Claus Højbjerg Gravholt

Aarhus University Hospital | AUH · Department of Endocrinology and Internal Medicine and Department of Molecular Medicine

Turner syndrome was recognized nearly 90 years ago as a distinctive condition and the understanding of pathophysiology, and phenotype has incrementally and substantially changed along with the goals of treatment. Today, multidisciplinary care is imperative, and the latest international consensus guideline has been crafted as a source of comprehensi...

Introduction: Congenital adrenal hyperplasia (CAH) is characterized by a broad spectrum of symptoms. This study aims to describe genotype-phenotype correlations, clinical manifestations at diagnosis, and the frequency of feminizing surgery in childhood. Methods: A nationwide retrospective cohort study of patients diagnosed with CAH, aged ≤18, betwe...

Background 46,XX testicular disorder/difference of sex development (46,XX DSD) is a rare congenital condition, characterized by a combination of the typical female sex chromosome constitution, 46,XX, and a variable male phenotype. In the majority of individuals with 46,XX DSD, a Y chromosome segment containing the sex-determining region gene ( SRY)...

Disclosure: J. Just: None. L. Ridder: None. E. Johannsen: None. H. Christensen: None. A. Skakkebæk: None. C.H. Gravholt: None. Turner syndrome (TS) is a clinical diagnosis with a karyotype containing one X chromosome and complete or partial absence of the second X chromosome. TS is typically associated with clinical manifestations such as short sta...

Background Beta-hydroxybuturate (β-OHB) supplements are commonly utilized in sports by both recreational and professional athletes. In a recent study, we observed a drop in testosterone levels following the oral ingestion of racemic sodium-β-OHB. In this investigation, we aim to determine whether a single oral dose of ketone ester (study I) and pro...

Study question Do sperm retrieval and pregnancy rates in men with Klinefelter syndrome (KS) depend upon sperm retrieval method, age, testicular volume, body weight, and hormone concentrations? Summary answer Successful sperm retrieval was significantly associated with total testicular volume but not with sperm retrieval method, age, body weight, B...

Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3 β -hydroxysteroid dehydrogenase type 2 (3 β HSD2D/ HSD3B2 ) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, men...

Context Klinefelter syndrome (KS) is associated with hypergonadotropic hypogonadism, which contributes to characteristic phenotypical manifestations including metabolic alterations. Extensive research has demonstrated important associations between androgens and liver function. Objectives Investigation of the association between metabolic paramete...

Turner syndrome affects 50 per 100,000 females, affects multiple organs through all stages of life, necessitating multidisciplinary care. This guideline extends previous ones and includes important new advances, within diagnostics and genetics, estrogen treatment, fertility, co-morbidities, and neurocognition and neuropsychology. Exploratory meetin...

Chronic testosterone (T) substitution and short-term T administration positively affect protein metabolism, however, data on acute effects in humans are sparse. This study aimed to investigate T's acute effects on whole-body protein metabolism in hypogonadal and eugonadal conditions. We designed a randomized, double-blind, placebo-controlled, cross...

Background Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT) and present with a more than fourfold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. Aim To assess effects of 18 months TRT on hemostasis in KS and id...

STUDY QUESTION Does Klinefelter syndrome (KS) lead to a distinct gene expression pattern at single-cell level in the testes that could provide insight into the reported microvascular dysfunction in the testes? SUMMARY ANSWER A distinct gene expression pattern within microvascular-associated cells of males with KS suggests excessive endothelial cel...

Objectives To investigate sleep among men with Klinefelter syndrome (KS). Method We compared the sleep domains latency, disturbance, and efficiency in 30 men with KS ( M age = 36.7 years, SD = 10.6) to 21 age-matched non-KS controls ( M age = 36.8 years, SD = 14.4). Actigraphs were used to objectively measure sleep across 7 days and nights. Partic...

Sex chromosome abnormalities (SCAs) are chromosomal disorders with either a complete or partial loss or gain of sex chromosomes. The most frequent SCAs include Turner syndrome (TS; 45,X), Klinefelter syndrome (KS; 47,XXY), Trisomy X syndrome (47,XXX) and Double Y syndrome (47,XYY). The phenotype seen in SCAs is highly variable and may not merely be...

