Anders Juul - Academia.edu (original) (raw)
Papers by Anders Juul
Human Reproduction, 2012
In adult women, the circulating level of anti-Müllerian hormone (AMH) is a novel marker of ovaria... more In adult women, the circulating level of anti-Müllerian hormone (AMH) is a novel marker of ovarian function, as it reflects the number of remaining ovarian follicles. Therefore, AMH has gained widespread attention in fertility clinics, and a low AMH is believed to predict impaired fertility and imminent menopause. However, the natural course of circulating AMH levels during female childhood and adolescence is not known. methods: Serum levels of AMH and FSH were measured in girls participating in The COPENHAGEN Puberty Study. Longitudinal part: 85 healthy girls and adolescents were examined, and blood samples were drawn every 6 months for an average of 3 years: median (range) number of samples per girl was 6 (2-10), age at baseline was 9.2 (5.9-12.9) years. Cross-sectional part: 224 prepubertal girls (age 8.3, 5.6-11.7 years) were examined and each girl had one blood sample drawn. results: The individual mean AMH levels in girls followed longitudinally ranged from 5 to 54 pmol/l (median 18 pmol/l). The mean intraindividual coefficient of variation of AMH was 22% (range 0-54%). Overall, each girl maintained her AMH level throughout childhood and adolescence although minor, but significant, changes occurred during pubertal transition. In prepubertal girls, AMH was negatively correlated with FSH (r ¼ 20.31, P , 0.001). Twelve per cent (10/85) had mean AMH below a cutoff value of 8 pmol/l, indicating that the interpretation of low AMH as a marker of approaching menopause may not apply to pre-and peri-pubertal girls. conclusions: Circulating AMH exhibits only minor fluctuations during childhood and adolescence, and a random AMH measurement seems representative for a given girl. The negative AMH-FSH correlation in prepubertal girls supports the notion that AMH is a quantitative marker of ovarian follicles even in young girls.
International Journal of Andrology, 2006
The decreasing trends in fertility rates in many industrialized countries are now so dramatic tha... more The decreasing trends in fertility rates in many industrialized countries are now so dramatic that they deserve much more scientific attention. Although social and behavioural factors undoubtedly play a major role for these trends, it seems premature, and not based on solid information, to conclude that these trends can be ascribed to social and behavioural changes alone. There is evidence to suspect that changing lifestyle and increasing environmental exposures, e.g. to endocrine disrupters, are behind the trends in occurrence of male reproductive health problems, including testis cancer, undescended testis and poor semen quality. These biological factors may also contribute to the extremely low fertility rates. However, the necessary research is complex and requires non-traditional collaboration between demographers, epidemiologists, clinicians, biologists, wild life researchers, geneticists and molecular biologists. This research effort can hardly be carried out without major support from governments and granting agencies making it possible to fund collaborative projects within novel research networks of scientists.
The Journal of Clinical Endocrinology & Metabolism, 2015
Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolesc... more Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolescent boys. It is thought to be caused by an imbalance between estrogen and testosterone, though this is rarely evident in analyses of serum. This study aimed to describe the frequency of physiological gynaecomastia, and to determine possible etiological factors (e.g. auxology and serum hormone levels) in a longitudinal set-up. Design, Settings and Participants: A prospective cohort study of 106 healthy Danish boys (5.8-16.4 years) participated in the longitudinal part of "the COPENHAGEN Puberty Study". The boys were examined every six months during an eight year follow-up. Median number of examinations was 10 (2-15). Blood samples and analysed for FSH, LH, testosterone, estradiol, SHBG, inhibin B, AMH, IGF-I and IGFBP-3 by immunoassays. Auxological parameters, pubertal development and the presence of gynaecomastia were evaluated at each visit. 52 of 106 boys (49 %) developed gynaecomastia of which 10 (19 %) presented with intermittent gynaecomastia. Boys with physiological gynaecomastia reached peak height velocity at a significantly younger age than boys who did not develop gynaecomastia (13.5 vs 13.9 years, p = 0.027), and they had significantly higher serum levels of IGF-I (p = 0.000), estradiol (p = 0.013), free-testosterone (p < 0.001) and FSH (p = 0.030) during pubertal transition. However, no differences in serum LH or in the estradiol to testosterone ratio were found. Gynaecomastia is frequent in pubertal boys. Increased IGF-I levels and pubertal growth appear to be associated, whereas changes in estrogen to testosterone ratio seem negligible.
