Arne Sunde

Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study

BACKGROUND Research suggests that singleton births following assisted fertilisation are associated with adverse outcomes; however, these results might be confounded by factors that affect both fertility and pregnancy outcome. We therefore compared pregnancy outcomes in women who had singleton pregnancies conceived both spontaneously and after assisted fertilisation. METHODS In a population-based cohort study, we assessed differences in birthweight, gestational age, and odds ratios (OR) of small for gestational age babies, premature births, and perinatal deaths in singletons (gestation >/=22 weeks or birthweight >/=500 g) born to 2546 Norwegian women (>20 years) who had conceived at least one child spontaneously and another after assisted fertilisation among 1 200 922 births after spontaneous conception and 8229 after assisted fertilisation. FINDINGS In the whole study population, assisted-fertilisation conceptions were associated with lower mean birthweight (difference 25 g, 95% CI 14 to 35), shorter duration of gestation (2.0 days, 1.6 to 2.3) and increased risks of small for gestational age (OR 1.26, 1.10 to 1.44), and perinatal death (1.31, 1.05 to 1.65) than were spontaneous conceptions. In the sibling-relationship comparisons, the spontaneous versus the assisted-fertilisation conceptions showed a difference of only 9 g (-18 to 36) in birthweight and 0.6 days (-0.5 to 1.7) in gestational age. For assisted fertilisation versus spontaneous conception in the sibling-relationship comparisons, the OR for small for gestational age was 0.99 (0.62 to 1.57) and that for perinatal mortality was 0.36 (0.20 to 0.67). INTERPRETATION Birthweight, gestational age, and risks of small for gestational age babies, and preterm delivery did not differ among infants of women who had conceived both spontaneously and after assisted fertilisation. The adverse outcomes of assisted fertilisation that we noted compared with those in the general population could therefore be attributable to the factors leading to infertility, rather than to factors related to the reproductive technology.

Europe the continent with the lowest fertility

INTRODUCTION Although fertility rates are falling in many countries, Europe is the continent with the lowest total fertility rate (TFR). This review assesses trends in fertility rates, explores possible health and social factors and reviews the impact of health and social interventions designed to increase fertility rates. METHODS Searches were done in medical and social science databases for the most recent evidence on relevant subject headings such as TFR, contraception, migration, employment policy and family benefits. Priorities, omissions and disagreements were resolved by discussion. RESULTS The average TFR in Europe is down to 1.5 children per woman and the perceived ideal family size is also declining. This low fertility rate does not seem directly caused by contraception since in Northern and Western Europe the fertility decline started in the second half of the 1960s. Factors impacting on lower fertility include the instability of modern partnerships and value changes. Government support of assisted human reproduction is beneficial for families, but the effect on TFR is extremely small. Government policies that transfer cash to families for pregnancy and child support also have small effects on the TFR. CONCLUSIONS Societal support for families and for couples trying to conceive improves the lives of families but makes no substantial contribution to increased fertility rates.

Health and fertility in World Health Organization group 2 anovulatory women

BACKGROUND Disruption of ovulation occurs in different types of clinical infertility. The World Health Organization (WHO) has provided a classification of ovulation disorders. This review focuses on WHO group 2 anovulation. METHODS Searches were performed in Medline/PubMed and EMBASE. Each subject summary was presented to the European Society of Human Reproduction and Embryology (ESHRE) Workshop Group, where omissions or disagreements were resolved by discussion. RESULTS Disorders resulting in ovulatory disturbances are a relatively common cause of infertility. They occur most frequently in the context of WHO group 2 anovulation as reflected, for example, in the polycystic ovary syndrome (PCOS). The aetiology of PCOS remains unclear but evidence exists for a multifactorial origin with a genetic predisposition. Women with PCOS show an increased time to pregnancy but their eventual family size is not necessarily reduced. Also their frequency of miscarriage does not appear increased. Clomiphene citrate is still the first-line treatment in subfertile anovulatory patients with PCOS, with gonadotrophins and laparoscopic ovarian surgery as second-line options. Aromatase inhibitors show promising results. CONCLUSIONS Long-term health risks in patients with WHO group 2 anovulation demand their general health be monitored, even after their reproductive needs have been fulfilled. Metabolic and cardiovascular risk prevention in women with PCOS should start as early as possible. It is not easy to analyse the possible role of PCOS, independent of obesity, metabolic syndrome, insulin resistance and diabetes, on long-term health.

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.

Genetic aspects of female reproduction

BACKGROUND Sexual reproduction provides the means for preserving genetic identity and in turn, genetic variability may affect the ability to reproduce. This review aims to summarize current research on genetic diagnosis and genetic causes of reproductive disorders. METHODS Searches were done by subject in Medline and other databases, and each subject summary was presented to the Workshop Group and omissions or disagreements were resolved by discussion. RESULTS Single-gene defects are most likely to be found among patients with hypogonadotropic hypogonadism, which may be due to defects in the KAL genes or the gonadotrophin-releasing hormone receptor genes. With premature ovarian failure there is an increased risk of having a premutation of the Fragile X syndrome gene. Complex genetic inheritance may explain the variable familial links in polycystic ovary syndrome and endometriosis, but no definitive genetic pathways are as yet known. With recurrent miscarriage, genetic defects causing thrombophilias are 2-fold more likely. Chromosome abnormalities account for approximately 60% of all spontaneous abortions, and the most common type, trisomy, is closely associated with advanced maternal age. Three percent of couples have a balanced chromosome abnormality, but live birth rates are better with natural conception than with preimplantation genetic diagnosis. CONCLUSIONS Understanding of the methods used for genetic diagnosis and research is becoming a standard requirement for the clinical practice of reproductive medicine.