Ketone bodies, such as 3‐hydroxybutyrate (3‐OHB), have been frequently used by endurance athletes, such as cyclists, to enhance performance and recovery and are recognized for their health benefits and therapeutic effects for decades. Testosterone is a potent regulator of red blood cell production. Evidence suggests that ketone bodies can increase...

Diagnosis and management of individuals who have differences of sex development (DSD) due to numerical or structural variations of sex chromosomes (NSVSC) remains challenging. Girls who have Turner syndrome (45X) may present with varying phenotypic features, from classical/severe to minor, and some remain undiagnosed. Boys and girls who have 45,X/4...

Context: Klinefelter syndrome (KS, 47,XXY) and 47,XYY syndrome are genetic conditions characterized by a supernumerary sex chromosome. The conditions share many traits, but considerable phenotypic differences are seen between the two. Focusing on morbidity, mortality, and socioeconomics, this review highlights similarities and differences. Method...

Background Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific...

Objective: Despite appropriate oral glucocorticoid replacement therapy, patients with hypocortisolism often suffer from impaired health and frequent hospitalizations. Continuous subcutaneous hydrocortisone infusion (CSHI) has been developed as an attempt to improve the health status of these patients. The objective of this study was to compare the...

Objective: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS) which increases mortality. Women with TS have varying phenotype and cardiovascular risk. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS particip...

The 3rd International Workshop on Klinefelter Syndrome, Trisomy X, and 47,XYY syndrome was held in Leiden, the Netherlands, on September 12–14, 2022. Here, we review new data presented at the workshop and discuss scientific and clinical trajectories. We focus on shortcomings in knowledge and therefore point out future areas for research. We focus o...

We investigated cognition and mentalization skills, defined as the ability to understand one's own and others' intentions and emotions, in men with Klinefelter Syndrome (KS). The sample was 26 men with KS and 26 non-clinical male controls aged 19–65 years. We measured mentalization with the Reading the Mind in the Eyes Test (RMET) and cognition wit...

Background: The prevalence of newborns with congenital adrenal hyperplasia (CAH) detected by neonatal screening is well-described, but data including patients diagnosed later in life are extremely limited. This study aimed to describe diagnostic trends for all patients with CAH in Denmark. Methods: A nationwide population-based registry study in...

Background: A subtype of Disorders of Sex Development (DSD) in individuals with a 46,XX karyotype who are phenotypically male is classified as testicular DSD (46,XX TDSD). These individuals develop testes but are infertile due to germ cell loss. However, little is known about their testicular architecture. Methods: We analyzed biopsies of four S...

Purpose To investigate the effects of resistance training with or without transdermal estrogen therapy (ET) on satellite cell (SC) number and molecular markers for muscle hypertrophy in early postmenopausal women. Methods Using a double-blinded randomized controlled design, we allocated healthy, untrained postmenopausal women to perform 12 weeks o...

Objectives: To investigate sleep among men with Klinefelter syndrome (KS). Method: We compared the sleep domains latency, disturbance, and efficiency in 30 men with KS (M age = 36.7 years, SD = 10.6) to 21 age-matched non-KS controls (M age = 36.8 years, SD = 14.4). Actigraphs were used to objectively measure sleep across 7 days and nights. Partici...

Purpose: We aimed to study variations in strength and power performance during the menstrual cycle (MC) in eumenorrheic young women and during the pill cycle in oral contraceptives (OC) users. Methods: Forty healthy, normal-weight women between 18 and 35 yr (n = 30 eumenorrheic women; n = 10 OC users) completed this prospective cohort study. Sev...

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular condition and Next Generation Sequencing (NGS) should represent the most appropriate approach. Therefore, we con...

Background: Men with Klinefelter Syndrome (KS) are routinely offered testosterone replacement therapy (TRT) suggested to potentially promote platelet aggregation and increase cardiovascular risk. Objective: We investigated platelet aggregation in men with KS before and during TRT. Materials and methods: Forty-one adult men with KS participated...

Background Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of futu...

Purpose: The landscape of circular RNAs (circRNAs), an important class of non-coding RNAs that regulate gene expression, has never been described in human disorders of sex chromosome aneuploidies. We profiled circRNAs in Turner syndrome females (45,X; TS) and Klinefelter syndrome males (47,XXY; KS) to investigate how circRNAs respond to a missing o...

