Top-quality embryo transfer is associated with lower odds of ectopic pregnancy.

INTRODUCTION: The incidence of ectopic pregnancy is up to four times higher after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) than in spontaneous pregnancies, and the risk of ectopic pregnancy is increased by tubal factor infertility and the transfer of multiple embryos. However, the effect of embryo quality on the probability of ectopic pregnancy has not been investigated until now and it is not clear whether ovarian stimulation parameters affect the incidence of ectopic pregnancy. MATERIAL AND METHODS: An historical cohort study of 15 006 clinical pregnancies (diagnosed by ultrasound at 6-8 gestational weeks) after non-donor IVF/ICSI with fresh embryo transfer (n = 8952) or frozen-thawed embryo transfer (n = 6054). Treatments were performed during 2000-2017 in Finland. A total of 9207 (61.4%) single and 5799 (38.6%) double embryo transfers of no more than one top-quality embryo were evaluated. We analyzed the effects of multiple factors on ectopic pregnancy by logistic regression, including type of cycle (fresh vs frozen embryo transfer), female age, number and quality of embryos transferred, tubal factor infertility and factors of ovarian response to gonadotropin stimulation. RESULTS: Ectopic pregnancy was observed in 2.3% of cycles. There was no significant difference in ectopic pregnancy rate after fresh embryo transfer and frozen embryo transfer (2.2% vs 2.4%, p = 0.3). The ectopic pregnancy rate was lower in cycles with top-quality embryo transfer (1.9%) than of those where only non-top quality embryos were transferred (2.7%, p < 0.0001). Tubal factor infertility was diagnosed more often in ectopic pregnancy than in intrauterine pregnancies (21.2% vs 11.0%, p < 0.0001). Logistic regression revealed lower odds for ectopic pregnancy after a top-quality embryo transfer than after transfer of a non-top quality embryo (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.56-0.92, p = 0.007). Transfer of two vs one embryo (OR 1.35, 95% CI 1.05-1.70, p = 0.02) and tubal factor infertility (OR 2.21, 95% CI 1.68-2.91, p < 0.0001) significantly increased the risk of ectopic pregnancy. CONCLUSIONS: Transfer of non-top quality embryos is associated with a higher rate of ectopic pregnancy. This is particularly important to keep in mind in treatments with only non-top embryos available even in the absence of tubal factor infertility. To minimize the risk of ectopic pregnancy, the number of embryos transferred should be as low as possible.

Childhood growth of term singletons born after frozen compared with fresh embryo transfer.

RESEARCH QUESTION: Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age? DESIGN: Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared. RESULTS: Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height. CONCLUSIONS: Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.

Uterine fibroids and cardiovascular risk.

