Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.

Testicular torsion and subsequent testicular function in young men from the general population.

STUDY QUESTION: Is prior testicular torsion associated with testicular function (semen quality and reproductive hormones) in young men from the general population? SUMMARY ANSWER: In young men from the general population, no differences in semen parameters were observed in those who had experienced testicular torsion compared to controls and observations of higher FSH and lower inhibin B were subtle. WHAT IS KNOWN ALREADY: Testicular function may be impaired after testicular torsion, but knowledge is sparse and based on studies with small sample sizes and no control group or a less than ideal control group. STUDY DESIGN, SIZE, DURATION: A cross-sectional population-based study was carried out including 7876 young Danish men with unknown fertility potential, examined from 1996 to 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: All men (median age 19.0 years) had a physical examination, provided a blood and semen sample, and filled in a questionnaire including information about prior testicular torsion, birth, lifestyle and current and previous diseases. Markers of testicular function, including testis volume, semen parameters and reproductive hormones, were compared between men operated for testicular torsion and controls, using multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The average participation rate was 24% for the entire study period. In total, 57 men (0.72%) were previously operated for testicular torsion (median age at surgery 13.4 years) of which five had only one remaining testicle. Men with prior testicular torsion were more often born preterm (25% versus 9.5% among controls), and they had significantly higher FSH and lower inhibin B levels, and a lower inhibin B/FSH ratio than controls in crude and adjusted models. The association was mainly driven by the subgroup of men who had undergone unilateral orchiectomy. No differences in semen parameters were observed. LIMITATIONS, REASONS FOR CAUTION: A limitation is the retrospective self-reported information on testicular torsion. Also, results should be interpreted with caution owing to the high uncertainty of the observed differences. WIDER IMPLICATIONS OF THE FINDINGS: Overall, the results of our study are reassuring for men who have experienced testicular torsion, especially when treated with orchiopexy, for whom reproductive hormone alterations were subtle and without obvious clinical relevance. Our study found no differences in semen parameters, but follow-up studies are needed to assess any long-term consequences for fertility. STUDY FUNDING/COMPETING INTEREST(S): Financial support was received from the Danish Ministry of Health; the Danish Environmental Protection Agency; the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); A.P. Møller and wife Chastine Mckinney Møllers Foundation; Svend Andersens Foundation; the Research Fund of the Capital Region of Denmark; and ReproUnion (EU/Interreg). The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Decrease in semen quality and Leydig cell function in infertile men: a longitudinal study.