Background Cardiovascular disease competes with breast cancer (BC) as the leading cause of death for females diagnosed with breast cancer. Not much is known concerning morbidity and medicine use in the short and long term after a BC diagnosis. Aim The aim of this study was to determine acute and long-term morbidity in Danish women treated for BC....

Turner syndrome is a condition in females missing the second sex chromosome (45,X) or parts thereof. It is considered a rare genetic condition and is associated with a wide range of clinical stigmata, such as short stature, ovarian dysgenesis, delayed puberty and infertility, congenital malformations, endocrine disorders, including a range of autoi...

Evidence suggests that prostate cancer (PC) patients undergoing androgen deprivation therapy (ADT) are at risk for cognitive decline (CD), but the underlying mechanisms are less clear. In the present study, changes in cognitive performance and structural brain connectomes in PC patients undergoing ADT were assessed, and associations of cognitive ch...

Turner syndrome (TS) is tightly associated with hypergonadotropic hypogonadism and ovarian dysgenesis, typically resulting in infertility in the great majority of patients. Therefore females with TS are usually treated with female sex steroids from 11-12 years of age until the normal age of natural menopause of around 53-54 years of age. Infertilit...

Background Ophthalmic complications are profound in Marfan syndrome (MFS). However, the overall burden is not well described. Our purpose was to evaluate the ocular morbidity in a nationwide perspective. Methods We identified the ocular morbidity in patients with MFS (n=407) by use of Danish national healthcare registers, using number and timing o...

Context: Turner syndrome women suffer from hypergonadotropic hypogonadism, causing a deficit in the gonadal hormone secretion. As a consequence, Turner syndrome women are treated with estrogen from the age of 12 years old, and later in combination with progesterone. However, androgens have been given less attention. Objective: To assess sex horm...

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of CAH due to 21-hydroxylase deficiency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries respond...

Background Marfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a life span, many patients with Marfan syndrome will need treatment; however, the musculoskeletal morbidity over a life span is not well described. The aim of the present...

An Endo-European Reference Network (ERN) guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult, and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was...

Objective: Klinefelter syndrome (KS) is associated with increased risk of thrombosis. Hypogonadism and accumulating body fat in KS have a potential impact on fibrinolysis. We assessed the fibrinolytic system and the association with testosterone levels in KS. Design: Cross-sectional comparison of men with KS and age-matched male controls. Methods:...

Introduction: Early detection of salt-wasting congenital adrenal hyperplasia (SW-CAH) is important to reduce CAH related morbidity. However, neonatal screening has shown to have a low positive predictive value (PPV), especially among preterm newborns. Here, the Danish CAH screening is evaluated by comparing incidence and morbidity of SW-CAH ten ye...

A higher incidence of cognitive impairment (CI) has previously been reported among orchiectomized testicular cancer patients (TCPs), but little is known about the underlying pathophysiology. The present study assessed CI in newly orchiectomized TCPs and explored the structural brain networks, endocrine status, and selected genotypes. Forty TCPs and...

Aims Adolescent offspring exposed to maternal diabetes during intrauterine life show a less favourable metabolic profile than the background population. Here, we hypothesize that offspring of women with type 1 diabetes (T1D), possess sex specific alterations in the serum profile of proteins involved in lipid, metabolic and transport processes and t...

The aims of this study were to examine presence of GAD65 autoantibodies (GAD65aab) in offspring born to women with type 1 diabetes (T1D) and controls and if more were GAD65aab-positive if diagnosed with diabetes or pre-diabetes. This EPICOM study is a prospective follow-up study focussing on pregnancies complicated by maternal T1D. The EPICOM study...

Background Marfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a life span, many patients with Marfan syndrome will need treatment; however, the musculoskeletal morbidity over a life span is not well described. The aim of the present...

Background: Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease in later in life. In this present study we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of f...

Objective: Women experience an unhealthy change in metabolic risk profile at menopause. The purpose of the present study was to determine effects of resistance training with or without transdermal estrogen therapy (ET) on adipose tissue mass and metabolic risk profile in early postmenopausal women. Methods: A double-blinded randomized controlled...

