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Background: Nutri-Score is a front-of-pack label grading foods and beverages from A to E indicating nutritional quality based on the foods' favorable and unfavorable components, and a contender in the ongoing debate on the possible implementation of a harmonized mandatory front-of-pack nutrition label in the European Union. NewTools is a research project on scoring systems for foods involving 28 partners representing actors involved in the Norwegian food system., Objective: This study aimed to explore views reported by Norwegian food system actors on the advantages and disadvantages with the updated Nutri-Score algorithms for food and beverages (2022-2023). This included Nutri-Score's performance in ranking foods according to the national food-based dietary guidelines and to the nutritional challenges in Norway., Design: A total of 28 project partners and 15 other food system stakeholders following the NewTools-project were invited to provide responses on the Nutri-Score algorithms and their application on foods and beverages in the Norwegian food composition table. Thirteen written responses were received and analyzed with qualitative content analysis., Results: The responses to the updated Nutri-Score varied in content, reflecting mainly concerns. Examples of perceived concerns included excessive penalty of salt content; insufficient differentiation based on fat content in meat, sausages, cheese, and milk; and several unreasonable comparisons across food categories. They also expressed a concern that Nutri-Score may stimulate to increased food processing, and some reported inconsistencies between Nutri-Score's classification of foods and national nutrition guidelines and policies., Discussion and Conclusion: Several concerns with the updated Nutri-Score algorithms were raised, including the weighting of specific nutrients, unfair outcomes when comparing across food categories, and inconsistencies with established Norwegian nutrition guidelines and policies. The results should be interpreted with caution, as some perspectives from the Norwegian food system may be missing., Competing Interests: The authors have nothing to declare. This manuscript is part of the NewTools-project involving actors from across the Norwegian food system, including partners with financial and political interests. Research integrity is secured through a defined framework of collaboration. ‘The NewTools-project – Developing tools for food system transformation, including food summary scores for nutrition and sustainability’ is funded by the Research Council of Norway (Project No. 326888). The 28 project partners also contribute to a varying degree through self-financing of own activities. Neither the Research Council of Norway nor the food system actors providing written submissions in the present study influenced the analysis or writing of this paper., (© 2024 Mari Mohn Paulsen et al.)

Introduction: Sustainable diets promote health and wellbeing and have low environmental impact. They should be accessible, affordable, safe, equitable and culturally acceptable. Translating these general principles into Norwegian-specific dietary recommendations is essential, as foods beneficial for health tend to also be environmentally sustainable. Following the dietary recommendations is an important step towards sustainability., Aim: To identify challenges and potential solutions for transitioning towards more sustainable diets in Norway., Methods: We used scientific articles, reports, policy documents, and statistics on Norwegian food production and consumption to discuss a sustainable diet in a Norwegian context., Results and Discussion: There is a large gap between dietary guidelines and actual consumption. More than 60% of the calories in the Norwegian diet are based on imported foods and feed. Changing people's diet is identified as central in transforming the food system to become more sustainable, as is prioritizing the use of local resources. Good animal health and welfare are also fundamental premises for a sustainable food system., Conclusions: Transitioning to a more sustainable diet requires comprehensive efforts at multiple levels. There is considerable room for action to increase the use of Norwegian resources in a sustainable and responsible way. Potential strategies include reducing meat intake in favour of plant-based foods and fish, consuming more local products, decreasing food waste and supporting agricultural practices that promote environmental and social sustainability. A more sustainable diet may also lead to significantly increased self-sufficiency and food security in Norway ., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Anne Lise Brantsæter was co-author on the background paper on iodine for Nordic Nutrition Recommendations 2023. Liv Elin Torheim was co-author on the background paper on legumes for Nordic Nutrition Recommendations 2023. Helle Margrete Meltzer was a member of the Nordic Nutrition Recommendations 2023 working group and co-author on three of the background papers on diet and sustainability.

Background: Nutrition interventions targeting early childhood can be cost-effective and may provide lifelong, intergenerational benefits. From October 2022 to April 2023 the Nutrition Now (NN) e-learning resource was implemented within Early Childhood Education and Care centres and the Maternal and Child Healthcare Centre (MCHC) in a southern Norwegian municipality. As part of the NN project, the present study aims to explore the MCHC staff's experiences with implementing the NN resource, to gain insights into measures important to scale up digital early-life nutrition interventions., Methods: Three group interviews were conducted among public health nurses and midwives alongside one individual interview with the department leader of a MCHC in May 2023. An inductive thematic analysis, as described by Braun and Clarke, was conducted to generate the key themes and subthemes regarding the implementation process of NN within the MCHC., Results: Three main themes were generated: [1] Important resource but not always utilized; [2] Parents are interested but had issues with access; and [3] Staff and stakeholder buy-in and commitment needed from the start. Overall, the staff viewed the NN resource as a potential tool for promoting diet-related topics and believed it could support the guidance they were already providing parents. However, few staff members fully familiarized themselves with the resource. While staff perceived parents as positive when informed about NN, they believed issues such as access challenges, competing platforms, and time constraints reduced parental engagement. Lastly, staff suggested improvements for NN's implementation, including enhanced training, better planning, assigning champions, and lowering the threshold for access., Conclusion: The findings of this study suggest that the real-world implementation of digital evidence-based health behaviour interventions is feasible but would be enhanced by employing strategies focusing on engagement and utilization., Trial Registration: The main study is registered in the ISRCTN registry with ID ISRCTN10694967, https://doi.org/10.1186/ISRCTN10694967 . (Registration date: 19-06-2022)., (© 2024. The Author(s).)

Background: Monitoring adherence to the Norwegian food-based dietary guidelines (FBDGs) could provide valuable insight into current and future diet-related health risks. This study aimed to develop and evaluate an index measuring adherence to the Norwegian FBDGs to be used as a compact tool in nutrition surveillance suitable for inclusion in large public health surveys., Methods: The Norwegian Dietary Guideline Index (NDGI) was designed to reflect adherence to the Norwegian FBDGs on a scale from 0-100, with a higher score indicating better adherence. Dietary intakes were assessed through 19 questions, reflecting 15 dietary components covered by the Norwegian FBDGs. The NDGI was applied and evaluated using nationally representative dietary data from the cross-sectional web-based Norwegian Public Health Survey which included 8,558 adults.​ RESULTS: The population-weighted NDGI score followed a nearly normal distribution with a mean of 65 (SD 11) and range 21-99. Mean scores varied with background factors known to be associated with adherence to a healthy diet; women scored higher than men (67 vs. 64) and the score increased with age, with higher educational attainment (high 69 vs. low 64) and with better self-perceived household economy (good 67 vs. restricted 62). The NDGI captured a variety of dietary patterns that contributed to a healthy diet consistent with the FBDGs., Conclusion: The NDGI serve as a compact tool to assess and monitor adherence to the Norwegian FBDGs, to identify target groups for interventions, and to inform priorities in public health policies.​ The tool is flexible to adjustments and may be adaptable to use in other countries or settings with similar dietary guidelines., (© 2024. The Author(s).)

Objective: Monitoring time trends in salt consumption is important for evaluating the impact of salt reduction initiatives on public health outcomes. There has so far not been available data to indicate if salt consumption in Norway has changed during the previous decade. We aimed to assess whether average 24-h salt intake estimated from spot urine samples in the adult population of mid-Norway changed from 2006-2008 to 2017-2019 and to describe variations by sex, age and educational level., Design: Repeated cross-sectional studies., Setting: The population-based Trøndelag Health Study (HUNT)., Participants: In each of two consecutive waves (HUNT3: 2006-2008 and HUNT4: 2017-2019), spot urine samples were collected from 500 men and women aged 25-64 years, in addition to 250 men and women aged 70-79 years in HUNT4. Based on spot urine concentrations of Na, K and creatinine and age, sex and BMI, we estimated 24-h Na intake using the International Cooperative Study on Salt and Blood Pressure (INTERSALT) equation for the Northern European region., Results: Mean (95 % CI) estimated 24-h salt intakes in men were 11·1 (95 % CI 10·8, 11·3) g in HUNT3 and 10·9 (95 % CI 10·6, 11·1) g in HUNT4, P = 0·25. Corresponding values in women were 7·7 (95 % CI 7·5, 7·9) g and 7·7 (95 % CI 7·5, 7·9) g, P = 0·88. Mean estimated salt intake in HUNT4 decreased with increasing age in women, but not in men, and it did not differ significantly across educational level in either sex., Conclusions: Estimated 24-h salt intake in adult men and women in mid-Norway did not change from 2006-2008 to 2017-2019.

