Niels Jørgensen

• MD, PhD
• Consultant at Rigshospitalet

Background and Objectives A few studies have explored the impairment of pituitary gonadotroph and Leydig cell function in men who recently ceased illicit androgen use, as assessed by stimulation tests. However, the capacity of the pituitary-testis axis in previous users who discontinued androgen use years ago remains unclear. This study evaluated t...

STUDY QUESTION Is semen quality associated with the lifespan of men? SUMMARY ANSWER Men with a total motile sperm count of >120 million could expect to live 2.7 years longer than men with total motile sperm count of >0–5 million. WHAT IS KNOWN ALREADY Male infertility and semen quality have been suggested to be markers of morbidity and thus morta...

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...

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Context: Clinical studies of psychiatric morbidity in patients with congenital adrenal hyperplasia (CAH) imply impaired mental health. Objective: To delineate psychiatric morbidity in a national CAH cohort by using complete data on psychiatric diagnoses from all Danish hospitals between 1977-2018 and on all psychiatric medication prescribed betw...

Introduction: Congenital adrenal hyperplasia (CAH) is characterized by a broad spectrum of symptoms. This study aimed 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, at the age...

Disclosure: M. Lind-Holst: None. D. Hansen: None. K.M. Main: None. A. Juul: None. M. Andersen: None. M. Dunø: None. Å.K. Rasmussen: None. N. Jørgensen: None. C.H. Gravholt: None. A. Berglund: None. Background: Clinical studies on psychiatric morbidity, quality of life and cognition in patients with congenital adrenal hyperplasia (CAH) imply impaire...

Disclosure: M. Lind-Holst: None. D. Hansen: None. K.M. Main: None. A. Juul: None. M. Andersen: None. M. Dunø: None. Å.K. Rasmussen: None. N. Jørgensen: None. C.H. Gravholt: None. A. Berglund: None. Background: Clinical studies on psychiatric morbidity, quality of life and cognition in patients with congenital adrenal hyperplasia (CAH) imply impaire...

Background Testosterone treatment is generally not recommended in men with obesity induced low serum testosterone. However, distinguishing this condition from overt testosterone deficiency in men with obesity where treatment should be initiated is a diagnostic challenge and tools to differentiate these conditions are scarce but could be of importan...

BACKGROUND The widespread interest in male reproductive health (MRH), fueled by emerging evidence, such as the global decline in sperm counts, has intensified concerns about the status of MRH. Consequently, there is a pressing requirement for a strategic, systematic approach to identifying critical questions, collecting pertinent information, and u...

Congenital cryptorchidism, also known as undescended testis, is the condition where one or both testes are not in place in the scrotum at birth and is one of the most common birth defects in boys. Temporal trends and geographic variation in the prevalence of cryptorchidism from 1% to 9% have been reported in prospective cohort studies. The testes d...

Background Vitamin D has been suggested to influence the immune system, and vitamin D metabolites and the vitamin D receptor (VDR) are generated and expressed in white blood cells (WBC). Moreover, vitamin D status has been associated with incidence and prognosis of some respiratory tract infections (RTI). Therefore, we investigated the effect of vi...

Fertility restoration using autologous testicular tissue transplantation is relevant for infertile men surviving from childhood cancer and, possibly, in men with absent or incomplete spermatogenesis resulting in the lack of spermatozoa in the ejaculate (non-obstructive azoospermia, NOA). Currently, testicular tissue from pre-pubertal boys extracted...

Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients g...

Obesity is associated with low vitamin D status and the optimal supplement and dosage of cholecalciferol (vitamin D 3 ) or calcidiol (25OHD) for individuals with obesity has been debated. We aimed to determine the effect of high-dose vitamin D 3 supplementation on achieving adequate vitamin D levels among infertile men with normal weight versus obe...

Disclosure: M. Lind-Holst: None. A. Berglund: None. M. Duno: None. G. Hvistendahl: None. M. Fossum: None. A. Juul: None. N. Jørgensen: None. K.M. Main: None. C.H. Gravholt: None. D. Hansen: None. Background: Congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency (21OHD) is a common autosomal recessive disorder caused by pathogenic va...

