The Third Edition of our widely acclaimed textbook Practical Urological Ultrasound was just published by Springer! We are so proud that this 477-page compendium of ultrasound knowledge has become the standard reference for Urologic ultrasound.0
Many of our new male fertility patients are perplexed about their inability to conceive. They have been told that it is not a female factor and that their semen quality is excellent. Their sperm have perfectly shaped oval heads, normal-sized mid-pieces, and straight, well-aligned tails, and they demonstrate great motility (i.e., sperm movement) and forward progression. On visual inspection, one would assume that their sperm could fertilize an egg with ease producing a normal embryo that would develop into a beautiful baby.
Unfortunately, in spite of their good looks, their sperm may never be baby-makers. The integrity of sperm DNA might be impaired. Even if sperm is able to fertilize an egg, DNA fragmentation will most likely prevent the normal development of an embryo, resulting in a failed pregnancy or miscarriage. I last wrote about sperm DNA fragmentation six years ago. New assays have been developed, and the literature updated.
It’s a growing concern amongst fertility specialists that sperm DNA fragmentation might be the cause of many couples’ inability to achieve a pregnancy naturally or through an assisted reproductive technology protocol using intrauterine insemination (IUI) or in-vitro fertilization (IVF) with or without the use of intracytoplasmic sperm injection (ICSI). I have added sperm DNA fragmentation testing to the battery of tests we perform to evaluate a man’s fertility potential. It can detect a reason for the couple’s subfertility and offer additional treatment options. We routinely screen our male patients with advanced male age, large varicoceles presence, or a history of miscarriages.
We now also screen the male partner of infertile couples with a normal semen analysis and no obvious female factors for DNA fragmentation. In doing this, we have found greater than 40% of these men have abnormal levels of fragmentation. For these patients, this has answered questions they had and has offered them a better understanding of why certain options might be better for them in their quest towards parenthood. I will discuss some of the biology and therapeutic options in this blog. We have provided links for those wanting additional information.
DNA is an organic molecule that consists of two strands of repeating building blocks called nucleotides. Each nucleotide consists of a sugar, a phosphate group, and a nitrogen base. The nucleotides in each strand are tightly bonded. The two strands however, are loosely held together by weaker bonds. DNA fragmentation occurs when separations and breaks occur in these bonds. Our chromosomes are composed primarily of DNA, and segments of that DNA form genes, whose specific sequence of nitrogen bases constitutes genetic code. DNA fragmentation can impair the transmission of this genetic code, disrupting the cell’s ability to function. For a sperm cell, DNA fragmentation can prevent fertilization or proper development of an embryo if fertilization occurs.
Scientists have identified several factors that contribute to an increase in sperm DNA fragmentation. Oxidative stress is a major cause of DNA damage. Oxidative stress is the damage caused by free radicals reacting with molecules like DNA and thus disrupting their bonds. Physical and environmental changes can increase the level of free radicals to which sperm DNA is exposed. Recent studies have linked environmental toxins in certain chemical air pollutants, pesticides, and plastics to elevated oxidative stress and sperm DNA fragmentation. Obesity, alcohol consumption, and tobacco have also been associated with DNA damage from increased oxidative stress.
Scrotal varicoceles have been shown to exacerbate sperm DNA fragmentation. Varicoceles elevate the temperature inside the testes to levels that disrupt the bonds of DNA molecules, resulting in fragmentation. Excess fat around the scrotum from being overweight will also elevate testicular temperatures to unfavorable levels that damage the DNA bonds.
Chemotherapy and radiation therapy have been linked to sperm DNA fragmentation, and further investigation is needed to determine if this is a long-term or even permanent side-effect of some cancer treatments. Reproductive aged men who have been diagnosed with cancer should be encouraged to cryopreserve sperm prior to starting treatment as a means of preserving their fertility. Post-treatment fertility evaluations should include an assessment of sperm DNA fragmentation, especially since men with normal semen analyses can have high levels of sperm DNA fragmentation.
Anomalies in the process of sperm maturation can cause sperm DNA fragmentation. The structure of the human sperm cell makes it more susceptible to DNA fragmentation than any other cell in the body. Its nucleus has 40% less space compared to most other cells, so sperm DNA has to be highly compacted and coiled to enable it to fit in the nucleus. This highly compacted and structured arrangement protects the sperm cell’s genetic material (DNA) as it travels through the male and female reproductive tracts, and it enables the proper fusion of DNA from both sperm and egg at fertilization. Sperm maturation is a process that transforms a round germ cell into an elongated mature sperm cell with a head, acrosome, midpiece, and a tail. During this process, DNA is uncoiled, transcribed (which is the process of reading the DNA’s genetic code), and recoiled a couple of times. Intentional nicks and breaks are made in sperm DNA to enable it to be tightly compacted and recoiled. These nicks are supposed to be repaired when the DNA is being transcribed, but external factors, such as oxidative stress and advanced paternal age, often prevent this and hence result in sperm DNA fragmentation.
Sertoli cells which function to support and nourish developing sperm cells in the testes also screen sperm cells and mark defective ones for elimination. Sometimes external factors disrupt this process, and marked sperm cells are not eliminated, or apoptosis (cell death) is initiated but not completed. These sperm cells have a much higher incidence of DNA fragmentation.
