Infertility causes, according to the current consensus include anovulation, male factor, tubal factor, cervical factor, endometriosis and unexplained infertility (UI) . UI is a diagnosis of exclusion [1]. Traditionally, the term has been used when the basic investigations such as tests for tubal patency, ovulation and semen analysis are all normal [2].

Moreover, there are two distinct categories of infertility:

Therefore, UI should also be classified into unexplained primary or secondary infertility. Unexplained female infertility should be a term used when the female reproductive system has been evaluated according to current agreed standards, and no abnormalities are detected. Male factor infertility should have been ruled out with at least two normal semen analyses and with no demonstrable physical or endocrine abnormalities [3].

The latest opinion paper by the Practice Committee of the American Society for Reproductive Medicine (ASRM) published in 2012 [4] on the diagnostic evaluation of the infertile female, which replaces the 2006 document titled “Optimal evaluation of the infertile female” is a step forward towards understanding female infertility.

Evaluation according to this document should include:

The post coital test for excluding cervical factor infertility is no longer recommended. This does not necessarily exclude a potential cervical factor such as aetiology for the infertility. It merely implies that our diagnostic ability to identify subtle defects in sperm–cervical mucousinteraction is limited.

All the above investigations will be discussed in more detail in this book. This document though clearly demonstrates a shift away from the concept of using the term UI as an ‘umbrella’ term for all women with normal ovulation and tubal patency tests, to a more elaborate assessment of the female and the couple. The potential for creation of new infertility categories arises.

The necessity for an accurate and globally accepted definition of UI, in both male and female, is undisputable. It is paramount for clinicians and healthcare providers alike in an era of increasing cost consciousness, to be able to monitor the incidence and prevalence of this condition in order to best understand how to investigate and treat the infertility efficiently.

Defining UI is far from straightforward. One of the reasons is that there is an inherent disparity between the clinical, the epidemiological and the demographic version of the definitions of infertility .

The differences correspond to:

There are therefore numerous definitions of infertility in textbooks and other publications, and this fact on its own proves that it is an area where controversies still exist. This necessity for a generally accepted definition, and a consensus in that matter has been extensively argued [5−8]. One widely used definition of infertility is 1 year of unwanted non-conception with unprotected intercourse in the fertile phase of the menstrual cycles [9].

Another definition by Gnoth et al. describes infertility as failure to conceive after six cycles of unprotected intercourse irrespective of age [10].

Τhe ASRM in 2008 also published a definition of infertility [11]. The document states that infertility is a disease, defined by the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse. The female age at presentation is also taken into account, distinguishing between those above and below the age of 35. The former category according to the ASRM warrants investigations and treatment after 6 months of failure to conceive. The same may apply for younger women, when indicated by history and clinical examination.

In 2009, the International Committee for Monitoring Assisted Reproductive Technology and the World Health Organization , produced a similar definition [12].

The shift towards taking into account the female age when defining infertility was also advocated by Bhattacharya et al. [8], who suggested defining infertility based on the length of trying (or exposure to pregnancy) adjusted for female age. This, according to the authors, is a more clinically meaningful definition and is already used in everyday practice.

The most up-to-date definition (2013) is a revised one by the ASRM [13], which replaced their 2008 definition:

Infertility is a disease, defined by the failure to achieve a successful pregnancy after 12 months or more of appropriate, timed unprotected intercourse or therapeutic donor insemination. Earlier evaluation and treatment may be justified based on medical history and physical findings and is warranted after 6 months for women over age 35 years.

It is an elaborate definition that has the potential to replace all the others.

On the other hand, it is debatable whether a universal definition of infertility is pragmatic. A global consensus between fertility physicians may remain a utopia.

When attempting to define UI, it is appropriate to define fecundity and childlessness in humans:

Once infertility has been ascertained, regardless of which definition one uses, the ‘diagnosis’ of unexplained female infertility is made when tubal patency and normal ovulatory function are established in the presence of a normal semen analysis. By definition this would mean that all the appropriate tests have been performed. The interpretation of some of the diagnostic tests though is operator-dependant such as the tests for tubal patency. It is well known that the sensitivity of many diagnostics tests (i.e., contrast infusion ultrasound (Hycosy) and Hysterosalpingogram) is far from 100 %, and the diagnosis of UI may vary depending on the individual performing or interpreting the results.

Most importantly, there could be causes accounting for female infertility that are not recognised, either due to lack or omission of appropriate and accurate testing, or even due to investigating a clinician’s beliefs and personal experience. In addition, an aetiology may also be assigned by some physicians with a bias towards specific diagnoses in the absence of objective evidence.

Below is a brief list of potential causes of female infertility that are generally thought to be associated with the “diagnosis” of UI and frequently unexplored.