title: Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts.
abstract: What are the primary causes of severe male factor infertility?
  
  
  
  Although 40% of all patients showed primary causes of infertility, which could be subdivided into three groups based on the severity of their effect, ~75% of oligozoospermia cases remained idiopathic.
  
  
  
  There are few large-scale epidemiological studies analyzing the causes of male factor infertility.
  
  
  
  A prospective clinical-epidemiological study was conducted at the Andrology Centre, Tartu University Hospital between 2005 and 2013, recruiting male partners of couples failing to conceive a child for over ≥12 months. Among 8518 patients, 1737 (20.4%) were diagnosed with severe male factor infertility. A reference group of fertile controls was comprised of 325 partners of pregnant women.
  
  
  
  The mean age of infertility patients and fertile controls was 33.2 ± 7.3 and 31.7 ± 6.3 years, respectively. All participants were examined using a standardized andrology workup, accompanied by a structured medical interview. Hormonal analysis included serum FSH, LH and testosterone. Semen quality was determined in accordance to the World Health Organization recommendations. Cases with spermatozoa concentrations of ≤5 million/ml were screened for chromosomal aberrations and Y-chromosomal microdeletions.
  
  
  
  The primary cause of infertility was defined for 695 of 1737 patients (~40%). The analyzed causal factors could be divided into absolute (secondary hypogonadism, genetic causes, seminal tract obstruction), severe (oncological diseases, severe sexual dysfunction) and plausible causal factors (congenital anomalies in uro-genital tract, acquired or secondary testicular damage). The latter were also detected for 11 (3.4%) men with proven fertility (diagnoses: unilateral cryptorchidism, testis cancer, orchitis, mumps orchitis). The causal factors behind the most severe forms of impaired spermatogenesis were relatively well understood; causes were assigned: for aspermia in 46/46 cases (100%), for azoospermia in 321/388 cases (82.7%), and for cryptozoospermia in 54/130 cases (41.5%). In contrast, 75% of oligozoospermia cases remained unexplained. The main cause of aspermia was severe sexual dysfunction (71.7% of aspermia patients). Azoospermia patients accounted for 86.4% of all cases diagnosed with secondary hypogonadism and 97.1% of patients with seminal tract obstruction. Of patients with a known genetic factor, 87.4% had extreme infertility (azoo-, crypto- or aspermia). The prevalence of congenital anomalies in the uro-genital tract was not clearly correlated with the severity of impaired sperm production. Previously defined 'potential contributing factors' varicocele and leukocytospermia were excluded as the primary causes of male infertility. However, their incidence was >2-fold higher (31.0 vs 13.5% and 16.1 vs 7.4%; P < 0.001) in the idiopathic infertility group compared to controls. In addition, the proportions of overweight (or obese) patients and patients suffering from a chronic disease were significantly increased in almost all of the patient subgroups.
  
  
  
  The study included only subjects with reduced total spermatozoa counts. Thus, these findings cannot be automatically applied to all male factor infertility cases.
  
  
  
  The novel insights and improved clarity achieved in the comprehensive analysis regarding the absolute, causative and plausible factors behind male infertility, as well as the 'potential contributing factors', will be valuable tools in updating the current clinical guidelines. The study highlights knowledge gaps and reiterates an urgent need to uncover the causes and mechanisms behind, and potential treatments of, oligozoospermic cases, representing the majority of idiopathic infertility patients (86.3%).
  
  
  
  The project was financed by the EU through the ERDF, project HAPPY PREGNANCY, no. 3.2.0701.12-004 (M.P., M.L.) and the Estonian Research Council: grants PUT181 (M.P.) and IUT34-12 (M.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We have no competing interests to declare. TRAIL  REGISTRATION NUMBER: Not applicable.
authors.affiliation: Andrology Center, Tartu University Hospital, 50406 Tartu, Estonia margus.punab@kliinikum.ee.
authors.forename: M
authors.initials: M
authors.lastname: Punab
authors.affiliation: Andrology Center, Tartu University Hospital, 50406 Tartu, Estonia.
authors.forename: O
authors.initials: O
authors.lastname: Poolamets
authors.affiliation: Andrology Center, Tartu University Hospital, 50406 Tartu, Estonia.
authors.forename: P
authors.initials: P
authors.lastname: Paju
authors.affiliation: Andrology Center, Tartu University Hospital, 50406 Tartu, Estonia.
authors.forename: V
authors.initials: V
authors.lastname: Vihljajev
authors.affiliation: Andrology Center, Tartu University Hospital, 50406 Tartu, Estonia.
authors.forename: K
authors.initials: K
authors.lastname: Pomm
authors.affiliation: Andrology Center, Tartu University Hospital, 50406 Tartu, Estonia.
authors.forename: R
authors.initials: R
authors.lastname: Ladva
authors.affiliation: Andrology Center, Tartu University Hospital, 50406 Tartu, Estonia.
authors.forename: P
authors.initials: P
authors.lastname: Korrovits
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology; Institute of Biomedicine and Translational Medicine, University of Tartu, 51010 Tartu, Estonia.
authors.forename: M
authors.initials: M
authors.lastname: Laan
mesh_terms: D000328:Adult; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007248:Infertility, Male / Q000097:blood / Q000209:etiology*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D055101:Semen Analysis; D012720:Severity of Illness Index; D013076:Sperm Count; D013091:Spermatogenesis / Q000502:physiology*; D013094:Spermatozoa; D013739:Testosterone / Q000097:blood; D055815:Young Adult
chemical_list: D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
keywords: aspermia; azoospermia; causal factors; contributing factors; cryptozoospermia; epidemiology; idiopathic infertility; male factor infertility; oligozoospermia