Sperm DNA fragmentation can occur during the movement of sperm from the seminiferous tubules through the vas deferens, an event that allows immature and mature sperm to be tightly packed together. Immature sperm produce a high level of reactive oxygen species (a type of free radical), which often react with and damage the DNA of mature sperm. Reactive oxygen species also activate enzymes called caspases and endonucleases that are part of the process of apoptosis, further damaging sperm DNA. This is the primary reason that sperm retrieved from the testes has less DNA damage than sperm from the ejaculate.
Men with high levels of DNA fragmentation now have options. For many men, simple lifestyle changes can improve sperm DNA fragmentation. Weight loss, healthy diet, cessation of smoking, reduced consumption of alcohol, and antioxidants have all been shown to improve DNA integrity. For older men, who typically experience DNA damage because the mechanisms of sperm maturation function less efficiently, and men who have undergone treatment for cancer, it may not be possible to reduce sperm DNA damage. However, testis sperm have less sperm with fragmented DNA. Therefore, sperm can be surgically retrieved from the testis and used in IVF/ICSI. For additional information on sperm DNA fragmentation testing please contact me at email@example.com.
Ribas-Maynou, J., García-Peiró, A., Fernández-Encinas, A., Abad, C., Amengual, M., Prada, E., Navarro, J., Benet, J. (2013). Comprehensive analysis of sperm DNA fragmentation by five different assays: TUNEL assay, SCSA, SCD test and alkaline and neutral Comet assay Andrology 1(5), 715 722. https://dx.doi.org/10.1111/j.2047-2927.2013.00111.x
Smit, M., Romijn, J., Wildhagen, M., Veldhoven, J., Weber, R., Dohle, G. (2013). Decreased Sperm DNA Fragmentation After Surgical Varicocelectomy is Associated With Increased Pregnancy Rate Journal of Urology 189(1S), S146-50. https://dx.doi.org/10.1016/j.juro.2012.11.024
Tirado, E., Barrett, B., Leader, B. (2012). Concurrent sperm DNA fragmentation and oxidative stress assessment on 2,281 male semen samples Fertility and Sterility https://dx.doi.org/10.2164/jandrol.110.010595/full
Bungum, M. (2012). Sperm DNA integrity assessment: a new tool in diagnosis and treatment of fertility. Obstetrics and gynecology international 2012(4), 531042 6. https://dx.doi.org/10.1155/2012/531042
Moskovtsev, S., Mullen, J., Lecker, I., Jarvi, K., White, J., Roberts, M., Lo, K. (2010). Frequency and severity of sperm DNA damage in patients with confirmed cases of male infertility of different aetiologies Reproductive BioMedicine Online 20(6), 759 763. https://dx.doi.org/10.1016/j.rbmo.2010.03.002
With the recent report that SARS-CoV-2 is found in semen, the answer now is; We probably should be concerned. This Research Letter published in JAMA Network Open by Li et al. (1) describes their findings in 38 participants who provided a semen specimen. They found
“23 participants (60.5%) had achieved clinical recovery, and 15 participants (39.5%) were at the acute stage of infection. Results of semen testing found that six patients (15.8%) had results positive for SARS-CoV-2, including 4 of 15 patients (26.7%) who were at the acute stage of infection and 2 of 23 patients (8.7%) who were recovering.”
The study, unfortunately, has several limitations. Thirty-eight patients are a small number, and there was no follow up to see when the virus that was found in semen was cleared from semen. Also, the two “recovering” patients were defined as patients that had a “clinical improvement,” which was not defined. They also did not measure the presence of the virus in the nasopharyngeal region at the same time as they test the semen. Other studies have found that SARS-CoV-2 can be found in oropharyngeal secretions for a mean of 9.5 days with a range of 2 to 22 days after symptoms began (2). This same study showed that the virus persisted in stool samples for 2 to 3 days longer than oropharyngeal secretions. Therefore, the two days that Li et al. study followed patients after symptoms started to improve was likely too short. In addition, studies are finding that as many as 20% of patients with the virus are asymptomatic and might be able to transmit the virus for a month or more (3). Therefore, a longitudinal study, following COVID-19 patients over time, measuring the time for viral clearance in several sites, including semen, is needed.
The results of this study also are in contrast to prior studies. I reported in two prior blogs that investigators did not find SARS-CoV-2 in semen or in testicular tissue (4) (NYCryo.com/blog). There is also a recent case report that also did not find SARS-CoV-2 in semen in a COVID-19 positive patient (5). All tests to date have used nasopharyngeal or oropharyngeal swabs to test semen specimens. However, not all body fluids are alike. They contain different proteins that might change the testing results. That is why a viral test must be validated for the body fluid it is being measured in. Validation minimizes the number of false positives (i.e., the test says the patient has the virus but actually the patient is free of the virus) and false negatives (i.e., the test says the patient does not have the virus but actually the patient has the virus). The lack of using validated tests is a possible reason why prior studies did not find the virus in semen (false negative). Conversely, it might also be the reason the Li et al. study found the virus in semen when it might not have been (false positive). To give valid results, the test must be validated for both the virus and the body fluid in which the virus is suspected to be residing.
We still don’t know if the virus in semen can be transmitted to the partner and cause disease. However, given the likely presence of the virus in semen, caution is advised for couples having relations. Especially when the male partner is positive for SARS-CoV-2. In an abundance of caution, until we have more information, abstinence or a barrier contraceptive should be recommended.