Background: In Norway, there is a lack of knowledge about the iodine status in the general and older adult population, and there is no established national monitoring programme for iodine. Several studies have indicated that iodine deficiency is prevalent in subgroups of the population. Salt iodisation is currently being considered as a measure to increase the population iodine status. In this cross-sectional study, the aim was to evaluate iodine status and determinants in the adult and older adult population in Mid-Norway, before salt iodisation is likely to be initiated., Methods: The study sample was a subsample of participants in the fourth wave of the population-based Trøndelag Health Study (HUNT4, 2017-2019) with available spot-urine samples. This subsample included participants with 25-64 years ( n = 500) and 70-79 years ( n = 250). The urine samples were analysed for iodine and creatinine. Information on the habitual intake of milk/yoghurt, fish, supplement use, use of thyroid medication and relevant background factors was collected through a general questionnaire. Multivariable quantile regression was used to model differences in the median urinary iodine concentration (UIC) by determinants. Estimates were weighted to match the age and sex distribution of the Norwegian population aged 25-79 years in 2019., Results: Median UIC was 97 µg/L (95% confidence interval [CI]: 92, 103) indicating borderline iodine deficiency at a group level. The median UIC increased with age, and iodine status was insufficient in participants below age 55 years (median 92 µg/L [95% CI: 85, 99]). Important determinants of UIC were habitual milk/yoghurt intake, daily supplement use and current use of thyroid medication, but not intake of lean or fatty fish. Risk of mild-to-moderate iodine deficiency was seen in those with a low intake of milk/yoghurt, no supplement use and who did not use thyroid medication. No group was identified as being at risk of iodine excess., Conclusion: Iodine status was adequate in older adults but mildly deficient in adults under 55 years. Milk intake, supplement use and use of thyroid medication are important determinants of iodine intake in Norway., Competing Interests: The authors declare no potential conflicts of interest., (© 2024 Marianne Hope Abel et al.)

Background: Few effective health interventions transition from smaller efficacy or effectiveness studies to real-world implementation at scale, representing a gap between evidence and practice. Recognising this, we have developed Nutrition Now - a tailored digital resource building on four efficacious dietary interventions, aiming to improve nutrition in the important first 1,000 days of life. Nutrition Now targets and guides expectant parents and parents of 0-2 year olds, serves as a reliable source of evidence-based information for midwives and public health nurses at maternal and child healthcare (MCH) centres, and offers pedagogical tools for early childhood education and care (ECEC) staff. The aim of this study is to implement Nutrition Now at scale and evaluate the impact of different sets of multifaceted implementation strategies on implementation outcomes., Methods: A quasi-experimental design with three study arms will be used, providing either low, medium or high implementation support, when rolled out in 50 municipalities in 2 counties in Norway. Nutrition Now will be implemented in MCH and ECEC settings and made available to expectant parents and parents of 0-2 year olds through social media and MCH. The implementation support builds on strategies described in the Expert Recommendations for Implementing Change (ERIC) implementation framework and is informed by dialogues with stakeholders. Impact of the different degree of implementation support will be assessed by examining reach, adoption, fidelity, and sustainability using usage data generated from the Nutrition Now resource , publicly available municipal data and qualitative interviews with MCH and ECEC staff., Discussion: Nutrition Now Phase 2 will break new ground by scaling up successively delivered and complementary dietary interventions in the first 1,000 days of life in a real-life context. The project also seeks to identify what level of implementation support is most effective when implementing digital, scalable, evidence-based early-life nutrition interventions in community settings. The project will inform implementation research and provide knowledge about effective implementation strategies to be used in a national scale-up of Nutrition Now ., Trial Registration: The study is registered prospectively (submitted 14/06/2022, registration date: 19/06/2022) in the International Standard Randomised Controlled Trial Number registry (ISRCTN): reg. Number: ISRCTN10694967, https://doi.org/10.1186/ISRCTN10694967., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Medin, Vik, Helle, Helland, Wills, Osorio, Lian, Ersfjord, Van Daele, Bjørkkjær, Valen, Gebremariam, Grasaas, Kiland, von Thiele Schwarz, Abel, Love, Campbell, Rutter, Barker, Hillesund and Øverby.)

Background: The Nutri-Score is a candidate for the harmonized mandatory front-of-pack nutrition label enabling consumers in the European Union to make healthier food choices. Nutri-Score classifies foods (including beverages) from A (high nutritional quality) to E (low nutritional quality) based on the foods' qualifying and disqualifying components. We aimed to evaluate the updated Nutri-Score for foods (2022) and beverages (2023) in a Norwegian setting by exploring its ability to discriminate the nutritional quality of foods within categories. Additionally, we assessed Nutri-Scores' ability to classify foods in accordance with the Norwegian food-based dietary guidelines (FBDGs)., Methods: The updated Nutri-Score was calculated for 1,782 foods in a Norwegian food database. The discriminatory ability of the updated Nutri-Score was considered by exploring the distribution of Nutri-Score within categories of foods using boxplots and frequency tables, and by examining which qualifying and disqualifying components that contributed most to the Nutri-Score class. Accordance with the Norwegian FBDGs was assessed by exploring Nutri-Score for foods specifically mentioned in the guidelines., Results: Overall, the updated Nutri-Score seemed to discriminate the nutritional quality of foods within categories, in a Norwegian setting. The foods' content of salt and the beverages' content of sugar were components contributing the most to Nutri-Scores' discriminatory ability. Furthermore, in most cases the updated Nutri-Score classified foods in accordance with the Norwegian FBDGs. However, there were minor inconsistencies in how Nutri-Score classified certain foods, such as the inabilities to discriminate between full-fat and low-fat/leaner cheeses, cremes and processed meats (sausages), and between whole grain and refined pasta/rice., Conclusions: We observed an overall acceptable discriminatory performance of the updated Nutri-Score in a Norwegian setting and in most cases the updated Nutri-Score classified foods in accordance with the Norwegian FBDGs. However, minor inconsistencies were observed. Together with the FBDGs, the updated Nutri-Score could be a useful tool in guiding consumers towards healthier food choices in Norway, but consumer evaluations are warranted to fully assess the performance of the updated Nutri-Score in a Norwegian context., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Norway is lacking a population-based national monitoring program for iodine, sodium, and vitamin D status., Objective: The aim of this study was to pilot-test a study design for collecting biological samples from a country-representative sample of 2-year-old children and their mothers and to report results for iodine, salt, and vitamin D at baseline, before initiation of salt iodization in Norway., Design: In a cross-sectional study, we recruited 2-year-old children and their mothers during the routine 2-year check-up through 38 randomly selected health clinics in 2021. Spot urine samples were analyzed for iodine, creatinine, and sodium, and dried blood spots from the mothers were analyzed for thyroglobulin (Tg) and 25-hydroxyvitamin D (25(OH)D)., Results: We aimed at including 400 mother-child pairs but recruited only 55 pairs. Major challenges were closed health clinics due to the COVID-19 pandemic, lack of motivation of the health personnel to prioritize recruiting, missing information about non-participation, and high workload for participants. The median urinary iodine concentration (UIC) was 123 (95% CI: 76, 228) µg/L in the toddlers and 83 (95% CI: 72, 99) µg/L in the mothers. The median urinary sodium concentration (UNaC) was 62 (95% CI: 37, 91) mmol/L in the toddlers and 93 (95% CI: 77, 107) mmol/L in the mothers. Of the mothers, 18% had levels of 25(OH)D <50 nmol/L (suboptimal status)., Discussion and Conclusion: Lessons learned from the pilot study will be used to design a national monitoring program for toddlers and women of childbearing age in Norway. The results indicate that 2-year-old children and women of childbearing age in Norway may have inadequate iodine intakes at the group level, while for vitamin D, most of the mothers had adequate status., Competing Interests: This study received funding from the Norwegian Ministry of Health and Care Services [the Norwegian Institute of Public Health and Oslo Metropolitan University]. The authors declare no potential conflicts of interest., (© 2023 Synne Groufh-Jacobsen et al.)