STUDY QUESTION: Are infertile men with reduced semen quality at risk of a further decrease in testicular function? SUMMARY ANSWER: Infertile men with severely reduced semen quality risk further deterioration of semen quality 15 years after treatment for infertility, and a lower baseline sperm concentration was associated with a more pronounced increase in LH and decrease in testosterone/LH ratio at follow-up. WHAT IS KNOWN ALREADY: Male factors account for up to 50% of human infertility. The most common finding is spermatogenic failure (SgF) yet the life course of semen quality and testosterone production in such men has not been described. STUDY DESIGN, SIZE, DURATION: A follow-up study of men with SgF was performed 15 years after the initial infertility assessment between January 1995 and December 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospital records were used to identify potential participants in the study. A total of 137 men with primary male infertility due to SgF and 70 controls with good semen quality from couples with female factor infertility who attended a tertiary referral centre were included: the participation rate was 31% and 26%, respectively. The men provided semen samples and underwent a physical examination. Blood samples were taken to measure levels of reproductive hormones (FSH, LH, testosterone, sex hormone-binding globulin, estradiol and inhibin B). Current results were compared with results from the initial assessments. MAIN RESULTS AND THE ROLE OF CHANCE: At the time of follow up the SgF men had significantly lower Leydig cell capacity than the control group as well as much lower semen quality. For the SgF men, between baseline sampling and follow up, the median sperm concentration decreased from 1.9 to 0.6 mill/ml and total sperm count from 7.7 to 2.0 million (P = 0.019 and 0.012, respectively), and 10% developed azoospermia. Calculated free testosterone (cFT), but not total testosterone (tT) decreased in the SgF group by ~0.6% (95% CI 0.1-1.2%) per year. In the SgF group, LH increased by 1.6% (CI 0.9-2.3%) annually, and consequently tT/LH and cFT/LH ratios had decreased by 1.3% (CI 0.5-2.1) and 2.1% (CI 1.2-3.0%), respectively. The increase in LH and the decreases in tT/LH and cFT/LH ratios were more pronounced in men with lower baseline sperm concentrations. LIMITATIONS, REASONS FOR CAUTION: We consider the case group as representative of infertile men not in need of testosterone treatment at baseline investigation, but do not have information on those that chose not to participate in the follow-up study. There were alterations in some hormone analysis methods during the follow-up period that may introduce uncertainty in interpretation of long-term changes in hormone levels despite rigorous quality control. The validity of the control group suffers from a lack of hormone values at baseline. Also, at follow-up, for practical reasons only one semen sample could be obtained, which makes the effect estimate more uncertain and there is a risk of non-differential misclassification. WIDER IMPLICATIONS OF THE FINDINGS: Without being able to predict individual outcomes, it is prudent to consider sperm cryopreservation or advise not to postpone fertility treatment when men present with infertility due to impaired semen quality. Whether partly compensated Leydig cell insufficiency in men with SgF will eventually develop into overt testosterone deficiency cannot be determined from our study. STUDY FUNDING/COMPETING INTEREST(s): Aase and Einar Danielsen (Grant no. 10-001053), Nordic Research Committee (Grant no. 5109), The Kirsten and Freddie Johansen Fund, and Rigshospitalet's Research Fund (grant no. R24-A812). There are no competing interests.

Average sperm count remains unchanged despite reduction in maternal smoking: results from a large cross-sectional study with annual investigations over 21 years.

STUDY QUESTION: How are temporal trends in lifestyle factors, including exposure to maternal smoking in utero, associated to semen quality in young men from the general population? SUMMARY ANSWER: Exposure to maternal smoking was associated with lower sperm counts but no overall increase in sperm counts was observed during the study period despite a decrease in this exposure. WHAT IS KNOWN ALREADY: Meta-analyses suggest a continuous decline in semen quality but few studies have investigated temporal trends in unselected populations recruited and analysed with the same protocol over a long period and none have studied simultaneous trends in lifestyle factors. STUDY DESIGN, SIZE, DURATION: Cross-sectional population-based study including ~300 participants per year (total number = 6386) between 1996 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study is based on men from the Greater Copenhagen area, Denmark, with a median age of 19 years, and unselected with regard to fertility status and semen quality. The men delivered a semen sample, had a blood sample drawn and a physical examination performed and answered a comprehensive questionnaire, including information on lifestyle and the mother's pregnancy. Temporal trends in semen quality and lifestyle were illustrated graphically, and trends in semen parameters and the impact of prenatal and current lifestyle factors were explored in multiple regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Throughout the study period, 35% of the men had low semen quality. Overall, there were no persistent temporal trends in semen quality, testicular volume or levels of follicle-stimulating hormone over the 21 years studied. The men's alcohol intake was lowest between 2011 and 2016, whereas BMI, use of medication and smoking showed no clear temporal trends. Parental age increased, and exposure in utero to maternal smoking declined from 40% among men investigated in 1996-2000 to 18% among men investigated in 2011-2016. Exposure to maternal smoking was associated with lower sperm counts but no overall increase in sperm counts was observed despite the decrease in this exposure. LIMITATIONS, REASONS FOR CAUTION: Information of current and prenatal lifestyle was obtained by self-report, and the men delivered only one semen sample each. WIDER IMPLICATIONS OF THE FINDINGS: The significant decline in in utero exposure to maternal smoking, which was not reflected in an overall improvement of semen quality at the population level, suggest that other unknown adverse factors may maintain the low semen quality among Danish men. STUDY FUNDING/COMPETING INTEREST(S): The study has received financial support from the ReproUnion; the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314,QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. TRIAL REGISTRATION NUMBER: N/A.

