Anxiety and depression in expectant parents: ART versus spontaneous conception.

STUDY QUESTION: Do expectant parents experience increased anxiety and depression during pregnancies conceived through ART compared to spontaneous conception? SUMMARY ANSWER: Among all expectant parents in the sample, those who conceived through ART reported overall lower levels of anxiety and depression in pregnancy compared to expectant parents who conceived spontaneously, while in the subsample of parents who conceived both through ART and spontaneous conception, expectant mothers experienced increased anxiety and depression in early pregnancy following ART compared to spontaneous conception. WHAT IS KNOWN ALREADY: Previous research on expectant parents' psychosocial adjustment in response to ART has found mixed results, with some studies suggesting ART is associated with increased anxiety and depression, and other studies suggesting improved mental health or no relationship. Mixed findings may relate to the use of cross-sectional designs that do not account for confounding differences between groups, or variability in the timing of assessment. STUDY DESIGN, SIZE, DURATION: This prospective cohort study used data from the Norwegian Mother, Father and Child Cohort Study (MoBa), which includes 2960 pregnant women who underwent ART and 108 183 women who conceived spontaneously. Of these, a subsample of expectant parents had two consecutive pregnancies with one pregnancy resulting from ART and one conceived spontaneously (n = 286 women, n = 211 partners). Women self-reported their composite symptoms of anxiety and depression at two timepoints during each pregnancy (gestational weeks 17 and 30). Their partners self-reported composite symptoms of anxiety and depression at 17 weeks gestation during each pregnancy. Couples reported their relationship satisfaction at 17 weeks gestation. MAIN RESULTS AND THE ROLE OF CHANGE: Using a conventional full-cohort analysis we found that ART was associated with less total anxiety and depression and greater relationship satisfaction, compared to spontaneous conception among both women and men. However, in the subsample of parents who experienced both ART and spontaneous pregnancies, ART was associated with increased levels of maternal anxiety and depression at gestational age 17 weeks (M = 1.19), compared to spontaneous pregnancies (M = 1.15), 95% CI of the mean difference 0.006, 0.074. At 30 weeks gestation, anxiety and depression were similar across both types of pregnancies. Expectant fathers reported similar levels of anxiety and depression at 17 weeks gestation during both pregnancies. Among women relationship satisfaction was higher following ART conception than spontaneous conception. LIMITATIONS, REASONS FOR CAUTION: There is potential for selection effects in the sample, as women who have conceived through both ART and spontaneous conception in their first two pregnancies are rare. In addition, several factors that may be important predictors of mental health in this context, such as previous miscarriages and long-term infertility, were not assessed in the current study. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that previous discrepancies in the literature may be related to inherent differences between the groups of parents receiving reproductive treatment and those who do not. This study addresses that limitation by prospectively comparing different types of pregnancies within the same expectant parents. Earlier inconsistencies may also relate to variations in gestational age when anxiety and depression were assessed. By examining symptoms at two timepoints in each pregnancy, we were able to examine the relation between gestational age and symptoms of anxiety and depression. STUDY FUNDING/COMPETING INTEREST(S): The MoBa is supported by the Norwegian Ministry of Health and the Norwegian Research Council/FUGE (grant number 151918/S10). This work was also supported by the Research Council of Norway grant number 288083 and 301004. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Can time to menopause be predicted?

Menopause represents the definite end of a woman's reproductive life and the onset of a persistent hypoestrogenic state. This postmenopausal period will for most women last several decades. Although mean menopausal age seems to have increased somewhat during the last century, there is a significant individual variation in age at natural menopause. With efficient contraception, women of reproductive age can now, to some extent, choose when they want to have children. As a consequence of this and other sociodemographic changes, age at first birth has increased significantly over the last 50 years. It is well documented that long before a woman enters the menopausal transition and subsequent menopause, fertility declines and finally ceases. Being able to predict when a woman will enter menopause would therefore, from a reproductive perspective, be of major interest. Several sociodemographic, morphometric, and endocrine factors are associated with age at menopause or time to menopause. Unfortunately the sensitivity and specificity of these in predicting time to or age at menopause are low. Therefore, with the exception of anti-Müllerian hormone measurements, either alone or in combination with chronological age close to menopause, there are as of now no reliable ways of predicting when a woman will enter menopause.