Disappointingly few efficacious health interventions are successfully scaled up and implemented in real world settings. This represents an evidence-to-practice gap, with loss of opportunity to improve practice. Aiming to improve nutrition in the first 1000 days of life, we have combined four efficacious dietary interventions into a single adapted digital resource (Nutrition Now) for implementation in a Norwegian community setting. Nutrition Now targets pregnant women and parents of 0-2-year-olds with messages focusing on healthy dietary behaviours. Early childhood education and care (ECEC) staff are provided with pedagogical tools addressing healthy food exposure and child food acceptance. Objectives: a) evaluate the effectiveness of provision of the Nutrition Now resource on child diet and diet-related outcomes, with special attention to the influence of socio-economic position, b) gather information on the effectiveness of the implementation process to inform forthcoming scale-up and c) perform trial- and model-based economic evaluations. This is a hybrid type 1 implementation study, focusing on evaluation of effectiveness. A quasi-experimental design with pre- and post-tests, where one municipality gets access to the resource (n~800), while a matched non-equivalent control municipality (n~800) does not, will be used. Effectiveness will be assessed by examining e.g., diet outcomes, developmental outcomes, and feeding practices. The resource will be implemented in ECEC settings and made available to pregnant women and parents through the Norwegian system of maternal and child health (MCH) care. The implementation process includes iterative adjustments and implementation strategies from the implementation framework Expert Recommendations for Implementing Change (ERIC) informed by dialogues with stakeholders. Implementation outcomes (e.g., acceptability and adoption) will be assessed through questionnaires and interviews with parents, ECEC and MCH staff, with particular attention to ethnic diverse groups. Both within-trial and modelling-based economic evaluation will be performed. Nutrition Now will bridge the existing evidence-to-practice gap through rigorous scientific effectiveness evaluation of municipal scale up and inform subsequent county scale up. The study is the first to implement efficacious nutrition interventions in early life with potential for health improvement using technology to maximise the reach and impact of both parental and MCH dietary guidance and ECEC practice., Clinical Trial Registration: https://www.isrctn.com/, identified ISRCTN10694967., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Øverby, Hillesund, Helland, Helle, Wills, Lamu, Osorio, Lian, Ersfjord, Van Daele, Bjørkkjær, Valen, Gebremariam, Grasaas, Kiland, Schwarz, Abel, Love, Campbell, Rutter, Barker, Vik and Medin.)

Background: The relationship between iodine intake and depression is unknown. The aim of the present study was to investigate whether iodine intake was associated with symptoms of perinatal emotional distress and depression in a mild- to moderately iodine deficient population., Methods: The study population comprised 67,812 women with 77,927 pregnancies participating in the Norwegian Mother, Father and Child Cohort Study. Self-reported emotional distress and depressive symptoms were reported in pregnancy and at six months postpartum. Iodine intake was assessed by a food frequency questionnaire in mid-pregnancy. Urinary iodine concentration (UIC) was available for 2792 pregnancies., Results: The median iodine intake from food was 121 μg/day and the median UIC was 68 μg/L. The prevalence of high scores for emotional distress was 6.6 % in pregnancy and 5.8 % six months postpartum, and for high scores on postpartum depression it was 10.3 %. In non-users of iodine supplements (63 %), a low maternal iodine intake from food (lower than ~100-150 μg/day) was associated with increased risk of high scores of emotional distress and depression both in pregnancy and six months postpartum (p < 0.001). Iodine supplement use was associated with increased risk of high scores of emotional distress in pregnancy compared to no supplement use or use of supplements without iodine., Limitations: Observational design, self-report information, and short scales to assess symptoms of emotional distress and depression., Conclusion: A low habitual iodine intake was associated with increased prevalence of perinatal emotional distress and depression. The potential non-beneficial effect of iodine supplements may have biological explanations. More studies are needed., Competing Interests: Conflict of Interest M.H.A. was until Dec. 2019 employed by the Norwegian dairy company TINE SA, and she participated in this project as an industrial Ph.D.-student financed partly by TINE SA and partly by The Research Council of Norway. This project is designed, owned, and administered by The Norwegian Institute of Public Health (NIPH) and analysis of the data follow from protocol. All results of analysis in the project are to be published regardless of the results. TINE SA supported the project to raise awareness on the importance of iodine and to gain more knowledge about the potential health effects of milk in the Norwegian diet. Today, M.H.A. is a full-time researcher at the NIPH. The other authors declare that they have no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Adequate iron supply in pregnancy is important for both the woman and the fetus, but iron status is often assessed late in first trimester, if assessed at all. Therefore, identification of factors associated with iron status is important to target vulnerable groups with increased risk of deficiency. Our objectives were to (1) describe iron status in mid-pregnancy and (2) identify sociodemographic and lifestyle predictors of pregnancy iron status. This cross-sectional study uses data from The Norwegian Mother, Father and Child Cohort Study (collected 2002-2008) and The Medical Birth Registry of Norway. Iron status was measured as non-fasting plasma ferritin (P-Fe) and transferrin in gestational week (GW) 18 (n 2990), and by lowest reported Hb in GW 0-30 (n 39 322). We explored predictors of iron status with elastic net, linear and log-binomial regression models. Median P-Fe was 33 μg/l, and 14 % had depleted iron stores (P-Fe <15 μg/l). P-Fe below 30 μg/l was associated with reduced Hb. We identified eleven predictors, with interpregnancy interval (IPI) and parity among the most important. Depleted iron stores was more common among women with IPI < 6 months (56 %) and 6-11 months (33 %) than among those with IPI 24-59 months (19 %) and among nulliparous women (5 %). Positively associated factors with iron status included hormonal contraceptives, age, BMI, smoking, meat consumption and multi-supplement use. Our results highlight the importance of ferritin measurements in women of childbearing age, especially among women not using hormonal contraceptives and women with previous and recent childbirths.

Background: Severe iodine deficiency impacts fertility and reproductive outcomes. The potential effects of mild-to-moderate iodine deficiency are not well known. The aim of this study was to examine whether iodine intake was associated with subfecundity (i.e. > 12 months trying to get pregnant), foetal growth, and adverse pregnancy outcomes in a mild-to-moderately iodine-deficient population., Methods: We used the Norwegian Mother, Father and Child Cohort Study (MoBa) and included 78,318 pregnancies with data on iodine intake and pregnancy outcomes. Iodine intake was calculated using an extensive food frequency questionnaire in mid-pregnancy. In addition, urinary iodine concentration was available in a subsample of 2795 pregnancies. Associations were modelled continuously by multivariable regression controlling for a range of confounding factors., Results: The median iodine intake from food was 121 μg/day and the median urinary iodine was 69 μg/L, confirming mild-to-moderate iodine deficiency. In non-users of iodine supplements (n = 49,187), low iodine intake (< 100-150 μg/day) was associated with increased risk of preeclampsia (aOR = 1.14 (95% CI 1.08, 1.22) at 75 vs. 100 μg/day, p overall < 0.001), preterm delivery before gestational week 37 (aOR = 1.10 (1.04, 1.16) at 75 vs. 100 μg/day, p overall = 0.003), and reduced foetal growth (- 0.08 SD (- 0.10, - 0.06) difference in birth weight z-score at 75 vs. 150 μg/day, p overall < 0.001), but not with early preterm delivery or intrauterine death. In planned pregnancies (n = 56,416), having an iodine intake lower than ~ 100 μg/day was associated with increased prevalence of subfecundity (aOR = 1.05 (1.01, 1.09) at 75 μg/day vs. 100 μg/day, p overall = 0.005). Long-term iodine supplement use (initiated before pregnancy) was associated with increased foetal growth (+ 0.05 SD (0.03, 0.07) on birth weight z-score, p < 0.001) and reduced risk of preeclampsia (aOR 0.85 (0.74, 0.98), p = 0.022), but not with the other adverse pregnancy outcomes. Urinary iodine concentration was not associated with any of the dichotomous outcomes, but positively associated with foetal growth (n = 2795, p overall = 0.017)., Conclusions: This study shows that a low iodine intake was associated with restricted foetal growth and a higher prevalence of preeclampsia in these mild-to-moderately iodine-deficient women. Results also indicated increased risk of subfecundity and preterm delivery. Initiating iodine supplement use in pregnancy may be too late.