The purpose of this article is to provide an explanation of the background behind a checklist that declares the laboratory methods used in a scientific study. It focuses primarily on implementing laboratory procedures to yield reliable results in basic semen examinations. While the World Health Organization (WHO) and international standards provide...

Objective: Vitamin D status has been associated with sex steroid production. The question is whether vitamin D supplementation has an impact on sex steroid production in infertile men with vitamin D insufficiency? Design: A single-center, double-blinded, randomized clinical trial. Differences in sex steroids and reproductive hormones were predef...

Introduction: Mild Leydig cell insufficiency affects a substantial proportion of testicular cancer survivors. Previous studies have not shown a beneficial effect of testosterone replacement therapy, however, with a pronounced interindividual effect. Thus, biomarkers identifying the subgroups that might benefit are wanted. We aimed to determine if...

Background: SARS-CoV-2 may affect the male reproductive system as it uses angiotensin-converting enzyme [ACE]2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long-term effects of mild COVID-19 on testicular function, and INSL3 levels have not previously been assessed during acute SARS-CoV-...

Background Testicular cancer survivors (TCS) are at risk of Leydig cell insufficiency, which is a condition characterized by elevated luteinising hormone (LH) in combination with low levels of testosterone. It has been suggested that this condition is associated with impaired metabolic profile and low bone mineral density (BMD). The primary aim of...

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...

Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitor...

Over the last twenty-five years it has become evident that exposure to several phthalates can have adverse effects on human health, such as endocrine disruption. This led to a series of EU regulations that resulted in a decrease in the production volumes of the restricted phthalates and an increased production of substitutes. The current study desc...

Background Anti-Müllerian hormone (AMH) is released by testicular Sertoli cells and of great importance during fetal male sexual development, but less is known about the role of circulating AMH during adulthood. In vitro studies have shown that vitamin D may induce AMH transcription, but a controlled trial investigating the possible effect of vitam...

Background: Phthalate exposure during fetal life may disrupt testicular development. Congruent with this, studies have found shorter anogenital distance, reduced penile size, and altered hormone levels in infant boys whose mothers were higher exposed to some phthalates during pregnancy. Few studies have explored if such adverse effects persist int...

Asthma is driven by an inflammatory response that may impact testicular function. In this cross-sectional study, we investigated the association between self-reported asthma and testicular function (semen parameters, reproductive hormone levels), and determined whether potential further inflammation due to self-reported allergy modified this associ...

STUDY QUESTION Is prior testicular torsion associated with testicular function (semen quality and reproductive hormones) in young men from the general population? SUMMARY ANSWER In young men from the general population, no differences in semen parameters were observed in those who had experienced testicular torsion compared to controls and observa...

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed N...

Background: Testicular function, including compensated Leydig cell function, has been indicated to be an early marker of morbidity. Objective: To study the association of testicular function and markers of metabolic and cardiovascular health in a population of young men. Materials and methods: Cross-sectional study of 2,289 men (median age 19...

Introduction Environmental exposure during fetal life may disrupt testicular development. In humans, a limited number of studies have investigated whether these adverse effects persist into adulthood. Using data from a prospective, population-based birth cohort study, The Copenhagen Mother-Child cohort, the objective was to assess if there is an as...

BACKGROUND Numerous studies have reported declines in semen quality and other markers of male reproductive health. Our previous meta-analysis reported a significant decrease in sperm concentration (SC) and total sperm count (TSC) among men from North America–Europe–Australia (NEA) based on studies published during 1981–2013. At that time, there wer...

Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain function of the pituitary-testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary-testis axis following adjuvant...

Background: It has been estimated that microorganisms are involved in the pathogenesis of approximately 20% of all cancers. Testicular germ cell tumours (TGCTs) are the most common type of malignancy in young men and arise from the precursor cell, germ cell neoplasia in situ (GCNIS). The microbiome of seminal plasma and testicular tissue has not b...

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination a...

Objective Self-reported psychological stress has been associated with decreased semen quality. Cortisol levels in scalp hair (hair cortisol concentration, HCC) has emerged as a potential objective marker of psychological stress. Thus, we investigated if HCC was associated with markers of testicular function. Furthermore, we examined whether three c...

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable with current medicine. Due to the biological complexity of sperm production, defining the genetic basis of NOA has proven challenging, and to date, the most advanced classification of NOA subforms is based on simple description of testis histology....

Background Infertility is a common problem globally and impaired semen quality is responsible for up to 40% of all cases. Almost all infertile couples are treated with either insemination or assisted reproductive techniques (ARTs) independent of the etiology of infertility because no medical treatment exists. Denosumab is an antibody that blocks RA...

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...

Background Infertile men with non-obstructive azoospermia (NOA) have impaired spermatogenesis. Dilated and un-dilated atrophic seminiferous tubules are often present in the testes of these patients, with the highest likelihood of active spermatogenesis in the dilated tubules. Little is known about the un-dilated tubules, which in NOA patients const...

Background Semen quality in men continues to decline in Western countries, but the contours of the issue remain obscure, in relation to contributing chemicals. Objectives To obtain more clarity about the chemicals that drive the deterioration of semen quality, we conducted a mixture risk assessment based on European exposures. Methods We included...

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...

Background Surgical extraction of testicular spermatozoa is needed in men with nonobstructive azoospermia (NOA) who wish to become biological fathers. Based on available uncontrolled studies with unspecific patient selection, microdissection testicular sperm extraction (mTESE), having a sperm retrieval rate (SRR) of 50%, is considered the most effi...

Background Testicular cancer (TC) treatment leaves many patients with low levels of testosterone. While most TC patients with low testosterone (< - 2 SD) and hypogonadal symptoms will initiate testosterone replacement therapy (TRT), the role of TRT in patients with mild Leydig cell insufficiency, defined as elevated luteinizing hormone in combinati...

Context: It remains unknown how the postnatal activation of the hypothalamic-pituitary-gonadal axis in infancy, also known as 'minipuberty', relates to adult testis function. Objective: To investigate how markers of reproductive function in three-month-old boys correlate with adult reproductive health parameters. Design: Population-based birth...

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 inferti...

A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are al...

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...

Context Vitamin D has been linked with glucose and lipid metabolism. Men with impaired gonadal function have a higher risk of metabolic syndrome and mortality, and vitamin D status may be a reversible modulator. Objective Determine the effect of daily vitamin D and calcium supplementation for 150 days on glucose and lipid homeostasis in infertile...

Background: P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells, where they regulate aberrant expression of transposable elements and postmeiotic gene expression. Critical to the processing of piRNAs is the protein poly(A)-specific R...

Background Infertility affects 15–25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques av...

Circulating miRNAs secreted by testicular germ cell tumors (TGCT) show great potential as novel non-invasive biomarkers for diagnosis of TGCT. Seminal plasma (SP) represents a biofluid closer to the primary site. Here, we investigate whether small RNAs in SP can be used to diagnose men with TGCTs or the precursor lesions, germ cell neoplasia in sit...

Background: Illicit use of anabolic androgenic steroids (AAS) has emerged as a public health concern among men, but the long-term effect on gonadal function is still unresolved. Serum insulin-like factor 3 (INSL3) has emerged as a novel and potentially superior marker of Leydig cell function than serum testosterone per se. INSL3 synthesis and secre...

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are agonists for the luteinizing hormone receptor (LHCGR) which regulates male reproductive function. LHCGR may be released into body fluids. We wish to determine whether soluble LHCGR is a marker for gonadal function. Cross-sectional, longitudinal, and intervention studies on 195 heal...