Pediatric Research, 2015
Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypot... more Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypothalamic-pituitary-gonadal axis leading to development of secondary sexual characteristics prior to 8 years in girls or 9 years in boys. Since the initial discovery of mutations in the maternally imprinted MKRN3 gene in 2013, several case reports have described mutations in this gene in ICPP patients from different populations, highlighting the importance of MKRN3 as a regulator of pubertal onset. We screened 29 Danish girls with ICPP for mutations in MKRN3. Expression of MKRN3 in human hypothalamic cDNA was investigated by PCR. One paternally inherited rare variant, c.1034G>A (p.Arg345His), was identified in one girl with ICPP and in her brother with early puberty. The variant is predicted to be deleterious by three different in silico prediction programs. Expression of MKRN3 was confirmed in adult human hypothalamus. Our results are in line with previous studies where paternally inherited MKRN3 mutations have been found both in males and females with ICPP or early puberty. Our report further expands the set of MKRN3 mutations identified in ICPP patients across diverse populations, thus supporting the major regulatory function of MKRN3 in pubertal onset.Pediatric Research (2015); doi:10.1038/pr.2015.159.
The Journal of Clinical Endocrinology & Metabolism, 2015
Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolesc... more Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolescent boys. It is thought to be caused by an imbalance between estrogen and testosterone, though this is rarely evident in analyses of serum. This study aimed to describe the frequency of physiological gynaecomastia, and to determine possible etiological factors (e.g. auxology and serum hormone levels) in a longitudinal set-up. Design, Settings and Participants: A prospective cohort study of 106 healthy Danish boys (5.8-16.4 years) participated in the longitudinal part of "the COPENHAGEN Puberty Study". The boys were examined every six months during an eight year follow-up. Median number of examinations was 10 (2-15). Blood samples and analysed for FSH, LH, testosterone, estradiol, SHBG, inhibin B, AMH, IGF-I and IGFBP-3 by immunoassays. Auxological parameters, pubertal development and the presence of gynaecomastia were evaluated at each visit. 52 of 106 boys (49 %) developed gynaecomastia of which 10 (19 %) presented with intermittent gynaecomastia. Boys with physiological gynaecomastia reached peak height velocity at a significantly younger age than boys who did not develop gynaecomastia (13.5 vs 13.9 years, p = 0.027), and they had significantly higher serum levels of IGF-I (p = 0.000), estradiol (p = 0.013), free-testosterone (p < 0.001) and FSH (p = 0.030) during pubertal transition. However, no differences in serum LH or in the estradiol to testosterone ratio were found. Gynaecomastia is frequent in pubertal boys. Increased IGF-I levels and pubertal growth appear to be associated, whereas changes in estrogen to testosterone ratio seem negligible.
Fertility and Sterility, 2015
To report normative data on uterine volume and endometrial thickness in girls, according to puber... more To report normative data on uterine volume and endometrial thickness in girls, according to pubertal stages; to evaluate factors that affect uterine volume; and to compare transabdominal ultrasound (TAUS) and magnetic resonance imaging (MRI). Cross-sectional study of a nested cohort of girls participating in The Copenhagen Mother-Child Cohort. General community. One hundred twenty-one healthy girls, aged 9.8-14.7 years. None. Clinical examination, including pubertal breast stage (Tanner classification: B1-B5). Uterine volume: ellipsoid TAUS (n = 112) and 3-dimensional TAUS (n = 111); ellipsoid MRI (n = 61). Endometrial thickness: TAUS (n = 110) and MRI (n = 60). Uterine volume and endometrial thickness were positively correlated with pubertal stages; e.g., ellipsoid TAUS: r = 0.753, and endometrium TAUS: 0.648. In multiple regression analyses, uterine volume was associated with the number of large follicles (TAUS >5 mm) (Beta 0.270); estradiol (E2) (Beta 0.504); and height (Beta 0.341). Volumes from ellipsoid vs. 3-dimensional TAUS were strongly correlated (r = 0.931), as were TAUS and MRI: ellipsoid volume (r = 0.891) and endometrial thickness (r = 0.540). Uterine volume was larger in TAUS compared with MRI; mean difference across the measured range: 7.7 (5.2-10.2) cm(3). Agreement was best for small uteri. Uterine volume and endometrial thickness increased as puberty progressed. Circulating E2 from large follicles was the main contributor to uterine and endometrial growth. The TAUS and MRI assessments of uterus and endometrium were strongly correlated.
American journal of physiology. Endocrinology and metabolism, 2001
In the present study, the effect of endurance training alone and endurance training combined with... more In the present study, the effect of endurance training alone and endurance training combined with recombinant human growth hormone (rhGH) administration on subcutaneous abdominal adipose tissue lipolysis was investigated. Sixteen healthy women [age 75 +/- 2 yr (mean +/- SE)] underwent a 12-wk endurance training program on a cycle ergometer. rhGH was administered in a randomized, double-blinded, placebo-controlled design in addition to the training program. Subcutaneous abdominal adipose tissue lipolysis was estimated by means of microdialysis combined with measurements of subcutaneous abdominal adipose tissue blood flow (ATBF; (133)Xe washout). Whole body fat oxidation was estimated simultaneously by indirect calorimetry. Before and after completion of the training program, measurements were performed both at rest and during 60 min of continuous cycling at a workload corresponding to 60% of pretraining peak oxygen uptake. Endurance training alone did not affect subcutaneous abdomina...
