Definitions and Relevance of Unexplained Infertility 1 in Reproductive Medicine Sandro C. Esteves, Glenn L. Schattman and Ashok Agarwal Infertility is customarily defined as the inability of a sexually infertility can result from congenital or acquired urogenital active couple with no contraception to achieve natural preg- abnormalities, urogenital tract infections, increased scrotal nancy within one year [1]. The American Society for Repro- temperature such as a consequence of varicocele, endocrine ductive Medicine (ASRM) considers infertility as a disease, disturbances, genetic abnormalities, immunological factors, which by definition is ‘‘any deviation from or interruption of lifestyle habits (e.g., obesity, smoking, and use of gonado- the normal structure or function of any part, organ, or system toxins), systemic diseases, erectile dysfunction, and incor- of the body as manifested by characteristic symptoms and rect coital habitus. Unfortunately, owed to limitations in our signs; the etiology, pathology, and prognosis may be known understanding of the events that take place during natural or unknown’’ [2, 3]. conception, and in view of the crude diagnostic tests avail- It has been estimated that 15 % of couples seek medical able to identify potential abnormalities, the cause of infertil- assistance for infertility, and the origins of the problem seem ity is not determined in nearly half of the cases. Moreover, to be equally distributed between male and female partners approximately 5 % of couples remain unwillingly childless [1]. Taking into account a global perspective and a world despite multiple interventions [1, 8, 9]. population of 7 billion people, these figures indicate that ap- Infertility of unknown origin comprises both idiopathic proximately 140 million people (2.2 %) face infertility [4, 5]. and unexplained infertility. Men presenting with idiopathic Infertility depends at large on the age of the female part- infertility have no obvious history of fertility problems, and ner. As such, the ASRM states that an early evaluation and both physical examination and endocrine laboratory testing treatment is warranted after 6 months for women aged 35 are normal. However, semen analysis as routinely performed years or older [3]. reveals sperm abnormalities that come alone or in combi- In men, about 8 % seek medical assistance for fertility- nation. The reported prevalence of men with unexplained related problems [6]. In its most updated version (2010) on reduction of semen quality ranges from 30 to 40 % [1, 10]. “the optimal evaluation of the infertile male,” the American In contrast to idiopathic infertility, the term “unexplained Urological Association (AUA) recommends that the initial infertility” is reserved for couples in whom routine semen screening should be done if pregnancy has not occurred analysis is within the reference values, and a definitive fe- within one year of unprotected intercourse, or earlier in cases male infertility factor has not been identified [11]. In females of known male or female infertility risk factors [7]. Male with unexplained infertility, no definitive abnormality can be identified, but a reduced fecundity potential may be suspect- S. C. Esteves () ed in ovulatory woman with evidence of diminished ovarian ANDROFERT, Andrology and Human Reproduction Clinic, Referral reserve testing, including elevated follicle stimulating hor- Center for Male Reproduction, Avenida Dr. Heitor Penteado, mone (FSH) or low anti-Mullerian hormone (AMH) levels. Campinas 1464, Sao Paulo, Brazil In addition, direct evidence of diminished ovarian reserve e-mail: [email protected] can be determined by low antral follicle counts or lack of G. L. Schattman response to exogenous gonadotropins despite normal ovar- Center for Reproductive Medicine, Weill Cornell Medical ian reserve testing. This category of ‘poor ovarian response College, 1305 York Avenue, 10021 New York, NY, USA e-mail: [email protected] (POR)’ or ‘diminished ovarian response (DOR)’ is difficult to define and the leading experts in the field were still unable A. Agarwal Center for Reproductive Medicine, Cleveland Clinic, 10681 Carnegie to arrive at a conclusive definition [12]. Avenue, Desk X-11, Cleveland, OH, 44195 USA The reported prevalence of unexplained infertility rang- e-mail: [email protected] es from 6 to 30 % [1, 8, 9, 11, 13], and this highly variable G. L. Schattman et al. (eds.), Unexplained Infertility, DOI 10.1007/978-1-4939-2140-9_1, 3 © Springer Science+Business Media, LLC 2015 4 S. C. Esteves et al. prevalence strongly depends on the criteria used for diagno- These considerations highlight the shortcomings of the sis. In countries with limited resources for testing, it is likely routine semen analysis. The