STUDY QUESTION: Are uterine fibroids associated with increased cardiovascular risk? SUMMARY ANSWER: This study reports an association between increased serum lipids and metabolic syndrome with an increased risk of uterine fibroids. WHAT IS KNOWN ALREADY: Recent studies suggest similarities in biological disease mechanisms and risk factors for fibroids and atherosclerosis: obesity, hypertension and abnormal serum lipids. These findings are awaiting confirmation that a population-based follow-up study could offer with extensive health examination data collection linked with a national hospital discharge register. STUDY DESIGN, SIZE, DURATION: The Northern Finland Birth Cohort (NFBC1966) is a population-based long-term follow-up study including all children with estimated date of delivery in 1966 in the Northern Finland area. The data were collected from national registries, postal questionnaires and clinical health examinations. The study population for this study comprised all females included in the NFBC1966 that underwent an extensive clinical health examination at age 46 years (n = 3635). PARTICIPANTS/MATERIALS, SETTING, METHODS: All females included in the NFBC1966 who were alive and traceable (n = 5118) were invited for the 46-year follow-up study; 3268 (63.9%) responded, returned the postal questionnaire and attended the clinical examination. Uterine fibroid cases were identified through the national hospital discharge register that has data on disease diagnoses based on WHO ICD-codes. Uterine fibroid codes, ICD-9: 218 and ICD-10: D25 were used for case identification. Self-reported fibroid cases were identified through the postal questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 729 fibroid cases were identified, including 293 based on hospital discharge registries. With adjustment for BMI, parity, education and current use of exogenous hormones the risk of prevalent fibroids rose significantly for every 1 mmol/l increase in LDL (OR = 1.13, 95% CI: 1.02-1.26 for all cases) and triglycerides (OR = 1.27, 95% CI: 1.09-1.49 for all cases). Metabolic syndrome associated with hospital discharge-based fibroid diagnosis (OR = 1.48, 95% CI: 1.09-2.01). Additionally every 1 unit increase in waist-hip ratio associated with fibroids (OR = 1.32, 95% CI: 1.10-1.57). LIMITATIONS, REASONS FOR CAUTION: The case ascertainment may present some limitations. There was likely an under-identification of cases and misclassification of some cases as controls; this would have diluted the effects of reported associations. The data analysed were cross-sectional and therefore cause and effect for the associations observed cannot be distinguished. WIDER IMPLICATIONS OF THE FINDINGS: Increased serum lipids and metabolic syndrome are associated with increased risk of uterine fibroids. Along with central obesity these findings add to an increased risk for cardiovascular disease among women with fibroids. These observations may suggest that there are shared predisposing factors underlying both uterine fibroids and adverse metabolic and cardiac disease risk, or that metabolic factors have a role in biological mechanisms underlying fibroid development. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Academy of Finland, University Hospital Oulu, University of Oulu, Finland, Northern Finland Health Care Foundation, Duodecim Foundation, ERDF European Regional Development Fund-Well-being and health: Research in the Northern Finland Birth Cohort 1966. The authors declare no conflict of interest.

A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Controlled ovarian hyperstimulation leads to high progesterone and estradiol levels during early pregnancy.

STUDY QUESTION: Are there differences in estrogen and progesterone secretion in singleton pregnancies, up to Week 11, between spontaneous pregnancies, after controlled ovarian hyperstimulation and fresh embryo transfer (COH + ET) and after frozen embryo transfer in a spontaneous cycle (FET)? SUMMARY ANSWER: Serum progesterone and estradiol (E2) concentrations after COH + ET were higher in early pregnancy, lasting up to Week 7-8, than FET and spontaneous pregnancies, while hormone levels after FET did not differ from spontaneous pregnancies. WHAT IS ALREADY KNOWN: The risk of adverse perinatal outcomes after COH + ET seems to be increased when compared with spontaneous pregnancies. One of the reasons suggested for this is related to ovarian hyperstimulation. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study consisting of three different groups of pregnant women which were followed-up weekly until Week 11 of their pregnancies. The spontaneous pregnancy group consisted of 41 women, the COH + ET group consisted of 39 and the FET group consisted of 30 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women in the control group with spontaneous conception were recruited from local prenatal clinics. Women in the COH + ET and FET groups were recruited from the Reproductive Unit of Oulu University Hospital. At each visit, a three-dimensional ultrasonography was performed to examine the ovarian volumes and vascularization. A blood sample was drawn to analyse progesterone and E2 levels. The pregnancy outcome was included in the analysis. MAIN RESULTS AND THE ROLE OF CHANCE: At pregnancy Week 5, the serum progesterone levels were higher after the COH + ET (median 312, inter-quartile range 183-480 nmol/l), when compared with the spontaneous (63, 52-80 nmol/l; P < 0.001) and FET (74, 48-96 nmol/l; P < 0.001) pregnancies. At Week 11, the P (189, 124-260 nmol/l) was still higher in the COH + ET group (FET 101, 78-120 nmol/l, P < 0.001; spontaneous 115, 80-139 nmol/l, P < 0.01) than the other two groups. The E2 levels at Week 5 were also significantly higher after COH + ET (4.1, 2.2-6.6 nmol/l) than in the spontaneous pregnancies (1.1, 0.7-1.6 nmol/l, P < 0.001) or after FET (0.7, 0.6-0.9 nmol/l, P < 0.001). The volume of the ovaries and the intraovarian vasculature in the COH + ET group were significantly higher when compared with the other two groups (P < 0.001). The birthweight was negatively correlated with the serum P (R -0.340, P < 0.01) and E2 (R= -0.275, P < 0.05) in pregnancy Weeks 5-8. In the multivariate analysis evaluating the factors affecting birthweight of the newborn, the significant factors were the length of gestation, maternal height and progesterone or E2 secretion during Weeks 5-8. LIMITATIONS, REASONS FOR CAUTION: Because of the low number of patients in this study, larger cohort studies are required to confirm the findings. WIDER IMPLICATIONS OF THE FINDINGS: The findings here indicate that COH-induced increased luteal activity should be evaluated by measuring steroid levels or the ovarian size or vascularity, rather than number of oocytes retrieved. If unphysiologically high steroid activity during pregnancy after COH contributes to the risk of adverse perinatal outcomes after fresh embryo transfer, milder stimulation protocols or even freezing of all of the embryos should be considered. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant from the Academy of Finland. The authors declare no conflicts of interest.