Risk of cardiovascular disease after preventive salpingo-oophorectomy.

INTRODUCTION: Breast cancer susceptibility gene (BRCA) mutation carriers are recommended to undergo early oophorectomy to prevent ovarian cancer. Premature loss of ovarian hormones may increase the risk of cardiovascular disease. Because women with preventive oophorectomy are mainly young and healthy, they rarely undergo specialized cardiological surveillance. We compared the risk of cardiovascular disease in women after preventive oophorectomy with reference women. METHODS: In an historical cohort study, we included 134 women aged ≤52 years after preventive oophorectomy and 268 age matched premenopausal reference women, aged 52 years or less, from the general population, excluding participants with diabetes or cardiovascular disease. The Norwegian risk assessment tool (NORRISK 2) was used to estimate 10 year cardiovascular risk. This algorithm was validated in a large Norwegian population and is based on age, smoking, systolic blood pressure, total and high density lipoprotein cholesterol, antihypertensive medication, and family history of cardiovascular disease. We also examined cardiometabolic factors (levels of triglycerides and high sensitivity C reactive protein, as well as body mass index and waist circumference) not included in the NORRISK 2 calculation. RESULTS: Median age in the preventive oophorectomy and reference groups were 47 (range 33-52) and 46 (31-52) years, respectively. Mean time since surgery in the preventive oophorectomy group was 4.2 years (standard deviation (SD) 2.8). Ten year cardiovascular risk was similar in women after preventive oophorectomy and reference women (mean 1.15% (SD 1.00) vs 1.25 (1.09), respectively, p=0.4). Women in the preventive oophorectomy group had a lower body mass index (24.7 kg/m2 (4.0) vs 26.2 (4.8), p=0.003) and waist circumference (86 cm vs 89, p=0.006). The overall cardiovascular risk estimation was comparable among hormone therapy users and non-users, but hormone therapy users had lower total cholesterol and waist circumference. DISCUSSION: Women who underwent preventive oophorectomy had a similar risk of cardiovascular disease as population based reference women, estimated according to risk factors easily measured in general practice. Cardiometabolic risks were not increased in the preventive oophorectomy group.

Childbirth close to natural menopause: does age at menopause matter?

RESEARCH QUESTION: Does a successful spontaneous pregnancy in the years close to natural menopause depend on age at menopause? DESIGN: This was a retrospective population-based study of 4157 parous postmenopausal women in Norway, born during the years 1925-1940. Data were obtained by two self-administered questionnaires in the HUNT2 Survey (1995-1997). We calculated the proportions of women who gave birth within 5 years and within 10 years prior to menopause both among all women, and according to categories of age at menopause. RESULTS: Overall, 2.7% (114/4157) of all women gave birth within 5 years, and 11.7% (487/4157) gave birth within 10 years, prior to menopause. Among women with menopause before the age of 45 years, 23.5% (81/344) gave birth within 5 years, and 55.5% (191/344) gave birth within 10 years, before menopause. Among the women with menopause at the age of 55 years or older, no women (0/474) gave birth within 5 years, and 0.2% (1/474) gave birth within 10 years, prior to menopause. CONCLUSIONS: More than half of the women with menopause before the age of 45 years gave birth within the 10 years before natural menopause, whereas virtually no women with menopause at the age of 55 years or older did. Thus, the length of the sterile interval before natural menopause may vary by age at menopause.

Cervical microbiota in women with cervical intra-epithelial neoplasia, prior to and after local excisional treatment, a Norwegian cohort study.