I again refer to an editorial by Feldmann in the New England Journal of Medicine who offers a modified view (6). Dr. Feldmann made a point of differentiating between the presence of a virus detected in a semen sample and the infectivity of that virus. Many viruses are found in semen. However, they are not infectious. A measurement of infectivity is needed. To measure infectivity, you need to know the amount of virus required to cause an infection as well as the pathway that results in infection. For example, if a pathogen such as a virus is in semen but needs to be aerosolized and inhaled to become infectious, then it is less likely to be transmitted to another person. However, other pathogens such as Zika and Ebola can be transmitted by semen to another person through sexual contact. It appears, from the limited information available, that SARS-COV-2 is transmitted through transfer into the lungs by the act of breathing in aerosolized particles containing the virus or transfer of the virus from a surface containing the virus to a person’s mouth or nose even from COVID-19 positive individuals without symptoms (7). Hence, the requirement for hand-hygiene and social distancing. However, Dr. Feldmann feels, it is unlikely that sex, even if the virus is in semen, would be a significant modality of transmission.
We also don’t know whether SARS-CoV-2 can be transmitted to the developing fetus. A recent case report (8) presented a second-trimester miscarriage in a suspected COBID-19 positive mother. The mother, placenta, and fetus were tested for SARS-CoV-2. The mother and placenta were positive, while the fetus was negative. The suspected cause of the miscarriage was SARS-CoV-2. It is difficult to make broad conclusions from this single case report. However, this report does raise additional concerns and challenges for pregnancies during this pandemic.
As I mentioned in a prior blog, the Society for Assisted Reproductive Technologies (SART) has recommended during this pandemic to stop new assisted reproductive procedures except for urgent cryopreservation (9). This is still good advice in light of the morbidity and potential mortality of this disease to the mother and child, as well as the poorly defined modality of transmission.
My closing thoughts are updated based on this new information: SARS-CoV-2 are likely found in semen, they can survive the freeze/thaw process of cryopreservation and potentially can be transmitted to the partner and offspring. However, there is presently no data suggesting that SARS-CoV-2 can be transmitted to the partner and offspring from either fresh or cryopreserved semen. Pregnant women and their unborn child are a vulnerable population that should take all precautions for preventing SARS-CoV-2 infection during their pregnancy. Couples considering starting a family during this pandemic might consider being tested for the presence of the virus to make a more informed decision. Cryopreservation of semen should continue during this time with testing the patient for the presence of SARS-CoV-2 and if positive, quarantining the specimens with cryopreserved aliquots available for viral testing once testing of semen and testicular specimens is validated. Patients, as always, should be made aware of the limited data available and that the specimens should be quarantined until validated testing is available, and high-quality evidence regarding the use of SARS-CoV-2 positive specimens is available.
#covid19 #infertility #semen #coronavirus
- Li, D., Jin, M., Bao, P., Zhao, W., Zhang, S. (2020). Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019 JAMA Network Open 3(5), 1-3
- Ling, Y., Xu, S., Lin, Y., Tian, D., Zhu, Z., Dai, F., Wu, F., Song, Z., Huang, W., Chen, J., Hu, B., Wang, S., Mao, E., Zhu, L., Zhang, W., Lu, H. (2020). Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients Chinese Medical Journal 133(9), 1039-1043. https://dx.doi.org/10.1097/cm9.0000000000000774
- Pan, Y., Yu, X., Du, X., Li, Q., Li, X., Qin, T., Wang, M., Jiang, M., Li, J., Li, W., Zhang, Q., Xu, Z., Zhang, L. (2020). Epidemiological and clinical characteristics of 26 asymptomatic SARS-CoV-2 carriers. The Journal of infectious diseases
- Song, C., Wang, Y., Li, W., Hu, B., Chen, G., Xia, P., Wang, W., Li, C., Sha, J., hu, z., Yang, X., Yao, B., Liu, Y.(2020). Detection of 2019 novel coronavirus in semen and testicular biopsy specimen of COVID-19 patients medRxiv https://dx.doi.org/10.1101/2020.03.31.20042333
- Paoli, D., Pallotti, F., Colangelo, S., Basilico, F., Mazzuti, L., Turriziani, O., Antonelli, G., Lenzi, A., Lombardo, F. (2020). Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab Journal of Endocrinological Investigation https://dx.doi.org/10.1007/s40618-020-01261-1
- Feldmann,H, Virus in Semen and the Risk of Sexual Transmission, New Engl J Medicine, 378;15, 2018
- Wei, W., Li, Z., Chiew, C., Yong, S., Toh, M., Lee, V. (2020). Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020 Morbidity and Mortality Weekly Report 69(14), 411-415. https://dx.doi.org/10.15585/mmwr.mm6914e1
- Baud, D., Greub, G., Favre, G., Gengler, C., Jaton, K., Dubruc, E., Pomar, L. (2020). Second-Trimester miscarriage in a Pregnant Woman With SARS-CoV-2 Infection JAMA 323(21)https://dx.doi.org/10.1001/jama.2020.7233
The current coronavirus pandemic has created a new reality. Eventually, we will get back to our lives, albeit very much aware of the invisible pathogens around us. My last blog discussed the possible presence of SARS-CoV-2 in the testis (NYCryo.com/blog). What about SARS-CoV-2 in semen? What about our future reproductive capabilities? Will there be a lasting effect of this novel virus? The simple answer is that we don’t know, and much work will be needed to determine the long-term impact on our fertility. I will present what we know about viruses in semen and their infectivity and potential impact on the partner and offspring.