Production and effects of 7α-hydroxytestosterone on testosterone and dihydrotestosterone metabolism in rat testis

1. Testicular 7 alpha-hydroxylation of testerone was assayed in cell extracts of rats between 12 and 79 days of age. Maximal 7 alpha-hydroxylase activity was observed about 60 days, while insignificant activity was obtained prior to 42 days of age. 2. 7 alpha-Hydroxytestosterone, a major metabolite of testosterone in mature rat testis, inhibited 5 alpha-reduction of testosterone in cell extracts of mature but not of immature rat testis. 3. Maximal testicular activity of 3 beta-hydroxysteroid dehydrogenase using dihydrotestosterone as substrate was obtained in the presence of NAD, while maximal 3 alpha-hydroxysteroid dehydrogenase activity was observed with NADP. Both enzyme activites were reversible. 4. Sensitivity toward testosterone inhibition of 3-hydroxysteroid dehydrogenase varied greatly with stage of testis development being highest at 25-27 days of age. In contrast to testosterone, 7 alpha-hydroxytestosterone was an inhibitor of 3 alpha-hydroxysteroid dehydrogenase only. In the mature rat testis 7 alpha-hydroxytestosterone may be a naturally occurring inhibitor of dihydrotestosterone and 5 alpha-androstane-3 alpha, 17 beta-diol formation.

Separation of urinary metabolites of radiolabelled estrogens in man by HPLC

A method to separate radiolabelled urinary estrogens by high performance liquid chromatography (HPLC) is described. Estrogen glucuronides were isolated from the urine of women receiving bolus injections of [4-14C]estrone or [4-14C]estradiol by adsorption on Sep-Pak C18 cartridges and subsequent DEAE Sephadex A25 column chromatography. Following enzyme hydrolysis, free estrogens were extracted and concentrated in methanol-water containing ascorbic acid. HPLC was performed either by C18 reversed phase chromatography using different concentrations of acetonitrile with or without tetrahydrofurane in phosphate buffer or methanol-water as mobile phases, or on a Diol column using chloroform-isooctane-n-hexane or isopropanol-isooctane-n-hexane as mobile phases. 3H-labelled estrogens were added as internal standards, and urinary [14C]estriol, [14C]estradiol and [14C]estrone concentrations could be measured with an interassay coefficient of variation less than 5%. Interassay coefficients of variation for [14C]2-hydroxyestriol, [14C]16 alpha-hydroxyestrone, [14C]2-hydroxyestradiol, [14C]2-hydroxyestrone and [14C]2-methoxyestrone were between 5 and 10%, while interassay coefficients of variation for [14C]4-hydroxyestrone was 14.6%. Recovery of the unstable catechol estrogen 2-hydroxyestrone was comparable to the recovery of the other estrogen metabolites, due to the addition of ascorbic acid throughout the different pre-chromatographic steps. Our method is suitable for the separation of the major labelled estrogen metabolites found in human urine following administration of radiolabelled estrone or estradiol.

The International Glossary on Infertility and Fertility Care, 2017†‡§

Abstract STUDY QUESTION Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as ‘fertility care’ and ‘fertility awareness’ together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of ‘infertility’ has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS None. TRIAL REGISTRATION NUMBER N/A.

Treatment of unexplained infertility: Fallopian tube sperm perfusion (FSP)

Patients and methods. Fifty‐one couples with unexplained infertility were enrolled in the fallopian tube sperm perfusion (FSP) program. FSP is in short a combination of ovarian hyperstimulation, ovulation induction and intrauterine and intrafallopian tube insemination using a sperm suspension of 4 ml volume.

Retinoic acid (RA): An inhibitor of 5α-reductase in human prostatic cancer cells

Abstract The effect of retinoic acid (RA) on testosterone metabolism was examined in a prostatic cancer cell line of human origin, PC-3. In cells growing as monolayers as well as in cell homogenates RA causes a dose-dependent inhibition of the 5α-reductase activity, thus preventing the conversion of testosterone into its hormonally active metabolite, dihydrotestosterone. Fifty per cent inhibition of the enzyme activity occurred at an RA concentration of 2 × 10 −5 M. The pattern of inhibition was that of a non-competitive inhibitor. However, when incubations were performed in the presence of varying amounts of NADPH, it turned out that RA exerts its effect by competitive inhibition of the cofactor action. Although the severe toxicity of RA precludes its systemic use as a 5α-reductase inhibitory drug in humans, the possible anti-androgenic effect of other, less toxic, retinoids should be investigated.