BACKGROUND: Local treatment for cervical intraepithelial neoplasia (CIN) by Loop Electrosurgical Excision Procedure (LEEP) has been correlated with reproductive morbidity, while the cervicovaginal microbiota is also known to affect the risk of preterm delivery. CIN and treatment by LEEP might change the cervical microbiota. The main aim of this study was to describe the cervical microbiota before and after LEEP and assess its associaton with cone depth and HPV persistence. Further, we aimed to compare the microbiota to references with normal cervical cytology. METHODS: Between 2005 and 2007, we prospectively identified 89 women planned for LEEP in a Norwegian hospital and recruited 100 references with a normal cervical cytology. Endocervical swabs were collected prior to treatment and at six (n = 77) and 12 months (n = 72) post LEEP for bacterial culture and PCR, and post LEEP for DNA testing for human papillomavirus (HPV). We compared the cervical microbiota composition before and after treatment and between women planned for LEEP vs references. RESULTS: There was a reduction in the number of non-Lactobacillus bacterial species six and 12 months after LEEP compared to before treatment and a tendency towards a concomitant increase in Lactobacillus. No association between the detection of cervical bacteria, HPV persistence or cone depth was found. Women planned for LEEP carried significantly more Bacteroides spp., Gardnerella vaginalis, Mycoplasma hominis and Ureaplasma parvum as well as a greater number of bacterial species than the references. CONCLUSIONS: Local excisional treatment appears to alter the cervical microbiota towards a less diverse microbiota. Women with CIN have a more diverse cervical microbiota compared to women with normal cervical cytology.

Maternal concentrations of human chorionic gonadotrophin in very early IVF pregnancies and duration of pregnancy: a follow-up study.

RESEARCH QUESTION: Are maternal concentrations of human chorionic gonadotropin (HCG) on a fixed day after embryo transfer associated with duration of pregnancy? DESIGN: A follow-up study of 1917 singleton pregnancies after IVF was performed. Embryos were cultured for 2 days and maternal HCG concentration quantified on day 12 after embryo transfer. Duration of pregnancy was obtained from the Medical Birth Registry of Norway. Association of HCG concentration (log2-transformed) with duration of pregnancy was estimated as hazard ratios (HR) with 95% confidence intervals (CI) by applying Cox regression proportional hazard models, where time to delivery for pregnancies shortened because of planned Caesarean delivery or induction of labour was treated as censored. RESULTS: The estimated median duration of pregnancy from embryo transfer was 266 days (95% CI 266-267 days). Maternal concentration of HCG on day 12 after embryo transfer varied from 1 to 588 IU/l (median 117 IU/l). Duration of pregnancy decreased by increasing HCG concentration, significantly in pregnancies delivered at full term ((257-270 days after embryo transfer; HR 1.127, 95% CI 1.026-1.238, P = 0.012). For each doubling of HCG concentration on day 12 after embryo transfer, duration of pregnancy was shortened by 0.51 days. Adjustment for maternal age, prepregnancy body mass index, being a first-time mother and number of embryos transferred did not change the association. CONCLUSION: High maternal HCG concentration on a fixed day after embryo transfer is likely to indicate early embryo implantation. After embryo transfer, pregnancies with early implantation are shorter than pregnancies with late implantation.

Ovulation induction in polycystic ovary syndrome.

The objective of this narrative review was to suggest a rational order of treatment choices in anovulatory women with polycystic ovary syndrome (PCOS), for whom a multitude of treatment options exist. In obese/overweight women with PCOS the importance of weight reduction should be stressed. Inositol, a dietary supplement with a documented effect on ovulation and without adverse effects in the doses recommended, may be suggested. Additional first-line medical alternatives include insulin sensitizers, selective estrogen receptor modulators, and aromatase inhibitors. Of these, the aromatase inhibitor letrozole and the combination of clomiphene citrate and metformin have the highest rates of ovulation and live birth. Second-line treatments are ovarian electrocautery and low-dose follicle-stimulating hormone stimulation. Controlled ovarian stimulation with in vitro fertilization, should be considered the last option as it carries a significant risk of ovarian hyperstimulation syndrome in patients with PCOS.

Health-related quality of life in women with endometriosis, compared with the general population and women with rheumatoid arthritis.

