Lise Aksglaede

• Rigshospitalet

Objective To describe the bioactivity of circulating androgens during pubertal transition as determined by an in vitro bioassay assessing androgen receptor (AR) activation, and to compare these findings with circulating concentrations of total testosterone (total T) measured by LC‐MS/MS. Methods This longitudinal study included ten healthy boys fr...

Objectives The insulin-like growth factors (IGFs) regulate growth in humans. IGF-I and IGF binding protein (IGFBP)-3 are biomarkers in children with growth disorders. We investigate a targeted proteomics method for absolute quantitation of eight IGF protein family members in human serum, including the peptide hormones IGF-I and -II, and the six bin...

Introduction Klinefelter syndrome (KS) is a genetic condition characterised by the presence of an extra X chromosome in males (47,XXY). KS is associated with various phenotypic characteristics in adult life, including infertility, hypogonadism and increased risk of type II diabetes, cardiovascular disease and osteoporosis. Additionally, individuals...

The manifestation of acne in adolescents coincides with the emergence of other androgen-dependent characteristics of puberty such as sweat odour, and pubic hair. Yet little is known about the associations with circulating levels of androgens. Thus, the objective was to study the prevalence of acne in healthy children and adolescents according to se...

STUDY QUESTION Is serum phosphate linked with semen quality and reproductive hormones in infertile men? SUMMARY ANSWER Hypophosphatemia is a frequent finding in infertile men and is associated with lower number of motile sperm. WHAT IS KNOWN ALREADY Phosphate is available in fluid from all segments of the male reproductive tract in concentrations...

Background It is well‐established that spermatogenesis, semen quality, and reproductive hormones are interlinked. It is, however, less well‐described how various specific testicular histopathologies are linked to reproductive hormones and semen quality. Objectives To describe the detailed relationship between specific testicular histopathologies a...

Objective To describe the natural history of inhibin B throughout life according to sex, age, and pubertal development. Methods Based on serum samples from 2707 healthy controls aged 0 to 80 years, sex- and age-specific reference ranges of inhibin B concentrations were constructed. Concentrations were evaluated according to pubertal development an...

Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like Sertoli cells, and occasionally focal spermatogenesis. Here, we show that the immature-like Sertoli cells highly expressed XIST and had two X-chromosomes, while the mature Sertoli cell...

Background Endogenous sex steroids influence the pubertal growth spurt and adult height. However, the impact of puberty suppression and sex steroids on growth in transgender adolescents is sparsely studied. Aim We investigated pubertal growth, serum IGF-I and IGFBP-3, and adult height of transgender adolescents receiving hormone therapy. Methods...

Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like Sertoli cells, and occasionally focal spermatogenesis. Here, we show that the immature Sertoli cells highly expressed XIST and have two X-chromosomes, while the mature Sertoli cells la...

Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well...

Adult patients with Klinefelter syndrome (KS) are characterized by a highly variable phenotype including tall stature, obesity and hypergonadotropic hypogonadism as well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis. Most adults need testosterone replacement therapy (TRT), whereas the use of TRT during...

Objective: Klinefelter syndrome (KS) is the most common sex chromosome disorder and genetic cause of infertility in males. A highly variable phenotype contributes to the fact that a large proportion of cases are never diagnosed. Typical hallmarks in adults include small testes and azoospermia which may prompt biochemical evaluation that typically s...

Objective To evaluate whether optimized and standardized diagnostic procedures would improve detection of germ cell neoplasia in situ (GCNIS) in the contralateral testis of patients with testicular germ cell tumour (TGCT) and decrease the rate of metachronous tumours, which in a nationwide Danish study was estimated to be 1.9%. Patients and Method...

Introduction Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subg...

Objectives 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency results in insufficient biosynthesis of testosterone and consequently dihydrotestosterone. This is important for the fetal development of male genitalia. Thus, most 46,XY patients with 17β-HSD3 deficiency have a female appearance at birth and present with virilization at puberty. T...

Background Quarterly intramuscular injections with long-acting testosterone undecanoate (TU) provide stable serum testosterone concentrations over time and is therefore preferred by many testosterone deficient patients. However, use of long-acting TU in elderly patients is limited due to lack of safety and feasibility studies. Objective To investi...

Congenital hypergonadotropic (primary) hypogonadism in males is most commonly due to anorchia or to Klinefelter syndrome (KS, 47, XXY). Anorchia is defined as the absence of testes in a 46,XY individual with a male phenotype. Male infants with anorchia typically present with normal penile size, although the presence of micropenis has been reported....

Objective Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism. Methods Retrospectively collected data from medical records...