male evaluation regarding fertil- that the prevalence of unexplained or unexplored infertility ity must go far beyond counting spermatozoa and assessing is increased [14]. Also, its prevalence is related to national or motility and morphology. It has to be complemented with a societies’ guidelines and infertility centers’ policies toward proper clinical examination, a comprehensive history-taking, infertility evaluation. In a group of 2383 subfertile males and relevant endocrine, genetic as well as other investigations. attending one of the editors’ (SE) tertiary center for male The goals of an andrological investigation are to identify po- reproduction, in which all male partners underwent a sys- tential life-threatening diseases and to treat reversible condi- tematic workup regardless of semen analyses results, 12.1 % tions, including poor lifestyle habits, subclinical infections, of the individuals were categorized as having infertility of hormone disorders, and clinical varicocele, to cite a few. Nev- unknown origin [9]. Depending on the method and criteria ertheless, it is still a matter of debate not only what is consid- used for semen analysis, the percentage of men defined as ered a thorough evaluation, but also which tests are useful in “normal” will be variable. The AUA guidelines state that the the evaluation of couples with unexplained infertility. initial evaluation for male infertility should include a repro- Potential etiologies of unexplained infertility (UI) en- ductive history and two properly performed semen analyses, compass a couple’s miscomprehension of the concept of the and that a full evaluation (which includes a throughout phys- female fertile window, improper coital techniques, erectile ical examination and additional testing) is warranted in the dysfunction, and molecular and functional causes of male following cases: (i) presence of abnormalities in the initial and female infertility. evaluation; (ii) presence of unexplained infertility; and (iii) Altogether, these considerations form the backbone of presence of persistent infertility despite proper treatment of this book, intended to unravel the mysteries of unexplained identified female factors. infertility. Modern insights on reproductive function are pro- In contrast, the European Association of Urology (EAU) vided, including a detailed appraisal of the conditions that recommends that the male examination should be under- affect reproductive health in both males and females. Further taken in individuals with abnormal semen analysis results insight is contemplated into the treatment options, including [10]. According to the EAU guidelines on male infertility, a expectant management as well as active interventions. The single seminal evaluation is sufficient if the semen analysis benefits of each intervention and its inherent risk are dis- results are within the reference limits according to the World cussed in detail, thus allowing appropriate patient counsel- Health Organization (WHO) criteria. The EAU recommen- ing. Our readers will find this book as the ultimate resource dations pose potential problems since semen analyses re- to unexplained infertility, and we recommend it not only to sults, as routinely performed, are limited in their validity as clinicians working in the field of infertility but also to every- surrogates for the assessment of male fertility status [15, 16]. one with an interest in reproductive medicine. First, the prognostic value of semen characteristics, such as sperm concentration, percent motility, and morphology, as surrogate markers for male fertility is confounded in several References ways; a man’s fertility potential is influenced by sexual ac- tivity, function of accessory sex glands, and other conditions. 1. World Health Organization. WHO Manual for the standardised Second, routine semen analysis has its own limitations, and investigation and diagnosis of the infertile couple. Cambridge: Cambridge University Press; 2000. it does not account for sperm dysfunctions such as imma- 2. Practice Committee of the American Society for Reproductive ture chromatin or DNA damage. It is known that about 30 % Medicine. Definitions of infertility and recurrent pregnancy loss of men misdiagnosed as having unexplained male infertility (Committee opinion). Fertil Steril. 2008;90:60. have sperm deficiencies that can be solely identified using 3. Dorland WAN, editor. Dorland’s illustrated medical dictionary, 31st ed. New York: Elsevier; 2007. p. 53. sperm functional tests, including DNA integrity, oxidative 4. US Census Bureau. Population estimates. U.S. Census Bureau, stress, and antisperm antibodies testing [17–19]. Third, it is Methodology and Standards Council: (updated: 17th August 2011; erroneous to assume