Factors affecting the outcome of frozen-thawed embryo transfer.

STUDY QUESTION: Which clinical and laboratory factors affect live birth rate (LBR) after frozen-thawed embryo transfer (FET)? SUMMARY ANSWER: Top quality embryo characteristics, endometrial preparation protocol, number of embryos transferred and BMI affected independently the LBR in FET. WHAT IS KNOWN ALREADY: FET is an important part of present-day IVF/ICSI treatment. There is limited understanding of the factors affecting success rates after FET. STUDY DESIGN, SIZE, DURATION: This is a two-centre retrospective cohort study. Analysis was carried out on 1972 consecutive FET cycles in 1998-2007, with embryos frozen on Day 2. The primary outcome was LBR per cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed the independent effect on LBR of the following variables: female age, female age at embryo freezing, BMI, diagnosis, primary versus secondary infertility, fertilization by IVF versus ICSI, pregnancy in the fresh cycle, type (spontaneous, spontaneous with luteal progesterone and estrogen/progesterone substitution) and rank of the FET cycle, as well as number and presence (yes versus no) of top quality embryo(s) at freezing, thawing and transfer, damaged thawed embryos and overnight culture. MAIN RESULTS AND THE ROLE OF CHANCE: In 78% of the cycles with top quality embryos frozen (n = 1319), at least one embryo still had high-quality morphology after thawing. Top quality embryo morphology observed at any stage of culture improved the outcome even if high-quality characteristics disappeared before transfer. LBRs after the transfer of a top quality embryo were similar in the FET (24.9%) and fresh cycles of the same period (21.9%). The chance of live birth increased significantly if ≥1 top quality embryo was present at freezing (odds ratio (OR) 1.85, 95% confidence interval (CI) 1.10-3.14), at thawing (OR 1.93, CI 1.20-3.11) or at transfer (OR 3.41, CI 2.12-5.48). Compared with spontaneous cycles with luteal support, purely spontaneous cycles (OR 0.58, CI 0.40-0.84) and hormonally substituted FET (OR 0.47, CI 0.32-0.69) diminished the odds of pregnancy. BMI (OR 0.96, CI 0.92-0.99) and transfer of two embryos versus one (OR 1.45, CI 1.08-1.94) were other factors that improved LBR after FET. LIMITATIONS, REASONS FOR CAUTION: The sample sizes available in some subanalyses were small, limiting the power of the study. WIDER IMPLICATIONS OF THE FINDINGS: The presence of ≥1 top quality embryo at any step of the freezing and thawing process increases the chance of pregnancy. The data do not support the freezing of all embryos for transfer in order to improve the outcome. A top quality embryo transferred in FET may even have the same potential as in a fresh cycle. On the contrary, LBR in the group with no top quality embryos frozen was quite low (10.4%), raising the question of whether a re-evaluation of freezing criteria is necessary to avoid costly treatments with a low success rate.

Metabolic and reproductive characteristics of first-degree relatives of women with self-reported oligo-amenorrhoea and hirsutism.

