Infertility is customarily defined as the inability of a sexually active couple with no contraception to achieve natural pregnancy within one year [1]. The American Society for Reproductive Medicine (ASRM) considers infertility as a disease, which by definition is ‘‘any deviation from or interruption of the normal structure or function of any part, organ, or system of the body as manifested by characteristic symptoms and signs; the etiology, pathology , and prognosis may be known or unknown’’ [2, 3].

It has been estimated that 15 % of couples seek medical assistance for infertility , and the origins of the problem seem to be equally distributed between male and female partners [1]. Taking into account a global perspective and a world population of 7 billion people, these figures indicate that approximately 140 million people (2.2 %) face infertility [4, 5].

Infertility depends at large on the age of the female partner. As such, the ASRM states that an early evaluation and treatment is warranted after 6 months for women aged 35 years or older [3].

In men, about 8 % seek medical assistance for fertility-related problems [6]. In its most updated version (2010) on “the optimal evaluation of the infertile male,” the American Urological Association (AUA) recommends that the initial screening should be done if pregnancy has not occurred within one year of unprotected intercourse, or earlier in cases of known male or female infertility risk factors [7]. Male infertility can result from congenital or acquired urogenital abnormalities, urogenital tract infections, increased scrotal temperature such as a consequence of varicocele, endocrine disturbances, genetic abnormalities, immunological factors, lifestyle habits (e.g., obesity, smoking, and use of gonadotoxins), systemic diseases, erectile dysfunction, and incorrect coital habitus. Unfortunately, owed to limitations in our understanding of the events that take place during natural conception, and in view of the crude diagnostic tests available to identify potential abnormalities, the cause of infertility is not determined in nearly half of the cases. Moreover, approximately 5 % of couples remain unwillingly childless despite multiple interventions [1, 8, 9].

Infertility of unknown origin comprises both idiopathic and unexplained infertility . Men presenting with idiopathic infertility have no obvious history of fertility problems, and both physical examination and endocrine laboratory testing are normal. However, semen analysis as routinely performed reveals sperm abnormalities that come alone or in combination. The reported prevalence of men with unexplained reduction of semen quality ranges from 30 to 40 % [1, 10].

In contrast to idiopathic infertility, the term “unexplained infertility” is reserved for couples in whom routine semen analysis is within the reference values , and a definitive female infertility factor has not been identified [11]. In females with unexplained infertility, no definitive abnormality can be identified, but a reduced fecundity potential may be suspected in ovulatory woman with evidence of diminished ovarian reserve testing, including elevated follicle stimulating hormone (FSH) or low anti-Mullerian hormone (AMH) levels. In addition, direct evidence of diminished ovarian reserve can be determined by low antral follicle counts or lack of response to exogenous gonadotropins despite normal ovarian reserve testing. This category of ‘poor ovarian response (POR)’ or ‘diminished ovarian response (DOR)’ is difficult to define and the leading experts in the field were still unable to arrive at a conclusive definition [12].

The reported prevalence of unexplained infertility ranges from 6 to 30 % [1, 8, 9, 11, 13], and this highly variable prevalence strongly depends on the criteria used for diagnosis . In countries with limited resources for testing, it is likely that the prevalence of unexplained or unexplored infertility is increased [14]. Also, its prevalence is related to national or societies’ guidelines and infertility centers’ policies toward infertility evaluation. In a group of 2383 subfertile males attending one of the editors’ (SE) tertiary center for male reproduction, in which all male partners underwent a systematic workup regardless of semen analyses results, 12.1 % of the individuals were categorized as having infertility of unknown origin [9]. Depending on the method and criteria used for semen analysis, the percentage of men defined as “normal” will be variable. The AUA guidelines state that the initial evaluation for male infertility should include a reproductive history and two properly performed semen analyses, and that a full evaluation (which includes a throughout physical examination and additional testing) is warranted in the following cases: (i) presence of abnormalities in the initial evaluation; (ii) presence of unexplained infertility ; and (iii) presence of persistent infertility despite proper treatment of identified female factors .