Background Illicit use of anabolic androgenic steroids (AAS) is frequently observed in men and is associated with subsequent testosterone deficiency although the long-term effect on gonadal function is still unclear. Serum insulin-like factor 3 (INSL3) has been suggested to be a superior biomarker of Leydig cell secretory capacity compared to testo...

Recent in vitro studies have shown that some chemical UV filters mimic the effect of progesterone in the activation of the CatSper Ca2⁺ channel in human spermatozoa. However, so far, the extent of exposure of human spermatozoa to chemical UV filters via the presence of these chemicals in seminal fluid has been unknown. Here, we present levels of UV...

STUDY QUESTION Is testicular function associated within father–son pairs? SUMMARY ANSWER Familial resemblance in testis volume and serum markers of spermatogenesis was observed in father–son pairs. WHAT IS KNOWN ALREADY Studies suggest familial clustering of male subfertility and impaired spermatogenesis, but in men from the general population li...

Background Spermatogenesis depends on stimulation by follicle‐stimulating hormone (FSH) which binds to FSH receptors (FSHR) on testicular Sertoli cells. Three FSH‐related single‐nucleotide polymorphisms (SNPs), FSHB ‐211G>T (rs10835638), FSHR ‐29G>A (rs1394205) and FSHR 2039A>G (rs6166) affect FSH action, and have been suggested to affect testicula...

Objective To evaluate the association between cannabis use and testicular function (as assessed through semen quality and serum hormone levels) in different populations. Evidence Review Systematic review and meta‐analysis of population‐based retrospective cohort studies. PRISMA guidelines were used for abstracting data and assessing data quality a...

Background Assessment of semen quality is a key pillar in the evaluation of men from infertile couples. Usually, semen parameters are interpreted individually because the interactions between parameters are difficult to account for. Objectives To determine how combinations of classical semen parameters and female partner age were associated with w...

Study question: What are the consequences of ageing on human Leydig cell number and hormonal function? Summary answer: Leydig cell number significantly decreases in parallel with INSL3 expression and Sertoli cell number in aged men, yet the in vitro Leydig cell androgenic potential does not appear to be compromised by advancing age. What is kno...

Study question: Is there a difference in testicular function in early adulthood between men born with cryptorchidism and men born with normally descended testes? Summary answer: In men from the general population, a history of cryptorchidism was associated with lower total testis volume and impaired semen quality as well as altered serum levels...

Background Studies have reported associations between psychological stress and semen quality, but most have been performed on selected populations using different stress measures. Thus, it is uncertain which stress scale best quantifies the effects of stress on testicular function. Objective To study the association between three different measure...

Background Testicular microlithiasis (TM) is sometimes found on scrotal ultrasound. The prevalence seems higher in populations of men with testicular dysfunction, and TM may be a risk factor for testicular germ cell neoplasia in situ in men with additional risk factors. The association between TM and testicular function is controversial, especially...

Study question: Are use of e-cigarettes and snuff associated with testicular function as previously shown for conventional cigarettes and marijuana? Summary answer: Use of e-cigarettes is associated with reduced semen quality but not with higher serum testosterone level as observed for conventional cigarette use. Snuff use was not associated wit...

Context. Determining the free or bioavailable testosterone level has gained increasing interest over the years and different indirect algorithms have been suggested. Objective. To compare commonly used algorithms of calculation of serum free testosterone, specifically free androgen index (FAI), free testosterone estimated using the Vermeulen algori...

Background Male infertility is associated with a higher long-term morbidity and mortality risk. However, it is not clear which diseases are contributing to this risk. Osteoporosis is a possible factor, as it is a frequent disease and sex steroids regulate both fertility and bone health. Furthermore, there are data indicating that high FSH levels in...

Background The peptide hormone Insulin-like factor 3 (INSL3) is a marker for Leydig cell function and the clinical use of serum INSL3 measurements has been suggested by several groups. Aim i) To establish a reference range for LC-MS/MS of serum INSL3 in healthy boys and men and ii) to compare the associations of serum INSL3 and testosterone (T) to...