American journal of physiology. Endocrinology and metabolism, 2000
The present study investigated whether recombinant human (rh) growth hormone (GH) combined with e... more The present study investigated whether recombinant human (rh) growth hormone (GH) combined with endurance training would have a larger effect on oxidative capacity, metabolism, and body fat than endurance training alone. Sixteen healthy, elderly women, aged 75 yr, performed closely monitored endurance training on a cycle ergometer over 12 wk. rhGH was given in a randomized, double-blinded, placebo-controlled design in addition to the training program. GH administration resulted in a doubling of serum insulin-like growth factor I levels. With endurance training, peak oxygen uptake increased by approximately 18% in both groups, whereas the marked increase in muscle citrate synthase activity was 50% larger in the GH group compared with the placebo group. In addition, only the GH group revealed an increase in muscle L-3-hydroxyacyl-CoA dehydrogenase activity. Body weight remained unchanged in both groups, but the GH group showed significant changes in body composition with a decrease in...
Molecular psychiatry, 1997
Circulating leptin concentrations are known to be low in acute anorexia nervosa (AN), which is ch... more Circulating leptin concentrations are known to be low in acute anorexia nervosa (AN), which is characterized by low weight, amenorrhea and specific psychopathological features. In this study plasma leptin concentrations were determined during inpatient treatment of 23 adolescent females with AN using a sensitive radioimmunoassay (RIA) and set into relationship to leptin levels of females matched for age, body mass index (BMI; kg m-2) and/or percent body fat. At referral patients had leptin concentrations well below the female controls. Weight gains led to steep increases of leptin levels which peaked at values well in excess of those observed in controls matched for BMI. In patients who reached the final treatment stage and who were followed-up after discharge, levels subsequently fluctuated and finally dropped into or below the control range. The low leptin levels at referral are likely to be involved in the pathogenesis of amenorrhea and the reduced metabolic state of acutely ill ...
European journal of endocrinology / European Federation of Endocrine Societies, 2015
Testicular adrenal rest tumours (TARTs) are a common finding in patients with congenital adrenal ... more Testicular adrenal rest tumours (TARTs) are a common finding in patients with congenital adrenal hyperplasia (CAH). These tumours constitute a diagnostic and management conundrum and may lead to infertility. TART cells share many functional and morphological similarities with Leydig cells (LCs), and masses consisting of such cells are occasionally misclassified as malignant testicular tumours, which may lead to erroneous orchiectomy in these patients. In this study, we aimed to investigate the potential of LC developmental markers and adrenal steroidogenic markers in the differential diagnosis of TARTs and malignant LC tumours (LCTs). We investigated mRNA and protein expression of testicular steroidogenic enzymes; CYP11A1 and HSD3B1/2, markers of adrenal steroidogenesis; CYP11B1, CYP21A2 and ACTH receptor/melanocortin 2 receptor (MC2R), and markers of LC maturation; and delta-like 1 homolog (DLK1) and insulin-like 3 (INSL3) in testicular biopsies with TART, orchiectomy specimens wit...
Fertility and sterility, 2015
To elucidate the natural course of circulating insulin-like peptide 3 (INSL3) levels according to... more To elucidate the natural course of circulating insulin-like peptide 3 (INSL3) levels according to puberty as well as its relation to other reproductive hormones. Population-based cohort study. Not applicable. Healthy peripubertal girls (n = 10) examined every 6 months; total number of examinations was 84; median (range) per girl: 9 (4-10), including staging of pubertal breast development and blood samples. None. Serum levels of INSL3, inhibin B, E2, antimüllerian hormone, LH, and FSH (validated immunoassays), and T and androstenedione (liquid chromatography-tandem mass spectrometry). Serum levels of INSL3 varied considerably between girls (range, 0.01-0.27 ng/mL) and within each girl as puberty progressed; intraindividual variation, median (range) 102% (65%-143%). Insulin-like peptide 3 increased in late puberty (B1 to B4+B5); geometric mean 0.03 ng/mL to 0.15 ng/mL. Insulin-like peptide 3 levels reflected markers of large follicles (T, androstendione, inhibin B, and E2) better than...
BMJ open, 2014
Study associations between three measures of alcohol consumption (recent, typical/habitual, bingi... more Study associations between three measures of alcohol consumption (recent, typical/habitual, binging), semen quality and serum reproductive hormones. Cross-sectional population based study. 1221 young Danish men, aged 18-28 years were recruited when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. Total alcohol consumption: (1) in the week preceding (habitual/typical) the visit (recent alcohol intake), (2) in a typical week and (3) frequency of 'binge drinking' (consuming more than 5 units/day)) in the past 30 days was estimated. Semen quality (volume, sperm concentration, total sperm count, and percentages of motile and morphologically normal spermatozoa) and serum concentration of reproductive hormones (follicle-stimulating hormone, luteinising hormone, testosterone, sex hormone binding globulin, oestradiol, free testosterone and inhibin B). Sperm concentration, total sperm count and percentage of spermatozoa ...