The care of transgender individuals is multidisciplinary including medical, surgical, psychiatric, and psychological health professionals. We here report 2 cases of nonclassic congenital adrenal hyperplasia (CAH) coincidently discovered during the clinical and biochemical evaluation prior to hormonal treatment for gender dysphoria. Elevated 17-OH-p...

STUDY QUESTION Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood? SUMMARY ANSWER AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone repl...

Study question: What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)? Summary answer: The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism...

Background: Knowledge about Klinefelter Syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalen...

Activation of the hypothalamic-pituitary-gonadal (HPG) axis happens in 3 phases during life. The first phase is during fetal life and is only separated from the second phase, called minipuberty, by the high concentration of placental hormones at birth. The third period of activation of the HPG axis is puberty and is well-described. Minipuberty cons...

Study question: How is timing of voice break related to other male pubertal milestones as well as to BMI? Summary answer: We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher...

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with T...

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A ( DNMT3A ) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatt...

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, in...

Objective: Only a few genetic loci are known to be associated with male pubertal events. The ability of excreting testosterone (T) and other steroids in the urine depends on sulfation and glucuronidation. One of several essential glucuronidases is encoded by the UGT2B17 gene. In a preliminary report, we found that homozygous deletion of UGT2B17 in...

Objective: Fetal Anti-Müllerian hormone (AMH) is responsible for normal male sexual differentiation and circulating AMH is used as a marker of testicular tissue in newborns with Disorders of Sex Development. Little is known about the mechanism of action in postnatal life. A recent genome wide association study (GWAS) reported genetic variation of...

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...

Context Clinical use of single serum gonadotropin measurements in children is limited by the pulsatile section of FSH and LH. However, first morning voided (FMV) urine may integrate the fluctuating gonadotropin serum levels. Objective We aimed to evaluate urinary and serum gonadotropin levels according to age, sex and pubertal stage in healthy chi...

Aim: The short stature homeobox containing gene (SHOX) plays an important role in short stature, but has not been explored in detail in a tall stature population before. This study explored the prevalence of SHOX aberrations in girls diagnosed with idiopathic tall stature with a normal karyotype. Methods: We studied SHOX aberrations in 81 girls...

Background: The aim of this clinical study was to determine the prevalence of SHOX haploinsufficiency in a population of short stature patients and describe their anthropometric measurements. Methods: 574 short statured patients were evaluated in a single center (1992-2015). SHOX copy number was detected by quantitative Polymerase Chain Reaction...

Objective: To study the pathologic findings among men evaluated for infertility. Design: A retrospective, single-center, cross-sectional study. Setting: University hospital-based research center. Participant(s): We included data from 1,213 medical records from infertile men referred for diagnostic work-up from 2005 to 2009. Interventions(s)...

BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343),...

A 30-yr-old woman presented with 2 consecutive miscarriages within 7 mo. Histopathologic examination of the placental tissue showed intracytoplasmic inclusion vacuoles with a strong reaction in Periodic acid-Schiff staining and a slightly pallor reaction in alcian blue staining. Additional molecular genetic analyses confirmed glycogen storage disea...

Context: The majority of Turner syndrome (TS) patients suffer from accelerated loss of primordial follicles. Low circulating levels of anti-Müllerian hormone (AMH) may predict the lack of spontaneous puberty in prepubertal girls and imminent premature ovarian insufficiency (POI) in TS women with preserved ovarian function. Objectives: To evaluat...

A neonate with low blood free carnitine level on newborn tandem mass spectrometry screening was evaluated for possible carnitine transporter defect (CTD). The plasma concentration of free carnitine was marginally reduced, and the concentrations of acylcarnitines (including C6, C8, and C10:1) were normal on confirmatory tests. Organic acids in urine...

Age at pubertal onset varies substantially in healthy girls. Although genetic factors are responsible for more than half of the phenotypic variation, only a small part has been attributed to specific genetic polymorphisms identified so far. Follicle-stimulating hormone (FSH) stimulates ovarian follicle maturation and estradiol synthesis which is re...

Objective: Pubertal gynaecomastia is a frequent phenomenon occurring in 20-40% of otherwise healthy adolescent boys. Little is known about the aetiology of pubertal gynaecomastia. Markedly elevated thyroid hormone levels in adults with hyperthyroidism are associated with gynaecomastia. Design: A cross-sectional examination of 444 healthy boys wi...

Objective To assess the relationship between fetal femur diaphysis length (FL) below the 5th percentile at the second trimester scan and pregnancy outcome, in a population where more than 90 % of women attend first trimester screening. Methods Retrospective study of all Danish singleton pregnancies with a 17–22 week malformation scan between 1 Janu...