Impact of lifestyle intervention for obese women during pregnancy on maternal metabolic and inflammatory markers.

BACKGROUND: Offspring of obese mothers have increased risk of developing obesity and related short- and long-term disease. The cause is multifactorial and may partly be explained by the unfavorable intrauterine environment. Intervention during pregnancy leading to a healthier lifestyle among obese may alter this. OBJECTIVE: To assess the effect of lifestyle intervention on markers of maternal metabolism and inflammation in 'the TOP (Treatment of Obese Pregnant Women) study', a randomized controlled trial. METHODS: In the TOP-study 425 participants with body mass index ⩾30 kg/m2 were randomized to intervention with dietary advices and physical activity assessed by pedometer (PA+D), physical activity assessed by pedometer (PA) or control (C). Of 389 participants completing the study 376 had available blood samples. Serum was analyzed for insulin, c-peptide, lipid profile, leptin, high-sensitivity CRP (hsCRP) and Soluble urokinase Plasminogen Activator Receptor (suPAR), in week 18-20 and 28-30, and simultaneously a 2-h oral glucose-tolerance-test was performed. Diet was assessed in gestational week 11-14 and 36-37 using a validated 360-item Food Frequency Questionnaire. RESULTS: Median levels of hsCRP in gestational week 28-30 were lower in each of the intervention groups (8.3 mg/l in PA+D group, P=0.03; and 8.8 mg/l in PA group, P=0.02) versus the control group (11.5 mg/l). Obtaining 11 000 steps per day as aimed for resulted in a 21% lower hsCRP compared to non-compliant women. Women reporting high carbohydrate intake had around 30% higher hsCRP concentrations in late gestation than women reporting the lowest intake. There were no differences in lipid profile or any of the metabolic markers in gestational week 28-30 when comparing the intervention and control groups. CONCLUSIONS: Lifestyle intervention in obese women can reduce hsCRP representing a marker of inflammation during pregnancy. The effect may partly be mediated by more physical activity and partly by changes in intake of carbohydrates and the glycaemic load.

Permissive and protective roles for neutrophils in leishmaniasis.

Leishmania parasites are the causative agents of leishmaniasis, a neglected tropical disease that causes substantial morbidity and considerable mortality in many developing areas of the world. Recent estimates suggest that roughly 10 million people suffer from cutaneous leishmaniasis (CL), and approximately 76,000 are afflicted with visceral leishmaniasis (VL), which is universally fatal without treatment. Efforts to develop therapeutics and vaccines have been greatly hampered by an incomplete understanding of the parasite's biology and a lack of clear protective correlates that must be met in order to achieve immunity. Although parasites grow and divide preferentially in macrophages, a number of other cell types interact with and internalize Leishmania parasites, including monocytes, dendritic cells and neutrophils. Neutrophils appear to be especially important shortly after parasites are introduced into the skin, and may serve a dual protective and permissive role during the establishment of infection. Curiously, neutrophil recruitment to the site of infection appears to continue into the chronic phase of disease, which may persist for many years. The immunological impact of these cells during chronic leishmaniasis is unclear at this time. In this review we discuss the ways in which neutrophils have been observed to prevent and promote the establishment of infection, examine the role of anti-neutrophil antibodies in mouse models of leishmaniasis and consider recent findings that neutrophils may play a previously unrecognized role in influencing chronic parasite persistence.

Newborn regional body composition is influenced by maternal obesity, gestational weight gain and the birthweight standard score.

