Male Infertility Update
Philip Werthman, MD
Director, Center for Male Reproductive Medicine
Los Angeles, CA
Of the 15% of couples having difficulty conceiving, almost half have male infertility as the sole or contributing cause. It is currently recognized that the quality as well as the quantity of sperm greatly influences reproductive outcomes. It was once thought that assisted reproductive technologies (ART) such as Intrauterine Insemination (IUI) and more so, In-Vitro Fertilization with Intracytoplasmic Sperm Injection (ICSI) had the power to overcome almost any sperm defect but data show that this is not true for many patients. New data has repeatedly demonstrated that significantly damaged sperm leads to lower pregnancy rates with IUI or IVF as well as an increased miscarriage rate up to fivefold that of a pregnancy achieved with normal sperm. It has been said that in the last 5 years there hasn’t been any significant improvement in pregnancy rates with IVF and that is most likely because scientific techniques to improve egg and embryo quality have been maximized. The next major jump will come from focusing on sperm quality and maximizing it. Using abnormal sperm without making any attempt to quantify the level of damage, search for the cause or treat it will not be the preferred initial approach to fertility treatment because for most couples, treating the male improves outcomes.
There are two fundamental treatment strategies used to address sperm deficiencies:
1. Identify and treat the problem to improve semen parameters, 2. Bypass the problem by using the sperm that are available. The classic approach is that if there are more than 5-8 million motile sperm in the washed semen sample and the strict morphology of the sperm is greater than 4% normal, the couple would be a candidate for a variable number of IUI cycles. If the semen parameters are worse than this, IVF would be employed because of higher success rates under these conditions.
Unfortunately, the way practice patterns have developed, too few men are referred for appropriate evaluation until treatment strategy #2 has failed and the couple has undergone a significant number of treatments, lost time and considerable expense. Even then only a fraction of men are referred for evaluation for their underlying problem and many couples are encouraged to use donor sperm unnecessarily.
The scope of male infertility is widespread but unfortunately the evaluation and treatment process has never been standardized among general urologists, gynecologists or reproductive endocrinologists. This has led to inconsistent diagnoses, recommendations, and treatments that patients receive from their physicians. Many clinicians are inadequately trained and ill-equipped to deal with complex patients presenting with male infertility and still provide advice based on the limited understanding of reproduction taught to them several decades ago resulting in couples undergoing inefficient care or being denied the opportunity to become biological parents. An attempt to address this problematic situation was undertaken by a joint panel of the American Urological Association and American Society of Reproductive Medicine. Best practice policy guidelines were put forth almost a decade ago but since then, many advances have been made in our understanding of male reproductive function and based on these, new treatment strategies have been developed.
Our goal in treating male infertility is to provide information and rationale for cost-effective treatment strategies by helping identify those patients who will benefit from improving their sperm such that they can conceive naturally, avoid ART procedures or decrease the number of IVF cycles needed to achieve a term pregnancy. Another important goal is to identify conditions that aside from causing infertility, directly impact a man’s health such as testicular cancer or hormonal imbalances.
Causes of Male Infertility
There are numerous causes of male infertility but no matter what the etiology, the final common pathway to sperm damage (DNA fragmentation) is through free radical peroxidation leading to overwhelming amounts of oxidative stress on the sperm. Ironically, oxidative stress is necessary for normal sperm function and sperm actually produce free radicals but when more stress is generated than the system can compensate for, the body is unable to neutralize the toxins which ultimately injure the sperm cell membrane and the sperm DNA. This leads to functional impairment of the sperm cell and ultimately infertility.
Since we now have a much better understanding of the mechanisms of sperm damage and locations in the reproductive tract where damage may occur, more sophisticated functional tests to identify problems have been developed and the information can be applied to statistically predict patient outcomes. Identifying the causes of infertility makes practical sense because the underlying source of sperm damage can potentially be removed, repaired, neutralized or bypassed to produce the desired outcome.
It is well known that heat is harmful to sperm; it causes cellular apoptosis in the testicles. This is why the testicles are located outside the body as spermatogenesis needs to occur 2 degrees cooler than core body temperature. Anything that causes scrotal temperature elevation can result in sperm damage. A high fever or prolonged use of a spa or sauna can cause a temporary decline in fertility. The most common cause of male infertility is varicocele. It is thought to cause damage to sperm by obliterating the counter-current heat exchange system normally present in the spermatic cord circulation as well as allowing reflux and pooling of venous blood with its toxins, back into the testicle. Varicocele has been shown to cause elevated levels of DNA fragmentation, heat generation and elevated seminal oxidative stress. Numerous studies demonstrated that varicocele repair can reverse these negative effects and decrease sperm DNA fragmentation.