INTRODUCTION: Women with endometriosis have reduced health-related quality of life (HRQoL). However, comparisons to the general population and other patient groups are lacking. MATERIAL AND METHODS: The present cross-sectional questionnaire study included 157 women with endometriosis, 156 women from the general population, and 837 women with rheumatoid arthritis (RA). During a period from 2012 to 2013, women aged 18-45 years were recruited from the Norwegian Endometriosis Association and from a random sample of women residing in Oslo, Norway. HRQoL data from women with RA were included from a survey conducted in 2009 among patients of the Oslo Rheumatoid Arthritis Register. The Short Form-36 (SF-36) questionnaire was used to measure HRQoL. RESULTS: Compared with the control group, the endometriosis group had significantly reduced mean scores for all SF-36 scales. The difference was largest for the scale bodily pain with a mean score of 47.6 in the endometriosis group vs 81.5 in the control group. Compared with the RA group, the endometriosis group had significantly reduced mean scores for the three SF-36 scales vitality, social functioning, and mental health. The mean scores of these scales in the endometriosis group were 33.4, 62.7, and 66.3, respectively, vs 42.7, 68.8, and 72.6 in the RA group. CONCLUSIONS: Women with moderate to severe endometriosis seem to have overall impaired HRQoL compared with women from the general population, and poorer mental HRQoL compared with women with RA.

Fertility after cryopreservation of ovarian tissue due to cancer treatment. / Fertilitet etter kryopreservering av ovarialvev ved kreftbehandling.

BAKGRUNN: Kryopreservering av ovarialvev som fertilitetsbevarende metode tilbys prepubertale jenter og kvinner i reproduktiv alder med høy risiko for å utvikle prematur ovarialsvikt i forbindelse med medisinsk eller kirurgisk behandling. I denne studien ønsket vi å kartlegge fertilitet og prematur ovarialsvikt hos kvinner som har fått gjort kryopreservering av ovarialvev i forbindelse med kreftbehandling. MATERIALE OG METODE: Et spørreskjema ble i 2014 sendt til 94 kvinner over 18 år som i perioden 2004-12 hadde fått kryopreservert ovarialvev i forbindelse med behandling for en malign tilstand. Skjemaet inneholdt spørsmål om menstruasjonsfrekvens, prevensjonsbruk, fertilitet, fremtidig barneønske og sannsynlighet for at de ville benytte ovarialvevet senere. Av de 77 kvinnene som returnerte spørreskjemaet, ble 74 kvinner inkludert i studien. RESULTATER: Totalt 20 av 74 kvinner (27 %) hadde prematur ovarialsvikt definert som opphør av ovarialfunksjonen før 40 års alder. Risikoen var lavest hos kvinner behandlet for brystkreft (5 %) og høyest hos kvinner behandlet for leukemi (75 %). Størst risiko for prematur ovarialsvikt fant man i pasientgruppene som hadde gjennomgått stamcelletransplantasjon, strålebehandling mot helkropp og/eller abdomen og bekken. Til sammen hadde 22 kvinner født 31 barn etter kreftbehandlingen, hvorav to etter reimplantasjon av ovarialvev. FORTOLKNING: Risikoen for å utvikle prematur ovarialsvikt er avhengig av pasientens kreftdiagnose. Hvilke fertilitetsbevarende tiltak som anbefales, bør differensieres avhengig av pasienten kreftdiagnose og planlagt behandling.

Endometriosis-associated infertility: aspects of pathophysiological mechanisms and treatment options.

Endometriosis is a common condition in women of reproductive age. In addition to pain, endometriosis may also reduce fertility. The causes of infertility in women with endometriosis may range from anatomical distortions due to adhesions and fibrosis to endocrine abnormalities and immunological disturbances. In some cases, the various pathophysiological disturbances seem to interact through mechanisms so far not fully understood. Whether surgery should be offered as a treatment option in endometriosis-associated infertility has become controversial, partly due to its modest or undocumented effect. Medical or hormonal treatment alone has little or no effect and should only be used in conjunction with assisted reproductive technology (ART). Of the various methods of ART, intrauterine insemination, due to its simplicity, can be recommended in women with minimal or mild peritoneal endometriosis, even though insemination may yield a lower success rate than in women without endometriosis. In vitro fertilization (IVF) is an effective treatment option in less-advanced disease stages, and the success rates are similar to the results in other causes of infertility. However, women with more advanced stages of endometriosis have lower success rates with IVF.