AIM: This study investigated whether newborn body composition is influenced by prepregnancy obesity and gestational weight gain (GWG) and explored any associations between body composition and birthweight standard score (z-score), categorised by size for gestational age. METHODS: We recruited 231 obese and 80 normal weight mothers and their newborn infants and assessed the babies' body composition using dual-energy X-ray absorptiometry. RESULTS: The total and abdominal fat masses of infants born to mother who were obese before pregnancy were 135 g (p < 0.001) and 18 g (p < 0.001) higher than the offspring of normal weight mothers. The infants' fat mass increased by 11 g (p < 0.001) for every kilogram of GWG. There were no associations between prepregnancy obesity and fat-free mass. The fat percentage was significantly higher in infants who were large for gestational age (15.3%) than small for gestational age (5.2%) and appropriate for gestational age (9.8%) (p < 0.001). Lower birthweight z-score was associated with a higher proportion of abdominal fat mass (p = 0.009). CONCLUSION: Infants born to obese mothers had higher fat mass at birth, with abdominal fat accumulation. Low birthweight was associated with a lower crude abdominal fat mass, but a higher proportion of total fat mass placed abdominally.

Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis.

BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.

Pheochromocytomas, PASS, and immunohistochemistry.

Differentiation between malignant and benign pheochromocytomas of the adrenal gland traditionally relies on the presence of clinically detectable metastases. The PASS system for differentiating between benign and malignant pheochromocytomas is based on defined morphological criteria, of which some are related to tumour cell proliferation and survival. Immunohistochemical markers for important events in the cell cycle were explored in order to characterise differences in apoptosis, G1 checkpoints, and S phase in more detail. A panel consisting of p53, tenascin, bcl-2, pRb, cyclin D1, mcm2, and p27 was employed. Only for pRb a statistically significant difference between PASS 3 and less and PASS 4+ tumours was detected, indicating qualitative differences in the mitotic cycle, probably immediately before early S phase. These results are discussed in relation to similar studies in recent literature.

Serum concentration of anti-Müllerian hormone is not associated with semen quality.

Impaired semen quality is frequent in Western countries and is the main reason or contributing reason in up to 50% of cases of couple infertility. Male factor infertility is mainly determined by examination of semen samples according to the World Health Organization's 2010 guidelines. AMH has both autocrine and paracrine properties through a direct effect via the AMH type II receptor and is therefore thought to be involved in spermatogenesis. We aimed to study the association between the serum concentration of AMH and semen quality in a cross-sectional study including 970 young Danish men from the general population. All participants provided a semen sample, had a blood sample drawn, underwent a physical examination, and answered a questionnaire including information on lifestyle and medical history. Serum concentrations of reproductive hormones [AMH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), calculated free T, oestradiol (E2) and inhibin B] and semen parameters (semen volume, sperm concentration, and percentages of motile and morphologically normal spermatozoa) were determined. We found no association between serum AMH and semen quality, except for a significant (p = 0.011) trend for lower percentage of normal morphology with higher AMH. AMH quartile was positively associated with serum inhibin B (p < 0.001), inhibin B/FSH ratio (p < 0.001) and T/E2 ratio (0.016), and negatively associated with FSH (p = 0.004), LH (p = 0.005) and E2 (p = 0.028). There was no association between AMH quartile and T, calculated free T or total T/LH ratio. In conclusion, serum AMH is not useful as a marker of semen quality, and semen analysis using WHO criteria is still the golden standard in the evaluation of the infertile man.

Parathyroid carcinoma in multiple endocrine neoplasia type 1 (MEN1) syndrome: two case reports of an unrecognised entity.

