Laure Morin-Papunen

Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study

Please cite this paper as: Ijäs H, Vääräsmäki M, Morin‐Papunen L, Keravuo R, Ebeling T, Saarela T, Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 2011;118:880–885.

Unfavorable hormonal, metabolic, and inflammatory alterations persist after menopause in women with PCOS.

CONTEXT Women with polycystic ovary syndrome (PCOS) are known to suffer from hyperandrogenism and impaired glucose tolerance, as well as chronic inflammation, exposing them to an increased risk of cardiovascular diseases. However, the degree to which these hormonal and metabolic alterations persist after menopause (MP) is not well documented. OBJECTIVE Our objective was to explore whether adverse metabolic and hormonal alterations persist after MP in women with PCOS. DESIGN We conducted a cross-sectional university hospital-based study. PATIENTS AND INTERVENTIONS Twenty-one pre-MP (n = 10) and post-MP (n = 11) women diagnosed with PCOS were compared with 29 healthy controls (pre-MP, n = 11; post-MP, n = 18). Two-hour oral glucose tolerance tests were performed, and ovarian steroid secretion capacity was assessed (human chorionic gonadotropin tests). Areas under the curves (AUC) were calculated. RESULTS Both pre-MP and post-MP women with PCOS had increased insulin response in oral glucose tolerance tests (AUC(ins) pre-MP = 6733.7 vs. 3382.9; post-MP = 9732.1 vs. 3265.3) and were more insulin resistant than controls. Androgen secretion capacity was increased before and after MP in PCOS (AUC of androstenedione; pre-MP: 1218.4 vs. 853.2; post-MP: 1000.0 vs. 531.3). High-sensitivity C-reactive protein remained elevated after MP in PCOS (pre-MP: 1.3 vs. 0.7; post-MP: 1.4 vs. 0.9 mg/liter). Adjustment for body mass index did not alter the results except for glucose metabolism. CONCLUSIONS The results indicate that impaired glucose metabolism, enhanced ovarian androgen secretion, and chronic inflammation observed in pre-MP women with PCOS persist after menopausal transition emphasizing life-long health risks related to this syndrome.

Adrenal Androgen Production Capacity Remains High up to Menopause in Women with Polycystic Ovary Syndrome

INTRODUCTION Hyperandrogenism is one of the main features of polycystic ovary syndrome (PCOS). Of circulating androgens, 50% of androstenedione and testosterone are of ovarian and adrenal origin, whereas dehydroepiandrosterone (DHEA) and DHEA sulfate are almost uniquely of adrenal origin. Our previous studies have indicated that ovarian androgen production capacity is enhanced in women with PCOS, and it remains high until late reproductive age. To study whether this also applies to adrenal androgen production, ACTH tests were performed in healthy women and in women with PCOS. MATERIALS Sixty-nine healthy women (aged 19-62 yr; body mass index 19.2-35.0 kg/m2) and 58 women with previously diagnosed PCOS (aged 18-59 yr; body mass index 19.0-42.9 kg/m2) participated in the study. METHODS The subjects underwent ACTH stimulation tests, and serum cortisol, 17-hydroxyprogesterone, androstenedione, testosterone, DHEA, and DHEA sulfate levels were analyzed at 0, 30, and 60 min. RESULTS Basal and ACTH-stimulated levels of most adrenal androgens decreased in healthy women with age, whereas in women with PCOS, only the concentrations of basal serum 17-hydroxyprogesterone decreased, and all areas under the curve (AUCs) remained unchanged and significantly higher (except for DHEA) than those in control women. Likewise, at the menopausal transition, pre- and postmenopausal women with PCOS exhibited mainly unchanged and higher basal androgen and AUC levels. CONCLUSIONS Similarly to ovarian endocrine function, serum adrenal steroid levels and adrenal steroid production capacity remain enhanced at least up to menopause in women with PCOS.