The Society for Assisted Reproductive Technologies (SART) has recommended during this pandemic to stop new assisted reproductive procedures except for urgent cryopreservation (1). Good advice in light of the morbidity and potential mortality of this disease, as well as the poorly defined modality of transmission. There is always the possibility of contamination in semen specimens stored in liquid nitrogen. However, viruses can result in poor quality sperm but not thought to be transmitted to the partner or offspring (2).
This leads to the two questions: What do we know about the presence of this virus in gametes and embryos and the potential for sexual transmission of the virus? Will the use of semen from infected individuals result in infection of the female recipient or offspring?
Can SARS-COV-2 be transmitted through sex? This seemingly simple question is more complicated to answer than it seems. An editorial by Feldmann in the New England Journal of Medicine addressed this issue in 2018 (3). Dr. Feldmann made a point of differentiating between the presence of a virus detected in a semen sample and the infectivity of that virus. Many viruses are found in semen. However, they are not infectious. A measurement of infectivity is needed. To measure infectivity, you need to know the amount of virus required to cause an infection as well as the pathway that results in infection. For example, if a pathogen such as a virus is in semen but needs to be aerosolized and inhaled to become infectious, then it is less likely to be transmitted to another person. However, other pathogens such as Zika and Ebola can be transmitted by semen to another person through sexual contact. It appears, from the limited information available, that SARS-COV-2 is transmitted through transfer into the lungs by the act of breathing in aerosolized particles containing the virus or transfer of the virus from a surface containing the virus to a person’s mouth or nose even from COVID-19 positive individuals without symptoms (4). Hence, the requirement for hand-hygiene and social distancing. However, it is unlikely that sex, even if the virus is in semen, would be a significant modality of transmission.
What do we know about the presence of SARS-CoV-2 in semen? There is only one small, non-peer reviewed study of 13 patients that I found online (5). In this study, all patients were confirmed positive by nasopharyngeal swab testing for real-time reverse transcription polymerase chain reaction (rRT-PCR) for SARS-CoV-2. They followed these patients with both repeat rRT-PCR testing as well as serology of blood for both IgM and IgG antibodies. They also tested semen (12 patients) and testicular biopsy specimen (1 patient) for SARS-CoV-2 RNA by rRT-PCR. None of the semen specimens or the testicular biopsy specimen was found to be positive for SARS-CoV-2. Several cautions should be noted in interpreting the results of this study besides the low number of patients. First, the methodology for testing semen and testicular biopsies has not been validated. Second, only one patient’s semen and one patient’s testis tissue was tested when the rRT-PCR was still positive.
If SARS-COV-2 is present in semen will it adversely affect the embryo, fetus, or child? Toga in insight into this question, one needs to look at the animal literature, in particular bovine and equine research. Viruses can attach to, and sometimes be integrated into spermatozoa (6). In turn, this can theoretically result in embryos with the virus. As reported by these authors, ‘It has never been demonstrated that infected embryos have resulted in infection of the recipients or offspring.’ Several viruses that are found in human semen (eg Mumps, HIV, Zika, Influenza, Coxsackie) are known to cause orchitis in susceptible men (7). Orchitis can result in impaired testicular function and sperm production but not the transmission of the virus to a partner or offspring. However, a few (eg HIV, Zika) appear to be sexually transmitted to the partner and at least one (eg Zika) is known to affect the developing fetus.
Closing thoughts: Viruses can be found in semen; they can survive the freeze/thaw process of cryopreservation and potentially can be transmitted to the partner and offspring. However, there is currently no data suggesting that SARS-CoV-2 can be transmitted to the partner and offspring from either fresh or cryopreserved semen. My recommendation follows the SART recommendation that urgent cryopreservation should continue for men requiring urgent gonadotoxic therapy. Patients should be made aware of the limited data available, and that the specimens should be quarantined until high-quality evidence is available.
#covid19 #infertility #semen #coronavirus
- Wiwanitkit,J, Semen banking: consideration on viral contamination in the era of new emerging viral infection, Iranian Journal of Reproductive Medicine, 9(2):145-146, 2011
- Feldmann,H, Virus in Semen and the Risk of Sexual Transmission, New Engl J Medicine, 378;15, 2018
- Song, C., Wang, Y., Li, W., Hu, B., Chen, G., Xia, P., Wang, W., Li, C., Sha, J., hu, z., Yang, X., Yao, B., Liu, Y. (2020). Detection of 2019 novel coronavirus in semen and testicular biopsy specimen of COVID-19 patients medRxiv https://dx.doi.org/10.1101/2020.03.31.20042333
- Wrathall, A., Simmons, H., Soom, A. (2006). Evaluation of risks of viral transmission to recipients of bovine embryos arising from fertilisation with virus-infected semen Theriogenology 65(2), 247-274. https://dx.doi.org/10.1016/j.theriogenology.2005.05.043
- Liu, W., Han, R., Wu, H., Han, D. (2018). Viral threat to male fertility. Andrologia 50(11), e13140. https://dx.doi.org/10.1111/and.13140
What effect does COVID-19 have on the testes and male fertility? I have been asked this question by many patients and some colleagues. The bottom line is that it is too early to know. However, there is a recent review article that raises some concerns (see full reference below and link to the online paper). This paper, published online, but not yet peer-reviewed, has received much following and comments on Twitter. I usually do not write about papers that have not gone through the rigorous process of peer review, however, due to the amount of discussion surrounding this paper I will summarize their findings and give my thoughts. I will update this blog as more information develops. Please note that I am not endorsing this paper, nor am I advocating undue concern. However, the authors present interesting findings that must undergo review by experts in the field and be supported or refuted by additional research. At present, there is just too little work done on this disease to make recommendations.
