title: Compensated reduction in Leydig cell function is associated with lower semen quality variables: a study of 8182 European young men.
abstract: OBJECTIVE
  Is the Leydig cell function of young European men associated with semen quality?
  
  
  CONCLUSIONS
  Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality.
  
  
  BACKGROUND
  Semen quality of young European men shows a heterogeneous pattern. Many have sperm counts below and in the lower WHO reference where there nevertheless is a significant risk of subfecundity. Little is known about differences in Leydig cell function between men with semen quality below and within the WHO reference range.
  
  
  METHODS
  A coordinated, cross-sectional population-based study of 8182 men undertaken in 1996-2010.
  Young men (median age 19.1 years) were investigated in centres in Denmark, Estonia, Finland, Germany Latvia, Lithuania, and Spain. The men originated from the general populations, all were young, almost all were unaware of their fecundity and each provided a semen and blood sample. Associations between semen parameters and serum levels of testosterone and luteinising hormone (LH), calculated free testosterone, and ratios between serum testosterone and LH were determined.
  Serum testosterone levels were not associated with sperm concentrations, total sperm counts, or percentage of motile or morphologically normal spermatozoa. There was an inverse association between the semen parameters and serum LH levels, and accordingly a positive association to testosterone/LH ratio and calculated-free-testosterone/LH ratio.
  
  
  CONCLUSIONS
  The size of the study mitigates the intra-individual variability concern. The distinction between different sub-categories of sperm motility and sperm morphology is subjective despite training. However, inter-observer variation would tend towards non-differential misclassification and would decrease the likelihood of detecting associations between reproductive hormone levels and semen variables, suggesting that the presented associations might in reality be even stronger than shown. Although we adjusted for confounders, we cannot of course exclude that our results can be skewed by selection bias or residual confounding.
  
  
  CONCLUSIONS
  Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality. This is apparent even within the WHO reference range of semen quality. It is unknown whether impaired Leydig cell function in young men may confer an increased risk of acquired testosterone deficiency later in life.
  
  
  BACKGROUND
  Support from The Research Fund of Rigshospitalet (grant no. R42-A1326) to N.J. made this study possible. The background studies of young men have been supported economically by several grants. ITALIC! Denmark: The European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603 and most recently FP7/2007-2013, DEER Grant agreement no. 212844), The Danish Research Council (grants nos. 9700833 2107-05-0006), The Danish Agency for Science, Technology and Innovation (Grant no. 271070678), Rigshospitalet (Grant no. 961506336), The University of Copenhagen (Grant no. 211-0357/07-3012), The Danish Ministry of Health and the Danish Environmental Protection Agency, A.P. Møller and wife Chastine McKinney Møllers foundation, and Svend Andersens Foundation. ITALIC! Finland: European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT- 2002-00603 and most recently FP7/2008-2012, DEER Grant agreement no. 212844), The Academy of Finland, Turku University Hospital Funds, Sigrid Juselius Foundation. ITALIC! Estonia, Latvia and Lithuania: European Union (QLRT-2001-02911), the Estonian Science Foundation, grant number 2991, Lithuanian Foundation for Research, Organon Agencies B.V. and the Danish Research Council, grant no. 9700833. ITALIC! Germany: European Union (contract numbers QLK4-CT-2002-00603). ITALIC! Spain: European Commission QLK4-1999-01422. M.F. received support from the Spanish Ministry of Science and Innovation (Program Ramon y Cajal). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors have any competing interests to declare.
authors.affiliation: University Department of Growth and Reproduction, Rigshospitalet, 2100 Copenhagen, Denmark niels.joergensen@rh.regionh.dk.
authors.forename: N
authors.initials: N
authors.lastname: Jørgensen
authors.affiliation: University Department of Growth and Reproduction, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: U N
authors.initials: UN
authors.lastname: Joensen
authors.affiliation: Department of Physiology, University of Turku, FI-20520 Turku, Finland Department of Paediatrics, University of Turku, FI-20520 Turku, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Andrology Unit, Tartu University Hospital, 50406 Tartu, Estonia.
authors.forename: M
authors.initials: M
authors.lastname: Punab
authors.affiliation: Biomedicine Study and Research center, Ratsupites 1, Riga LV 1047, Latvia.
authors.forename: J
authors.initials: J
authors.lastname: Erenpreiss
authors.affiliation: Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
authors.forename: B
authors.initials: B
authors.lastname: Zilaitiene
authors.affiliation: Department of Dermatology, University of Leipzig, Philipp-Rosenthal-Strasse 23, 04103 Leipzig, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Paasch
authors.affiliation: Department of Andrology, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Salzbrunn
authors.affiliation: University of Granada, San Cecilio University Hospital, Instituto de Investigación Biosanitaria ibs.GRANADA 18071 Granada, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Fernandez
authors.affiliation: Department of Physiology, University of Turku, FI-20520 Turku, Finland.
authors.forename: H E
authors.initials: HE
authors.lastname: Virtanen
authors.affiliation: Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
authors.forename: V
authors.initials: V
authors.lastname: Matulevicius
authors.affiliation: University of Granada, San Cecilio University Hospital, Instituto de Investigación Biosanitaria ibs.GRANADA 18071 Granada, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Olea
authors.affiliation: University Department of Growth and Reproduction, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: T K
authors.initials: TK
authors.lastname: Jensen
authors.affiliation: University Department of Growth and Reproduction, Rigshospitalet, 2100 Copenhagen, Denmark Department of Biostatistics, University of Copenhagen, Øster Farimagsgade 5, Box 2099, 1014 Copenhagen, Denmark.
authors.forename: J H
authors.initials: JH
authors.lastname: Petersen
authors.affiliation: University Department of Growth and Reproduction, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: N E
authors.initials: NE
authors.lastname: Skakkebæk
authors.affiliation: University Department of Growth and Reproduction, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: A-M
authors.initials: AM
authors.lastname: Andersson
mesh_terms: D000328:Adult; D003430:Cross-Sectional Studies; D005060:Europe; D005298:Fertility; D006801:Humans; D007985:Leydig Cells / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D011446:Prospective Studies; D012016:Reference Values; D055101:Semen Analysis; D013739:Testosterone / Q000097:blood
chemical_list: D013739:Testosterone; D007986:Luteinizing Hormone
keywords: Leydig cell failure/function; luteinising hormone; semen quality; testosterone; young men