Fecundability and spontaneous abortions in women with self-reported oligo-amenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 Study

BACKGROUND Women with polycystic ovary syndrome (PCOS) suffer from anovulatory infertility and hospital-based studies suggest that they have an increased risk of spontaneous abortion. Our aim was to investigate the proportion of women, with self-reported oligo-amenorrhea and/or hirsutism in a general population, who had suffered from infertility, the percentage of them managing to conceive and their rate of spontaneous abortion. METHODS At age 31, a postal questionnaire including questions about hirsutism and oligo-amenorrhea was sent to all women from the population-based Northern Finland Birth Cohort 1966 (total n = 5889). Of these, 4535 (79.5%) answered the questionnaire, 1103 reported hirsutism and/or oligo/amenorrhea (symptomatic women) and 3420 were non-symptomatic. The fecundability ratio (FR) was defined as the probability of conception of a clinically detectable pregnancy within 12 months. RESULTS The overall pregnancy (77.7% versus 75.6%) and spontaneous abortion (19.3% versus 18.6%) rates did not differ between the two groups and the risk of spontaneous abortion was not associated with body mass index (BMI), waist-to-hip ratio (WHR) or waist circumference. Symptomatic women had suffered more often from infertility than non-symptomatic women (19.4% versus 11.1%, P < 0.01). Oligo-amenorrhea and/or hirsutism (FR = 0.74, P < 0.001) and obesity (FR = 0.68, P = 0.002) were both independently associated with decreased fecundability, but symptomatic women had become pregnant and had one or two successful deliveries as often as non-symptomatic women. CONCLUSIONS Women with self-reported oligo-amenorrhea and/or hirsutism had lower fecundability and suffered more often from infertility, but had at least one delivery as often as non-symptomatic women, and did not exhibit an increased risk of spontaneous abortion.

Comparison of metabolic and inflammatory outcomes in women who used oral contraceptives and the levonorgestrel-releasing intrauterine device in a general population

OBJECTIVE We compared the metabolic and cardiovascular parameters of a reference group of women with those of women who used 2 contraceptive regimes that are used worldwide: the levonorgestrel-releasing intrauterine device and oral contraceptives. STUDY DESIGN We investigated a cohort of 2814 women at age 31 years from the general population-based Northern Finland Birth Cohort who were born in 1966. Women were classified as oral contraceptive users (n = 687 women), levonorgestrel-releasing intrauterine device users (n = 168 women), or no use of hormonal contraception (reference group; n = 1959 women). The analyses were adjusted for body mass index, current alcohol use, household income, and area of residence. RESULTS Compared with the reference group, oral contraceptive users had higher systolic and diastolic blood pressure, raised levels of inflammatory indices (C-reactive protein), and impaired insulin sensitivity. Levonorgestrel-releasing intrauterine device users displayed a lower high-density lipoprotein and total cholesterol, but a similar cholesterol/ high-density lipoprotein ratio, and higher leukocyte count compared with the reference group. Oral contraception users were insulin-resistant compared with levonorgestrel-releasing intrauterine device users with higher blood pressure, raised lipid levels (such as total cholesterol and triglycerides) and insulin levels, and lower homeostasis model assessment and insulin sensitivity, despite smaller waist and lower waist-hip ratio. CONCLUSION Oral contraception usage was associated with adverse findings in several metabolic, cardiovascular, and inflammatory parameters, which is consistent with an increased future risk of cardiovascular and metabolic disease. These findings should invite more criticism of recent trends that encourage the prescription of oral contraceptives for years during reproductive life and especially in premenopausal women. In contrast, levonorgestrel-releasing intrauterine device or progestin-only pills may offer long-term health benefits over oral contraceptives and should be preferred to oral contraceptives for women in their forties and/or with metabolic risk factors for cardiovascular diseases and type 2 diabetes mellitus.

Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study

BACKGROUND To study the effect of metformin before and during assisted reproductive technology (ART) on the clinical pregnancy rate (CPR) in non-obese women with polycystic ovary syndrome (PCOS). METHODS A multi-centre, prospective, randomized, double-blind study was conducted in eight IVF clinics in four Nordic countries. We enrolled 150 PCOS women with a body mass index <28 kg/m(2), and treated them with 2000 mg/day metformin or identical placebo tablets for ≥ 12 weeks prior to and during long protocol IVF or ICSI and until the day of pregnancy testing. The primary outcome measure was CPR. Secondary outcome measures included spontaneous pregnancy rates during the pretreatment period, and the live birth rate (LBR). RESULTS Among IVF treated women (n = 112), biochemical pregnancy rates were identical in both groups (42.9%), and there were no significant differences in the metformin versus the placebo group in CPR [39.3 versus 30.4%; 95% confidence interval (CI): -8.6 to 26.5]. The LBR was 37.5 versus 28.6% (95% CI: -8.4 to 26.3). However, prior to IVF there were 15 (20.3%) spontaneous pregnancies in the metformin group and eight (10.7%) in the placebo group (95% CI: -1.9 to 21.1; P = 0.1047). According to intention to treat analyses (n = 149); significantly higher overall CPR were observed in the metformin versus placebo group (50.0 versus 33.3%; 95% CI: -1.1 to 32.3; P = 0.0391). LBR was also significantly higher with use of metformin versus placebo (48.6 versus 32.0; 95% CI: 1.1 to 32.2; P = 0.0383). No major unexpected safety issues or multiple births were reported. More gastrointestinal side effects occurred in the metformin group (41 versus 12%; 95% CI: 0.15 to 0.42; P < 0.001). CONCLUSIONS Metformin treatment for 12 weeks before and during IVF or ICSI in non-obese women with PCOS significantly increases pregnancy and LBRs compared with placebo. However, there was no effect on the outcome of ART per se. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00159575.

Statin Therapy Worsens Insulin Sensitivity in Women With Polycystic Ovary Syndrome (PCOS): A Prospective, Randomized, Double-Blind, Placebo-Controlled Study

CONTEXT Statins have been shown to improve hyperandrogenism in women with polycystic ovary syndrome (PCOS). However, their use has also been associated with impairment of glucose metabolism and an increased risk of type 2 diabetes mellitus. Because women with PCOS are prone to disturbances in glucose metabolism, statin therapy could also have negative effects. OBJECTIVE Our objective was to explore the effects of atorvastatin therapy on hormonal and metabolic parameters in women with PCOS. DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled 6-month follow-up study conducted at Oulu University Hospital, Finland. PATIENTS Women with PCOS (Rotterdam criteria) were treated with atorvastatin (20 mg/d, n = 15) or placebo (n = 13) for 6 months. INTERVENTIONS Fasting serum samples were collected at baseline and at 3 and 6 months. Oral and iv glucose tolerance tests were performed at 0 and 6 months. MAIN OUTCOME MEASURES Androgen secretion and glucose metabolism were measured. RESULTS Fasting levels and area under the curve of insulin increased significantly and insulin sensitivity (insulinogenic and Matsuda indexes) decreased during 6 months of atorvastatin therapy. Serum levels of dehydroepiandrosterone sulfate decreased in the atorvastatin group, whereas no change was observed in serum testosterone levels. Levels of C-reactive protein, total and low-density lipoprotein-cholesterol, and triglycerides decreased significantly during statin therapy. CONCLUSIONS Atorvastatin therapy improves chronic inflammation and lipid profile, but it impairs insulin sensitivity in women with PCOS. Because women with PCOS have an increased risk of developing type 2 diabetes mellitus, the results suggest that statin therapy should be initiated on the basis of generally accepted criteria and individual risk assessment of cardiovascular disease, and not only because of PCOS.

Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study

STUDY QUESTION What is the effect of alternative administration routes of combined contraceptives (CCs) on androgen secretion, chronic inflammation, glucose tolerance and lipid profile? SUMMARY ANSWER The use of oral, transdermal and vaginal CCs impairs glucose tolerance and induces chronic inflammation. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Oral CCs worsen insulin sensitivity and are associated with increased levels of circulating inflammatory markers, whereas the metabolic effects of transdermal and vaginal CCs have been reported to be minimal. This is the first study comparing three different administration routes of CCs on metabolic variables. STUDY DESIGN, SIZE AND DURATION This randomized (computer-generated) open-label 9-week follow-up study was conducted at the Oulu University Hospital, Finland. Fasting blood samples were collected at baseline and thereafter at 5 and 9 weeks of treatment, and serum levels of 17-hydroxyprogesterone, androstenedione, testosterone, C-reactive protein (CRP), sex hormone-binding globulin (SHBG), glucose, insulin, C-peptide, total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured. Oral glucose tolerance tests were performed and plasma levels of pentraxin 3 (PTX-3) were measured at 0 and 9 weeks. The randomization list, with an allocation ratio of 1:1:1 and block size of six, was computer generated and constructed by a pharmacist at the Oulu University Hospital. The research nurse controlled the randomization list and assigned participants to their groups at the first visit. PARTICIPANTS AND SETTING Forty-two of 54 healthy women who entered the study used oral contraceptive pills (n = 13), transdermal contraceptive patches (n = 15) or contraceptive vaginal rings (n = 14) continuously for 9 weeks. Inclusion criteria were regular menstrual cycles, at least a 2-month washout as regards hormonal contraceptives and no medication. MAIN RESULTS AND THE ROLE OF CHANCE Serum levels of SHBG increased and consequently the free androgen index (FAI) decreased in all study groups from baseline to 9 weeks of treatment [FAI, oral: 1.3 (95% confidence interval, CI: 0.94; 1.62) to 0.40 (0.25; 0.54); transdermal: 1.2 (0.96; 1.4) to 0.36 (0.30; 0.43); vaginal: 1.6 (1.1; 2.1) to 0.43 (0.29; 0.58), P < 0.001 in all groups]. Insulin sensitivity was reduced at 9 weeks in all three groups according to the Matsuda index [oral: 7.3 (5.5; 9.0) to 5.6 (3.9; 7.3); transdermal: 9.1 (6.7; 11.4) to 6.6 (4.5; 8.8); vaginal: 7.7 (5.9; 9.5) to 5.4 (3.9; 7.0), P= 0.004-0.024]. Levels of HDL cholesterol, triglycerides and CRP rose in all three groups [CRP, oral: 0.70 (0.38; 1.0) to 5.4 (1.0; 9.9) mg/l; transdermal: 0.77 (0.45; 1.1) to 2.9 (1.4;4.4) mg/l; vaginal: 0.98 (0.52; 1.4) to 3.7 (-0.25; 7.7, a negative value due to skewed distribution to right) mg/l, P≤ 0.002 in all groups] and PTX-3 levels increased in the oral and transdermal study groups (P = 0.007 and P = 0.002). WIDER IMPLICATIONS OF THE FINDINGS Although the long-term consequences of the present results remain undetermined, these findings emphasize the importance of monitoring glucose metabolism during the use of CCs, especially in women with known risks of type 2 diabetes or cardiovascular diseases. BIAS, LIMITATIONS, GENERALIZABILITY: The number of subjects was relatively low. Moreover, the 9-week exposure to CCs is too short to draw conclusions about the long-term health consequences. However, as the subjects were healthy, normal-weight young women, the possible alterations in the glucose and inflammatory profiles among women with known metabolic risks might be even greater. STUDY FUNDING/COMPETING INTERESTS This work was supported by grants from the Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Medical Foundation, the Research Foundation of Obstetrics and Gynecology, Oulu University Scholarship Foundation, the North Ostrobothnia Regional Fund of the Finnish Cultural Foundation, the Tyyni Tani Foundation of the University of Oulu and the Finnish-Norwegian Medical Foundation. No competing interests. TRIAL REGISTRATION NUMBER NCT01087879.