Their work is a review paper from the Departments of Urology of the Nanjing Medical University in China, located approximately 300 miles from Wuhan China. Wuhun, was the epicenter of the coronavirus disease in 2019 (abbreviated COVID-19). The virus itself has been named “SARS-CoV-2”. Their review included a total of 146 cases from three prior published papers.
The authors reviewed studies demonstrating that the Angiotensin Converting Enzyme 2 receptor (ACE2) was a major cellular receptor that mediated the entrance of the SARS-CoV-2 into a human cell. ACE2 receptors have been implicated in other severe acute respiratory syndrome coronavirus (SARS). They also noted that a percentage (3% to 10%) of those infected with this virus exhibited kidney damage. They wanted to know if other cell types, that had large numbers of ACE2 receptors, were also affected by this virus. The cells they looked at were renal tubular cells, important for kidney function. They also reviewed two types of cells located in the testis, the Leydig cells, which produce testosterone, the major male hormone and the seminiferous tubule cells which are important in sperm production.
Their results were enlightening.
- The number of receptors in the renal tubular cells was high. The implication was that the ACE2 receptors provided access to the SARS-CoV-2 to these kidney cells and adversely affected kidney function. They suggested monitoring kidney function, especially if the patient is on medications that require modification when kidney function is compromised.
- In their review, they were surprised to find that ACE2 receptors in the seminiferous tubules and Leydig cells were some of the highest in the body. Their takeaway was that the testis is a potential target of SARS-CoV-2. Also, that follow-up evaluation of fertility is important in reproductive-aged men that have had COVID-19. This is particularly concerning in men that had orchitis (ie, an inflammation or infection of the testis) during their COVID-19 infection.
The authors concluded that reproductive function might be compromised in young males recovering from COVID-19. However, there are several concerns with the methodology of this study that need to be kept in mind.
- They reviewed prior work, which identifies a high density of ACE2 receptors in the testis. Although this might imply that the testis would be a target for SARS-CoV-2 it does not document damage that has occurred or provide data on the disease process that might occur.
- Their review included 146 cases in total compared to the 156,433 cases with 5,821 deaths that have occurred at the time of this blog. To make a conclusion based on such a small sample is at best challenging.
Nonetheless, we are only starting to identify the pathogenesis of this disease. We need to gather data continually. Only by the questions we ask, and meticulous collection of data will we get closer to the answers. I will continue to update the impact of COVID-19 on male fertility as we learn more.
#covid19 #infertility #semen #coronavirus
C Fan et al, ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection, MEDRXIV 2020. HTTPS://WWW.MEDRXIV.ORG/CONTENT/10.1101/2020.02.12.20022418V10
Many of the men seen in my practice for male infertility are azoospermic. This means they have no measurable amount of sperm in their ejaculate. This is a significant issue for these men wanting to have a biological child. Approximately half of these men have Obstructive Azoospermia (OA). Their testes produce enough sperm, but a blockage exists in either the vas deferens or the epididymal tubules that prevent the transport of sperm from the testes to the tip of the penis. Sometimes the vas deferens and epididymal tubules are missing. The remaining half of our azoospermic patients have Non-Obstructive Azoospermia (NOA). Their vas deferens and tubules are clear and open, but the ability of their testes to produce sperm is impaired.
Medical interventions exist that enable many men with azoospermia to father their own biological children. Blockages can be surgically removed, and sperm production can sometimes be improved with pharmacological treatments. However, for most men with NOA and many with OA, the only avenue available for achieving a pregnancy with a partner is to have sperm surgically retrieved from the testes and then used in an assisted reproductive technology (ART) treatment protocol involving in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).
What is TESE?
In conventional testicular sperm extraction (TESE), a small incision is made in the scrotum exposing the testes. An incision is then made in one of the testes, through the tunica albuginea (protective outer covering of the testis) to expose its parenchymal (working) tissue. Special care is taken to avoid blood vessels. Pressure is applied along the incision until tissue containing seminiferous tubules protrudes through the incision site. This tissue is surgically removed and set aside for cryopreservation and/or immediate use in IVF/ICSI. The procedure is then repeated on the other testis.
Seminiferous tubules are the site of spermatogenesis (sperm production). However, spermatogenesis is not uniform throughout the testes, and so at any given time, some seminiferous tubules will have much higher concentrations of sperm than others. It is not possible to evaluate the degree of spermatogenesis in seminiferous tubules with the naked eye. So a surgeon has no way of visually assessing the tissue he intends to extract during a TESE for the presence of sperm. For men with OA this conundrum is usually not problematic. They produce plenty of sperm, so chances are quite good that testis tissue retrieved by conventional TESE will contain sufficient sperm for IVF/ICSI. This is not the case however for men with NOA. Because their ability to produce sperm is impaired, the sperm concentration in their seminiferous tubules can range from adequate in some tubules to non-existent in others. As a result, they run the very real risk of having testis tissue retrieved by conventional TESE that is devoid of sperm and therefore unsuitable for IVF/ICSI despite having sufficient sperm production in another portion of the testicle.
When sperm are not found in conventional TESEs, fertility specialists often counsel patients that no viable option exists to achieve a pregnancy with a partner. Patients are encouraged to start looking at sperm donors. This is outdated advice given by professionals who are unfamiliar with microdissection testicular sperm extraction (micro TESE).
What is microTESE?