Purpose: Some studies indicate that mild-to-moderate iodine deficiency in pregnant women might negatively affect offspring neurocognitive development, including previous results from the Norwegian Mother and Child Cohort study (MoBa) exploring maternally reported child development at age 3 years. The aim of this follow-up study was to investigate whether maternal iodine intake in pregnancy is associated with language and learning at 8 years of age., Methods: The study sample includes 39,471 mother-child pairs participating in MoBa with available information from a validated food frequency questionnaire covering the first half of pregnancy and a questionnaire on child neurocognitive development at 8 years. Multivariable regression was used to explore associations of iodine intake from food and supplements with maternally reported child outcomes., Results: Maternal iodine intake from food less than ~ 150 µg/day was associated with poorer child language skills (p-overall = 0.013), reading skills (p-overall = 0.019), and writing skills (p-overall = 0.004) as well as poorer school test result in reading (p < 0.001), and increased likelihood of the child receiving special educational services (p-overall = 0.042) (in non-iodine supplement users). Although significant, differences were generally small. Maternal use of iodine supplements in pregnancy was not significantly associated with any of the outcomes., Conclusions: Low habitual iodine intake in pregnant women, i.e., lower than the recommended intake for non-pregnant women, was associated with mothers reporting poorer child language, school performance, and increased likelihood of special educational services. We found no indications of benefits or harm of using iodine-containing supplements in pregnancy. Initiating use in pregnancy might be too late.

Background: In 2016, the Norwegian National Nutrition Council concluded that inadequate iodine intake is widespread in sections of the Norwegian population, and that effective measures should be undertaken immediately. This literature review aims to summarise articles published since January 2016 that describe the iodine intake in Norway., Material and Method: Literature searches were conducted in PubMed and Embase. Altogether thirteen articles that reported intake of iodine from the diet or urinary iodine concentration were included., Results: The recent studies confirm that inadequate iodine intake is widespread among women of fertile age, pregnant and breastfeeding women, infants who are exclusively breastfed, elderly persons, vegans and immigrants. There are few sources of iodine in the diet, and persons who avoid or have a low intake of milk and white fish are particularly vulnerable., Interpretation: Inadequate iodine intake is a matter of particular concern in women of fertile age. Healthcare personnel should be aware of this and in certain cases recommend iodine-rich foods or iodine supplements to these and other vulnerable groups.

Background: Studies indicate that mild to moderate iodine deficiency in pregnancy may have a long-term negative impact on child neurodevelopment. These effects are likely mediated via changes in maternal thyroid function, since iodine is essential for the production of thyroid hormones. However, the impact of iodine availability on thyroid function during pregnancy and on thyroid function reference ranges are understudied. The aim of this study was to investigate the association between iodine intake and thyroid function during pregnancy., Design: In a population-based pregnancy cohort including 2910 pregnant women participating in The Norwegian Mother and Child Cohort Study, we explored cross sectional associations of maternal iodine intake measured (1) by a food frequency questionnaire and (2) as iodine concentration in a spot urine sample, with plasma thyroid hormones and antibodies., Results: Biological samples were collected in mean gestational week 18.5 (standard deviation 1.3) and diet was assessed in gestational week 22. Median iodine intake from food was 121 μg/day (interquartile range 90, 160), and 40% reported use of iodine-containing supplements in pregnancy. Median urinary iodine concentration (UIC) was 59 μg/L among those who did not use supplements and 98 μg/L in the women reporting current use at the time of sampling, indicating mild to moderate iodine deficiency in both groups. Iodine intake as measured by the food frequency questionnaire was not associated with the outcome measures, while UIC was inversely associated with FT3 (p = 0.002) and FT4 (p < 0.001). Introduction of an iodine-containing supplement after gestational week 12 was associated with indications of lower thyroid hormone production (lower FT4, p = 0.027, and nonsignificantly lower FT3, p = 0.17). The 2.5th and 97.5th percentiles of TSH, FT4, and FT3 were not significantly different by groups defined by calculated iodine intake or by UIC., Conclusion: The results indicate that mild to moderate iodine deficiency affect thyroid function in pregnancy. However, the differences were small, suggesting that normal reference ranges can be determined based on data also from mildly iodine deficient populations, but this needs to be further studied. Introducing an iodine-containing supplement might temporarily inhibit thyroid hormone production and/or release.

Inadequate iodine status affects the synthesis of the thyroid hormones and may impair brain development in fetal life. The aim of this study was to explore the association between maternal iodine status in pregnancy measured by urinary iodine concentration (UIC) and child neurodevelopment at age 6, 12 and 18 months in a population-based cohort. In total, 1036 families from nine locations in Norway were enrolled in the little in Norway cohort. The present study includes n = 851 mother-child pairs with singleton pregnancies, no use of thyroid medication in pregnancy, no severe genetic disorder, data on exposure (UIC) in pregnancy and developmental outcomes (Bayley Scales of Infant and Toddler Development, third edition). Data collection also included general information from questionnaires. We examined associations between UIC (and use of iodine-containing supplements) and repeated measures of developmental outcomes using multivariable mixed models. The median UIC in pregnancy was 78 µg/L (IQR 46⁻130), classified as insufficient iodine intake according to the WHO. Eighteen percent reported use of iodine-containing multisupplements. A UIC below ~100 was associated with reduced receptive ( p = 0.025) and expressive language skills ( p = 0.002), but not with reduced cognitive or fine- and gross motor skills. Maternal use of iodine-containing supplements was associated with lower gross motor skills (b = -0.18, 95% CI = -0.33, -0.03, p = 0.02), but not with the other outcome measures. In conclusion, an insufficient iodine intake in pregnancy, reflected in a UIC below ~100 µg/L, was associated with lower infant language skills up to 18 months. The use of iodine-containing supplements was not associated with beneficial effects.

Background: The Sertoli cells act to induce testis differentiation and subsequent development in fetal and post-natal life which makes them key to an understanding of testis biology. As a major step towards characterisation of factors involved in Sertoli cell function we have identified Sertoli cell-specific transcripts in the mouse testis and have used the data to identify Sertoli cell-specific transcripts altered in mice lacking follicle-stimulating hormone receptors (FSHRKO) and/or androgen receptors (AR) in the Sertoli cells (SCARKO)., Results: Adult iDTR mice were injected with busulfan to ablate the germ cells and 50 days later they were treated with diphtheria toxin (DTX) to ablate the Sertoli cells. RNAseq carried out on testes from control, busulfan-treated and busulfan + DTX-treated mice identified 701 Sertoli-specific transcripts and 4302 germ cell-specific transcripts. This data was mapped against results from microarrays using testicular mRNA from 20 day-old FSHRKO, SCARKO and FSHRKO.SCARKO mice. Results show that of the 534 Sertoli cell-specific transcripts present on the gene chips, 85% were altered in the FSHRKO mice and 94% in the SCARKO mice (mostly reduced in both cases). In the FSHRKO.SCARKO mice additive or synergistic effects were seen for most transcripts. Age-dependent studies on a selected number of Sertoli cell-specific transcripts, showed that the marked effects in the FSHRKO at 20 days had largely disappeared by adulthood although synergistic effects of FSHR and AR knockout were seen., Conclusions: These studies have identified the Sertoli cell-specific transcriptome in the mouse testis and have shown that most genes in the transcriptome are FSH- and androgen-dependent at puberty although the importance of FSH diminishes towards adulthood.