OBJECTIVE: To investigate the occurrence of oligo-amenorrhoea and hirsutism, infertility and metabolic morbidity among first-degree relatives of women with and without self-reported oligo-amenorrhoea and hirsutism. DESIGN: Nested case-control study. SETTING, POPULATION AND METHODS: A postal questionnaire about symptoms of oligo-amenorrhoea and hirsutism was sent to all women of the Northern Finland Birth Cohort 1966 (n = 5889). From this population were randomly selected 98 women with both symptoms and 163 without symptoms. A further questionnaire on the occurrence of oligo-amenorrhoea, hirsutism, infertility, early balding and metabolic morbidity in their relatives was sent to this subpopulation. MAIN FINDINGS: We obtained data on 183 relatives of 43 women with symptoms and 412 relatives of 86 symptomless women. Compared with relatives of symptomless women, mothers of women with symptoms suffered significantly more often from hirsutism and menstrual disorders, and sisters more often from hirsutism and infertility, and had fewer children and were more often childless. There was an increased prevalence of diabetes in the sisters and of hypertension in the fathers of women with symptoms. CONCLUSIONS: These results strengthen earlier findings of significantly increased metabolic and reproductive morbidity in the relatives of women with symptoms of PCOS.

Low-dose aspirin therapy and hypertensive pregnancy complications in unselected IVF and ICSI patients: a randomized, placebo-controlled, double-blind study.

BACKGROUND: Low-dose aspirin therapy could improve remodelling of maternal spiral arteries during early placentation and prevent subsequent pregnancy-related hypertensive disorders. We investigated whether low-dose aspirin therapy reduces the incidence of hypertensive pregnancy complications in unselected IVF and ICSI patients when medication was started prior to pregnancy. METHODS: A total of 487 patients who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n = 242) or placebo (n = 245) daily, starting on the first day of gonadotrophin stimulation. Pregnant women continued the medication until delivery. A total of 107 patients (52 with aspirin and 55 with placebo) experienced live birth and were included in this follow-up study. The main outcome measure was the incidence of hypertensive pregnancy complications. RESULTS: Embryo transfer took place in 227 (94%) women in the aspirin group and in 229 (93%) women in the placebo group. The live birth rate between the aspirin (22.9%) and placebo (24.0%) groups did not differ significantly (P = 0.78). The overall incidence of hypertensive pregnancy complications was 15.4% (8/52) in the aspirin group and 18.2% (10/55) in the placebo group (P = 0.70, 95% confidence interval for the difference of proportions -17 to 11%). There were two cases of severe pre-eclampsia in the aspirin group and three cases in the placebo group. CONCLUSIONS: In the present study, the incidence of hypertensive pregnancy complications did not differ statistically significantly between low-dose aspirin and placebo groups in unselected IVF/ICSI patients, when medication was started concomitantly with gonadotrophin stimulation and continued until delivery. The study was registered at clinicaltrials.gov. NCT00683202.

Improved pregnancy rate with administration of hCG after intrauterine insemination: a pilot study.

BACKGROUND: In natural cycles, women conceive when intercourse takes place during a six-day period ending on the day of ovulation. The current practice in intrauterine insemination (IUI) cycles is to perform the IUI 24-36 hours after the hCG administration, when the ovulation is already imminent. In this study hCG was administered after the IUI, which more closely resembles the fertilisation process in natural cycles. METHODS: All the IUIs performed since the beginning of 2007 were analysed retrospectively. Our standard protocol has been to perform the IUI 24-32 hours after hCG administration. From the end of 2008, we started to inject hCG after the IUI at random. The main outcome measure was the result of a urinary pregnancy test. Generalized Estimating Equations (GEE) was used to identify independent factors affecting the cycle outcome. RESULTS: The analysis included 228 cycles with hCG administered before and 104 cycles hCG administered after the IUI. The pregnancy rates were 10.9% and 19.6% (P = 0.040), respectively. Independent factors (OR, 95% CI) affecting the cycle outcome were sperm count (2.65, 1.20-5.81), number of follicles > 16 mm at IUI (2.01, 1.07-3.81) and the time of hCG administration (2.21, 1.16-4.19). CONCLUSION: Improved pregnancy rate was observed with administration of hCG after IUI.

Low-dose aspirin and uterine haemodynamics on the day of embryo transfer in women undergoing IVF/ICSI: a randomized, placebo-controlled, double-blind study.