Purpose This study aimed to describe the comorbidity pattern in 47,XXX syndrome. Methods This was a registry-based study of hospital diagnoses and prescribed medication in a nationwide cohort of females with 47,XXX (n = 103) and 46,XX/47,XXX (n = 57) in which they were compared with 16,000 age-matched general population female controls. Results T...

The literature about eye, ear, nose, skin, and nervous system disorders in women with Turner syndrome is equivocal. Impaired vision and hearing in women with Turner syndrome have been described, and case reports of Turner syndrome girls suffering from epilepsy have been published, but no large population-based-studies have explored the occurrence o...

Sex is a modulator of health that has been historically overlooked in biomedical research. Recognizing this knowledge gap, funding agencies now mandate the inclusion of sex as a biological variable with the goal of stimulating efforts to illuminate the molecular underpinnings of sex biases in health and disease. DNA methylation (DNAm) is a strong m...

Objective Previous research has indicated cognitive decline (CD) among testicular cancer patients (TCPs), even in the absence of chemotherapy, but little is known about the underlying pathophysiology. The present study assessed changes in cognitive functions and structural brain connectomes in TCPs and explored the associations between cognitive ch...

Objectives Studies indicate that other cardiovascular problems than aortic disease are a burden for patients with Marfan syndrome (MFS). The aim of the study was to assess the extent of this issue. Methods A registry-based population study of patients with a Ghent II verified MFS diagnosis. Each patient was matched with up to 100 controls on age a...

Klinefelter syndrome (KS) is a frequent genetic condition caused by the presence of an extra X chromosome with the resultant karyotype being 47,XXY. The condition is in males and results in hypergonadotropic hypogonadism, small testis, and infertility, although recent research has shown that some KS males harbour sparse amounts of spermatocytes tha...

Aim Klinefelter Syndrome (KS) is the most frequent sex chromosome disorder in males. Due to hypergonadotropic hypogonadism treatment with testosterone replacement therapy (TRT) is commonly indicated. There are no international guideline for the most appropriate TRT in KS. We aimed to evaluate how different routes of testosterone administration impa...

The article What microRNAs could tell us about the human X chromosome.

Marfan syndrome (MFS), a rare genetic disease, has a prevalence of 6.5 in 100,000. Studies show that patients with MFS have reduced areal bone mineral density (BMD) compared with non-MFS individuals. We have previously shown that patients with MFS have reduced volumetric BMD and compromised trabecular and cortical bone microarchitecture. The presen...

Background: Liver and gastrointestinal diseases are frequent in women with Turner syndrome. However, their association with bleeding disorders, anaemia and the impact of hormone replacement therapy is unknown. Aims: To investigate the risk of liver and gastrointestinal diseases, haemorrhage and anaemia in women with Turner syndrome compared with...

In Marfan syndrome (MFS), pregnancy is considered as high risk due to the deficiency of fibrillin in the connective tissue and increased risk of aortic dissection. The objective was to demonstrate the consequences on maternal health, in women with diagnosed and undiagnosed MFS at the time of pregnancy and childbirth. By using national health care r...

The differential diagnoses of pubertal delay include hypergonadotropic hypogonadism and congenital hypogonadotropic hypogonadism (CHH), as well as constitutional delay of growth and puberty (CDGP). Distinguishing between CDGP and CHH may be challenging, and the scientific community has been struggling to develop diagnostic tests that allow an accur...

Context Women show an accelerated loss of muscle mass around menopause, possibly related to the decline in estrogen. Furthermore, the anabolic response to resistance exercise seems to be hampered in postmenopausal women. Objective We aimed to test the hypothesis that transdermal estrogen therapy (ET) amplifies the skeletal muscle response to resis...

Turner syndrome (TS) is a disorder of phenotypic females who have one intact X chromosome and complete or partial absence of their second sex chromosome. This results in a constellation of features that includes—but is not limited to: lymphedema, cardiac anomalies, short stature, primary ovarian failure, and neurocognitive difficulties, as the most...

Klinefelter syndrome (47,XXY) is a frequent chromosomal disorder among males, often presenting with hypergonadotropic hypogonadism, small firm testicles, metabolic disorders, neurocognitive challenges, and increased height. Neurologic disorders such as epilepsy, seizures, and tremor as well as psychiatric disorders are also seen more frequently. Th...