Nature reviews. Endocrinology, 2014
Although common reproductive problems, such as male infertility and testicular cancer, present in... more Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth-cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli-cell-only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Int...
International journal of pediatric endocrinology, 2014
Fibroblast Growth Factor 21 (FGF21) is a novel metabolic factor with effect on glucose and lipid ... more Fibroblast Growth Factor 21 (FGF21) is a novel metabolic factor with effect on glucose and lipid metabolism, and shown to be elevated in diseases related to metabolic syndrome. Due to the increasing frequency of metabolic syndrome in the pediatric population, and as FGF21 studies in children are limited, we investigated baseline serum levels of FGF21 in healthy children during an oral glucose tolerance test. A total of 179 children and adolescents from the COPENHAGEN Puberty Study were included. An OGTT with glucose and insulin measurements, a dual energy X-ray absorptiometry (DXA) scan and a clinical examination including pubertal staging were done on all subjects. Serum levels of FGF21, adiponectin, and leptin were determined by immunoassays at baseline. The girls had significantly higher levels of FGF21 compared with boys (155 pg/mL vs. 105 pg/mL, P = 0.04). 38 children (21%) had levels below detection limit of assay. Baseline levels of FGF21 showed positive correlation with trig...
Ugeskrift for laeger, Jan 15, 2007
Brain injury following head trauma is a potential cause of acquired hypopituitarism, although reg... more Brain injury following head trauma is a potential cause of acquired hypopituitarism, although regarded as uncommon. Consequently, such patients do not routinely undergo neuroendocrine evaluation. Recent data suggest hypopituitarism to be more common than previously stated, with a prevalence of at least 25% in long-term survivors. As untreated hypopituitarism is likely to delay recovery and rehabilitation, this calls for a change in the current management of patients suffering traumatic brain injury. In this article, we will review current knowledge in this field.
Growth regulation, 1993
A specific radioimmunoassay for human IGFBP-2 was developed using a polyclonal antiserum directed... more A specific radioimmunoassay for human IGFBP-2 was developed using a polyclonal antiserum directed against a partial sequence (hIGFBP-2(176-190)). The tracer was prepared by radioiodination of a [Tyr]o-hIGFBP-2(176-190) derivative. The assay was used to study IGFBP-2 levels in numerous clinical and experimental situations. There was little circadian fluctuations of serum level which showed a marked age-dependence with high levels at birth and senescence and low levels during puberty. Decreased IGFBP-2 levels were present in untreated insulin-dependent diabetes mellitus (IDDM), in acromegaly and during dexamethasone suppression test. GH deficiency, fasting, IGF-I administration to patients with GH receptor deficiency, hepatic failure and insulinomas caused a moderate increase of serum IGFBP-2. Markedly elevated levels were found in chronic renal failure, non-islet cell tumour induced hypoglycemia and leukaemias. The fact that all possible relationships between insulin secretion and IG...
Ugeskrift for laeger, Jan 4, 1995
No previous Danish growth charts have been published for sitting height, subischial leg length, a... more No previous Danish growth charts have been published for sitting height, subischial leg length, armspan or the ratio of sitting height to stature. These growth charts are useful in the evaluation of dysproportional growth retardation. Foreign standards have previously been used. However, due to population-specific differences and "the secular trend", the construction of Danish growth charts was found to be appropriate. We examined 1977 children (927 boys and 1050 girls) from the Copenhagen area, aged six to 20 years. Height, sitting height and armspan were measured. Growth charts were constructed using local linear regression and smoothing of residuals. We found sitting height values in Danish children to be comparable to English and Norwegian children. Sitting height values were lower than values of Dutch children, but higher than values of Swiss and Swedish children. The extremities of Danish children were 3-4 cm longer than the extremities of English children, but Dutch...
International Journal of Endocrinology, 2013
Using measurements of circulating anti-Müllerian hormone (AMH) in diagnosing and managing reprodu... more Using measurements of circulating anti-Müllerian hormone (AMH) in diagnosing and managing reproductive disorders in pediatric patients requires thorough knowledge on normative values according to age and gender. We provide age-and sex-specific reference ranges for the Immunotech assay and conversion factors for the DSL and Generation II assays. With this tool in hand, the pediatrician can use serum concentrations of AMH when determining the presence of testicular tissue in patients with bilaterally absent testes or more severe Disorders of Sex Development (DSD). Furthermore, AMH can be used as a marker of premature ovarian insufficiency (POI) in both Turner Syndrome patients and in girls with cancer after treatment with alkylating gonadotoxic agents. Lastly, its usefulness has been proposed in the diagnosis of polycystic ovarian syndrome (PCOS) and ovarian granulosa cell tumors and in the evaluation of patients with hypogonadotropic hypogonadism.