Current knowledge about the relationship between mild to moderately inadequate maternal iodine intake and/or supplemental iodine on child neurodevelopment is sparse. Using information from 77,164 mother-child pairs in the Norwegian Mother and Child Cohort Study, this study explored associations between maternal iodine intake and child attention-deficit/hyperactivity disorder (ADHD) diagnosis, registered in the Norwegian Patient Registry and maternally-reported child ADHD symptoms at eight years of age. Pregnant women reported food and supplement intakes by questionnaire in gestational week 22. In total, 1725 children (2.2%) were diagnosed with ADHD. In non-users of supplemental iodine (53,360 mothers), we found no association between iodine intake from food and risk of child ADHD diagnosis ( p = 0.89), while low iodine from food (<200 µg/day) was associated with higher child ADHD symptom scores (adjusted difference in score up to 0.08 standard deviation (SD), p < 0.001, n = 19,086). In the total sample, we found no evidence of beneficial effects of maternal use of iodine-containing supplements ( n = 23,804) on child ADHD diagnosis or symptom score. Initiation of iodine supplement use in gestational weeks 0-12 was associated with an increased risk of child ADHD (both measures). In conclusion, insufficient maternal iodine intake was associated with increased child ADHD symptom scores at eight years of age, but not with ADHD diagnosis. No reduction of risk was associated with maternal iodine supplement use., Competing Interests: The first author of this paper is employed by a Norwegian dairy company (TINE SA), and she participates in this project as an industrial PhD-student financed partly by the dairy company and partly by The Research Council of Norway. This project is designed, owned and administered by The Norwegian Institute of Public Health and analysis of the data follow from protocol. All results of analysis in the project are to be published regardless of the results. The dairy company supports the study to raise awareness on the importance of iodine and to gain more knowledge about the potential health effects of milk in the Norwegian diet. Apart from the PhD-student, no one from the dairy company has been involved in the study, and in itself, the company had no direct influence on the analysis and interpretation of the results. The other authors had no conflicts of interest.

Background: Severe iodine deficiency in pregnancy has major effects on child neurodevelopment, but less is known about the potential consequences of mild-to-moderate deficiency and iodine supplement use. Objective: We explored the associations between maternal iodine intake and child neurodevelopment at 3 y of age and the potential impact of maternal intake of iodine from supplements on the same outcomes. Methods: This population-based prospective observational study included 48,297 mother-child pairs recruited during pregnancy from 2002 to 2008. Maternal iodine intake was calculated based on a validated food-frequency questionnaire answered during midpregnancy that covered mean intake since the beginning of pregnancy. Associations between iodine intake and maternal-reported child language and motor development and behavior problems were explored by multivariable regression analyses. Results: In 33,047 mother-child pairs, excluding iodine supplement users, maternal iodine intake was associated with child language delay ( P = 0.024), externalizing and internalizing behavior problems (both P < 0.001), and fine motor skills ( P = 0.002) but not gross motor skills or the risk of not walking unaided at 17 mo of age. In 74% of the participants who had an iodine intake <160 μg/d (Estimated Average Requirement), suboptimal iodine intake was estimated to account for ∼5% (95% CI: -5%, 14%) of the cases of language delay, 16% (95% CI: 0%, 21%) of the cases of externalizing behavior problems >1.5 SD, and 16% (95% CI: 10%, 21%) of the cases of internalizing behavior problems >1.5 SD. In 48,297 mother-child pairs, including iodine supplement users, we found no protective effects of supplemental iodine during pregnancy on neurodevelopment. Conclusions: Maternal iodine intake below the Estimated Average Requirement during pregnancy was associated with symptoms of child language delay, behavior problems, and reduced fine motor skills at 3 y of age. The results showed no evidence of a protective effect of iodine supplementation during pregnancy., Competing Interests: Author disclosures: IHC, HMM, MH, REB, HA, JA, LET, and A-LB, no conflicts of interest. MHA is employed by TINE SA. This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited., (© 2017 American Society for Nutrition.)

Background: Dairy products account for approximately 60% of the iodine intake in the Norwegian population. The iodine concentration in cow's milk varies considerably, depending on feeding practices, season, and amount of iodine and rapeseed products in cow fodder. The variation in iodine in milk affects the risk of iodine deficiency or excess in the population., Objective: The first goal of this study was to develop a model to predict the iodine concentration in milk based on the concentration of iodine and rapeseed or glucosinolate in feed, as a tool to securing stable iodine concentration in milk. A second aim was to estimate the impact of different iodine levels in milk on iodine nutrition in the Norwegian population., Design: Two models were developed on the basis of results from eight published and two unpublished studies from the past 20 years. The models were based on different iodine concentrations in the fodder combined with either glucosinolate (Model 1) or rapeseed cake/meal (Model 2). To illustrate the impact of different iodine concentrations in milk on iodine intake, we simulated the iodine contribution from dairy products in different population groups based on food intake data in the most recent dietary surveys in Norway., Results: The models developed could predict iodine concentration in milk. Cross-validation showed good fit and confirmed the explanatory power of the models. Our calculations showed that dairy products with current iodine level in milk (200 µg/kg) cover 68, 49, 108 and 56% of the daily iodine requirements for men, women, 2-year-old children, and pregnant women, respectively., Conclusions: Securing a stable level of iodine in milk by adjusting iodine concentration in different cow feeds is thus important for preventing excess intake in small children and iodine deficiency in pregnant and non-pregnant women.

To investigate the relationship between gonadotroph function and ultrastructure, we have compared, in parallel in female mice, the effects of several different mutations that perturb the hypothalamic-pituitary-gonadal axis. Specifically, serum and pituitary gonadotrophin concentrations, gonadotrophin gene expression, gonadotroph structure and number were measured. Follicle-stimulating hormone β knockout (FSHβKO), follicle-stimulating hormone receptor knockout (FSHRKO), luteinising hormone receptor knockout (LuRKO), hypogonadal (hpg) and ovariectomised mice were compared with control wild-type or heterozygote female mice. Serum levels of LH were elevated in FSHβKO and FSHRKO compared to heterozygote females, reflecting the likely decreased oestrogen production in KO females, as demonstrated by the threadlike uteri and acyclicity. As expected, there was no detectable FSH in the serum or pituitary and an absence of expression of the FSHβ subunit gene in FSHβKO mice. However, there was a significant increase in expression of the FSHβ and LHβ subunit genes in FSHRKO female mice. The morphology of FSHβKO and FSHRKO gonadotrophs was not significantly different from the control, except that secretory granules in FSHRKO gonadotrophs were larger in diameter. In LuRKO and ovariectomised mice, stimulation of LHβ and FSHβ mRNA, as well as serum protein concentrations, were reflected in subcellular changes in gonadotroph morphology, including more dilated rough endoplasmic reticula and fewer, larger secretory granules. In the gonadotophin-releasing hormone deficient hpg mouse, gonadotrophin mRNA and protein levels were significantly lower than in control mice and gonadotrophs were correspondingly smaller with less abundant endoplasmic reticula and reduced numbers of secretory granules. In summary, major differences in pituitary content and serum concentrations of the gonadotrophins LH and FSH were found between control and mutant female mice. These changes were associated with changes in expression of the gonadotrophin subunit genes and were reflected in the cellular structure and secretory granule appearance within the gonadotroph cells., (© 2014 British Society for Neuroendocrinology.)

