Micro-video: The Diagnosis of Male Infertility: From the Bench to the Bedside
TRANSCRIPTI will be focusing my presentation on “The Diagnosis and Treatment of Male Infertility: From the Bench to the Bedside.” Since the theme of this year’s meeting is “Celebrating 75 Years of History and Innovation,” I thought I would start with my personal history and involvement in the subspecialty of male reproduction and then introduce innovations when appropriate.
The year was 1975, the Spanish dictator Franco died; the Vietnam war ended; Sony introduced Betamax videotapes; Margaret Thatcher became the leader of the Conservative Party in the United Kingdom; Jaws was released, and I gave my first talk on male infertility. The presentation was at the College of Surgeons in Philadelphia as part of the Philadelphia Urology Resident's Research Competition and was entitled “A Systematic Approach to the Evaluation of the Infertile Male.” Certainly, much has changed since that presentation. I will present an update today, but progress would have been much slower were it not for the work of the 120 fellows that Dr. Dolores Lamb and I trained, beginning in 1981.
In the past 30 years, the most important innovation in male factor therapy has, in my opinion, been the introduction of intracytoplasmic sperm injection, or ICSI. ICSI has revolutionized the treatment of male infertility, enabling the injection of a single sperm into an egg and the production of an embryo. This therapy has enabled men to become biologic fathers, despite overwhelming testicular damage or obstruction. Furthermore, only approximately 20 sperm are needed for a successful outcome. This decreased need for high sperm numbers has changed the entire paradigm of how male infertility patients are triaged and certainly the involvement of the urologist. So what is the role of the urologist in the era of ICSI? Is it to only assist in sperm retrieval, or is it to treat the affected male patient? As a urologist, I believe it is the latter.
I think the urologist’s role in evaluation and treatment of the infertile male is fourfold:
- To diagnose serious or life-threatening conditions associated with infertility.
- To identify and successfully treat reversible causes of infertility.
- To define untreatable causes of testis failure and offer appropriate consultation and referral.
- Lastly, to perform sperm procurement procedures to enable IVF/ICSI when these procedures are necessary.
I want to start by addressing the concept of “life-threatening conditions associated with infertility.” What we have come to realize over the years is that male infertility may be a potential barometer of a man’s total health. We have found through numerous clinical studies that male infertility increases the chance of all malignancies, increases the incidence of chronic health conditions, increases the likelihood of low testosterone or hypogonadism and, lastly, even increases mortality.
We also know that urologists can successfully treat reversible causes of infertility. Certainly pivotal in completing a male factor evaluation is the examination of the patient’s scrotal contents, noting the normality of the testis, epididymis, vas, and whether or not there is a varicocele present.
Because varicoceles are frequently associated with male infertility, it is important that we know how to accurately diagnose them. Clearly, the physical examination is the most important part, having the patient stand in a warm room, perform a Valsalva maneuver, and carefully palpate tactile reflux into the spermatic veins. Sometimes this diagnostic process is extremely difficult due to unusual scrotal anatomy or previous surgery. Subsequently, duplex ultrasonography to quantitate venous size and reversal of flow has become very important in this diagnosis of difficult-to-identify varicoceles.
Going back to the concept of ICSI and that “only 20 sperm are needed for successful pregnancy,” one could question our concern about varicoceles in the era of ICSI. What we and others have found through extensive meta-analyses and clinical studies is that undergoing a varicocele repair before assisted reproduction may improve both pregnancy and live birth rates in azoospermic and oligospermic men. In addition, an extensive literature review was published by several of my fellows, in which they concluded, “In a couple seeking fertility using assisted reproduction, varicocele repair offers both improved sperm health and fertilization rates with IVF/ICSI.”
It is important when evaluating the infertile male to understand the hypothalamic-pituitary-gonadal axis. We know that there are two trophic hormones, LH and FSH, acting through the Leydig cells and Sertoli cells, respectively, with each having its corresponding negative feedback arm, with Leydig cells relying on testosterone and the Sertoli cells inhibin. To evaluate the infertile male, FSH is the most important hormone to assess the functional capability of the germinal epithelium. LH and testosterone are important for assessing Leydig cell function. Prolactin is important, especially when gonadotropins are abnormally decreased, because if elevated, it may indicate a pituitary tumor. Lastly, in the obese patient, testosterone is excessively aromatized to estrogen, increasing central negative feedback.
We also perform more sophisticated testing of the sperm in addition to determining count, motility, and shape. We know that there is a relationship between the production of reactive oxygen species, or oxidants, in the semen and DNA denaturation in sperm from infertile men. What we have found in multiple studies is that excess reactive oxygen species (ROS) can lead to increased DNA fragmentation. In addition, these reactive oxygen species, or oxidants, may be predictors of impaired fertilization.
Tests of sperm function are also important, determining if fertilization will take place and if the embryo will grow normally. Especially important among these assays are those that quantitate DNA fragmentation and sperm strict morphology. The concept of strict morphology was introduced by Kruger in 1988, when he found that patients with fewer than 4% normal sperm forms had a marked decrease in fertilization rates in IVF. However, we have questioned the natural history of achieving pregnancies in men with abnormal strict morphologies. To address this, we investigated our patients who had strict morphologies of less than 1%, often of 0%. We contacted them and found out that 52% had achieved pregnancy using natural means and another 16% using intrauterine insemination. It seems clear that we need to reassess the process of rapidly progressing to IVF in this patient population.
Ultrasound has become extremely important in diagnosing the terminal portion of the male ductal system. This technique enables us to noninvasively look at the anatomical integrity of the seminal vesicles, the ampulla of the vas, and to identify cysts that might obstruct the ejaculatory ducts.
It is also important for the urologist to be able to define untreatable causes of testis failure and offer appropriate consultation and referral. The core of this concept is an understanding of the genetics of male infertility. We know that there are several different categories of genetic failure. There may be numerical chromosomal defects, as one sees in Klinefelter’s syndrome or aneuploidy; chromosome translocations or rearrangements; Y chromosome microdeletions in the AZFa, b, and c regions, as well as single gene deletion and mutations. The most important of this latter genetic abnormality is that within the cystic fibrosis transmembrane regulator gene (CFTR), in which a mutation can cause vasal agenesis.
What about the future? I think there are several exciting and promising early scientific innovations in male infertility. Genomic engineering may become increasingly possible using CRISPR/Cas9 technology in the human germline. Our understanding of epigenetics may become more important in the infertile male both for diagnosis and therapy. Rapid progress is being made in our investigation of extracellular vesicles or exosomes, which may lead to novel diagnostic tests and even therapy. Lastly, sperm created from stem cells may offer hope in cases of otherwise untreatable nonobstructive azoospermia, or NOA.
- Kirby EW, Wiener LE, Rajanahally S, Crowell K, Coward RM: Undergoing varicocele repair before assisted reproduction improves pregnancy rate and live birth rate in azoospermic and oligospermic men with a varicocele: a systematic review and meta-analysis. Fertil Steril 2016 Nov; 106(6):1338-1343. PMID: 27526630.
- Kruger TF, Acosta AA, Simmons KF, Swanson RJ, Matta JF, Oehninger S: Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil Steril 1988 Jan; 49(1):112-117. PMID: 333525.
- Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN: Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003 Aug; 18(8):1660-1665.