Human Reproduction, 2012
In adult women, the circulating level of anti-Müllerian hormone (AMH) is a novel marker of ovaria... more In adult women, the circulating level of anti-Müllerian hormone (AMH) is a novel marker of ovarian function, as it reflects the number of remaining ovarian follicles. Therefore, AMH has gained widespread attention in fertility clinics, and a low AMH is believed to predict impaired fertility and imminent menopause. However, the natural course of circulating AMH levels during female childhood and adolescence is not known. methods: Serum levels of AMH and FSH were measured in girls participating in The COPENHAGEN Puberty Study. Longitudinal part: 85 healthy girls and adolescents were examined, and blood samples were drawn every 6 months for an average of 3 years: median (range) number of samples per girl was 6 (2-10), age at baseline was 9.2 (5.9-12.9) years. Cross-sectional part: 224 prepubertal girls (age 8.3, 5.6-11.7 years) were examined and each girl had one blood sample drawn. results: The individual mean AMH levels in girls followed longitudinally ranged from 5 to 54 pmol/l (median 18 pmol/l). The mean intraindividual coefficient of variation of AMH was 22% (range 0-54%). Overall, each girl maintained her AMH level throughout childhood and adolescence although minor, but significant, changes occurred during pubertal transition. In prepubertal girls, AMH was negatively correlated with FSH (r ¼ 20.31, P , 0.001). Twelve per cent (10/85) had mean AMH below a cutoff value of 8 pmol/l, indicating that the interpretation of low AMH as a marker of approaching menopause may not apply to pre-and peri-pubertal girls. conclusions: Circulating AMH exhibits only minor fluctuations during childhood and adolescence, and a random AMH measurement seems representative for a given girl. The negative AMH-FSH correlation in prepubertal girls supports the notion that AMH is a quantitative marker of ovarian follicles even in young girls.
International Journal of Andrology, 2006
The decreasing trends in fertility rates in many industrialized countries are now so dramatic tha... more The decreasing trends in fertility rates in many industrialized countries are now so dramatic that they deserve much more scientific attention. Although social and behavioural factors undoubtedly play a major role for these trends, it seems premature, and not based on solid information, to conclude that these trends can be ascribed to social and behavioural changes alone. There is evidence to suspect that changing lifestyle and increasing environmental exposures, e.g. to endocrine disrupters, are behind the trends in occurrence of male reproductive health problems, including testis cancer, undescended testis and poor semen quality. These biological factors may also contribute to the extremely low fertility rates. However, the necessary research is complex and requires non-traditional collaboration between demographers, epidemiologists, clinicians, biologists, wild life researchers, geneticists and molecular biologists. This research effort can hardly be carried out without major support from governments and granting agencies making it possible to fund collaborative projects within novel research networks of scientists.
The Journal of Clinical Endocrinology & Metabolism, 2015
Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolesc... more Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolescent boys. It is thought to be caused by an imbalance between estrogen and testosterone, though this is rarely evident in analyses of serum. This study aimed to describe the frequency of physiological gynaecomastia, and to determine possible etiological factors (e.g. auxology and serum hormone levels) in a longitudinal set-up. Design, Settings and Participants: A prospective cohort study of 106 healthy Danish boys (5.8-16.4 years) participated in the longitudinal part of "the COPENHAGEN Puberty Study". The boys were examined every six months during an eight year follow-up. Median number of examinations was 10 (2-15). Blood samples and analysed for FSH, LH, testosterone, estradiol, SHBG, inhibin B, AMH, IGF-I and IGFBP-3 by immunoassays. Auxological parameters, pubertal development and the presence of gynaecomastia were evaluated at each visit. 52 of 106 boys (49 %) developed gynaecomastia of which 10 (19 %) presented with intermittent gynaecomastia. Boys with physiological gynaecomastia reached peak height velocity at a significantly younger age than boys who did not develop gynaecomastia (13.5 vs 13.9 years, p = 0.027), and they had significantly higher serum levels of IGF-I (p = 0.000), estradiol (p = 0.013), free-testosterone (p < 0.001) and FSH (p = 0.030) during pubertal transition. However, no differences in serum LH or in the estradiol to testosterone ratio were found. Gynaecomastia is frequent in pubertal boys. Increased IGF-I levels and pubertal growth appear to be associated, whereas changes in estrogen to testosterone ratio seem negligible.