Sexual activity and functioning after risk-reducing salpingo-oophorectomy: Impact of hormone replacement therapy.

OBJECTIVE: To examine sexual activity and functioning in women after risk-reducing salpingo-oophorectomy (RRSO) compared with the general population (NORM). METHODS: Retrospective cohort study. 294 women who underwent RRSO and 1228 women from the NORM group provided written information based on mailed questionnaires. Sexual pleasure and discomfort scores and frequency of sexual activity were evaluated using the Sexual Activity Questionnaire. RESULTS: The RRSO group reported less sexual pleasure (10.5 vs. 11.9, P=0.009), more discomfort (1.9 vs. 0.83, P<0.001), and less frequent sex than did the controls. Significant associations were observed between a lower pleasure score and being in the RRSO group, older age, history of cancer, low body image, high level of role functioning, and low level of global quality of life (QoL). Further, significant associations were detected between more discomfort and being in the RRSO group, older age, history of cancer, poor body image, and low level of global QoL. Hormone replacement therapy (HRT) use had no impact on pleasure or discomfort score in regression analyses among all the sexually active women. However, in subanalyses of the RRSO group, users of systemic HRT reported less discomfort (1.2 vs. 2.4, P=0.001) than did the nonusers. CONCLUSIONS: After RRSO, women reported significantly less sexual pleasure, more discomfort, and less frequent sex compared with the controls. In the RRSO group, systemic HRT users reported less discomfort than did the nonusers. Health care providers should be attentive to these issues when counseling before and after prophylactic surgery.

The associations of maternal body mass index with birthweight and placental weight. Does maternal diabetes matter? A population study of 106 191 pregnancies.

INTRODUCTION: The aim of this study was to study whether the associations of maternal body mass index with offspring birthweight and placental weight differ by maternal diabetes status. MATERIAL AND METHODS: We performed a population study of 106 191 singleton pregnancies by using data from the years 2009-2012 in the Medical Birth Registry of Norway. We estimated changes in birthweight and in placental weight (in grams) by maternal body mass index by linear regression analysis. RESULTS: In pregnancies of women without diabetes, birthweight increased by 14.7 g (95% confidence interval 14.1-15.2) per unit increase in maternal body mass index, and the increase in placental weight was 4.2 g (95% confidence interval 4.0-4.4). In pregnancies of women with gestational diabetes, the corresponding figures were 11.8 g (95% confidence interval 8.3-15.4) and 2.9 g (95% confidence interval 1.7-4.0). In pregnancies of women with type 1 diabetes we found no significant changes in birthweight or in placental weight by maternal body mass index. Overall, mean birthweight was 513.9 g (95% confidence interval 475.6-552.1) higher in pregnancies involving type 1 diabetes than in pregnancies of women without diabetes. Mean placental weight was 102.1 g (95% confidence interval 89.3-114.9) higher. Also, in pregnancies of women with gestational diabetes, both birthweight and placental weight were higher than in women without diabetes (168.2 g and 46.5 g, respectively). Adjustments were made for maternal body mass index and gestational age at birth. CONCLUSIONS: Birthweight and placental weight increased with increasing maternal body mass index in pregnancies of women without diabetes and in pregnancies of women with gestational diabetes, but not in pregnancies of women with type 1 diabetes. Independent of body mass index, mean birthweight and mean placental weight were highest in pregnancies of women with type 1 diabetes.

Elective cesarean section or not? Maternal age and risk of adverse outcomes at term: a population-based registry study of low-risk primiparous women.