To investigate brain-pituitary-gonadal inter-relationships, we have compared the effects of mutations that perturb the hypothalamic-pituitary-gonadal axis in male mice. Specifically, serum and pituitary gonadotrophin concentrations, gonadotrophin gene expression, and gonadotroph structure and number were measured. Follicle-stimulating hormone (FSH)β knockout (FSHβKO), FSH receptor knockout (FSHRKO), luteinising hormone (LH) receptor knockout (LuRKO), hypogonadal (hpg), testicular feminised (tfm) and gonadectomised mice were compared with control wild-type mice or heterozygotes. Serum levels of LH were similar in FSHβKO, FSHRKO and heterozygote males despite decreased androgen production in KO males. As expected, there was no detectable FSH in the serum or pituitary and an absence of expression of the FSHβ subunit gene in FSHβKO mice. However, there was a significant increase in expression of the common α and LHβ subunit genes in FSHRKO males. The morphology of FSHβKO and FSHRKO gonadotrophs was not significantly different from controls, except that the subpopulation of granules consisting of an electron-dense core and electron-lucent 'halo' was not observed in FSHβKO gonadotrophs and the granules were smaller in diameter. In the gonadotrophin-releasing hormone deficient hpg mouse, gonadotrophin mRNA and hormone levels were significantly lower compared to control mice and gonadotrophs were correspondingly smaller, with less abundant endoplasmic reticulum and reduced secretory granules. In LuRKO, tfm and gonadectomised mice, hyperstimulation of LHβ and FSHβ mRNA and serum protein concentrations was reflected by subcellular changes in gonadotroph morphology, including more dilated rough endoplasmic reticulum and more secretory granules distributed adjacent to the plasma membrane. In summary, major differences in pituitary content and serum concentrations of the gonadotrophins LH and FSH have been found between normal and mutant male mice. These changes are associated with changes in transcriptional activity of the gonadotrophin subunit genes and are reflected by changes in the cellular structure and secretory granule architecture within the gonadotroph cells., (© 2013 British Society for Neuroendocrinology.)

Pregnant women and infants are exceptionally vulnerable to iodine deficiency. The aims of the present study were to estimate iodine intake, to investigate sources of iodine, to identify predictors of low or suboptimal iodine intake (defined as intakes below 100 μg/day and 150 μg/day) in a large population of pregnant Norwegian women and to evaluate iodine status in a sub-population. Iodine intake was calculated based on a validated Food Frequency Questionnaire in the Norwegian Mother and Child Cohort. The median iodine intake was 141 μg/day from food and 166 μg/day from food and supplements. Use of iodine-containing supplements was reported by 31.6%. The main source of iodine from food was dairy products, contributing 67% and 43% in non-supplement and iodine-supplement users, respectively. Of 61,904 women, 16.1% had iodine intake below 100 μg/day, 42.0% had iodine intake below 150 μg/day and only 21.7% reached the WHO/UNICEF/ICCIDD recommendation of 250 μg/day. Dietary behaviors associated with increased risk of low and suboptimal iodine intake were: no use of iodine-containing supplements and low intake of milk/yogurt, seafood and eggs. The median urinary iodine concentration measured in 119 participants (69 μg/L) confirmed insufficient iodine intake. Public health strategies are needed to improve and secure the iodine status of pregnant women in Norway.

Luteinizing hormone (LH) is a key regulator of male fertility through its effects on testosterone secretion by Leydig cells. Transcriptional control of this is, however, currently poorly understood. Mice in which the LH receptor is knocked out (LuRKO) show reduced testicular size, reduced testosterone, elevated serum LH, and a spermatogenic arrest that can be rescued by the administration of testosterone. Using genome-wide transcription profiling of LuRKO and control testes during postnatal development and following testosterone treatment, we show that the transcriptional effects of LH insensitivity are biphasic, with an early testosterone-independent phase and a subsequent testosterone-dependent phase. Testosterone rescue re-enables the second, testosterone-dependent phase of the normal prepubertal transcription program and permits the continuation of spermatogenesis. Examination of the earliest responses to testosterone highlights six genes that respond rapidly in a dose-dependent fashion to the androgen and that are therefore candidate regulatory genes associated with the testosterone-driven progression of spermatogenesis. In addition, our transcriptional data suggest a model for the replacement of fetal-type Leydig cells by adult-type cells during testicular development in which a testosterone feedback switch is necessary for adult Leydig cell production. LH signaling affects the timing of the switch but is not a strict requirement for Leydig cell differentiation.

Androgens act to stimulate spermatogenesis through androgen receptors (ARs) on the Sertoli cells and peritubular myoid cells. Specific ablation of the AR in either cell type will cause a severe disruption of spermatogenesis. To determine whether androgens can stimulate spermatogenesis through direct action on the peritubular myoid cells alone or whether action on the Sertoli cells is essential, we crossed hypogonadal (hpg) mice that lack gonadotrophins and intratesticular androgen with mice lacking ARs either ubiquitously (ARKO) or specifically on the Sertoli cells (SCARKO). These hpg.ARKO and hpg.SCARKO mice were treated with testosterone (T) or dihydrotestosterone (DHT) for 7 d and testicular morphology and cell numbers assessed. Androgen treatment did not affect Sertoli cell numbers in any animal group. Both T and DHT increased numbers of spermatogonia and spermatocytes in hpg mice, but DHT has no effect on germ cell numbers in hpg.SCARKO and hpg.ARKO mice. T increased germ cell numbers in hpg.SCARKO and hpg.ARKO mice, but this was associated with stimulation of FSH release. Results show that androgen stimulation of spermatogenesis requires direct androgen action on the Sertoli cells.

FSH and androgen act to stimulate and maintain spermatogenesis. FSH acts directly on the Sertoli cells to stimulate germ cell number and acts indirectly to increase androgen production by the Leydig cells. In order to differentiate between the direct effects of FSH on spermatogenesis and those mediated indirectly through androgen action, we have crossed hypogonadal (hpg) mice, which lack gonadotrophins, with mice lacking androgen receptors (AR) either ubiquitously (ARKO) or specifically on the Sertoli cells (SCARKO). These hpg.ARKO and hpg.SCARKO mice were treated with recombinant FSH for 7 days and testicular morphology and cell numbers were assessed. In untreated hpg and hpg.SCARKO mice, germ cell development was limited and did not progress beyond the pachytene stage. In hpg.ARKO mice, testes were smaller with fewer Sertoli cells and germ cells compared to hpg mice. Treatment with FSH had no effect on Sertoli cell number but significantly increased germ cell numbers in all groups. In hpg mice, FSH increased the numbers of spermatogonia and spermatocytes, and induced round spermatid formation. In hpg.SCARKO and hpg.ARKO mice, in contrast, only spermatogonial and spermatocyte numbers were increased with no formation of spermatids. Leydig cell numbers were increased by FSH in hpg and hpg.SCARKO mice but not in hpg.ARKO mice. Results show that in rodents 1) FSH acts to stimulate spermatogenesis through an increase in spermatogonial number and subsequent entry of these cells into meiosis, 2) FSH has no direct effect on the completion of meiosis and 3) FSH effects on Leydig cell number are mediated through interstitial ARs.

Background: Testicular microliths are calcifications found within the seminiferous tubules. In humans, testicular microlithiasis (TM) has an unknown etiology but may be significantly associated with testicular germ cell tumors. Factors inducing microlith development may also, therefore, act as susceptibility factors for malignant testicular conditions. Studies to identify the mechanisms of microlith development have been hampered by the lack of suitable animal models for TM., Methods: This was an observational study of the testicular phenotype of different mouse models. The mouse models were: cryptorchid mice, mice lacking androgen receptors (ARs) on the Sertoli cells (SCARKO), mice with a ubiquitous loss of androgen ARs (ARKO), hypogonadal (hpg) mice which lack circulating gonadotrophins, and hpg mice crossed with SCARKO (hpg.SCARKO) and ARKO (hpg.ARKO) mice., Results: Microscopic TM was seen in 94% of hpg.ARKO mice (n=16) and the mean number of microliths per testis was 81+/-54. Occasional small microliths were seen in 36% (n=11) of hpg testes (mean 2+/-0.5 per testis) and 30% (n=10) of hpg.SCARKO testes (mean 8+/-6 per testis). No microliths were seen in cryptorchid, ARKO or SCARKO mice. There was no significant effect of FSH or androgen on TM in hpg.ARKO mice., Conclusion: We have identified a mouse model of TM and show that lack of endocrine stimulation is a cause of TM. Importantly, this model will provide a means with which to identify the mechanisms of TM development and the underlying changes in protein and gene expression.