Background: Accurate and selective assessment of testosterone requires use of a sensitive LC-MS/MS method, especially at low levels as those seen in young children. Methods: The present longitudinal study of 20 healthy children from the Copenhagen Puberty Study followed every 6 months for 5 years evaluates the longitudinal increase in serum test...

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We ide...

To construct new Danish growth charts for 0 to 20-year-olds and compare them with Danish references from 1982 and with World Health Organization (WHO) standards for children aged 0 to five years from 2006, by applying similar inclusion and exclusion criteria. Anthropometric data from three contemporary Danish population-based studies were combined....

Pubertal gynaecomastia is a very common condition. Although the underlying etiology is poorly understood, it is generally accepted that excess of estrogens and/or deficit of androgens are involved in the pathogenesis. Furthermore, adiposity as well as the GH/IGF-I axis may play a role. In the present study we elucidate the association of adiposity...

In a recent study, we found that Greenlandic Inuit children had a more adverse metabolic profile than Danish children. Aerobic fitness and adiposity could only partly account for the differences. Therefore, we set out to evaluate and compare plasma leptin and adiponectin levels in Danish and Inuit children. In total, 187 Inuit and 132 Danish childr...

To investigate whether genetic polymorphisms in the FSH pathway (FSHB-211 G→T and FSHR 2039 A→G) affect serum levels of FSH, antimüllerian hormone (AMH), and age at pubertal onset. FSH secretion and FSH signal transduction are enhanced in carriers of FSHB GG and FSHR AA, respectively. Furthermore, the combined genotype FSHB GG+FSHR AA is the most f...

Background Little is known about the possible deleterious effects of phthalate exposure on endogenous sex steroid levels in children.Objective To investigate if urinary phthalate metabolite levels are associated with circulating adrenal androgen levels and age at puberty.MethodsA longitudinal stydy of 168 healthy children (84 girls) examined every...

During recent decades, the prevalence of metabolic morbidity has increased rapidly in adult Greenlandic Inuit. To what extent this is also reflected in the juvenile Inuit population is unknown. The objective was, therefore, in the comparison with Danish children, to evaluate metabolic profiles in Greenlandic Inuit children from the capital in the s...

Objective: To investigate whether genetic polymorphisms in the FSH pathway (FSHB-211 G/T and FSHR 2039 A/G) affect serum levels of FSH, antim€ ullerian hormone (AMH), and age at pubertal onset. FSH secretion and FSH signal transduction are enhanced in carriers of FSHB GG and FSHR AA, respectively. Furthermore, the combined genotype FSHB GGþFSHR AA...

Introduction: The presence of glandular breast tissue in males around puberty, pubertal gynaecomastia, is a very common (40–60%) condition although the aetiology behind is poorly understood. It is generally accepted that pubertal gynaecomastia is caused by an excess of estrogens and/or a deficit of androgens. However, other hormones such as prolact...

Background: Little is known about the possible deleterious effects of phthalate exposure on endogenous sex steroid levels in children Design: A longitudinal study. Materials and methods: 168 Healthy children (84 girls) were examined every 6 months for 5 years, with pubertal staging, measurements of serum levels of DHEAS and Δ4-androstenedione (Adio...

Klinefelter syndrome, 47,XXY (KS), is the most frequent sex chromosome aberration in males, affecting 1 in 660 newborn boys. The syndrome is characterized by testicular destruction with extensive fibrosis and hyalinization of the seminiferous tubules resulting in small testes, hypergonadotropic hypogonadism, and azoospermia in the majority of cases...

Bisphenol A (BPA), triclosan (TCS), benzophenone-3 (BP-3), dichoro- and phenyl phenols are industrial chemicals present in numerous consumer products such as polycarbonate plastics, preservatives in personal care products, sun screens, pesticides and fungicides, respectively, and they are all suspected endocrine disrupters. In this study the urinar...

47,XXY (Klinefelter syndrome) is the most frequent sex chromosomal disorder and affects approximately one in 660 newborn boys. The syndrome is characterized by varying degrees of cognitive, social, behavioral, and learning difficulties and in adulthood additionally primary testicular failure with small testes, hypergonadotropic hypogonadism, tall s...

Background: Longer androgen receptor gene CAG trinucleotide repeats, AR (CAG)n, have been associated with reduced sensitivity of the androgen receptor (AR) in vitro as well as in humans. Furthermore, short AR (CAG)n have been associated with premature adrenarche. Objective: The aim of the study was to evaluate associations between the AR (CAG)n...

Background: Pubertal onset is usually defined by breast development in girls and testicular growth in boys. Pubarche is defined as the attainment of pubic hair and is considered as a sign of pubertal transition. Pubarche is preceded by a gradual increase in production of adrenal androgens, DHEA and Δ4-androstenedione (Adione), a process termed adr...