BACKGROUND: Maternal age at delivery and cesarean section rates are increasing. In older women, the decision on delivery mode may be influenced by a reported increased risk of surgical interventions during labor and complications with increasing maternal age. We examined the association between maternal age and adverse outcomes in low-risk primiparous women, and the risk of adverse outcomes by delivery modes, both planned and performed (elective and emergency cesarean section, operative vaginal delivery, and unassisted vaginal delivery) in women aged ≥ 35 years. METHODS: A population-based registry study was conducted using data from the Medical Birth Registry of Norway and Statistics Norway including 169,583 low-risk primiparas with singleton, cephalic labors at ≥ 37 weeks during 1999 - 2009. Outcomes studied were obstetric blood loss, maternal transfer to intensive care units, 5-min Apgar score, and neonatal complications. We adjusted for potential confounders using relative risk models and multinomial logistic regression. RESULTS: Most adverse outcomes increased with increasing maternal age. However, the increase in absolute risks was low, except for moderate obstetric blood loss and transfer to the neonatal intensive care unit (NICU). Operative deliveries increased with increasing maternal age and in women aged ≥ 35 years, the risk of maternal complications in operative delivery increased. Neonatal adverse outcomes increased mainly in emergency operative deliveries. Moderate blood loss was three times more likely in elective and emergency cesarean section than in unassisted vaginal delivery, and twice as likely in operative vaginal delivery. Low Apgar score and neonatal complications occurred two to three times more often in emergency operative deliveries than in unassisted vaginal delivery. However, comparing outcomes after elective cesarean section and planned vaginal delivery, only moderate blood loss (higher in elective cesarean section), neonatal transfer to NICU and neonatal infections (both higher in planned vaginal delivery) differed significantly. CONCLUSIONS: Most studied adverse outcomes increased with increasing maternal age, as did operative delivery. Although emergency operative procedures were associated with an increased risk of adverse outcomes, the absolute risk difference in complications between the modes of delivery was low for the majority of outcomes studied.

Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience.

INTRODUCTION: The aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries. MATERIAL AND METHODS: A questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation. RESULTS: Among the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow-freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients' clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1:3). CONCLUSIONS: Overall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.

Autotransplantation of cryopreserved ovarian tissue after treatment for malignant disease - the first Norwegian results.

INTRODUCTION: With increasing survival rates after treatment for cancer in prepubertal girls and women of reproductive age, an increasing focus on quality of life has emerged. Both irradiation and cytotoxic drugs can be detrimental to future fertility, consequently several treatment alternatives have been developed to spare or restore fertility in young females diagnosed with cancer. One of these options is cryopreservation of ovarian tissue before treatment and autotransplantation at a later time. MATERIAL AND METHODS: We present the Norwegian experience after 11 years of practice with ovarian tissue cryopreservation. A total of 164 patients have had ovarian tissue cryopreserved during the period 2004-2014. Fifteen patients died during the observation period. Six patients requested autotransplantation, which was performed in two women. RESULTS: Both patients conceived, one spontaneously and one after assisted reproduction due to a concomitant male factor. The pregnancies were uneventful and they each gave birth to a healthy child. CONCLUSIONS: Cryopreservation with later autotransplantation of ovarian tissue should be offered to a selected group of young women with cancer.

Advanced glycation end products and their receptor contribute to ovarian ageing.

STUDY QUESTION: Do advanced glycation end products (AGE) and the receptor for advanced glycation end products (RAGE) affect the cells of the human ovarian follicle? SUMMARY ANSWER: AGE accumulate on the surface of ovarian granulosa-lutein (GL) cells and monocytes by binding to RAGE and other receptors with possible functional effects on these cells. WHAT IS KNOWN ALREADY: AGE and RAGE are expressed in granulosa and theca cells, as well as in luteinized cells derived from the ovary. STUDY DESIGN, SIZE, DURATION: In this prospective cohort study, human follicle fluid-derived cells were isolated from aspirates of ovarian follicles of women who underwent assisted reproduction treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunofluorescence microscopy and multi-colour flow cytometry were used to determine the presence of AGE and RAGE on the surface of follicular fluid-derived cells and to characterize downstream effects of RAGE activation. MAIN RESULTS AND THE ROLE OF CHANCE: GL cells and ovarian monocytes were found to contain AGE and RAGE and to bind AGE-bovine serum albumin (BSA) in correlation with the patients' chronological age. AGE-BSA and BSA failed to induce significantly the cleavage of caspase-3, phosphorylation of nuclear factor-κB or the binding of annexin V (the latter was marginally increased). AGE-fibronectin was found to induce detachment of cultured GL cells in vitro. LIMITATIONS, REASONS FOR CAUTION: The impact of AGE and RAGE in the ovary, shown here in cells in culture, remains to be affirmed in clinical settings. WIDER IMPLICATIONS OF THE FINDINGS: The ligands of RAGE and their effects in the ovary remain uncertain but this study implies that AGEs in the form of structural long-lived extracellular matrix proteins, rather than soluble AGEs, may play a role in the decline of ovarian function during ageing. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by the Norwegian Resource Centre for Women's Health, Oslo University Hospital. The authors have no conflicts of interests.