Pediatric Research, 2015
Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypot... more Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypothalamic-pituitary-gonadal axis leading to development of secondary sexual characteristics prior to 8 years in girls or 9 years in boys. Since the initial discovery of mutations in the maternally imprinted MKRN3 gene in 2013, several case reports have described mutations in this gene in ICPP patients from different populations, highlighting the importance of MKRN3 as a regulator of pubertal onset. We screened 29 Danish girls with ICPP for mutations in MKRN3. Expression of MKRN3 in human hypothalamic cDNA was investigated by PCR. One paternally inherited rare variant, c.1034G>A (p.Arg345His), was identified in one girl with ICPP and in her brother with early puberty. The variant is predicted to be deleterious by three different in silico prediction programs. Expression of MKRN3 was confirmed in adult human hypothalamus. Our results are in line with previous studies where paternally inherited MKRN3 mutations have been found both in males and females with ICPP or early puberty. Our report further expands the set of MKRN3 mutations identified in ICPP patients across diverse populations, thus supporting the major regulatory function of MKRN3 in pubertal onset.Pediatric Research (2015); doi:10.1038/pr.2015.159.
The Journal of Clinical Endocrinology & Metabolism, 2015
Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolesc... more Physiological gynaecomastia is common and affects a large proportion of otherwise healthy adolescent boys. It is thought to be caused by an imbalance between estrogen and testosterone, though this is rarely evident in analyses of serum. This study aimed to describe the frequency of physiological gynaecomastia, and to determine possible etiological factors (e.g. auxology and serum hormone levels) in a longitudinal set-up. Design, Settings and Participants: A prospective cohort study of 106 healthy Danish boys (5.8-16.4 years) participated in the longitudinal part of "the COPENHAGEN Puberty Study". The boys were examined every six months during an eight year follow-up. Median number of examinations was 10 (2-15). Blood samples and analysed for FSH, LH, testosterone, estradiol, SHBG, inhibin B, AMH, IGF-I and IGFBP-3 by immunoassays. Auxological parameters, pubertal development and the presence of gynaecomastia were evaluated at each visit. 52 of 106 boys (49 %) developed gynaecomastia of which 10 (19 %) presented with intermittent gynaecomastia. Boys with physiological gynaecomastia reached peak height velocity at a significantly younger age than boys who did not develop gynaecomastia (13.5 vs 13.9 years, p = 0.027), and they had significantly higher serum levels of IGF-I (p = 0.000), estradiol (p = 0.013), free-testosterone (p < 0.001) and FSH (p = 0.030) during pubertal transition. However, no differences in serum LH or in the estradiol to testosterone ratio were found. Gynaecomastia is frequent in pubertal boys. Increased IGF-I levels and pubertal growth appear to be associated, whereas changes in estrogen to testosterone ratio seem negligible.
Fertility and Sterility, 2015
To report normative data on uterine volume and endometrial thickness in girls, according to puber... more To report normative data on uterine volume and endometrial thickness in girls, according to pubertal stages; to evaluate factors that affect uterine volume; and to compare transabdominal ultrasound (TAUS) and magnetic resonance imaging (MRI). Cross-sectional study of a nested cohort of girls participating in The Copenhagen Mother-Child Cohort. General community. One hundred twenty-one healthy girls, aged 9.8-14.7 years. None. Clinical examination, including pubertal breast stage (Tanner classification: B1-B5). Uterine volume: ellipsoid TAUS (n = 112) and 3-dimensional TAUS (n = 111); ellipsoid MRI (n = 61). Endometrial thickness: TAUS (n = 110) and MRI (n = 60). Uterine volume and endometrial thickness were positively correlated with pubertal stages; e.g., ellipsoid TAUS: r = 0.753, and endometrium TAUS: 0.648. In multiple regression analyses, uterine volume was associated with the number of large follicles (TAUS >5 mm) (Beta 0.270); estradiol (E2) (Beta 0.504); and height (Beta 0.341). Volumes from ellipsoid vs. 3-dimensional TAUS were strongly correlated (r = 0.931), as were TAUS and MRI: ellipsoid volume (r = 0.891) and endometrial thickness (r = 0.540). Uterine volume was larger in TAUS compared with MRI; mean difference across the measured range: 7.7 (5.2-10.2) cm(3). Agreement was best for small uteri. Uterine volume and endometrial thickness increased as puberty progressed. Circulating E2 from large follicles was the main contributor to uterine and endometrial growth. The TAUS and MRI assessments of uterus and endometrium were strongly correlated.
American journal of physiology. Endocrinology and metabolism, 2001
In the present study, the effect of endurance training alone and endurance training combined with... more In the present study, the effect of endurance training alone and endurance training combined with recombinant human growth hormone (rhGH) administration on subcutaneous abdominal adipose tissue lipolysis was investigated. Sixteen healthy women [age 75 +/- 2 yr (mean +/- SE)] underwent a 12-wk endurance training program on a cycle ergometer. rhGH was administered in a randomized, double-blinded, placebo-controlled design in addition to the training program. Subcutaneous abdominal adipose tissue lipolysis was estimated by means of microdialysis combined with measurements of subcutaneous abdominal adipose tissue blood flow (ATBF; (133)Xe washout). Whole body fat oxidation was estimated simultaneously by indirect calorimetry. Before and after completion of the training program, measurements were performed both at rest and during 60 min of continuous cycling at a workload corresponding to 60% of pretraining peak oxygen uptake. Endurance training alone did not affect subcutaneous abdomina...
