Eszter Vanky

Metformin Versus Placebo from First Trimester to Delivery in Polycystic Ovary Syndrome: A Randomized, Controlled Multicenter Study

CONTEXT Metformin is widely prescribed to pregnant women with polycystic ovary syndrome (PCOS) in an attempt to reduce pregnancy complications. Metformin is not approved for this indication, and evidence for this practice is lacking. OBJECTIVES Our objective was to test the hypothesis that metformin, from first trimester to delivery, reduces pregnancy complications in women with PCOS. DESIGN AND SETTING We conducted a randomized, placebo-controlled, double-blind, multicenter study at 11 secondary care centers. PARTICIPANTS The participants were 257 women with PCOS, in the first trimester of pregnancy, aged 18-42 yr. INTERVENTION We randomly assigned 274 singleton pregnancies (in 257 women) to receive metformin or placebo, from first trimester to delivery. MAIN OUTCOME MEASURES The prevalence of preeclampsia, gestational diabetes mellitus, preterm delivery, and a composite of these three outcomes is reported. RESULTS Preeclampsia prevalence was 7.4% in the metformin group and 3.7% in the placebo group (3.7%; 95% CI, -1.7-9.2) (P=0.18). Preterm delivery prevalence was 3.7% in the metformin group and 8.2% in the placebo group (-4.4%; 95%, CI, -10.1-1.2) (P=0.12). Gestational diabetes mellitus prevalence was 17.6% in the metformin group and 16.9% in the placebo group (0.8%; 95% CI, -8.6-10.2) (P=0.87). The composite primary endpoint prevalence was 25.9 and 24.4%, respectively (1.5%; 95% CI, -8.9-11.3) (P=0.78). Women in the metformin group gained less weight during pregnancy compared with those in the placebo group. There was no difference in fetal birth weight between the groups. CONCLUSIONS Metformin treatment from first trimester to delivery did not reduce pregnancy complications in PCOS.

Anti-Mullerian hormone in the diagnosis of polycystic ovary syndrome: can morphologic description be replaced?

STUDY QUESTION Can anti-Müllerian hormone (AMH) level replace the morphologic description in the diagnosis of polycystic ovary syndrome (PCOS) and what is the relationship between AMH and different diagnostic criteria of PCOS? SUMMARY ANSWER AMH may be a good substitute for polycystic ovarian morphology (PCOM) in diagnosing PCOS. WHAT IS KNOWN ALREADY AMH has been suggested as an alternative to antral follicle count (AFC) in diagnosing PCOS. Cut-off values for AMH studied so far show an acceptable specificity but a rather poor sensitivity, leaving up to one-third of PCOS women undiagnosed. STUDY DESIGN, SIZE, DURATION We used data from a cross-sectional, case-control study on women with prior preterm birth and their controls, i.e. women with prior full-term birth. Among 262 women, 56 met the Rotterdam criteria (PCOS-R) and 44 the Androgen Excess-PCOS Society (PCOS-AES) criteria of PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS Fasting blood samples were collected, a transvaginal ultrasound investigation and a clinical examination were performed. PCOS-R and PCOS-AES were re-diagnosed by replacing PCOM with AMH. Main outcome measures were the prevalence of PCOS, PCOM, hirsutism, oligoamenorrhoea and serum levels of AMH and androgens. MAIN RESULTS AND THE ROLE OF CHANCE When replacing PCOM with AMH, the specificity and sensitivity for identifying PCOS were 97.1 and 94.6% according to the PCOS-R criteria and 97.2 and 95.5% according to the PCOS-AES criteria, respectively, at an AMH cut-off value of 20 pmol/l. LIMITATIONS, REASONS FOR CAUTION The results need to be confirmed when international standards and methods for AMH measurements are established. WIDER IMPLICATIONS OF THE FINDINGS AMH may be a good substitute for PCOM in diagnosing PCOS. STUDY FUNDING/COMPETING INTEREST(S) This study was financed by the Cooperative of Central Norway Regional Health Authority and Norwegian University of Science and Technology. The authors have no interests to disclose. TRIAL REGISTRATION NUMBER This study is registered at www.clinicaltrials.gov as NCT01355536.

Metformin treatment in pregnant women with polycystic ovary syndrome - is reduced complication rate mediated by changes in the uteroplacental circulation?

To study a possible effect of metformin on the uteroplacental circulation.

Association of size at birth with adolescent hormone levels, body size and age at menarche : relevance for breast cancer risk

Birth size has been positively associated with age at menarche and height in adolescence and adulthood, but the relevant biological mechanisms remain unclear. Among 262 Norwegian term-born singleton girls, birth size measures (weight, length, ponderal index, head circumference and subscapular skin-fold thickness) were analysed in relation to adolescent hormone levels (oestradiol, prolactin, dehydroepiandrosterone sulphate, androstenedione and free testosterone index), age at menarche and adolescent (ages 12.7–15.5 years) and body size (height, weight, body mass index and waist-to-hip ratio) using survival analysis and general linear modelling. The results were adjusted for gestational age at birth, age and menarcheal status at measurement in adolescence and maternal age at menarche. Birth weight, birth length and head circumference were positively associated with adolescent weight and height, and small birth size was associated with earlier age at menarche. Subscapular skin-fold thickness at birth was not associated with adolescent body size, but low fold-thickness was associated with earlier age at menarche. Measures of birth size were inversely related to circulating levels of dehydroepiandrosterone sulphate in adolescence, but there was no clear association with other hormones. These results suggest that physical and sexual development in puberty and adolescence is influenced by prenatal factors, and in combination, these factors may influence health and disease later in life.

Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero

Objectives. To investigate the possible long-term effects of metformin exposure on growth and development of the offspring born to mothers with polycystic ovary syndrome (PCOS). The drug passes through the placenta and can potentially influence the fetus. Patients and methods. This is a follow-up study of a randomized, controlled trial on PCOS women, randomized to metformin or placebo in pregnancy. Out of 37 children aged 7–9 years, 25 agreed to participate. Primary outcome measures were growth, body composition and metabolic parameters. Results. There were no differences in height, weight or body composition between those exposed to metformin and those exposed to placebo. We found a higher fasting glucose level in the metformin group (4.93 mmol/L vs. 4.60 mmol/L, p = 0.04). In the metformin group there was a trend towards higher systolic blood pressure (106 mmHg vs. 101 mmHg, p = 0.05) and a lower LDL cholesterol level (2.42 mmol/L vs. 2.99 mmol/L, p = 0.07). Conclusion. Metformin exposure during fetal life does not seem to influence growth and body composition at the age of 8 years. A higher fasting glucose level and a possible higher systolic blood pressure and lower LDL cholesterol level in the metformin group may be coincidental and should be further explored.

Homocysteine levels are unaffected by metformin treatment in both nonpregnant and pregnant women with polycystic ovary syndrome

Background. Women with polycystic ovary syndrome have elevated homocysteine levels. Elevated homocysteine levels associate with pregnancy complications. Women with polycystic ovary syndrome are often treated with metformin, a drug that may increase homocysteine levels. Hence, we investigated the effect of metformin treatment on homocysteine levels in nonpregnant and pregnant women with polycystic ovary syndrome. Methods. Two prospective randomized placebo‐controlled studies included women with polycystic ovary syndrome in a university hospital setting. Sixty‐three infertile women were treated with metformin 1,000 mg bid or placebo for 16 weeks and 38 pregnant women with metformin 850 mg bid or placebo from the first trimester and throughout pregnancy. All the women had polycystic ovary syndrome and all participants received diet and lifestyle advice, and oral folate and vitamin B12 substitution, and a daily oral multivitamin tablet. The main outcome measures were serum levels of homocysteine, folate, and vitamin B12. Results. Serum homocysteine levels were unaffected by metformin treatment both in nonpregnant and pregnant women with polycystic ovary syndrome. However, in nonpregnant women both serum folate and vitamin B12 levels decreased with treatment. At inclusion in nonpregnant women, serum homocysteine levels associated negatively with serum levels of folate and methyl malonic acid and positively with free testosterone index. No such associations were seen in pregnant women. Conclusions. Metformin treatment in women with polycystic ovary does not increase serum homocysteine levels in the nonpregnant or the pregnant state.

Mid-pregnancy androgen levels are negatively associated with breastfeeding

Objective. Breastfeeding depends on endocrine changes during pregnancy. The association between gestational hormones and lactation has been sparsely investigated. Previously, androgens were used for lactation inhibition. We investigated a possible association between second trimester maternal androgen levels and breastfeeding. Design. Prospective observational study.

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.

Metformin has no major effects on glucose homeostasis in pregnant women with PCOS: results of a randomized double-blind study.

Objective. Previous non‐randomized and uncontrolled studies indicate major metformin effects on glucose homeostasis in pregnant women with polycystic ovary syndrome (PCOS). We investigated metformin effects on glucose homeostasis in a prospective controlled study. Material and methods. Forty pregnant women with PCOS and without known diabetes mellitus were included in the first trimester and randomized to either metformin 850 mg twice daily or placebo. Outcome measures were fasting glucose and insulin at inclusion and changes to pregnancy weeks 19, 32 and 36 and 2 h glucose levels during a 75 g oral glucose tolerance test (OGTT) carried out at inclusion and pregnancy weeks 19 and 32. Insulin resistance (HOMA‐IR) and beta‐cell function (HOMA‐β) were calculated using the homeostasis assessment model. Results. At inclusion, 2 h glucose levels during OGTT were higher in the placebo group (7.14 versus 6.03 mmol/L; p = 0.012). Accordingly, 6 out of 22 in the metformin group versus 2 out of 18 women in the placebo group (p = 0.21) had gestational diabetes mellitus at inclusion. At gestational weeks 19 and 32, 2‐h plasma glucose levels were equal between the groups. The total proportion of women with gestational diabetes did not differ between the groups, nor did any of the other indices of glucose metabolism and insulin resistance. Conclusions. Metformin seems to be without major effects on glucose homeostasis in pregnant women with PCOS.

Breastfeeding in polycystic ovary syndrome

Background. To investigate the breastfeeding rate in new mothers with polycystic ovary syndrome (PCOS). Methods. Case‐control study. Thirty‐six women with PCOS and 99 controls matched for age, gestational length and parity, answered a questionnaire. Breastfeeding at one‐, three‐ and six‐months postpartum was registered and the two groups were compared. In the women with PCOS, androgen levels through pregnancy were analysed and related to breastfeeding rate. Results. At one‐month postpartum, 27 (75%) of the women with PCOS were breastfeeding exclusively, whereas five (14%) did not breastfeed at all. Among controls, 88 (89%) were breastfeeding exclusively and two (2%) did not breastfeed (p = 0.001). At three‐ and six‐months postpartum, breastfeeding was equal in the two groups. Problems with sore nipples and seeking professional lactation support were also equal. Dehydroepiandrosterone‐sulphate levels at gestational week 32 and 36 showed a weak negative association with breastfeeding in PCOS women. Breastfeeding rate was not associated with maternal gestational levels of androstenedione, testosterone, sex‐hormone binding globulin, or free testosterone index in PCOS. Conclusions. Women with PCOS appear to have a reduced breastfeeding rate in the early postpartum period. Possibly, gestational dehydroepiandrosterone‐sulphate might negatively influence breastfeeding rate in women with the syndrome.