Paediatric reference intervals based on samples from healthy children are difficult to establish and consequently data are often from hospitalized children. Furthermore, biases may present in published data due to differences in the analytical methods employed. Blood samples from 1429 healthy Danish children were collected for establishing referenc...

47,XXY Klinefelter syndrome (KS) is the most common sex chromosome disorder affecting 1 in 660 newborn boys (1). Adolescent and adult patients with KS are characterised by hypergonadotropic hypogonadism, tall stature with eunuchoid body proportions, increased truncal fat and small testes, whereas no specific clinical or physical hallmarks have been...

Puberty is characterized by a series a hormonal events leading to the attainment of adult reproductive capacity. Clinical manifestations of the pubertal processes include breast development, pubic hair development, menarche and regular menstrual bleedings. Abnormal pubertal development includes a spectrum of disorders such as premature thelarche, p...

Pubertal gynaecomastia is a clinical sign of an oestrogen-androgen imbalance, which occurs in 40-60% of adolescent Caucasian boys. In most cases no underlying endocrinopathy can be identified. A recent study reports higher plasma phthalate levels in Turkish boys with pubertal gynaecomastia. Therefore, we asked whether there was an association betwe...

The decline in age at puberty in the general population has been paralleled by an increase in the number of girls referred for evaluation of precocious puberty (PP). In 1999, The Lawson Wilkins Pediatric Endocrine Society recommended a lowering of the age limit for evaluation of PP in girls. However, the limited evidence on which these recommendati...

To describe available markers of male puberty, discuss associations between adiposity and pubertal timing and to review recent evidence of a possible secular trend in male pubertal timing. An expert panel reviewing existing American pubertal data from boys in 2005 could not confirm a secular trend in male pubertal timing. National Health and Nutrit...

Phthalates are a group of chemicals present in numerous consumer products. They have anti-androgenic properties in experimental studies and are suspected to be involved in human male reproductive health problems. A few studies have shown associations between phthalate exposure and changes in pubertal timing among girls, although controversies exist...

Contemporary American and European girls experience breast development at earlier ages compared with 15-20 years ago. Alterations in BMI alone cannot account for these changes. Several currently used pesticides possess endocrine disrupting properties and may interfere with reproductive development, but human data are sparse. We examined girls whose...

IGF1 plays an important role in growth and metabolism during puberty. IGF1 levels are increased in girls with central precocious puberty (CPP). However, the relationship with insulin before and during gonadal suppression is unknown. In addition, the influence of the exon 3-deleted GH receptor gene (GHRd3) on IGF1 levels was evaluated. Nine hundred...

Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with...

Human growth is a highly complicated process influenced by genetic, hormonal, environmental, dietary, metabolic and socioeconomic factors. Although the interaction between sex steroids and the growth hormone (GH)-IGF-axis is of major importance in regulating growth, multiple genetic factors, including genes located on the sex chromosomes play indep...

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 cir...

ABSTRACT: Pubertal timing is a strongly heritable trait, but no single puberty gene has been identified. Thus, the genetic background of idiopathic central precocious puberty (ICPP) is poorly understood. Overall, the genetic modulation of pubertal onset most likely arises from the additive effect of multiple genes, but also monogenic causes of ICPP...

Determination of postnatal AMH levels in circulation has been used for decades when evaluating a child with ambiguous genitalia. We describe the age- and gender-specific changes of postnatal AMH serum levels to enable an appropriate clinical use of AMH assessment in pediatric endocrinology. In males, cord blood AMH is measurable at high levels (mea...

This study investigates the pituitary-Leydig cell axis in patients with stage I testicular germ cell cancer (TGCC) followed with surveillance only, in order to evaluate the risk of Leydig cell dysfunction one year after orchiectomy. A retrospective evaluation of reproductive hormones in patients with unilateral stage I TGCC (N=72) without relapse d...

Anti-Müllerian hormone (AMH) is produced by foetal Sertoli cells at the time of sexual differentiation and is responsible for the regression of the Müllerian ducts in the male foetus. AMH is a testis-specific marker of diagnostic value in infants with ambiguous genitalia or with bilateral cryptorchidism. However, little is known about AMH in boys a...

Klinefelter syndrome (KS) is the most frequent sex chromosome disorder in males, but the phenotype varies greatly and is therefore highly under-diagnosed. We aimed at describing the phenotypic characteristics throughout life from clinical follow-up of our large cohort of patients with KS. A retrospective observational study of 166 males with nonmos...

Phthalates are a group of chemicals with widespread use in the industrial production of numerous consumer products. They are suspected to be involved in male reproductive health problems and have also been associated with several other health problems in children including obesity and asthma. To study the urinary excretion of phthalate metabolites...