CONTEXT: Primary hyperparathyroidism occurs in almost all patients with the syndrome of multiple endocrine neoplasia type 1 (MEN1), but the association of MEN1 with parathyroid carcinoma has only been described previously in a single patient. In this report, we describe two further cases of parathyroid carcinoma presenting in MEN1 syndrome. CASE REPORTS: The first patient was a 69-yr-old woman, who presented with severe primary hyperparathyroidism and tracheal compression by a large mediastinal mass, which was shown histologically to be a parathyroid carcinoma with a second similar lesion in the neck. She was treated with total parathyroidectomy followed by resection of the mediastinal mass with resolution of the hypercalemia. Remarkably, she also reported primary amenorrhea and was found to have an invasive pituitary lactotroph adenoma, which was treated with cabergoline and external beam radiotherapy. Magnetic resonance imaging (MRI) of the pancreas revealed a small lesion characteristic of an islet-cell tumor, which was clinically and biochemically non-functioning. The second patient was a 32-yr-old man who presented with symptomatic hypercalemia and markedly raised serum PTH concentration. Neck exploration revealed two parathyroid glands only. One of the parathyroid glands contained a tumor with fibrous banding, atypical mitoses, extra-capsular extension and moderate Ki 67 staining; features which are highly suggestive of carcinoma. He also had intractable dyspepsia associated with raised serum gastrin concentration. A lesion was localized to the neck of the pancreas by endocopic ultrasound, and a selective arterial calcium stimulation catheter suggested the presence of both a gastrinoma and an insulinoma, although he had no hypoglycemic symptoms. Pituitary MRI was normal. The patient's mother had primary hyperparathyroidism. CONCLUSIONS: This case report describes two further patients in whom parathyroid carcinomas occurred in the context of MEN1, which gives a new insight to the possible presenting phenotype of this condition. Both patients had negative genetic screening for classic MEN1 gene mutation, which may suggest that one or more novel occult mutations may be responsible for this aggressive phenotype.

Resection rectopexy for external rectal prolapse reduces constipation and anal incontinence.

BACKGROUND AND AIMS: The main aim was to examine constipation and anal incontinence in patients before and after resection for external rectal prolapse. MATERIAL AND METHODS: Twenty patients had ligament preserving suture rectopexy and sigmoid resection (resection rectopexy) for external rectal prolapse by laparoscopic (n = 15) or open (n = 5) technique during 2001-2005. They were prospectively evaluated for constipation and anal incontinence using validated incontinence and KESS-constipation scores. RESULTS AND CONCLUSIONS: Constipation score was significantly reduced from mean 7.7 (5.4-9.9) to 4.5 (2.5-6.4) after median 4 months (1-19) and to 4.3 (2.2-6.3) after median 17 months (4-51). Six and four patients were constipated preoperatively and 17 months postoperatively, respectively. The four symptoms feeling incomplete evacuation of stool, minutes in lavatory per attempt, use of enemas/digitation and painful evacuation effort were significantly reduced, whilst stool consistency increased. Fourteen patients (70%) had anal incontinence. Corresponding and significant reduction in their scores were from mean 12.5 (9.4-15.5) to 5.1 (2.1-8.1) and to 3.6 (1.3-5.9). Incontinence was improved in 13 and unaltered in one patient(s). Two patients with worse outcome had increased stool consistency and constipation scores. Resection rectopexy for rectal prolapse reduced anal incontinence and constipation.

Quality of life and functional outcome following anterior or abdominoperineal resection for rectal cancer.

AIMS: The aims of the study were (1) to evaluate quality of life (QoL) and functional outcome in patients following anterior resection (AR) or abdominoperineal resection (APR) for rectal cancer, and (2) whether these outcomes were dependent on the level of anastomosis. METHODS: Patients who were without recurrent or metastatic disease were identified from the Norwegian Rectal Cancer Registry. QoL was assessed by the EORTC questionnaires QLQ-C30 and QLQ-CR38, and rectal function by a short questionnaire. Of 319 patients studied, 229 had undergone AR and 90 APR. The median age was 73 years, and the median time since surgery was 64 months. RESULTS: Mean QoL scores for body image and male sexual problems were better following AR than APR (P<0.01), also in patients with a low (< or = 3 cm) anastomosis. Patients who had undergone AR had higher mean scores for constipation (P<0.001) and more often used anti-diarrhoeal medication (P=0.005), than patients who had undergone APR. Patients with a low anastomosis (< or = 3 cm) had more incontinence for gas and solid stools (P<0.05), and had more incontinence (P=0.006) compared with patients with higher anastomosis, but there was no difference in QoL. Subgroup analysis showed that irradiated patients (n=34) had worse rectal function in terms of frequency, urgency, and incontinence (P<0.01). CONCLUSIONS: Although rectal function was impaired in patients with low anastomosis, patients who had undergone AR had better QoL than patients who had undergone APR.

