Zoran J. Pavlovic, M.D.1, Megan R. Sax, M.D.2, Ashley S. Kim, M.D.3, Shane T. Russell M.D., M.P.H.4, Alan H. DeCherney, M.D.5
1Department of Obstetrics and Gynecology, Rush University Medical Center
2University of Cincinnati, Department of Obstetrics and Gynecology
3Kaiser Permanente Los Angeles Medical Center
4The Urology Group
5Program in Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Male factor is estimated to play a role in approximately 20-70% of infertile couples, yet is often a secondary focus of the fertility workup (1). Despite the prevalence of male factor infertility, many Reproductive Endocrinology and Infertility (REI) fellowships focus training on female patients, attempting to determine causes related to structural uterine malformations, intrauterine cavity and endometrial abnormalities, tubal patency, ovarian reserve and disruptions of normal hormonal function (2). Male factor infertility evaluation and counseling in REI practices is frequently limited to a single semen analysis (SA). This is especially concerning as recent research has shown that there is considerable variability in the SA between samples of the same individual over a short period of time. In fact, World Health Organization now recommends obtaining multiple SAs for each patient to accurately assess parameters and decrease variability (3,4). REI specialists in training should receive training in the evaluation and counseling of the male partner and understand available treatments and when a Urology referral is prudent. When evaluating a patient for Urology referral, it is also important to identify Urologists who have completed advanced fellowship training in Andrology. In order to successfully accomplish all the above, there needs to be a shift in the focus, training and education of REIs to include aspects of male infertility.
Reproductive Endocrinologists were initially experts in the endocrinology and physiology of reproduction for both females and males, with roots in Internal Medicine and General Endocrinology, beginning with the Association of the Study of Internal Secretions that later became The Endocrine Society. In 1944, the field of REI evolved into the American Society for the Study of Sterility (a precursor to the American Society for Reproductive Medicine) and was not an official subspecialty of Obstetrics and Gynecology until the 1970s (5,6). During this evolution of the field, research became more focused on anatomic, embryologic, molecular and genetic causes of female infertility, thereby shifting most of the responsibility of male infertility management and counseling to Andrologists. Although Andrologists provide excellent care to males seeking infertility treatment, REIs should also be able to address the basics of male infertility to help improve the outcomes of infertile couples.
There are multiple areas within Andrology that REIs can expand upon to improve the care of infertile couples. As with all patient encounters in medicine, a thorough history, including reproductive, medical, family and social histories, is of the utmost importance. Although the physical exam should be delegated to Andrologists to avoid missing critical malformations, structural abnormalities and concerning masses, REIs could start the evaluation process at the new patient visit when they are also examining the female partner. History intake should include details about coital frequency and timing, duration of infertility and previous fertility, childhood illnesses and developmental history, systemic medical illnesses such as diabetes or other vascular disease, previous reproductive or pituitary surgery, genital trauma, medications including exogenous steroid use, sexual history and gonadotoxin exposure via radiation or chemotherapy (7).
Despite its shortcomings, the SA remains the cornerstone of the initial male reproductive investigation and is still the best male-based predictor of fertility outcomes. REI offices are often where male patients receive counseling surrounding SA collection, processing, and examination, but best practice may vary greatly (7). Understanding the clinical reference ranges and meaning of SA abnormalities can allow for superior counseling on addressing reversible risk factors for decreased sperm quality before jumping to IUI, ICSI or referral. This bears importance since the Andrology Research Consortium found that before being evaluated at a male factor infertility center, 12.1% and 4.9% of couples underwent IUI and IVF, respectively, and that 73% of those patients reported an abnormal SA (8). These patients could have benefitted from better initial management and referral for semen parameter optimization before undergoing expensive procedures.
Beyond the semen analysis
When an REI encounters an abnormal SA, further labs and work-up may be recommended based on specific abnormalities within the SA and clinical suspicion (see Figure 1). Such algorithms can help REIs delineate obstructive vs. nonobstructive azoospermia and determine necessary next steps. Congenital or acquired obstructive azoospermia will require a physical exam and possibly microsurgery that only Urologists/Andrologists will be able to perform and therefore prompt referral is warranted. Non-obstructive azoospermia (NOA) is where REI specialists can potentially become more useful (9,10). History, hormonal and karyotype analyses can efficiently triage males with NOA. Hormonal testing includes FSH, LH, estrogen, total and free testosterone, TSH and prolactin (7,10). As REIs are highly trained in normal and abnormal physiology of the hypothalamus-pituitary-gonadal axis, they should have adequate background knowledge to be able to understand male hormonal abnormalities. This can help distinguish between primary and secondary testicular failure and determine treatment modalities. Secondary causes such as exogenous steroid use or a pituitary tumor can be treated with lifestyle changes, medications or imaging and surgical referral. Primary causes may warrant genetic testing and subsequent counseling.