BACKGROUND: Increased uterine artery (UtA) vascular impedance at the time of embryo transfer can decrease implantation and pregnancy rates in women undergoing IVF/ICSI. We hypothesized that low-dose aspirin decreases UtA vascular impedance on the day of embryo transfer in unselected IVF/ICSI patients when medication is started concomitantly with controlled ovarian stimulation. In addition, as secondary outcome measures, we investigated whether low-dose aspirin decreases the incidence of non-optimal (bilateral UtA PI > or = 3.0) uterine haemodynamics and whether it affects arcuate, radial and spiral artery vascular impedances and endometrial thickness. METHODS: A total of 122 women who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n = 61) or placebo (n = 61) daily, starting on the first day of gonadotrophin stimulation. Doppler ultrasonography was performed on the day of embryo transfer. RESULTS: Embryo transfer took place in 57 women in the aspirin group and in 56 women in the placebo group. UtA mean PI values did not differ significantly between the groups. The incidence of non-optimal uterine haemodynamics was lower in the aspirin group than in the placebo group (P = 0.03). Other secondary outcome measures did not differ between the groups. CONCLUSIONS: In unselected IVF/ICSI women, low-dose aspirin therapy, when started concomitantly with controlled ovarian stimulation, did not affect UtA vascular impedance on the day of embryo transfer. However, the incidence of non-optimal uterine haemodynamics was significantly lower in the aspirin group than in the placebo group. ClinicalTrials.gov: NCT00683202.

Elective single embryo transfer with cryopreservation improves the outcome and diminishes the costs of IVF/ICSI.

BACKGROUND: Although elective single embryo transfer (eSET) minimizes the multiple birth rate after in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI), there remain concerns in many countries that it is less effective and more expensive than conventional double embryo transfer (DET). METHODS: We compared the clinical outcome achieved in the years 1995-1999, in which eSET was rarely used (4.2% of women, DET period) with that of the years 2000-2004, in which eSET was more widely used (46.2%, eSET period). In the DET period, 826 women had 1359 fresh embryo cycles followed by 589 frozen-thawed embryo transfer (FET) cycles. In the eSET period, 684 women had 1027 fresh and 683 FET cycles. The cumulative term live birth rate/woman was the primary clinical outcome measure. An incremental cost-effectiveness ratio of a term live birth was also calculated based on hospital charges and medication prices of IVF/ICSI treatment. RESULTS: The cumulative pregnancy rate/oocytes pickup (38.2 versus 33.1%, P = 0.01), cumulative live birth rate/oocytes pickup (28.0 versus 22.5%, P = 0.002) and cumulative live birth rate/woman (41.7 versus 36.6%, P = 0.04) were all higher in the eSET period than in the DET period. The cumulative multiple birth rate was significantly lower in the eSET period than in the DET period (8.9 versus 19.6%, P < 0.0001). A term live birth in the eSET period was 19 889 euros less expensive than in the DET period. CONCLUSIONS: This study shows that eSET with cryopreservation is more effective and less expensive than DET and should be adopted as a treatment of choice.

High and low BMI increase the risk of miscarriage after IVF/ICSI and FET.

BACKGROUND: The extremes of BMI are associated with an increased risk of miscarriage both in spontaneously conceived pregnancies and after fertility treatment. The aim of the present study was to study the effect of BMI on miscarriage rate (MR) in fresh IVF/ICSI, and in spontaneous and hormonally substituted frozen-thawed embryo (FET) cycles. METHODS: Analysis was carried out on 3330 first pregnancy cycles, performed during the years 1999-2004, of which 2198 were fresh, 666 were spontaneous and 466 were hormonally substituted FET cycles. A categorical, a linear and a quadratic models of the effect of BMI on miscarriage were studied by logistic regression. Factors related to patient characteristics, protocol and embryo parameters were also examined. RESULTS: MR was higher in hormonally substituted FET (23.0%), compared with the fresh cycles (13.8%) and spontaneous FET (11.4%, P < 0.0001). Multivariate logistic regression revealed that the relationship between BMI and the risk of miscarriage is not linear but quadratic (U-shaped) (P = 0.01), indicating a higher risk of miscarriage in underweight and obese women. Hormonal substitution for FET was also associated with a 1.7-fold higher MR, compared with the fresh cycles (P = 0.002, 95% confidence interval 1.2-2.3). CONCLUSIONS: Obese and underweight women have an increased risk of miscarriage, and hormonally substituted FET is associated with an even higher MR.