Other causes of sperm damage are those caused by a defect in sperm storage and transport such as partial/ complete obstruction, ejaculatory dysfunction, prostatitis, pyospermia, and STDs. In these conditions, sperm are produced normally but are injured as they make their way through the reproductive tract. Numerous toxins, either environmental or medicinal can have deleterious effects on sperm. Some commonly prescribed medications as well as chemotherapy and antibiotics are well-know offenders.
Some men are born with genetic conditions such as Kleinfelter’s Syndrome, chromosomal translocations, Y-chromosome microdeletions or carriers of cystic fibrosis and these lead to either azoospermia (absence of sperm in the ejaculate) or severely low sperm counts. For obvious reasons, it is important to detect these conditions prior to using sperm from patients with genetic abnormalities as diseases may be passed on to the child through IVF and we now have the technology to genetically screen embryos.
The semen analysis is an excellent screening tool for male infertility in that it identifies most men who might have a problem conceiving. The semenalysis is quite variable and normally fluctuates to some degree over time, which is why it is recommended that at least 2 tests be performed separated by some degree of time. Unfortunately, the semen analysis is a poor predictive tool as to who will eventually be able to father a child. The reason is that the test is observational, not functional, meaning we can tell patients how many sperm are present compared to normal (sperm count), how many are moving (motility) and what the sperm look like (morphology) but unless a patient is at the very low ends of the spectrum, we can’t tell much about how the sperm will work or how damaged they really are. Newer tests have been developed that measure the level of sperm susceptibility to DNA damage, the degree of sperm maturity and the level of oxidative stress in the semen sample. All of these parameters independently correlate with infertility and give some predictive information as to how and in what ways we should be using the sperm to most efficiently establish a healthy pregnancy and who might be at higher risk for miscarriage. They also allow us to differentiate those patients who will most benefit from attempting to improve their sperm quality versus those who might go directly to ART with an expected high level of success. Of course no single test has 100% positive predictive value and all give a different piece of the puzzle that allows us to draw conclusions and make recommendations to patients. With fertility things get even more complicated because there are so many variables or “moving parts” including timing and the ability of a woman’s egg to overcome certain deficiencies within a given sperm cell.
The exciting thing is that with these newer tests, our understanding of the causes of infertility have increased, more research is being undertaken and with that, our ability to tailor treatment to a patient’s situation is leading to higher pregnancy rates and couples achieving their ultimate goal.
Who Should be Evaluated
The recommendation of the ASRM and AUA joint panel on best practice policies for male infertility is that all men with 2 abnormal semen analyses be evaluated by a physician with expertise in treating male infertility. The evaluation should consist of a detailed patient history and well as a complete physical examination. Advanced sperm testing as well as hormone evaluation, genetic testing and radiological imaging may be performed as indicated
New Treatment Strategies
Research on sperm DNA fragmentation has led to the development of new treatment alternatives for men with abnormal sperm. It ha shown that men with high levels of DNA fragmentation who have varicoceles benefit from surgical repair of the condition because it lowers the amount of damage to normal and thereby allows for increased chances of conception. It has also shown that the source of the sperm does influence outcomes of IVF. Sperm retrieved from the testicles seems to have lower levels of damage than poor quality ejaculated sperm in men with sperm storage and transport problems. In these cases, sperm are damaged in the reproductive tract after they leave the testicle. Sperm inside the testicle seem to be protected because of the high level of antioxidants within the testicle. In couples who have failed multiple cycles of IVF, using testicular sperm during a subsequent IVF cycle has lead to over 60% pregnancy rate in several studies and provides a new option to help improve outcomes in these selected patients.
This research has also provided the rationale for treating male infertility with high levels of antioxidants and supplements. If free radical peroxidation leads to sperm DNA fragmentation and if antioxidants can neutralize or reduce oxidative stress in the semen, then it would make sense that supplements containing a combination of vitamins, minerals, bioflavinoids and antioxidants can improve sperm quality to some extent. Research is currently ongoing in this area.
Another condition where new techniques have helped improve outcomes is non-obstructive azoospermia (no sperm in the ejaculate because of a production problem). Over the last decade, it has become evident that sperm production in the abnormal testicle is not uniform, it can be limited to small pockets in some situations. Rondom testicular biopsies may miss a pocket of sperm production and fail to retrieve sperm in a percentage of men who may actually have small amount of sperm production. A microsurgical approach allows these pockets to be visually detected and increases the sperm retrieval rate to up to 75% of patients. The technique is called testicular microdissection or MicroTESE and this can be the difference between failure and the ability to father a biological child. Men who have had prior negative random biopsies may have sperm retrieved via this approach.
New testing methods and treatments for male infertility continue to evolve and improve our ability to help men become fathers such that very few men can not become a biological parent.