Genetics has already become a key component of the female infertility workup and often both counterparts of a couple with infertility or recurrent pregnancy loss may undergo genetic analysis via karyotyping or expanded carrier screening. Genetic testing and counseling can be even further expanded for the male partner at the REI visit. Certain abnormalities such as Y chromosome microdeletions, as is found in azoospermia factor deletions (AZFa, AZFb, and AZFc), can lead the REI to discuss preimplantation genetic testing, IVF/ICSI, donor sperm and the inheritance patterns in their male offspring. Moreover, conditions such as Kallmann syndrome can cause hypogonadotropic hypogonadism and these patients can benefit from medical management. Current American Urologic Association (AUA) guidelines are to consider checking karyotype and Y-chromosome microdeletion testing in men with sperm densities of <5 million sperm/cc and who do not have other apparent causes of their low sperm count such as obstruction or exogenous androgen use. Hypogonadotropic hypogonadism (HH), whether genetic, acquired (exogenous steroid use, trauma, gonadotoxic radiation or chemotherapy) or idiopathic, can be treated with gonadotropins such as HCG and FSH or clomiphene citrate stimulation that can help induce spermatogenesis and improve fertility (10). Although REIs are comfortable utilizing these medications, there are medical-legal aspects of the REI-male patient relationship and the importance of long-term follow-up of treated male patients that an REI will likely not want to become involved with, and therefore a collaborative relationship with a local Andrologist partnerships may allow for further insight into appropriately treating these patients, especially since men with an abnormal SA are at a higher risk of potentially serious health programs. In fact, a diagnosis of male factor infertility has been correlated with a 30% higher chance of developing diabetes mellitus and 48% higher chance of being diagnosed with ischemic heart disease when followed over 8 years as well as a 20-fold increased risk of testicular cancer (11,12). Such studies highlight the importance of identifying and developing a relationship with a local Andrologist, if possible, to provide men found to have semen abnormalities with the evaluation and counseling needed to both maximize their fertility potential as well as safeguard their overall general health. Nonetheless, an REI with appropriate fellowship training can initiate a workup and in certain cases (such as complex genetic abnormalities, obstructive azoospermia, and HH) provide an Andrology referral or utilize a multidisciplinary management plan developed by a clinical team that includes an Andrologist.
DNA fragmentation is another quickly evolving and potentially powerful clinical tool in the REI arsenal. However, appropriate training and knowledge of the methodology, implications and limitations of such testing is needed. DNA fragmentation refers to damaged or denatured sperm that cannot be repaired and is theorized to have an impact on fertilization, embryo development and ultimately a successful pregnancy. Some common techniques to evaluate the DNA fragmentation index (DFI) include the sperm chromatin structure assay (SCSA) and the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay (7). The thresholds of what is considered to be a normal DFI level can vary significantly based upon the particular lab and type of testing performed, but the most clinically used SCSA assay is generally felt to have a normal range of £ 25-30% in most studies (7). Although controversial, patients with an SCSA >25% are often counseled on ICSI and >50% are counseled to consider TESE/ICSI (13). REI specialists who are trained to understand the utility of DFI testing and the implications, as well as the limitations of the results, can better counsel and manage male patients with increased DFI. Potential reversible causes of elevated levels of sperm DNA fragmentation include pyospermia, varicoceles, and various lifestyle-related factors such as tobacco use. The use of antioxidants can potentially decrease sperm DNA fragmentation resulting from oxidative stress, and in some circumstances a fresh testicular sperm extraction can yield sperm with lower DFI levels for use with IVF/ICSI (14).
Another more recent development is the use of microfluidics over standard density-gradient centrifugation, since microfluidic sperm sorting was found to have a 0% DFI for both median and high DFI sperm samples compared to 6% and 15%, respectively, for centrifugation (15). Preliminary data from studies have shown that microfluidic sorting can decrease sperm DFI and potentially increase a couple’s chances of obtaining a euploid conceptus while also increasing implantation and pregnancy rates (16). REIs can assist their Andrology colleagues by improved counseling and discussion of general DFI implications, sperm sorting techniques, ICF/ICSI or referral for TESA/TESE.
Psychosocial counseling as part of the management of male factor infertility is another area often overlooked by REIs, despite being within the scope of practice. Infertility of any etiology is stressful for both counterparts in a relationship, Men seek infertility services largely for the same reasons that their female partners do, namely the desire to enter fatherhood and experience the joy found in creating life, and the stigma towards those seeking infertility management can exacerbate preexisting emotional and physical stress (17). For men, these frustrations may revolve around preconceived notions of masculinity and feelings of inadequacy, as well as helplessness as their female partner is forced to endure physical discomfort with further testing or intervention. This may be exacerbated further when a male partner perceives a sense of being considered an afterthought in the reproductive process, especially when working with a provider who was trained to care primarily for women (17,18). To combat this, an REI may instead focus on the couple as a whole, openly address emotional and psychologic concerns from both partners, and be prepared to provide guidance regarding supportive resources and counseling. With adequate exposure and training to the components of male fertility discussed above, REIs will be better equipped to address psychosocial constraints of infertility treatment and expand further to complex topics such as third-party gestation for same-sex or single male intended parents.
Male infertility is a significant part of the infertility process that deserves careful attention. REIs can aid their andrology colleagues since often male infertility patients initially present to an REI, in-part due to some limitations of access to Andrologists. Although most REI groups now have access to a fellowship trained andrologist, there remain some geographical areas which still lack a specialist in male infertility. In these circumstances, identifying and fostering a relationship with a local general Urologist who has a special interest in male infertility may be adequate to provide good comprehensive care to infertile couples. The emergence of telemedicine also offers a potential opportunity to provide specialty male fertility care to couples living in remote areas. In addition, REI fellowship programs can assist in the goal of comprehensive couples’ care by increasing the time spent in elective or mandatory andrology rotations caring for male patients under the supervision of an Andrologist. This enhanced exposure will help REIs become better versed in the needs of our male patients as well as those of our andrology colleagues, allowing us to appropriately workup and refer male patients beyond just a SA. REIs of the future, after appropriate guidance and training in conjunction with Andrologists, can help remove the stigma of male infertility and improve patient care.
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