Objective To assess the association between psychological stress and male factor infertility as well as testicular function (semen quality, serum reproductive hormones) and erectile dysfunction. Design Cross-sectional study. Setting University Hospital-based research center. Patients Men with impaired semen quality were included from infertile c...

Importance Diet may play a role in testicular function, but data on how adherence to different diet patterns influences human testicular function are scarce. Objective To determine whether adherence to specific dietary patterns is associated with testicular function in young men. Design, Setting, and Participants This cross-sectional study includ...

Importance Many young men have poor semen quality, and the causes are often unknown. Supplement intake of ω-3 polyunsaturated fatty acid has been found to improve semen quality among men with infertility, but the association with semen quality among healthy men is unknown. Objective To determine if intake of ω-3 fatty acid supplements is associate...

Production of testosterone is under tight control by human chorion gonadotropin (hCG) during fetal life and luteinizing hormone (LH) in adulthood. Several animal and human studies have linked vitamin D status with sex steroid production although it is not clear whether there exist a direct or indirect involvement in androgen production. Few studies...

During the past two decades human exposure to bisphenol A (BPA) and phthalates such as di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP) and di-(2-ethyl-hexyl) phthalate (DEHP) has received substantial interest due to widespread population exposures and potential endocrine disrupting effects. Therefore, these...

Background: Relatively low sperm count was reported among young Spanish men in 2013. Several potential culprits have been suggested as explanations for reported trends in sperm counts in Western men, including lifestyles. Although controversial, some studies suggest that semen parameters, such as low sperm motility or abnormal morphology, may be a...

Study question: Is adherence to an a priori defined diet quality indices [Alternate Healthy Index 2010 (AHEI-2010), relative Mediterranean diet score (rMED) or dietary approaches to stop hypertension (DASH)] associated with semen quality and reproductive hormone levels in young men? Summary answer: Greater adherence to the DASH diet is related t...

Introduction: The FSH receptor (FSHR) has been found to be expressed in human bone cells and bone marrow-adipocytes, and highly-debated mouse studies have suggested extra-gonadal effects of gonadotropins on glucose, adipocyte and bone homeostasis. These putative effects could be direct or indirectly mediated by endocrine factors released from bone...

The aim of this study was to assess the associations of intake of different types of meat with semen parameters and reproductive hormones in healthy young men. This cross-sectional study included 206 men, 18–23 years, from Southern Spain. All men completed a validated FFQ, underwent a physical examination, and provided blood and semen samples. Mult...

Background: The filaggrin gene (FLG) encodes an epidermal protein, filaggrin, which is important for normal skin barrier functions. We previously showed that FLG loss-of-function mutation carriers have a higher internal exposure to some non-persistent chemicals such as certain phthalates and parabens, suggesting increased trans-epidermal penetrati...

Semen quality may be adversely affected by exposure to environmental chemicals such as polychlorinated biphenyls (PCBs) and perfluorinated alkylate substances (PFASs) that are persistent and may act as endocrine disrupting compounds. The aim of this study was to explore whether PCBs or PFASs exposure were associated with abnormalities in semen qual...

Background The circulating level of the peptide hormone insulin-like factor 3 (INSL3) is a promising diagnostic marker reflecting Leydig cell function in the male. Few commercial immunoassays of varying quality exist. Therefore, we decided to develop and validate a precise method for quantification of INSL3 by mass spectrometry. Methods We develop...

Background: Benzophenone (BP)-type ultraviolet (UV) light filters are chemicals frequently added to personal care products, insect repellents, sunscreens, and beverage and food packaging to diminish the harmful effects of UV sunlight on human skin or foodstuffs. BP-type UV filters have shown negative effects on male reproduction function in in vit...

Study question: Is it possible, in an unbiased and clinical relevant way, to determine the number of viable acrosome-intact human spermatozoa in ejaculates and to use this as a measure of fertility chances? Summary answer: Image cytometry enables easy and unbiased quantification of viable acrosome-intact spermatozoa and it correlates with semen...