Variant-beta luteinizing hormone is not associated with poor ovarian response to controlled ovarian hyperstimulation.

BACKGROUND: The most common genetic variant of luteinizing hormone (LH), variant-betaLH, has a different bioactivity than the wildtype. Carrying the variant allele was associated with an increased consumption of exogenous gonadotropin to achieve optimal ovarian response for in vitro fertilization procedures (IVF). The aim of this study was to examine if variant-betaLH was also more common in patients with a poor ovarian response to exogenous gonadotropin which negatively influenced treatment outcome. FINDINGS: 36 patients with poor ovarian response to ovarian stimulation for IVF and 98 controls with a normal response were genotyped for variant-betaLH using DNA sequencing. The carrier frequency in the control group was 17%. No association was found between poor ovarian response and variant-betaLH. CONCLUSIONS: Testing patients for variant-betaLH prior to IVF is unlikely to predict poor ovarian response.

Pregnancy outcome according to male diagnosis after ICSI with non-ejaculated sperm compared with ejaculated sperm controls.

The aim of this study was to describe pregnancy outcome in couples who had undergone ICSI using non-ejaculated sperm from men with non-obstructive azoospermia, obstructive azoospermia and aspermia compared with the outcome of ICSI with ejaculated sperm from men with severe oligozoospermia, treated during the same time period. This nationwide cohort study included all children born after ICSI with non-ejaculated sperm in Norway, from when the method was first permitted in Norway in April 2004 to the end of 2010, resulting in 420 pregnancies and a total of 359 children. In 235 of these children, the father was diagnosed with obstructive azoospermia, in 72 with non-obstructive azoospermia, in 31 with aspermia, and in 21 the male cause was unclassifiable. The control group consisted of 760 children from 939 pregnancies conceived by ICSI with ejaculated sperm. Sex ratio, birth weight, rate of pregnancy loss and congenital malformations were not significantly associated with sperm origin or the cause of male factor infertility.

Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy.

OBJECTIVE: To study whether maternal age is associated with serum concentration of human chorionic gonadotropin in early pregnancy. DESIGN: Cross-sectional study. SETTING: Oslo University Hospital in Oslo, Norway. POPULATION: All vital pregnancies in gestational week 8 conceived by in vitro fertilization between February 1996 and February 2013 (n = 4472). METHODS: Serum concentrations of human chorionic gonadotropin were measured on day 12 after embryo transfer/day 16 following ovulation induction. Trends in geometric means of human chorionic gonadotropin concentrations by maternal age group were tested by linear regression analysis. We also studied the association of maternal age (years) with log-transformed human chorionic gonadotropin concentrations, and adjustments were made for number of embryos transferred, method of in vitro fertilization and year (period) of embryo transfer. MAIN OUTCOME MEASURE: Serum concentration of human chorionic gonadotropin. RESULTS: Geometric mean concentrations of human chorionic gonadotropin decreased with increasing maternal age (p = 0.024, test for trend by weighted linear regression). Also, we estimated a significant negative association of maternal age with log-transformed human chorionic gonadotropin concentrations (adjusted regression coefficient -0.011, standard error 0.003, p < 0.001). CONCLUSIONS: Serum concentrations of human chorionic gonadotropin in very early pregnancy decreased with maternal age. Since human chorionic gonadotropin is synthesized in trophoblast cells only, the lower human chorionic gonadotropin concentrations in women of advanced age may reflect functional impairment or delayed proliferation of trophoblast cells in early pregnancy in these women.