Reviewed research

Authors Punab M, Poolamets O, Paju P, et al.

Review Date November 2016

Citation Human Reproduction (Advance Access) 2016; November 17: doi:10.1093/humrep/dew284



In about half of infertile couples the problem lies either solely with the male or in both the male and female partners. However, the cause of infertility in the male partner is often difficult to determine and many men are diagnosed with ‘idiopathic male infertility’. Furthermore, with the increasing use of assisted reproductive technologies (ART), there may be less incentive for a proper investigation, diagnosis and treatment of male infertility. Understanding the aetiology of male infertility can lead to treatments that may preclude the need for ART.



To determine the primary causes of severe male factor infertility by i) comparing the prevalence of generally accepted causal and contributing factors between men with severe male infertility and fertile controls, and ii) comparing the distribution of suspected causes of primary causes of severe male factor infertility for sub-groups based on semen analysis (aspermia, azoospermia, cryptozoospermia, severe and moderate oligozoospermia)



A prospective clinical-epidemiological study from a single andrology centre at a university hospital in Estonia was conducted between 2005 and 2013. Male partners of couples failing to conceive for ≥12 months were recruited. Among these 8518 patients, 1737 (20.4%) were diagnosed with severe male factor infertility (<39 million sperm per ejaculate in at least two consecutive semen analyses). A group of fertile controls comprising 325 male partners of pregnant women was recruited for comparison.

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 according to the World Health Organization recommendations. Cases with spermatozoa concentrations of ≤5 million/mL were screened for chromosomal aberrations and Y-chromosomal micro-deletions.



Patients with severe male factor infertility had a mean age of 33 years, and had been infertile for a mean of 3 years. The primary cause of infertility was defined for 40% of patients (695 of 1737). 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 the 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.



In this study, the current guidelines and routine work-up for male infertility were able to assign a primary cause in only 40% of cases of severe infertility, suggesting that much is still not understood about male factor infertility. The causal factors for the most severe forms of infertility are reasonably well understood but there is a need for more research to understand the causes and mechanisms of oligozoospermia. The authors believe that this study is of higher quality than some previous studies and will contribute to updating guidelines for diagnosing and treating male infertility.


Points to Note
  1. In many cases of male infertility, a causal factor cannot be ascertained with routine workups and testing.
  2. Causal factors for the most severe forms of infertility are well characterised.
  3. Although infertility is often accompanied by overweight/obesity and chronic disease, the causal nature of these factors needs to be investigated. Similarly for varicocele.
  4. Advantages of this study were its prospective design, including up to date diagnostic testing, and the inclusion of a control group.
  5. The study findings are limited to  men with reduced total sperm counts and cannot be applied to all infertile men.


Website: https://www.ncbi.nlm.nih.gov/pubmed/27864361

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