The Research Group of Reproductive Epidemiology, Testicular Function and Pathology

Through work in large-scale cohorts, epidemiological studies and laboratory investigations we explore trends in and determinants of testicular function and pathology.

The group has a rich history of making important contributions to the understanding of reduced testicular function. Through work in large-scale cohorts, epidemiological studies and laboratory investigations we explore trends in and determinants of testicular function and pathology.

Main research areas

Since 1996 the group has undertaken and coordinated Danish and international scientific projects addressing testicular function in more than 12,000 young men from the general population and amongst groups of fertile or infertile men. The studies have made important internationally recognised scientific contributions including: 

  • Describing testicular function (semen quality, endocrine function and their interactions) of men from the general population
  • Describing time trends in semen quality in young men from the general population
  • Assessing determinants of reduced testicular function such as exogenous exposures, lifestyle and genetic factors
  • Ascertaining the important differences in fertile and infertile men, for example differences in psychological stress according to validated scales as well as differences in lifestyle.

Testicular dysgenesis syndrome (TDS)

Impaired semen quality, testicular cancer, cryptorchidism and hypospadias are highly correlated, and TDS has been put forward to explain that observation. TDS implies that disturbed testicular development in early fetal life as a shared patho-physiological aetiology results in increased risk of the four disease entities. It seems likely that the rapid rise in TDS-associated conditions can, at least partly, be explained by environmental factors. Fetal exposure to endocrine disrupting substances may play a role, although genetic factors are probably also involved. However, determining causal relationships is a pivotal research theme of our group although we acknowledge that this is inherently difficult to establish in humans.

Postnatal modification of testicular capacity

It is also well established that events not linked to early development of testicles may also impair semen quality and reproductive hormone production. Our work has shown that an association between exposure to some endocrine disrupting chemicals and lifestyle factors in adulthood and reduced testis function does also exist. We continue work in this area to establish the degree to which such potential effects are reversible. 

Semen quality as a biomarker of general health

Reduced semen quality may represent a universal biomarker of later health and survival as the “the canary in the coal mine”. We know that associations between semen quality in young adulthood and health later in life may be confounded by current health and lifestyle factors. Despite the adverse effects of such factors, they do, however, not explain the overall associations between semen quality and morbidity. We have recently recognised that men seeking help for infertility could be a relevant target for preventive measures aiming to achieve healthy aging. Our work in understanding semen as a biomarker of general health will provide information that is presently lacking so that preventive actions can be taken to reduce the long-term negative health effect that are associated with reduced semen quality.

About some of our cohorts 

Danish Young Men Study (DYMS, ongoing)

In Denmark, it is compulsory for all young men, except those suffering from severe or chronic diseases, to attend a medical examination before being considered for military service. In collaboration with the military health authority, young men attending these examinations in the greater Copenhagen area, Denmark have since 1996 been asked to participate in our “Danish Young Men Study” (DYMS). Those who consent are examined at the Department of Growth and Reproduction at Rigshospitalet. Participants, representing the general population, complete a questionnaire covering demographics, lifestyle and reproductive and general health, they deliver a semen sample, a urine sample and have a blood sample drawn. Semen samples are immediately assessed for classical as well as new, potentially relevant quality parameters. Blood samples are analysed for reproductive hormone levels and basic health markers and DNA is extracted. The men also undergo a physical examination including ultrasonography of their testicles (volume and texture) and whole body DEXA-scan for determination of bone mineral density and body composition. Urine, remaining semen, blood and DNA are stored in our biobank for future analyses. These men can be followed up in the national CPR, health and prescription registries for vital status and disease incidence.

Infertile men

More than 500 men are annually investigated in the outpatient clinic at Department of Growth and Reproduction at Rigshospitalet due to severely impaired semen quality and infertility. We have a long tradition for including these men in various projects including follow-up studies. During 2020 we will launch a large novel study of men from infertile couples in collaboration with the four public fertility clinics in the Capital Region of Denmark and the Reproductive Medicine Centre at Skåne University Hospital, Sweden (“The ReproUnion Infertility Cohort” (ReCo)). During the coming years we aim to include 5,000 men and 5,000 women from infertile couples (2,500 couples in Denmark and 2,500 in Sweden). The overarching goal of this joint Danish-Swedish project is to phenotypically characterize couples referred due to infertility and collect biological specimens in order to establish a biobank from a well characterized prospective cohort. Once established, the joint Danish-Swedish infertility cohort and biobank will represent a valuable resource for identifying causes of infertility. All participants will answer a detailed questionnaire. At our department, the Danish male participants will undergo a physical examination (a rectal swap, ultrasonography of the testicles), and have a DEXA scan performed,  deliver urine/ semen samples as well as have a blood sample drawn. The Danish female participants will likewise be assessed at the Fertility Clinics. Long term follow-up in national CPR, health and prescription registries for vital status and disease incidence as well as follow-up visits are planned.

Fertile men

Fertile men have been examined in 1996-1998 and again in 2012-2014 and constitute a control group for our study of young men and infertile men. The fertile men were 20-45 years old and were invited to participate in the study when their female partners were examined routinely during the second trimester of pregnancy. The pregnancies were achieved by natural conception and not the result of fertility treatment. The men were examined according to the same protocol as the young men (cf. DYMS). For these fertile men urine, semen and blood have also been stored in our biobank.