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.

Endometrial thermal balloon ablation has a beneficial long-term effect on menorrhagia.

BACKGROUND: More data on the long-term results of thermal balloon endometrial ablation are needed. METHODS: A retrospective observational study of 190 women who underwent endometrial thermal balloon ablation in the treatment of menorrhagia. The mean follow-up period was 6 years. RESULTS: Of the 172 women analysed after exclusion, 28 (16%) had a hysterectomy during follow-up. Women with regular menstrual periods had the best outcome. Some 152 (89%) women filled in a questionnaire concerning their satisfaction with the procedure, and 76% were satisfied. Amenorrhoea was reported by 14% and eumenorrhoea by 54% of the women who completed the questionnaire. CONCLUSION: Endometrial thermal balloon ablation has good long-term efficacy and can be considered an applicable alternative in the treatment of menorrhagia, especially for women who have regular periods and are over 40 years of age.

Detailed analysis of variation at and around mitochondrial position 16189 in a large Finnish cohort reveals no significant associations with early growth or metabolic phenotypes at age 31 years.

CONTEXT: Mitochondrial dysfunction is increasingly implicated in pathogenesis of adult metabolic disease. Rare mitochondrial (mt) DNA mutations impair glucose homeostasis, but the contribution of common variants is unclear. In small studies, variation within the OriB origin of replication (at mt16189 in particular) has been associated with both early growth and adult metabolic phenotypes and may contribute to life-course relationships between the two. OBJECTIVE: The aim was to study a large well-characterized cohort to determine whether previously reported small-scale associations between OriB sequence variation and early growth and adult metabolic phenotypes are robust. DESIGN/SETTING/PARTICIPANTS: This was a genetic association study of 5470 individuals from the population-based Northern Finland Birth Cohort of 1966, followed prospectively from pregnancy to age 31 yr. MAIN OUTCOME MEASURES: We measured indices of early growth (including birth weight, placental weight, and ponderal index) and adult metabolic homeostasis (including body mass index, fasting glucose and insulin, indices of insulin action and secretion) and their relationship to variation in the OriB region. RESULTS: Previously reported associations could not be confirmed. There were no significant (P < 0.01, uncorrected) associations between OriB sequence variation and measures of early growth including birth weight (P = 0.52, comparing individuals with mt16189T to those with a homopolymeric C-tract) and placental weight (P = 0.49). There were no significant associations with adult metabolic phenotypes including fasting glucose (P = 0.07), fasting insulin (P = 0.42), and homeostatic model assessment-derived measures of insulin sensitivity or secretion (P = 0.45 and P = 0.56, respectively). CONCLUSION: Despite substantial power to detect previously reported effects, mtDNA variations around OriB are not major contributors to variation in early growth and metabolic phenotypes during early adulthood.

Relationship between E23K (an established type II diabetes-susceptibility variant within KCNJ11), polycystic ovary syndrome and androgen levels.

Polycystic ovary syndrome (PCOS) is strongly associated with hyperinsulinaemia and type II diabetes (T2D). Sequence variation within KCNJ11 (encoding Kir6.2, the beta-cell inwardly rectifying potassium channel) is implicated in the pathogenesis of neonatal diabetes, hyperinsulinaemia of infancy and multifactorial T2D. Comprehensive tagging studies have demonstrated that the KCNJ11 E23K variant (or ABCC8 A1369S in LD>0.9) is responsible for the known association between KCNJ11 and T2D. Given the phenotypic overlap between PCOS and T2D, we investigated whether E23K is involved in susceptibility to PCOS and related traits. Case-control analyses for the KCNJ11 E23K variant were performed in (a) 374 PCOS cases and 2574 controls of UK British/Irish origin, and (b) 550 women with PCOS symptoms and 1114 controls from a Finnish birth cohort. The relationship between E23K genotype and androgen levels (a key intermediate phenotype relevant to PCOS) in 1380 samples was studied. The UK case-control analysis revealed no association between E23K genotypes and PCOS status (P=0.49; Cochran-Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (P=0.19). Similarly, the Finnish case-control analysis showed no association between E23K genotypes and PCOS status (P=0.75; Cochran-Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (Finnish controls, P=0.25; Finnish cases, P=0.08). In conclusion, these data (involving >4600 subjects) provide no evidence that common variants of the KCNJ11 E23K polymorphism have a major influence on PCOS susceptibility, though modest effect sizes (OR<1.25) cannot be excluded.

Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits.

CONTEXT: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent and all studies have featured small sample sizes. OBJECTIVE: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. DESIGN: Case-control, family-based association and quantitative trait analyses. SETTING AND PARTICIPANTS: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the -23HphI variant. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. RESULTS: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). CONCLUSIONS: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.

Variation at the insulin gene VNTR (variable number tandem repeat) polymorphism and early growth: studies in a large Finnish birth cohort.

Variation at the insulin gene (INS-)VNTR (variable number of tandem repeats) minisatellite polymorphism has been reported to be associated with both early growth and adult metabolic phenotypes. However, the samples studied have been small and the relationship between INS-VNTR variation and parameters of early growth inconsistent, with four previous studies producing conflicting results. We have studied the relationship between INS-VNTR class (measured by genotyping the nearby -23HphI variant with which it is in tight linkage disequilibrium) and early growth in 5,646 members of the Northern Finnish Birth Cohort of 1966. Comparing class III homozygotes with other genotypes using multivariate linear regression analysis, we found no significant associations with any early growth measure (birth weight, birth length, ponderal index, and head circumference at 1 year), even after stratifying subjects by growth trajectory during infancy and/or birth order. For example, among infants with limited postnatal growth realignment (n = 2,470), class III/III infants were no heavier at birth (difference [+/-SE] in the means [fully adjusted], 58 +/- 51 g; P = 0.26) than class I/- infants. No significant associations were detected following reanalysis with an additive model (for example, for birth weight, beta = 20 g [95% CI -3 to 44], P = 0.09). Studies of this large population-based cohort have failed to generate convincing evidence that INS-VNTR variation influences early growth.

Embryo quality is the main factor affecting cumulative live birth rate after elective single embryo transfer in fresh stimulation cycles.

OBJECTIVE: The study was aimed to evaluate which factors affect the cumulative live birth rate after elective single embryo transfer in women younger than 36 years. Additionally, number of children in women with more than one delivery per ovum pick-up after fresh elective single embryo transfer and subsequent frozen embryo transfers was assessed. STUDY DESIGN: Retrospective cohort study analysing data of a university hospital's infertility clinic in 2001-2010. A total of 739 IVF/ICSI cycles with elective single embryo transfer were included. Analyses were made per ovum pick-up including fresh and subsequent frozen embryo transfers. Factors affecting cumulative live birth rates were examined in uni- and multivariate analyses. A secondary endpoint was the number of children born after all treatments. RESULTS: In the fresh cycles, the live birth rate was 29.2% and the cumulative live birth rate was 51.3%, with a twin rate of 3.4%. In the multivariate analysis, having two (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.12-2.67) or ≥3 top embryos (OR 2.66; 95% CI 1.79-3.95) was associated with higher odds for live birth after fresh and frozen embryo cycles. Age, body mass index, duration of infertility, diagnosis or total gonadotropin dose were not associated with the cumulative live birth rate. In cycles with one top embryo, the cumulative live birth rate was 40.2%, whereas it was 64.1% in those with at least three top embryos. Of women who had a live birth in the fresh cycle, 20.4% had more than one child after all frozen embryo transfers. Among women with three or more top embryos after ovum pick-up, 16.1% gave birth to more than one child. CONCLUSION: The cumulative live birth rate in this age group varies from 40% to 64% and is dependent on the quality of embryos. Women with three or more top embryos have good chance of having more than one child per ovum pick-up without elevated risk of multiple pregnancies.

Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study.

Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m(2)) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 microg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 +/- 5.1 (SE) to 29.8 +/- 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 +/- 0.01 to 0.75 +/- 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 +/- 0.3 to 2.0 +/- 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 +/- 0.2 to 1.4 +/- 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment.