The varicocele dilemma – Solutions or Hype?
Varicoceles have been associated with male factor infertility for years. The term “varicocele “was first reported in 1843. Yet even today, there continues to be considerable controversy about varicoceles and what to do about them as well as associated male factor infertility. There are a large number of couples having difficulty conceiving where a varicocele will be present. Therefore, understanding varicoceles might lead to higher pregnancy rates. Estimates suggest that 15 % of couples attempting to conceive will fail to do so within a year of initiating trying to conceive. Infertility is defined as the failed to conceive within one year of attempting to conceive. Male factor infertility, as the only cause of the infertility, will be present in 20% of these couples and will contribute to the infertility on another 30-50% of the couples. These figures emphasize the need for a complete fertility evaluation for couples seeking help in conceiving. Focusing on just the female, a tendency for gynecologists, or just the males, a tendency for urologists, will miss the diagnosis for many couples and may lead to ineffective treatment.
Case: A couple had been trying to conceive for over a year. The woman was 34 YO and had never been pregnant. Her evaluation was normal. The male was 36 YO and had never fathered a pregnancy. His semen analysis demonstrated a low % of normally shaped sperm which was called a low morphology score with 1% normal forms. The male was placed on antioxidants and the couple was instructed to attempt conception with well- timed intercourse. For a variety of reasons, the couple sought a different fertility clinic. This clinic did a hormonal evaluation for the male which was normal. The woman was placed on clomid, and the couple was instructed to have well- timed intercourse. Intrauterine inseminations were not suggested, and the male was never examined. After a number of failed clomid cycles the couple sought a third fertility clinic. A repeat semen analysis confirmed the low normal morphology (2% normal forms) and an exam revealed a subclinical varicocele for the male. Thus, the working diagnosis for this couple was male factor secondary to a subclinical varicocele.
What is a varicocele?
A varicocele is when the veins that drain the blood from the testes enlarge forming a collection of varicose veins in the scrotum. Varicoceles are present in 15-20% of the general male population and 30-40% of males with male factor infertility with up to 80% in couples with secondary infertility. Not all males with a varicocele have male factor infertility. In fact, only about 20% of those with varicoceles will experience male factor infertility. However, there has not been a well-defined cause for the infertility of these 20%. Clinically evident varicoceles are more likely to be on the left side. One reason for this is that the veins that drain the left testicle are vertical and empty at right angles to the renal vein. This creates a vertical column of fluid increasing the pressure in the vein. The right vein crosses across the abdomen to enter the vena cava at an angle and thus generates less pressure. Ultrasound studies have found that while the presence of a varicocele on the left seems more common, most men with varicoceles have some increased varicosity on both sides. There are a number of theories as to how a varicocele may impair male fertility including increased scrotal temperatures (the most popular theory), increased metabolites, altered hormones, low oxygen, and immune causes to name just a few. There may also be a genetic component since men with a first degree relative with a varicocele are more likely to also have a varicocele. The genetic component may reduce male fertility independently of the presence of a varicocele so the picture of how varicoceles cause male infertility remains cloudy at best.
Considerable research has been done in the last ten years on sperm biochemistry to try to improve pregnancy rates. One area that has sparked research is the roles oxidative stress and reactive oxygen species (ROS) play in male factor infertility. A number of factors can increase the oxidative stress for sperm such as age, environmental pollution, heat, diet, obesity, and relevant to this case, varicoceles. Oxidative stress is a byproduct of metabolism. Sperm are highly motile cells, and it takes energy to move. Sperm have 50-70 structures called mitochondria in their midpiece to produce the energy necessary for movement. The mitochondrial metabolism creates molecules (reactive oxygen species: ROS) that are highly reactive but exist for a matter of nanoseconds. There needs to be a balance between having some ROS in order for the sperm to function but excessive ROS can damage the sperm. When sperm are forming, they contain molecules that remove excess ROS, thus preventing damage to the sperm. However, mature sperm lose their cytoplasm and do not contain DNA repair molecules nor molecules to scavenge the ROS. Thus, mature sperm are susceptible to the damage caused by ROS. Oxidative stress can also cause DNA to partially decondense, exposing segments of the DNA making then susceptible to breaks and increasing the percentage of DNA fragments in the semen specimen. Finally, the ROS can cause alteration in the sperm membrane making is less elastic and reducing the percentage of normally shaped sperm. This can be reflected in the semen analysis by the morphology score. Counteracting the susceptibility of sperm to increased levels of ROS is the seminal plasma which is an excellent antioxidant fluid.
A leading theory as to how varicoceles impair male fertility is the fact that sperm from males with varicoceles have increased amounts of ROS. Exactly how this situation reduces fertility remains to be determined. The mechanism for the impaired fertility postulates that the varicocele impairs blood flow and thus the temperature of the testicle is elevated an average of two degrees Celsius. While this theory seems plausible for rats and mice, it is less certain that this is true for humans. For one thing, there is a tremendous overlap in scrotal temperatures between men with varicoceles and men without varicoceles. Heat stress has been correlated with increased oxidative stress, and there is a direct correlation between scrotal temperature and ROS generation. The severity of the varicocele has been correlated with the amount of oxidative stress. The amount of ROS generated is correlated with sperm DNA fragmentation. Thus, ROS can alter sperm function by altering the sperm membrane or because of increased DNA fragmentation. Human oocytes (eggs) have the ability to repair some of the damage to the sperm DNA. The effect of the ROS on the membrane can be overcome by using IVF and injecting the sperm into the eggs (ICSI).
Antioxidants: Buyer Beware
Based upon the theory that oxidative stress is a leading cause of impaired infertility in men with varicocele, the use of antioxidant treatment seems natural. The use of antioxidant therapy for male factor infertility has skyrocketed and there are numerous over-the-counter products claiming to be effective. Evaluating the data, it is difficult to prove that antioxidants are effective in treating male factor infertility. For example, a 2021 literature review evaluated studying the effectiveness of antioxidants that were published over the last ten years. The authors identified 30 studies but only a third included information about pregnancy rates. This is a common problem with the literature for male factor since many studies look at the semen analysis to determine if the treatment is effective. However, the endpoint of interest is the live-birth rate. The authors identified four studies for final consideration and of these, only two found any improvement in pregnancy rates. A review from 2019 looked specifically at the use of antioxidants after varicocelectomy to determine if adding antioxidants improved the pregnancy rates. The studies did show an improvement on the semen parameters but no improvement in the pregnancy rates. Perhaps the best evidence was from a well-constructed randomized controlled trial published in 2020, designed to evaluate the effectiveness of antioxidants used for male factor infertility. The study used a mixture of a number of commonly recommended over the counter substances: vitamin C, vitamin E, selenium, L- carnitine, zinc, folic acid and lycopene. The authors concluded that antioxidants did not improve semen parameters, DNA fragmentation, or cumulative live birth rate. There is some evidence that overuse of some antioxidants, such as vitamin E, may actually be detrimental. Therefore, even though there is widespread use and recommendation for the use of antioxidants, the sum of the literature does not support the use of antioxidants. With reference to the case, the recommendation for antioxidants was the current standard of care with the proviso that evidence is lacking concerning the effectiveness of this treatment option.
Varicocelectomy: Proceed with Caution
Once the diagnosis of a varicocele is made, one treatment option iz to perform a varicocelectomy, thus removing the varicocele. Both the American Society for Reproductive Medicine and the American Urological Association published a joint statement discussing the diagnosis and treatment of male factor infertility. The recommendations began with the statement that for the initial evaluation, both male and female partners should undergo evaluation concurrently. The initial evaluation of the male needs to include at least one, and preferably two semen analyses (SA). If there is an abnormality in the SA, then further evaluation of the male would include a physical exam of the male and testing determined by the abnormality in the SA. Varicoceles are grouped as visible, clinical, and those only detected by ultrasound. Current recommendations are consistent with previous recommendations, that varicocelectomy is only indicated for visible varicoceles. There are a number of surgical approaches, and a recent analysis of the literature suggests that any method is better than no varicocelectomy for those men with visible varicoceles. Furthermore, varicoceles can be treated with embolization, but the evidence suggest this is best reserved when there has been a failure of a surgical varicocelectomy. The patient in this case has a clinical varicocele and thus varicocelectomy is not indicated. From a practical standpoint, once a varicocelectomy is performed, the couple must spend time to conceive. Maximum pregnancy rates from the varicocelectomy take between one to two years to be achieved. For younger couples, this time requirement is reasonable. However, for couples where the female is over the age of 35 or where there is evidence of a reduced ovarian reserve, the delay in treatment for over a year may reduce the couple’s chance to conceive.
Intrauterine insemination: Getting Closer
The use of intrauterine insemination almost always combined with clomid (or letrozole) treatment for the female is currently the initial treatment for many patients with male factor infertility. The rational is that by placing a high concentration of sperm into the uterine cavity, the filtering effect of the cervical mucus is bypassed and significantly more sperm reach the eggs in the fallopian tubes. The use of clomid results in the release of more eggs. So overall the concept is more bullets, more targets, the higher the overall chance of success. While this is the current clinical practice, it is not without its critics. Furthermore, pregnancy rates vary with the cumulative pregnancy rate after three attempts are somewhere between 15 and 30%. There is no indication for treating the female only for male factor.
Invitro fertilization with intracytoplasmic sperm injection (IVF/ICSI): Your Best Shot?
IVF/ICSI remains the most successful form of treatment for male factor infertility. Males with a visible varicocele may consider doing a varicocelectomy prior to the IVF cycle but the use of ICSI seems to correct for the presence of the varicocele. Overall pregnancy rates using IVFD/ ICSI are influenced by female factors especially female age. However, given today’s technology including preimplantation genetic testing of embryos for chromosome number, the cumulative pregnancy rates are very high. A recently published study evaluated the cumulative pregnancy rage after the transfer of three euploid embryos. In that study the rate was over a 90% clinical pregnancy rate.
Returning to the case at hand, the couple are pursing three cycles of clomid- IUI. If that is unsuccessful, they will pursue IVF/ ICSI. Because the woman is young with a normal evaluation and the factor that the male has a clinical varicocele, the overall prognosis for this couple is extremely positive. That is not to ignore the fact that their path requires considerable effort and persistence. But modern developments in the field of reproductive medicine have given many couples that chance to have children whereas thirty years ago this would have been impossible.