Should we watch what we eat and drink? Report on the International Workshop on Hormones and Endocrine Disrupters in Food and Water: possible impact on human health, Copenhagen, Denmark, 27-30 May 2000.

The aim of this Workshop was to bring together scientists with different backgrounds, including clinical endocrinologists, basic researchers and epidemiologists, to discuss the complex and controversial topic of endocrine disrupters, and their impact on human health. Nearly 250 scientists attended the Workshop, and 50 lectures and 90 posters were presented and discussed. The most important scientific findings and reviews are to be published in Human Reproduction and Human Reproduction Update. Some of the highlights are presented here.

Maternal obesity and offspring dietary patterns at 9 months of age.

BACKGROUND/OBJECTIVES: Differences in the quality of complementary feeding between infants of obese and nonobese mothers have not been examined sufficiently. The aim of this paper was to compare dietary patterns, foods, nutrients and energy intakes of 9-month-old Danish infants in a cohort comprising obese mothers (SKOT II, n=184; SKOT, Danish abbreviation of small children's diet and well-being) with a cohort consisting mainly of nonobese mothers (SKOT I, n=329). SUBJECTS/METHODS: Dietary intake was assessed by 7-day records, and dietary patterns were identified by principal component analysis. RESULTS: SKOT I was characterized by a lower maternal body mass index (BMI) and a higher social class than SKOT II in relation to parental education and occupation. Infants in SKOT II had lower scores on a Health-Conscious Food pattern reflected at the food group level, for example, with lower intake of the food groups Fruit and Vegetable but higher intake of WheatBreadNoWholegrain in SKOT II compared with SKOT I. Moreover, SKOT II had shorter durations of breastfeeding, earlier introductions of complementary feeding, higher energy intake from protein but lower energy intakes from monounsaturated fatty acids and polyunsaturated fatty acids at 9 months. SKOT II had higher weight-for-age and length-for-age z-scores, but no differences in BMI z-scores, as compared with SKOT I at 9 months. CONCLUSIONS: Infants of obese mothers from a lower social class seem to have a less healthy diet and higher weight and length z-scores at 9 months. Therefore, the promotion of healthy complementary feeding might be beneficial for the prevention of health implications, such as obesity, later in life for these infants.

Diurnal rhythm in serum levels of inhibin B in normal men: relation to testicular steroids and gonadotropins.

Inhibin B is a testicular glycoprotein that is secreted from the Sertoli cells and believed to play a role in FSH secretion. We characterized the diurnal profile of serum inhibin B and the relation to gonadotropins and testicular steroids. Serum inhibin B was measured in 13 healthy normal male volunteers (median age, 30 yr) by continuous blood drawing, with sampling every 30 min for 24 h. Blood samples were also analyzed for FSH, LH, testosterone, estradiol, and sex hormone-binding globulin. We found a significant diurnal variation in inhibin B, with peak values in the early morning and nadirs in the late afternoon, followed by gradual increasing nocturnal values. An average decline of 3%/h from 0900 until 1700 h was calculated. Significant cross-correlation was found between inhibin B and testosterone as well as estradiol, whereas no cross-correlation was found between inhibin B and FSH. Two-dimensional time-series analyses revealed a statistically significant influence of testosterone on inhibin B. In addition, estradiol and inhibin B had a significant influence on one another. In conclusion, we found a significant diurnal variation in inhibin B levels in normal men, with a pattern of higher values in the early morning hours and lower values in the late afternoon and evening. We did not find evidence for a role of FSH in this diurnal variation of inhibin B. However, covariation with serum levels of testosterone and estradiol suggested that these hormones might play a role in the diurnal rhythm of inhibin B, although some other common influence could not be excluded.