Danish Semen quality database (DaSe)

The database consists of semen quality data from 1963-2015 from two public semen analysis laboratories in the Copenhagen area (The Copenhagen Primary Care Laboratory (N=80,000) and the Frederiksberg Semen Laboratory (N=5,000).  The men were referred to the laboratories for a semen quality screen due to reported couple infertility. The database includes semen quality data representing a wide spectrum from azoospermia (no sperm) to men having superior semen quality. Men will be linked to Danish nationwide registries to obtain follow-up information on vital status and diseases to examine associations between semen quality and health.

Disrupt - The National Danish Biobank maintained by Staten’s Serum Institute

In Denmark, all women are offered a free screen for congenital diseases and chromosomal defects in offspring in the first trimester of their pregnancy, consisting of an ultrasound scan as well as an amniotic fluid and blood sample. Samples were collected, according to informed signed consent, from over 120,000 of the screened pregnant women in the 20-year period from 1976-1996 and stored for research purposes in the Danish National Biobank. Data from the biobank are linked to demographic information from national administrative registries on an individual level and can be linked to any registry via the unique id number of each individual in Denmark. In our DISRUPT study we incorporate prenatal measures of endocrine disrupting chemicals quantified in serum and amniotic fluid collected from these pregnancies and these are related to the subsequent risk of testicular cancer (cf. TDS) in adult male off-spring.

Histology

Our research group perform histological evaluation of testicular biopsies mainly from infertile men and from patients with Disorders of Sexual Development (DSD). The biopsies are described for dysgenetic patterns, including presence of Germ-Cell-Neoplasia in-situ (GCNIS) and spermatogenesis. Introduction and validation of immunohistochemical staining with FAAH (fatty acid amid hydrolase) for optimizing the evaluation of spermatogenesis is ongoing. FAAH is a cannabinoid-metabolising enzyme that is expressed in late spermatocytes and post-meiotic germ cells.

Other activities

National and international clinical guidelines

Members of our research group are co-authors of Danish national guidelines on male hypogonadism (LINK) and gynecomastia (LINK) as well as the European guideline on gynecomastia (LINK). We are currently drafting a European guideline on evaluation of testis biopsies and a European guideline on Klinefelter syndrome together with international colleagues.

Editorial work

Niels Jørgensen is associate editor at “Andrology” and Lærke Priskorn at “Human Reproduction”.

Current members

Rigshospitalet, Copenhagen, Denmark

  • Niels Jørgensen, MD, PhD, Head of Clinical Andrology Section, specialist in medical endocrinology and certified Andrologist
  • Lærke Priskorn, PhD
  • Elvira Bräuner, MSc, PhD
  • Niels Erik Skakkebæk, Professor, MD, PhD
  • Ann Holm Hansen, MSc
  • Trine Koch, MSc
  • Lise Aksglæde, MD, PhD, specialist in Clinical Genetics and EAA certified clinical Andrologist

Rigshospitalet, Copenhagen, Denmark and Department of Environmental Medicine, University of Southern Denmark

  • Tine Kold Jensen, Professor, MD, PhD

External group members, University of Copenhagen, Denmark

  • Christen Lykkegaard Andersen, associate professor, MD, DMSc, PhD, project leader for The Copenhagen Primary Care Laboratory Database (CopLab) including the semen quality data for this project and many other health data. 
  • Jørgen Holm Petersen, Associate professor, PhD, Statistician. Expertice in calculating reference curves for reproductive parameters, and analyses of reproductive health exposures. General statistics consultant.

Current key collaborators

University of Southern Denmark

  • Professor Rune Lindahl-Jacobsen leads the Biodemography research group at the Department of Epidemiology, Biostatistics and Biodemography where his research has focused on male and female reproduction/fecundity, their patterns and their link to health and mortality.

Harvard University, Chan School of Public Health, USA:

  • Russ Hauser, MD, Professor, Chair of Department of Environmental Health, has expertise within the fields of reproductive epidemiology and children’s health in relation to exposure to endocrine disrupting chemicals. 
  • Jorge E. Chavarro, MD, ScD, Associate Professor of Nutrition, Epidemiology and Medicine, has extensive experience conducting research evaluating how nutrition and other modifiable lifestyle factors impact human reproduction, including testicular function and men’s contribution to fertility and pregnancy health. 

Icahn School of Medicine at Mount Sinai, New York, USA:

  • Dr. Shanna Swan, Professor of Environmental Medicine and Public Health has expertise in conducting multi-center pregnancy cohorts to better understand how prenatal and early childhood exposure to stressors, including environmental chemicals and pharmaceuticals, impact childrens’ reproductive health and development. 

Stanford, USA:

  • Michael Eisenberg, MD, Associate Professor of Urology, has conducted several studies on the association between reproductive and general health in US male populations. 

University of Tartu and Tartu University Hospital, Estonia:

  • Maris Laan, Professor, has expertise in genetics and genomics, covering a broad spectrum of male and female reproductive phenotypes and disorders.
  • Margus Punab, MD, Professor, has established the andrology discipline in Estonia and has a long-term and comprehensive experience of clinical research in andrology.

University of Turku, Finland:

  • Professor Jorma Toppari has extensive expertise in pediatric endocrinology and reproductive medicine. He has conducted joint studies with our group in Finland. These include a large birth cohort study on development of male reproductive organs and repeated cohort studies on semen quality in general population.


Responsible editor