American journal of physiology. Endocrinology and metabolism, 2000
The present study investigated whether recombinant human (rh) growth hormone (GH) combined with e... more The present study investigated whether recombinant human (rh) growth hormone (GH) combined with endurance training would have a larger effect on oxidative capacity, metabolism, and body fat than endurance training alone. Sixteen healthy, elderly women, aged 75 yr, performed closely monitored endurance training on a cycle ergometer over 12 wk. rhGH was given in a randomized, double-blinded, placebo-controlled design in addition to the training program. GH administration resulted in a doubling of serum insulin-like growth factor I levels. With endurance training, peak oxygen uptake increased by approximately 18% in both groups, whereas the marked increase in muscle citrate synthase activity was 50% larger in the GH group compared with the placebo group. In addition, only the GH group revealed an increase in muscle L-3-hydroxyacyl-CoA dehydrogenase activity. Body weight remained unchanged in both groups, but the GH group showed significant changes in body composition with a decrease in...
Molecular psychiatry, 1997
Circulating leptin concentrations are known to be low in acute anorexia nervosa (AN), which is ch... more Circulating leptin concentrations are known to be low in acute anorexia nervosa (AN), which is characterized by low weight, amenorrhea and specific psychopathological features. In this study plasma leptin concentrations were determined during inpatient treatment of 23 adolescent females with AN using a sensitive radioimmunoassay (RIA) and set into relationship to leptin levels of females matched for age, body mass index (BMI; kg m-2) and/or percent body fat. At referral patients had leptin concentrations well below the female controls. Weight gains led to steep increases of leptin levels which peaked at values well in excess of those observed in controls matched for BMI. In patients who reached the final treatment stage and who were followed-up after discharge, levels subsequently fluctuated and finally dropped into or below the control range. The low leptin levels at referral are likely to be involved in the pathogenesis of amenorrhea and the reduced metabolic state of acutely ill ...
European journal of endocrinology / European Federation of Endocrine Societies, 2015
Testicular adrenal rest tumours (TARTs) are a common finding in patients with congenital adrenal ... more Testicular adrenal rest tumours (TARTs) are a common finding in patients with congenital adrenal hyperplasia (CAH). These tumours constitute a diagnostic and management conundrum and may lead to infertility. TART cells share many functional and morphological similarities with Leydig cells (LCs), and masses consisting of such cells are occasionally misclassified as malignant testicular tumours, which may lead to erroneous orchiectomy in these patients. In this study, we aimed to investigate the potential of LC developmental markers and adrenal steroidogenic markers in the differential diagnosis of TARTs and malignant LC tumours (LCTs). We investigated mRNA and protein expression of testicular steroidogenic enzymes; CYP11A1 and HSD3B1/2, markers of adrenal steroidogenesis; CYP11B1, CYP21A2 and ACTH receptor/melanocortin 2 receptor (MC2R), and markers of LC maturation; and delta-like 1 homolog (DLK1) and insulin-like 3 (INSL3) in testicular biopsies with TART, orchiectomy specimens wit...
Fertility and sterility, 2015
To elucidate the natural course of circulating insulin-like peptide 3 (INSL3) levels according to... more To elucidate the natural course of circulating insulin-like peptide 3 (INSL3) levels according to puberty as well as its relation to other reproductive hormones. Population-based cohort study. Not applicable. Healthy peripubertal girls (n = 10) examined every 6 months; total number of examinations was 84; median (range) per girl: 9 (4-10), including staging of pubertal breast development and blood samples. None. Serum levels of INSL3, inhibin B, E2, antimüllerian hormone, LH, and FSH (validated immunoassays), and T and androstenedione (liquid chromatography-tandem mass spectrometry). Serum levels of INSL3 varied considerably between girls (range, 0.01-0.27 ng/mL) and within each girl as puberty progressed; intraindividual variation, median (range) 102% (65%-143%). Insulin-like peptide 3 increased in late puberty (B1 to B4+B5); geometric mean 0.03 ng/mL to 0.15 ng/mL. Insulin-like peptide 3 levels reflected markers of large follicles (T, androstendione, inhibin B, and E2) better than...
BMJ open, 2014
Study associations between three measures of alcohol consumption (recent, typical/habitual, bingi... more Study associations between three measures of alcohol consumption (recent, typical/habitual, binging), semen quality and serum reproductive hormones. Cross-sectional population based study. 1221 young Danish men, aged 18-28 years were recruited when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. Total alcohol consumption: (1) in the week preceding (habitual/typical) the visit (recent alcohol intake), (2) in a typical week and (3) frequency of 'binge drinking' (consuming more than 5 units/day)) in the past 30 days was estimated. Semen quality (volume, sperm concentration, total sperm count, and percentages of motile and morphologically normal spermatozoa) and serum concentration of reproductive hormones (follicle-stimulating hormone, luteinising hormone, testosterone, sex hormone binding globulin, oestradiol, free testosterone and inhibin B). Sperm concentration, total sperm count and percentage of spermatozoa ...