Development and maintenance of the male phenotype and establishment of fertility are all dependent upon the activity of the Sertoli cells and Leydig cells of the testis. This review examines the regulation and function of these cell during fetal and post-natal development. Fetal Leydig cells are sensitive to both luteinising hormone (LH) and adrenocorticotrophic hormone (ACTH) but Leydig cell function appears normal in fetal mice lacking both hormones or their receptors. Post-natally, the Sertoli cells and Leydig cells are reliant upon the pituitary gonadotrophins. Leydig cells are critically dependent on LH but follicle-stimulating hormone (FSH), presumably acting through the Sertoli cell, can also affect Leydig cell function. Testosterone secreted by the Leydig cells acts with FSH to stimulate Sertoli cell activity and spermatogenesis. Study of animals lacking FSH-receptors and androgen-receptors shows that both hormones can act to maintain the meiotic germ cell population but that androgens are critical for completion of meiosis.

FSH acts through the Sertoli cell to ensure normal testicular development and function. To identify transcriptional mechanisms through which FSH acts in the testis, we have treated gonadotrophin-deficient hypogonadal (hpg) mice with recombinant FSH and measured changes in testicular transcript levels using microarrays and real-time PCR 12, 24 and 72 h after the start of treatment. Approximately 400 transcripts were significantly altered at each time point by FSH treatment. At 12 h, there was a clear increase in the levels of a number of known Sertoli cell transcripts (e.g. Fabp5, Lgals1, Tesc, Scara5, Aqp5). Additionally, levels of Leydig cell transcripts were also markedly increased (e.g. Ren1, Cyp17a1, Akr1b7, Star, Nr4a1). This was associated with a small but significant rise in testosterone at 24 and 72 h. At 24 h, androgen-dependent Sertoli cell transcripts were up-regulated (e.g. Rhox5, Drd4, Spinlw1, Tubb3 and Tsx) and this trend continued up to 72 h. By contrast with the somatic cells, only five germ cell transcripts (Dkkl1, Hdc, Pou5f1, Zfp541 and 1700021K02Rik) were altered by FSH within the time-course of the experiment. Analysis of canonical pathways showed that FSH induced a general decline in transcripts related to formation and regulation of tight junctions. Results show that FSH acts directly and indirectly to induce rapid changes in Sertoli cell and Leydig cell transcript levels in the hpg mouse but that effects on germ cell development must occur over a longer time-span.

Spermatogenesis in the adult male depends on the action of FSH and androgen. Ablation of either hormone has deleterious effects on Sertoli cell function and the progression of germ cells through spermatogenesis. In this study we generated mice lacking both FSH receptors (FSHRKO) and androgen receptors on the Sertoli cell (SCARKO) to examine how FSH and androgen combine to regulate Sertoli cell function and spermatogenesis. Sertoli cell number in FSHRKO-SCARKO mice was reduced by about 50% but was not significantly different from FSHRKO mice. In contrast, total germ cell number in FSHRKO-SCARKO mice was reduced to 2% of control mice (and 20% of SCARKO mice) due to a failure to progress beyond early meiosis. Measurement of Sertoli cell-specific transcript levels showed that about a third were independent of hormonal action on the Sertoli cell, whereas others were predominantly androgen dependent or showed redundant control by FSH and androgen. Results show that FSH and androgen act through redundant, additive, and synergistic regulation of spermatogenesis and Sertoli cell activity. In addition, the Sertoli cell retains a significant capacity for activity, which is independent of direct hormonal regulation.

Testicular apoptosis is involved in the regulation of germ cell numbers, allowing optimal sperm production. Apoptosis has been described to occur in response to the absence of hormonal stimulation of the testis. Here we investigate the effect of the physiological lack of gonadotropins from birth using the hypogonadal (homozygous for the mutant allele Gnrh1(hpg)) mouse as a model. We pursued a concerted strategy using microarray analysis and RT-PCR to assess transcript levels, TUNEL to quantify the incidence of apoptosis, and Western blotting to assess the respective contribution of the extrinsic and intrinsic apoptotic pathways. Our results indicate a large increase in apoptosis of both somatic and germ cell compartments in the hpg testis, affecting Sertoli cells as well as germ cells of all ages. We confirmed our observations of Sertoli cell apoptosis using anti-Mullerian inhibiting substance staining and staining for cleaved fodrin alpha. In the somatic compartment, apoptosis is primarily regulated via the membrane receptor (extrinsic) apoptotic pathway, while in the germ cell compartment, regulation occurs via both the mitochondrial (intrinsic) and membrane receptor (extrinsic) apoptotic pathways, the latter potentially in a stage-specific manner. This study is the first report of spermatogonial apoptosis in response to gonadotropin deficiency as well as the first report of Sertoli cell apoptosis in response to gonadotropin deficiency in the mouse.

The authors found an interaction between sex of participant and sex of defendant in the leniency bias toward a smiling defendant. Differences occurred for male participants when levying punishment for a smiling male defendant vs. a smiling female defendant and for a smiling male defendant vs. a nonsmiling male defendant, whereas differences did not occur for female participants. The authors found moderating effects of physical attractiveness and smiling between guilt and punishment. The only significant positive relationship between guilt and punishment occurred for the defendant whom participants rated low in physical attractiveness and who was not smiling. When guilty, the smiling and unattractive defendant received less punishment than did the smiling and attractive defendant. The authors discussed complex relationships between physical attractiveness, smiling, guilt, and punishment.

Measurement of inhibins A and B in the serum of normal cyclic rodents has implicated FSH in the regulation of these peptides within the ovary. To extend these observations we have used a panel of mutant mice carrying mutations which affect either the production of, or the ability to respond to, FSH and LH. As a consequence, the females are infertile and show different degrees of follicular development. The aim of this study was to measure inhibin gene transcription in the ovaries of these mutant females together with inhibin protein levels in ovaries and serum and to relate these to follicular development within the ovary. Comparison was made with a pool of normal/heterozygous females. In hpg females where lack of GnRH production results in the absence of gonadotropin synthesis, in FSHbeta knockout (FSHbetaKO) females where disruption of the gene encoding FSHbeta results in the absence of FSH production, and in FSH receptor knockout (FSHRKO) females which are unable to respond to circulating FSH, follicular development remains at the pre-antral stage in these three mutants. Only in the hpg females were common inhibin alpha subunit mRNA levels significantly lower than normal. In these three mutants, however, mRNA levels for both the betaA and betaB subunits were extremely low compared with normal mice. At the protein level, neither inhibin A nor B was detected in the serum of these three mutants; however inhibin B, albeit at very low levels, was detectable within the ovaries. These observations confirm a major role for FSH in the control of transcription of the betaA and betaB genes but suggest that the constitutive transcription of the alpha subunit is less dependent on FSH. In contrast, in LH receptor knockout (LuRKO) female mice inhibin betaA subunit mRNA levels were similar to those measured in normal/heterozygous females but levels of inhibin alpha and betaB subunit mRNAs were significantly higher than in the normal group. This was reflected in significantly higher inhibin B protein levels in ovaries and serum. An inability to respond to LH combined with high circulating levels of FSH leads to a high proportion of antral follicles in LuRKO females, with granulosa cells constituting the major cell type within the ovary. The high percentage of antral granulosa cells is likely to account for the significantly higher levels of inhibin B production in these ovaries.

Previous studies have suggested that FSH may be involved in regulation of Leydig cell function. We have examined this directly using two mouse models with null mutations in either the FSH beta-subunit (FSHbetaKO mice) or the FSH receptor (FSHRKO mice). Circulating LH levels were normal in adult FSHbetaKO mice, but were significantly increased in FSHRKO mice. Intratesticular testosterone levels increased normally in FSHbetaKO mice from birth to adulthood, whereas testosterone levels in FSHRKO mice failed to increase normally after puberty and were significantly reduced in adult animals. This was associated with reduced levels of mRNA encoding cytochrome P450 side-chain cleavage, 3beta-hydroxysteroid dehydrogenase type VI, and steroidogenic acute regulatory protein in FSHRKO mice. Leydig cell number was normal in FSHbetaKO mice during development, but in FSHRKO mice Leydig cell number increased slowly after puberty and was significantly reduced in the adult animal. Transfection studies showed that the FSHR exhibits constitutive activity in the absence of agonist stimulation. The results indicate, therefore, that Sertoli cells regulate the development of Leydig cell number and that constitutive activity within the FSHR is sufficient to stimulate this process. The presence of the hormone itself is not required when circulating LH levels are adequate.