Alterations in the pulsatile mode of growth hormone release in men and women with insulin-dependent diabetes mellitus.

The mechanisms responsible for the elevated levels of circulating GH observed in diabetes mellitus (DM) remain incompletely defined. To assess the episodic fluctuations in serum GH as a reflection of hypothalamic-pituitary activity, we accumulated GH concentration-time series in a total of 48 adult men and women with and without insulin-dependent DM by obtaining serum samples at 10-min intervals over 24 h. Significant pulses of GH release were subsequently identified and characterized by an objective, statistically based pulse detection algorithm (Cluster) and fixed circadian (24-h) periodicities of secretory activity, resolved using Fourier expansion time-series analysis. Compared to those in age-matched controls, integrated 24-h concentrations of GH were 2- to 3.5-fold higher in diabetic men (P = 0.002) and women (P = 0.0005). Both men and women with DM had over 50% more GH pulses per 24 h than their non-DM counterparts. In addition, maximal GH pulse amplitude was markedly elevated in the men and women with DM (P = 0.0019 and 0.0189, respectively). That the increase in maximal pulse amplitude was accounted for by greater baseline levels was documented by a higher interpulse valley mean GH concentration in the diabetics compared to the controls (P = 0.0437 and 0.0056, men and women, respectively) and the absence of any difference in incremental pulse amplitude for either sex (P greater than 0.05). DM men had larger GH pulse areas (P = 0.039) than control men, apparently accounted for by greater pulse width (P = 0.0037). Pulse areas in DM and non-DM women were indistinguishable. Time-series analysis revealed that the 24-h (circadian) rhythms of serum GH concentrations exhibited significantly increased amplitudes in the diabetic group as a whole (compared to the controls, P = 0.011). However, the times of maximal GH concentrations (acrophases) were not significantly different. As a group, serum insulin-like growth factor-I was lower in DM vs. non-DM individuals (P = 0.0014), although when separated by sex this difference did not reach statistical significance in women (P = 0.317). The present data confirm the higher circulating levels of GH previously reported to occur in individuals with poorly controlled DM. The altered frequency of GH pulses together with enhanced interpulse GH concentrations and an amplified circadian GH rhythm are compatible with hypothalamic dysfunction associated with dysregulation of somatostatin and/or GHRH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Attenuated pulsatile release of prolactin in men with insulin-dependent diabetes mellitus.

Pulsatile and circadian patterns of PRL release were studied in 11 insulin-dependent diabetic men by sampling blood every 10 min for 24 h and comparing the results to those obtained in 12 normal nondiabetic men. The diabetic men had a mean (+/- SE) 24-h serum PRL concentration of 5.5 +/- 0.42 micrograms/L, which was significantly lower than that in the nondiabetic men (9.3 +/- 0.86; P = 0.0008). Quantitative Cluster analysis of pulsatile PRL time series revealed a normal pulse frequency, but decreased maximal peak amplitude (6.6 +/- 0.5 vs. 11.8 +/- 1.1 micrograms/L; P = 0.0009), peak increment (2.6 +/- 0.24 vs. 4.0 +/- 0.3 micrograms/L; P = 0.009), peak area (126 +/- 15 vs. 192 +/- 19 micrograms/L.min; P = 0.03), and interpulse valley mean concentration (4.8 +/- 0.4 vs. 8.6 +/- 1.2 micrograms/L; P = 0.0007). PRL pulse incremental amplitude correlated significantly (r2 = 0.577; P = 0.007) and negatively with duration of disease. Fourier analysis disclosed a normal circadian rhythm of PRL release in diabetic men, with a mean circadian amplitude of 1.5 micrograms/L +/- 0.31, which peaked at 0201 h +/- 89 min (+/- SE). In summary, we have demonstrated significantly reduced mean 24-h serum PRL concentrations in men with poorly controlled insulin-dependent diabetes mellitus. The concomitant suppression of spontaneous PRL pulse amplitude, peak increment, and interpulse valley mean concentrations in the presence of normal pulse frequency is consistent with a reduced mass of PRL secreted per burst and/or accelerated metabolic clearance of PRL in men with type I diabetes mellitus.