Nature reviews. Endocrinology, 2014
Although common reproductive problems, such as male infertility and testicular cancer, present in... more Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth-cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli-cell-only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Int...
International journal of pediatric endocrinology, 2014
Fibroblast Growth Factor 21 (FGF21) is a novel metabolic factor with effect on glucose and lipid ... more Fibroblast Growth Factor 21 (FGF21) is a novel metabolic factor with effect on glucose and lipid metabolism, and shown to be elevated in diseases related to metabolic syndrome. Due to the increasing frequency of metabolic syndrome in the pediatric population, and as FGF21 studies in children are limited, we investigated baseline serum levels of FGF21 in healthy children during an oral glucose tolerance test. A total of 179 children and adolescents from the COPENHAGEN Puberty Study were included. An OGTT with glucose and insulin measurements, a dual energy X-ray absorptiometry (DXA) scan and a clinical examination including pubertal staging were done on all subjects. Serum levels of FGF21, adiponectin, and leptin were determined by immunoassays at baseline. The girls had significantly higher levels of FGF21 compared with boys (155 pg/mL vs. 105 pg/mL, P = 0.04). 38 children (21%) had levels below detection limit of assay. Baseline levels of FGF21 showed positive correlation with trig...
Ugeskrift for laeger, Jan 15, 2007
Brain injury following head trauma is a potential cause of acquired hypopituitarism, although reg... more Brain injury following head trauma is a potential cause of acquired hypopituitarism, although regarded as uncommon. Consequently, such patients do not routinely undergo neuroendocrine evaluation. Recent data suggest hypopituitarism to be more common than previously stated, with a prevalence of at least 25% in long-term survivors. As untreated hypopituitarism is likely to delay recovery and rehabilitation, this calls for a change in the current management of patients suffering traumatic brain injury. In this article, we will review current knowledge in this field.
Growth regulation, 1993
A specific radioimmunoassay for human IGFBP-2 was developed using a polyclonal antiserum directed... more A specific radioimmunoassay for human IGFBP-2 was developed using a polyclonal antiserum directed against a partial sequence (hIGFBP-2(176-190)). The tracer was prepared by radioiodination of a [Tyr]o-hIGFBP-2(176-190) derivative. The assay was used to study IGFBP-2 levels in numerous clinical and experimental situations. There was little circadian fluctuations of serum level which showed a marked age-dependence with high levels at birth and senescence and low levels during puberty. Decreased IGFBP-2 levels were present in untreated insulin-dependent diabetes mellitus (IDDM), in acromegaly and during dexamethasone suppression test. GH deficiency, fasting, IGF-I administration to patients with GH receptor deficiency, hepatic failure and insulinomas caused a moderate increase of serum IGFBP-2. Markedly elevated levels were found in chronic renal failure, non-islet cell tumour induced hypoglycemia and leukaemias. The fact that all possible relationships between insulin secretion and IG...
Ugeskrift for laeger, Jan 4, 1995
No previous Danish growth charts have been published for sitting height, subischial leg length, a... more No previous Danish growth charts have been published for sitting height, subischial leg length, armspan or the ratio of sitting height to stature. These growth charts are useful in the evaluation of dysproportional growth retardation. Foreign standards have previously been used. However, due to population-specific differences and "the secular trend", the construction of Danish growth charts was found to be appropriate. We examined 1977 children (927 boys and 1050 girls) from the Copenhagen area, aged six to 20 years. Height, sitting height and armspan were measured. Growth charts were constructed using local linear regression and smoothing of residuals. We found sitting height values in Danish children to be comparable to English and Norwegian children. Sitting height values were lower than values of Dutch children, but higher than values of Swiss and Swedish children. The extremities of Danish children were 3-4 cm longer than the extremities of English children, but Dutch...
International Journal of Endocrinology, 2013
Using measurements of circulating anti-Müllerian hormone (AMH) in diagnosing and managing reprodu... more Using measurements of circulating anti-Müllerian hormone (AMH) in diagnosing and managing reproductive disorders in pediatric patients requires thorough knowledge on normative values according to age and gender. We provide age-and sex-specific reference ranges for the Immunotech assay and conversion factors for the DSL and Generation II assays. With this tool in hand, the pediatrician can use serum concentrations of AMH when determining the presence of testicular tissue in patients with bilaterally absent testes or more severe Disorders of Sex Development (DSD). Furthermore, AMH can be used as a marker of premature ovarian insufficiency (POI) in both Turner Syndrome patients and in girls with cancer after treatment with alkylating gonadotoxic agents. Lastly, its usefulness has been proposed in the diagnosis of polycystic ovarian syndrome (PCOS) and ovarian granulosa cell tumors and in the evaluation of patients with hypogonadotropic hypogonadism.