Weight Gain and Dyslipidemia in Early Adulthood Associate With Polycystic Ovary Syndrome: Prospective Cohort Study

CONTEXT Obesity affects the majority of women with polycystic ovary syndrome (PCOS), but previous studies are inconsistent about the prevalence of obesity and the importance of weight gain in the development of the syndrome. OBJECTIVE Our objective was to explore the association between weight, weight gain, hyperandrogenism, and PCOS from adolescence to late adulthood. DESIGN The study includes a prospective Northern Finland Birth Cohort 1966 study including 5889 females born in 1966 and followed at the ages of 14, 31, and 46 years. SETTING The setting was the general community. PARTICIPANTS Women presenting both oligo/amenorrhea (OA) and hirsutism (H) at age 31 (N = 125) or with formally diagnosed PCOS by age 46 (N = 181) were compared with women without PCOS symptoms or diagnosis (n = 1577). INTERVENTIONS None. MAIN OUTCOME MEASURES Body mass index (BMI), weight change through life, waist circumference, Free Androgen Index, lipids, glucose, insulin, high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance, and PCOS. RESULTS Women with OA+H at age 31 or diagnosis of PCOS by age 46 had the highest BMI at all ages compared with the controls. Increase of BMI between ages 14 and 31, but not between 31 and 46, was greater in women with isolated OA (P = .006), OA+H (P = .001), and diagnosis of PCOS (P = .001) compared with controls. In the multivariate analysis, PCOS was significantly associated with BMI at all ages (BMI at age 31: odds ratio [OR] = 1.05 [95% confidence interval (CI), 1.00-1.10], Free Androgen Index (OR = 1.08 [95% CI, 1.03-1.14]), serum levels of insulin (OR = 1.05 [95% CI, 1.00-1.09]), and triglycerides (OR = 1.48 [95% CI, 1.08-2.03]). CONCLUSIONS Symptoms or diagnosis of PCOS are associated with dyslipidemia, hyperandrogenemia, and significantly increased weight gain, especially in early adulthood. This observation is important because it may identify a sensitive time period when weight gain plays a crucial role in the emergence of PCOS and when preventive actions against metabolic and cardiovascular diseases should be implemented.

Androgen Profile Through Life in Women With Polycystic Ovary Syndrome: A Nordic Multicenter Collaboration Study

CONTEXT Women with polycystic ovary syndrome (PCOS) have increased androgen secretion throughout fertile life; however, the data on the effect of menopause on hyperandrogenemia in these women are scarce. Nevertheless, large comprehensive comparative studies on age-related androgen levels in women with PCOS are lacking. OBJECTIVE The objective of the study was to investigate the effect of age on serum androgen levels in women with PCOS and to determine cutoff values for androgens and SHBG associated with a PCOS diagnosis. DESIGN This was a case-control study. SETTING The study was conducted in five university sites in the Nordic countries. PATIENTS In all, 681 women with PCOS and 230 referent women were grouped according to age into seven age groups (18 to > 50 y). INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES T, SHBG, free androgen index (FAI), calculated free T (cFT), androstenedione (A4), and dehydroepiandrosterone sulfate were measured. RESULTS Androgen levels in women with PCOS decreased with age toward menopause. The difference between women with PCOS and the referent women narrowed and individual variation increased as they approached menopause. T levels, FAI, and cFT were significantly higher in women with PCOS aged 18-44 years (P < .001, adjusted for body mass index). The best predictive factors for having PCOS were cFT (≥0.40 ng/dL, odds ratio [OR] 7.90), FAI (≥2.0, OR 6.71), and A4 (≥277.94 ng/dL, OR 6.16). CONCLUSIONS Women with PCOS had elevated serum androgen levels also after menopause. The parameters that best predicted PCOS at all ages were cFT, A4, and FAI.