A microTESE is a very different, far more complex type of surgical sperm retrieval compared to a conventional TESE. It is performed by an experienced urologic surgeon, who is an expert in the use of an operating microscope. The surgeon is assisted by a team of laboratory andrologists (specialists in the laboratory techniques required to identify and extract sperm from testicular tissue). An incision is made in the scrotum exposing the testes. Thirty or more microscopic specimens containing seminiferous tubules are taken from multiple sites on each testis. Individual seminiferous tubules in each of these samples are examined in the operating room by the laboratory andrologist to determine the presence of sperm. Seminiferous tubules containing sperm are usually plumper, light yellow in color, and often situated close to blood vessels. The surgeon is thus able to extract only tissue with the best potential to contain sperm, which is key to the success of the procedure (1). Once the tissue has been extracted, the laboratory andrologist will further examine it to assess sperm quality (concentration, maturation, morphology). The andrologist will also prepare the tissue for immediate use or cryopreservation. Using this approach, the operating team can focus on sites that appear to yield the best sperm concentration and quality, ensuring that a sufficient quantity of the most “promising” tissue is extracted. A microTESE typically takes several hours from the first incision to last suture. A conventional TESE is usually completed in under an hour.
MicroTESE offers several advantages over conventional TESE (2,3). Studies show that for men with NOA, sperm retrieval rates (SRR) by micro TESE are significantly higher than conventional TESE. “Sperm was recovered from those with hypospermatogenesis in 84% and 92.9% by conventional and microdissection TESE, respectively. In the case of maturation arrest, SRR was 27.3% and 36.4% respectively. In cases of Sertoli-cell-only syndrome (SCOS), the SRR was 6.2% and 26.9% respectively.”1 The use of an operating microscope minimizes the amount of tissue that is removed, as many microscopic specimens are taken rather than larger biopsies. The use of an operating microscope also enables the surgeon to avoid disrupting blood vessels, decreasing the likelihood of damaging vascularized areas of the testes. This minimizes trauma and the resulting loss of functionality, such as a decline in testosterone production. Better retrieval rates enable andrologists to cryopreserve testicular tissue for later use. Using cryopreserved sperm eliminates the need for synchronizing egg and sperm retrievals. It also eliminates the trauma and potential tissue damage caused by multiple sperm retrievals.
There has been some debate over the use of fresh versus thawed sperm for ICSI (4). Many fertility specialists believed better outcomes are achieved with fresh sperm, as cryopreservation damages both cell and acrosome membranes and increases the damage caused by sperm oxidative stress. However several recent studies refute this assumption. A recent review of data from 224 studies focusing on men with NOA revealed no difference in fertilization and pregnancy rates with fresh versus cryopreserved sperm used for ICSI.
The Bottom Line
Microdissection testicular sperm retrieval is offering new hope to men with NOA. However, I am ending this blog on a cautionary note. This is not a procedure that can be done by all urologic surgeons. It requires a highly skilled urologic surgeon who has extensive experience using an operating microscope and doing testicular sperm retrievals. In addition, it requires a fertility laboratory with experienced and well-trained staff. Together, the surgeon’s and laboratory’s skill and experience is key to the success of this procedure (5).
- Caroppo E, Colpi EM et al. The seminiferous tubule caliber pattern as evaluated at high magnification during microdissection testicular sperm extraction predicts sperm retrieval in patients with non-obstructive azoospermia. Andrology 2019; 7: 8-14
- Ghalayini IF, A-Ghazo M, et al. Clinical Comparison of Conventional Testicular Sperm Extraction and Microdissection Techniques for Non-Obstructive Azoospermia. J Clin Med Res. 2011; 3(3): 124-131.
- Ravissini PC, Azevedo M, et al. Success rate in ICSI treatment of men with non-obstructive azoospermia (NOA): a comparative study between TESE (testicular sperm extraction) and microdissection-TESE. Fertil Steril. 2008; 90: S382-S383.
- Ohlander S, Hotaling J, et al. Impact of fresh versus cryopreserved testicular sperm upon intracytoplasmic sperm injection pregnancy outcomes in men with azoospermia due to spermatogenic dysfunction: a meta-analysis. Fertil Steril. 2014; 101(2): 344-349.
- Ishikawa T, Nose R, et al. Learning curves of microdissection testicular sperm extraction for nonobstructive azoospermia. Fertil Steril 2010; 94(3): 1008-1011.
A little-known fertility option is Directed Donation. I thought a brief overview would be appreciated by those seeking additional options. I have included links at the end for those looking for additional information. A Directed Donor is a man storing sperm for use by a known recipient with whom he is not sexually intimate. This is in contradistinction to an Anonymous Donor who is a donor whose identity is unknown to the recipient or a male Client Depositor who is an individual who deposits reproductive tissue prior to intended or potential use in artificial insemination or assisted reproductive procedures performed on his regular sexual partner.
The recipient for a Directed Donor might be a woman without a male partner who would like to have a child with sperm from an individual she knows, a woman in a relationship with a male partner who is not able to produce sperm or a transgender female wanting to have a child with a female partner or surrogate.
There are several steps by which the Medical Director qualifies a directed donor for specimen use by a recipient. These steps are similar to those required for an anonymous donor. If the qualification is performed in NY State the Directed Donor must be found eligible by the Medical Director of the facility prior to collection of the first semen sample for processing and storage. Determination of Eligibility includes the following components:
- A physical examination of the Directed Donor, as well as blood testing for indications of sexually transmissible diseases.
