diseases, future research with well characterized and adequately sized PCOS populations are needed as well as studies aiming to improve their HRQoL.Peer reviewe

Identification of the LH surge by measuring intact and total immunoreactivity in urine for prediction of ovulation time

Objectives In our earlier study, we separated three different molecular forms of urinary LH-ir (U-LH-ir) by gel filtration and identified them by immunoassay in urine from regularly menstruating women on periovulatory days. U-LH-ir is composed of intact luteinizing hormone (LH), its free beta-subunit (LH beta), and the core fragment of LH beta (LH beta cf), the latter two establishing the non-intact portion of LH-ir. The aim was to determine whether timing of ovulation can be improved by detecting different molecular forms of U-LH-ir in women of reproductive age. Methods We determined intact and total U-LH-ir in 14 regularly menstruating women on consecutive periovulatory days during the menstrual cycle. Non-intact LH-ir was calculated as the arithmetic difference between total and intact LH-ir. In addition, LH-ir was determined in both serum and urine from four of the women throughout the menstrual cycle. Results During the LH surge, U-LH-ir consisted mainly of intact LH and presented with an abrupt increase. Intact U-LH-ir dropped rapidly within 1 day after the surge, reaching baseline levels at the end of the luteal phase. In contrast, LH beta cf in urine increased further 1 day after the surge. After this, most of the U-LH-ir consisted of LH beta cf and it remained strongly elevated (over fivefold compared to intact LH) for the first 3 days after the LH surge, moderately elevated (over threefold) thereafter until day + 5, and mildly elevated until day + 7. Conclusions Total and non-intact LH-ir are potential add-on characteristics which can be utilized in ovulation predictor kits to measure LH-ir in urine beyond the LH surge during a broader time frame, thereby paving the way for more precise prediction of the timing of ovulation than that obtained with currently available products.Peer reviewe

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

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.Peer reviewe

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

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.Peer reviewe

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

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 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. (C) 2018 by the American Pain SocietyPeer reviewe