To investigate further brain-pituitary-gonadal interrelationships we have generated mice in which the gene encoding the FSH receptor has been disrupted. Female FSH receptor knockout (FSHRKO) mice were infertile. The ovaries were significantly reduced in size, with follicular development arrested at the preantral stage, but there was evidence of stromal hypertrophy. The vagina was imperforate, and the uterus was atrophic. There was no response to administration of PMSG. Inhibins A and B were undetectable in both the serum and gonads. Compared with those in control animals, serum concentrations of FSH and LH were significantly elevated in mutant females. The pituitary content of FSH, but not LH, was also significantly elevated. Estrogen administration in FSHRKO female mice suppressed serum LH levels to those seen in control mice, whereas FSH levels were reduced by only 50%. Male FSHRKO mice were fertile, although testis weight was significantly reduced. However, testicular inhibin A and B concentrations did not differ from those in normal littermates. Serum levels of FSH and LH were elevated in the null mutant male mice, whereas no differences were found in the pituitary content of these hormones. In conclusion, ovarian follicular development cannot progress beyond the preantral stage without FSH. In the absence of mature follicles ovarian estrogen remains low, and consequently accessory sex tissue growth and negative feedback regulation of gonadotropin secretion are severely compromised. In the male, however, inability to respond to FSH does not impair fertility, although testicular weight is reduced, and feedback regulation of pituitary gonadotropins and intratesticular paracrine interactions may be disturbed.

This study is an examination of the interaction of humor and gender in moderating relationships among perceived stress, anxiety, and physical symptoms. Introductory psychology students (70 women, 61 men) completed self-report scales measuring perceived stress, humor, and symptomology. Multiple regression analyses revealed a moderating effect for humor between stress and anxiety, but only for men. When humor was low, a positive relationship was obtained between stress and anxiety; no relationship existed when humor was high. No gender differences were found in the significant moderating effect of humor between stress and physical symptoms. When humor was low, stress was related to physical symptoms; no relationship was found when humor was high. Overall, the findings supported humor as a moderator of stress; gender differences also existed for some outcomes.

The effects of traditional risk factors on low birth weight were examined, using logistic regression analyses and adjusting for interactions between multiple factors. Data for 11,936 births were obtained from a state birth cohort file. The effect for maternal ethnicity was dependent on education and marital status; the effect of marital status was dependent on ethnicity, medical risk, and level of prenatal care; and the effect of prenatal care was dependent on marital status. Results suggest that examining only main effects and ignoring interactions can produce overgeneralized conclusions about the influence of individual risk factors on low birth weight.

Self-esteem was explored as a factor in appropriate (typical) and inappropriate (atypical) changes in performance expectations across trials of a nonthreatening success condition vs. a threatening failure condition. Participants (51 women, 45 men) were randomly assigned to one of the conditions and completed a self-esteem scale and 8 trials of a timed digit-substitution task. Moderated multiple regression revealed significant interactions between self-esteem and condition for typical and atypical changes. A significant positive relationship between self-esteem and typical changes was found under success and between self-esteem and atypical changes under failure. Differences between conditions were evident only for high self-esteem, with greater typical changes for success and greater atypical changes for failure.

This study examined the effects of traditional risk factors on receipt of inadequate prenatal care when controlling for interactions of multiple factors. Birth certificate data on 11,936 births were obtained from a state birth cohort file. A logistic regression model indicated significant interactions between maternal ethnicity (black vs white), marital status, and education in the prediction of inadequate prenatal care. Examining only main effects and ignoring interactions can produce oversimplified conclusions about individual risk factors.

Relationships between perceived stress, self-esteem, and expectancy of success were examined, and the moderating and mediating effects of self-esteem between perceived stress and expectancy of success were explored. Participants (48 women, 27 men) completed self-rating scales measuring perceived stress, self-esteem, and expectancy of success. Negative relationships were obtained between perceived stress and self-esteem and between perceived stress and expectancy of success. Self-esteem and expectancy of success were positively associated. Moderated multiple regression analysis yielded no moderating effect of self-esteem between perceived stress and expectancy of success; however, a moderating effect of self-esteem was obtained using regression techniques.

The National Institute on Alcohol Abuse and Alcoholism, in consultation with the National Institute on Drug Abuse, awarded nine demonstration grants in 1988 for community-based programs addressing issues of the homeless alcohol and other drug (AOD) abusers. Project Connect in Louisville, Kentucky, was one of the nine demonstration grants. The three-year project was designed to address a multitude of needs of the homeless male AOD abuser, including housing, medical, employment/economic, and social support, in addition to treatment for AOD abuse. The present article details the evolution and implementation of Project Connect and describes characteristics of the target population. In addition, the article presents issues and problems that surfaced during program implementation in order to assist other communities that are considering similar programs for their homeless populations.

We have raised a monoclonal antibody, 4G6, against gut manually isolated from stage 42Xenopus laevis embryos. It is specific for endoderm and recognises an epitope that is first expressed at stage 19 and which persists throughout subsequent development. The antibody maintains gut specificity through metamorphosis and into adulthood. The epitope is conserved in the mouse, where it is also found in the gut. Isolated vegetal poles fromXenopus blastula stage embryos express the epitope autonomously after culturing to the appropriate stage. This shows that certain aspects of endoderm differentiation do not require germ layer interactions. Animal cap cells from stage 9 blastulae cultured in the presence of the mesodermal growth factors FGF, XTC-MIF and PIF form both endodermal and mesodermal tissues, assessed by the binding of tissue-specific monoclonal antibodies. Endoderm is typically found in those caps which form intermediate and ventral forms of mesoderm, that is muscle and lateral plate.

THe main metabolite of prostaglandin E2 (PGE2) 13,14-dihydro-15-keto-PGE2 readily dehydrates and can subsequently form a cyclic derivative. This problem can be overcome by the immediate formation of oximes of the 9 and 15 ketones in aqueous solution followed by subsequent extraction, methylation and t-butyldimethyl silylation of the free hydroxyl groups at 11 and on the oximes. Deuterogenated 13,14-dihydro-15-keto-PGE2 is used as the internal standard and can be stored as the oxime and added with the oximating solution immediately the biological sample is obtained. The sensitivity of the method allows measurement of 2 ng of 13,14-dihydro-15keto-PGE2 in tissue incubates. The intra-batch precision is 11.8% and the inter-batch precision for measurement of 100 ng of metabolite is 8.1%.

We have tested the action of a catechol oestrogen -2,3,17 beta-trihydroxy oestra-1,3,5 (10)-triene (2-OH oestradiol) in stimulating prostaglandin (PG) production by an homogenate of rat uterus. Marked and dose dependent stimulation was observed in PGF2 alpha and PGE2 production using 20-250 microM concentrations of catechol oestrogen; a concentration of 250 microM 2-OH oestradiol resulted in a 23 fold increase in PGF2 alpha production with a 50% reduction in the synthesis of 6-keto PGF1 alpha. Tryptophan, catechol and glutathione were without effect on PGF2 alpha and PGE2 production whereas adrenalin stimulated the production of all PGs, although the increase was less than that seen with 2-OH oestradiol. Oestradiol had a slight stimulatory action on PGF2 alpha production which reached a maximum at around 40 microM but had a more marked stimulation of 6-keto PGF1 alpha formation. Stimulation of prostaglandin production by oestradiol and 2-OH oestradiol showed no variation at different stages of the rat oestrous cycle. The use of 5 to 100 mg of tissue/ml gave similar product distribution although the effect of catechol oestrogen both in terms of stimulation of E and F formation (expressed per mg of tissue) and in its action on product distribution was more marked at lower concentrations of tissue.