- A complete medical history, both individual and family, including first-degree and second-degree relatives.
- Genetic testing for major genetic disorders in consultation with a geneticist.
- Psychological evaluation and counseling to access psychological risks and evaluate financial and emotional coercion.
- Evaluation of a semen specimen
- Written informed consent must be obtained, and discussion had with the Recipient, Recipient’s Partner (if any) and Directed Donor about the results of the evaluation and use of the specimens.
The cryopreserved specimens are then quarantined as required by state regulations. In New York State this is 6 months but can be waived by the Recipient after a discussion of the potential risks of doing so. In all non-traditional fertility options, it is always prudent to seek advice from your Physicians assisting you with your fertility treatment as well as your legal advisors.
If you have any questions, please contact us at 516-487-2700.
Links to NY State and Federal Regulations:
- NY State Department of Health Reproductive Tissue Banking Regulations
- FDA Code of Regulations Title 21
You can sign up for my Blog at Men’s Reproductive Health Blog0
The desire to have children is common among individuals transitioning with 38% of respondents of the National Transgender Discrimination Survey indicating they are parents1. A Belgium study surveyed 121 patients transitioning and found that 40% would want children and that half of these would like a biologic child2. Also in this study, 77% of 101 transgender women wanted the professionals treating them to discuss fertility options with 51% stating that they would have cryopreserved sperm, or at least seriously considered this if it had been discussed.
The World Professional Organization for Transgender Health (WPATH, http://www.wpath.org) first developed the Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People in 1979. However, it wasn’t until 2011 that they introduced specifics on the Reproductive Health needs of transgender people3. In the current WPATH Standards (http://bit.ly/2msEoQl) they recommend that prior to the initiation of therapy fertility preservation options are discussed, even if the person is currently not interested in future fertility.
Ideally, sperm should be collected before hormones are prescribed. However, it is possible in male to female transitioning that stopping feminizing hormones might provide a window to retrieve sperm. Even in the individual who does not have sperm in the ejaculate, or cannot produce an ejaculate, the potential for sperm retrieval and banking is possible with other modalities. Testicular biopsy with banking of tissue excised during the procedure can be used for conception with in vitro fertilization (IVF) couple with single sperm injection (ICSI). In addition, a recent study4 found normal spermatogenesis in 24% of testes removed at the time of sex reassignment surgery for individuals on long term estrogen therapy. This suggests that banking of testicular tissue may still be possible in 1/4 of patients treated with long term hormonal therapy. However, it must be noted that 75% of patients treated with long term estrogen therapy did not have sperm in the ejaculate or on biopsy.
At one fertility clinic5 11 patients were referred for sperm banking between January 2010 and May 2014. Nine of these patients banked sperm for future potential use. During this 52 month period, 1 couple used the stored sperm, which resulted in a pregnancy. It should be noted, however, that the mean age of the patients preserving sperm was 26.5 years of age which might account for the low usage rate of the banked sperm during this study. What was interesting in this study is that there was an increase in yearly referrals to their clinic over the 4.3 years they collected data. However, they found that referrals remained low which they postulated was due to both cost of sperm banking as well as lack of awareness that fertility preservation was an option.
Unfortunately, the reproductive needs of transgender individuals are still largely unmet6. Hopefully, this will be changing as more health professionals provide much-needed information on reproductive health to individuals undergoing gender transition.
- James SE, Herman JL, Rankin S, Keisling M, Mottet L, Anafi M. 2015 U.S. Transgender Survey. December 2016:1-302.
- De Sutter P, Kira K, Verschoor A, Hotimsky A. The Desire to Have Children and the Preservation of Fertility in Transsexual Women: a Survey. International Journal of …; 2002.
- Coleman E, Bockting W, Botzer M, et al. Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7. International Journal of Transgenderism. 2012;13(4):165-232. doi:10.1080/15532739.2011.700873.
- Schneider F, Neuhaus N, Wistuba J, et al. Testicular Functions and Clinical Characterization of Patients with Gender Dysphoria (GD) Undergoing Sex Reassignment Surgery (SRS). The journal of sexual medicine. 2015;12(11):2190-2200. doi:10.1111/jsm.13022.
- Jones CA, Reiter L, Greenblatt E. Fertility preservation in transgender patients. International Journal of Transgenderism. 2016;17(2):76-82. doi:10.1080/15532739.2016.1153992.
- HUNGER S. Commentary: Transgender People Are Not That Different after All. Cambridge Quarterly of Healthcare Ethics. 2012;21(2):287-289. doi:10.1017/S0963180111000818.
Many people facing cancer know about some of the side effects of common treatment options. Chemotherapy can cause you to lose your hair and change the way food tastes to you. It can make you nauseous and fatigued. These are symptoms that cancer patients expect to face during treatment. But one side effect you may not have thought about is infertility. For both men and women, treatments can affect the ability to conceive children1. If you are planning on starting or expanding your family, this may be a concern you should talk about with your doctor. A medical professional can help you understand your risk for infertility due to cancer and treatments.
Sperm production can be temporarily reduced by certain cancers and treatments2. Some treatments, however, permanently alter your ability to reproduce. Cancer cells are fast-growing. Cancer treatments are designed to target and eliminate fast-growing cells in the body. This is intended to eradicate cancer cells, but other fast-growing cells, like hair and sperm, are destroyed in the process3. Both radiation and chemotherapy treatments can slow or stop sperm production, and the effects can be permanent3. Additionally, chemotherapy and radiation therapy may alter the DNA of sperm, and it is recommended that a cancer survivor waits for 1 to 2 years before trying to conceive a child for this effect to dissipate4.