Alterations in luteinizing hormone secretory activity in women with insulin-dependent diabetes mellitus and secondary amenorrhea.

To investigate hypothalamic and/or pituitary abnormalities in women with poorly controlled insulin-dependent diabetes mellitus (IDDM) and secondary amenorrhea, we measured serum LH every 10 min for 24 h and for 2 additional h after the administration of exogenous GnRH in 8 women with IDDM and amenorrhea and compared these to data from 15 eumenorrheic nondiabetic women. LH pulses were characterized by the pulse detection algorithm Cluster, and secretory episodes were evaluated using the multiple parameter deconvolution procedure Deconv. Cluster analysis revealed fewer LH pulses per 24 h (14.3 +/- 1.2 vs. 19.9 +/- 0.6; P < 0.001; mean +/- SEM), a greater peak width (63 +/- 4.9 vs. 44 +/- 2.2 min; P < 0.01), and greater peak area (136 +/- 17 vs. 89 +/- 13 IU/L.min; P < 0.01) in the diabetic women. Analysis with Deconv revealed fewer LH secretory episodes per 24 h in the diabetic women (14.4 +/- 0.9 vs. 20.4 +/- 0.5; P < 0.001) and no statistical difference in LH half-lives. The IDDM women responded to a 10-micrograms GnRH bolus with LH pulses of larger total (51 +/- 15.9 vs. 15 +/- 1.4 IU/L; P < 0.01) and incremental (29 +/- 7.6 vs. 9 +/- 1.2; P < 0.001) amplitude. In summary, we observed that amenorrheic diabetic women have fewer LH pulses/secretory episodes than normal women. However, they respond well to exogenous GnRH, suggesting that compromise of the GnRH pulse generator, rather than pituitary dysfunction, is responsible for their menstrual dysfunction.

Reproductive history and cigarette smoking as risk factors for thyroid cancer in women: a population-based case-control study.

A population-based case-control study was conducted in Northern Norway and Central Sweden to investigate hormonal and reproductive factors and cigarette smoking as determinants of papillary and follicular thyroid carcinoma in women. Information on 191 histologically confirmed cases and 341 age-matched controls was included. No clear association was found with regard to the number of live births, number of pregnancies, a history of incomplete pregnancies, or the use of oral contraceptives or hormonal replacement therapy. However, an early first childbirth (before 20 years of age, or less than 5 years after menarche) was associated with an increased risk of thyroid cancer. There was an increased risk of thyroid cancer among women with a history of artificial menopause compared to those with a spontaneous menopause [odds ratio (OR), 2.52; 95% confidence interval (CI), 0.96-6.62], which was more pronounced for the papillary carcinoma and after adjustment for age at menopause and use of replacement therapy. Cigarette smokers had a decreased risk of borderline statistical significance compared to nonsmokers (OR, 0.69; 95% CI, 0.47-1.01), particularly among premenopausal women (OR, 0.60; 95% CI, 0.38-0.96). This negative association persisted after adjustment for parity, hormonal treatments, and education. Women who started smoking before the age of 15 experienced a marked reduction in risk (OR, 0.38%; 95% CI, 0.18-0.80¿). Moreover, there was a suggestion of a dose-response effect with the amount of cigarettes smoked daily and with duration of the habit. Both the increased risk of artificial menopause and the negative association with smoking are compatible with a relation between levels of estrogens and thyroid cancer among women.