If you have been diagnosed with cancer and are worried that treatment may interfere with your plans to have a family, there are options you can pursue to preserve your fertility before you begin treatment. Cryogenic sperm freezing is a simple process that can save your viable genetic material for years, in case you need it to aid in intrauterine insemination or in vitro fertilization. Sperm must be collected and banked before your cancer treatment begins4 to ensure the best possible sample of undamaged cells. These frozen samples of genetic material preserve your ability to grow your family, whether due to permanent side effects of infertility, or whether you just don’t want to wait a few years after treatment to have a baby.
- American Society of Clinical Oncology. Side effects of chemotherapy. Retrieved from http://www.cancer.net/all-about-cancer/cancernet-feature-articles/treatments-tests-and-procedures/side-effects-chemotherapy
- Livestrong Foundation. Male fertility preservation. Retrieved from http://www.livestrong.org/we-can-help/just-diagnosed/male-fertility-preservation/
- Roswell Park Cancer Institute. Cancer and male infertility. Retrieved from https://www.roswellpark.org/patients/fertility-guide/male-infertility
- New York Cryo. FAQs: 3. When does one bank sperm? Retrieved from https://nycryo.com/faqs/
20% of all men have erectile dysfunction (ED) with men of increasing age being disproportionally affected. The incidence of ED can be as high as 60% in men with Diabetes or cardiovascular disease. Although previously considered a quality of life issue, the presence of erectile dysfunction in an otherwise healthy man is now considered a harbinger of cardiovascular disease. Vascular factors are the leading cause of ED. A multitude of treatment options exists for those men with minimal or moderate erectile dysfunction, including pills, injections, and external devices. Unfortunately, these don’t work for every man and may interact with medications or underlying diseases. Also, they treat the symptoms and not the underlying cause of ED. Besides, most man would like not to have to take drugs to function sexually.
What is LI-SWT?
Low intensity extracorporeal (i.e., outside the body) shockwave therapy (LI-SWT) is a treatment that has been in use since 2010. Patients are usually treated in the office setting once or twice a week for 4 to 6 weeks. The device applies a low-intensity shockwave to the surface of the penis using an ultrasound gel as the coupling agent. LI-SWT appears to have minimal side effects and is well-tolerated without any anesthesia. However, it has not received FDA approval for treatment of erectile dysfunction as of the date of this writing. It has been approved for the treatment of plantar fasciitis. Most of the current research has been directed towards erectile dysfunction. A few studies have evaluated the use of LI-SWT in Peyronie’s disease. This article will address the use of LI-SWT in the treatment of erectile dysfunction.
How Does LI-SWT Work?
It is not definitively known how LI-SWT works. However, the current theory is that the shockwave produced by the device causes stress on cell-membranes and release of growth factors and recruitment of stem cells that promote the development of new penile arteries and reducing inflammatory and cellular stress. In animal studies, there is also evidence to suggest nerve regeneration (Fode et al., Nat. Rev. Urolo. 14:593, 2017). LI-SWT is unique in that it could provide a treatment option that corrects the underlying problem instead of just treating the symptoms of erectile dysfunction.
Literature Reviews of LI-SWT?
Several reviews of studies evaluating the use of LI-SWT have been published this year. The first was an analysis of ten randomized controlled studies completed over the past two years by Sokolakis and Hatzichristodoulou (Int Jour Impot Res, 31:177-194, 2019) has concluded that LI-SWT significantly improved erectile function in patients with vascular ED. All ten studies used a validated questionnaire as the assessment tool and included men with moderate to severe ED. Their analysis also contained only 873 studies followed for less than one year. Three studies also measured penile hemodynamics.
A second systematic review by Brunckhorst et al. (Int Urol Neph, 51:773-781, 2019) reviewed eleven studies with 799 patients. Nine studies found an improvement in ED at six months after treatment with the improvement remaining above baseline out to 12 months.
A third review included seven randomized controlled studies evaluating the effect of LI-SWT on erectile function (Dong et al., Am J Men’s Health, March-April:1-14, 2019). Evaluating outcomes by validated questionnaires (ie., International Index of Erectile Function – erectile function domain [IIEF-EF] and the Erectile Hardness Score [EHS]) they found improvement in erectile function after treatment with LI-SWT.
Although the results have been encouraging, there are still many questions to be answered. What patients will respond to LI-SWT? Will the patients with worse erectile dysfunction, Diabetes and/or heart disease respond better or worse? Does patient age or use of oral or injectable medications used to treat erectile dysfunction affect the results of LI-SWT? What are the contraindications for the use of LI-SWT? Should we be treating men on blood thinners? How does the frequency and length of treatments affect the results? Is it better to use fewer treatments/week over a longer period of time? How does the intensity and number of shocks affect the outcome? Does the type of device matter (linear vs. focused shockwaves)? Focused shockwaves have shown their effectiveness while the results of linear shockwaves are still conflicting. When do the effects of LI-SWT occur and how long does the improvement last? These, among other questions, will need to be answered
Current literature demonstrates an improvement of erectile dysfunction with LI-SWT. However, large, multicentered, randomized controlled studies which include not only qualitative (e.g. validated questionnaires) but also quantitative data (e.g. spectral ultrasound vascular data) are needed before LI-SWT becomes the standard of care. For additional information, please contact us.0