Options for Male Fertility Preservation: Pediatric Oncofertility 2017

Awesome. Great. So that seems like a pause that we could maybe transition on to the options for male, and we'll have that with Doctor Shrine. Thank you, Leslie. I'm gonna be providing a brief introduction to some of the options for male fertility preservation. If you have any further questions or want me to elaborate more, please post on the live chat, and we can address that later during the broadcast. Before discussing these specific options, I want to mention a few unique considerations in males. First and foremost, the testes has a greater chemo and radio sensitivity than the ovaries. The chemotherapeutic agents that are typically used for treatment of pediatric cancer readily cross the blood testes barrier and primarily affect the cells that are undergoing spermatogenesis due to their high mitotic rate. Um, the other cells that produce testosterone, which are known as the lated cells are less sensitive to chemotherapy, um, but they can have sensitivity to radiation at very high doses. Another consideration is the fact that males have no protective effect of receiving treatment and having exposure at a younger age, which doesn't seem to be the case in females. And then lastly, males can have a number of negative effects on sexual function after treatment. One example of that would be children, adolescents, and adults who are diagnosed with testicular cancer, which is one of the most common cancers in adolescents and adults, particularly young adults. Some of these patients develop retroperitoneal lymph node disease due to the spread of their cancer from their testes and undergo retroperitoneal lymph node dissections, which can actually damage the sympathetic nerves that control antegrade ejaculation. So sometimes you can have effects such as that that can lead to issues with fertility. Um, as has been alluded to in several of the prior presentations, um, sperm cryopreservation is the most established option for fertility preservation and is a great benefit for preserving fertility in, uh, males, um, as was mentioned by our oncology colleagues, the, um, American Society of Clinical Oncology recommends that sperm cryopreservation should be offered to all peri and postpubertal adolescents who are able to provide a semen specimen. For those who cannot provide one via masturbation, there are several other options. They can do electro ejaculation with insertion of a probe into the rectum and then harvest a specimen that way. That type of procedure needs to be performed under general anesthesia and then you can also do penile vibratory stimulation for some of these patients that can't do masturbation for various reasons. Sperm cryopreservation should be offered prior to treatment, as the quality of semen analysis and DNA integrity can be compromised after even a single course of treatment. In a recent analysis of semen parameters in a large cohort of adolescents and young adults from Philadelphia, they showed that the early initiation of treatment prior to sperm cryopreservation can have a significant effect on the semen quality. In that study, azoospermia, which is the absence of sperm, was present in only 16.9% of untreated patients versus 84% of patients who were treated and then subsequently tried to perform sperm cryopreservation. As was also mentioned previously, balancing sperm cryopreservation with the need for the initiation of treatment in a timely fashion can be challenging but is feasible. This is often mentioned as one of the most common barriers to offering sperm cryopreservation prior to the initiation of therapy. However, several centers have demonstrated successful sperm baking in greater than 80% of patients in the prior study that I mentioned from Philadelphia. The number of attempts was a median of 1.5 with a median of 7 samples per patient, as would be expected, the number of attempts was less in patients with leukemia, hematologic disorders, non-Hodgkin lymphoma, and PTLD due to the need to often urgently initiate treatment. However, despite those differences, a majority of patients were at least able to attempt sperm cry preservation on at least one occasion regardless of their clinical presentation. The age at which to offer sperm cryopreservation is unclear, as it is difficult to predict the onset of spermay or when you start to undergo spermatogenesis and produce mature sperm. Several studies have demonstrated an improved quality of semen analysis with an increasing age. Some studies have even shown that you can obtain an adequate specimen in adolescents as young as 11 years of age. Therefore, we really don't recommend age to be considered in isolation when deciding whether to offer sperm cryopreservation to a patient. Uh, most would suggest that stage of puberty development is a better, um, indicator to mark you than age, and typically most centers are offering it to adolescents who are at least 10 or stage 3. Um, this is a chart from the, um, study that I previously mentioned from Philadelphia, um. This study provides a good insight into the quality of semen analysis in adolescents given the large number of young patients in this cohort. As you can see here, the volume, the total moltal count, as well as the rate of ACE zoospermia improved as age increased both on univariate and multivariate analysis. What was also interesting is that in the youngest age group between 11 to 14 years of age 65% of the patients were able to successfully sperm bank, which is a fairly high percentage. Um, this is another, um, chart from their, um, article, and what is difficult is to determine what is considered a quote unquote normal semen analysis in the adolescent because there aren't really any published guidelines. Um, the criteria from the World Health Organization was generated from fertile male adults, which they defined as men whose partner was able to conceive within 12 months of discontinuing some type of contraceptive method. And they're included here in that cohort that I previously mentioned they actually fared well in terms of their semen parameters with the mean and median volume, concentration and motility greater than the WHO criteria. The next option that I'm going to discuss is testicular sperm extraction. This is an emerging option for non-obstructive azoospermia in adolescents prior to treatment, as well as adults with a remote history of treatment for pediatric cancer. Testicular sperm extraction involves the retrieval of sperm from focal areas of spermatogenesis in the semiffes tubules and later used for ICSI. As you can see on the image on the right, a transverse incision is made in the tunica albinia of the testes, exposing the sper exposing the internal structure within the testes, and what you can do is you can actually identify the dilated and opaque seminiferous tubules that likely contain sperm compared to the other ones that don't and excise those and eventually use them later for ICSI. A successful retrieval of sperm has been reported in 47% of patients prior to chemotherapy, and then in several studies it was 37 to 65% after chemotherapy. Only one of these studies included a subset of adolescents and young adults between the ages of 11 and 19 years where they reported a 33% retrieval of sperm prior to treatment. Does that mean that the rest of the patients, um, the, the 53%. Uh, they went and retrieved it, but it didn't work, correct? OK, um, so they were only able to actually find successful, um, sperm that they could use later for ICSI in those percentages. So, um, it's almost a fifty-fifty chance on average on whether it's successful, but these are patients that really have no other option because they're zoospermic when they're providing a semen specimen. And is it technique that leads to the, so that's an interesting question. It is partly related to technique because, um, earlier when they were doing this. Technology they weren't doing it under microscopic assistance, but now you can do it with microscopic assistance and be able to better identify the tubules that potentially contain sperm. Do you think the numbers have gone up since the microscopic so it has in the adult literature. There's really nothing in terms of the pediatric literature in terms of improving sperm retrieval rate, but it has in the adults. Um, this is another chart from that, um, article, um, mentioning the, um, small cohort of patients that were in their adolescence and young adulthood, um, as you can see, um, they were able to successfully extract sperm from an adolescent as young as 11 years of age, um, and then as you can also see that they weren't able to do it in any child that was below 10 or stage 3 development. As has been alluded to previously, fertility preservation before puberty is much more of a challenging issue to address, particularly in males where you have a limited ability to do or no ability to do sperm cryopreservation. And this is due to the fact that you do not have any mature sperm that can be provided by the patient and stored for later use. The ability to preserve fertility in this age group is contingent on the future development of experimental therapies for the maturation of spermatogonial stem cells that you can see at the top of that figure on the right to sperm at the bottom of the figure on the right. Also, although outside the scope of my discussion today, a variety of spermatogonal stem cell therapies have been developed over the last several years, and they've been primarily done in animal models. This includes things such as doing transplantation of. Spermatogonal stem cells directly into the testicle as well as transplantation of testicular tissue into an autologous graft or potentially doing it as a xenograph and then lastly they've been able to mature sperm in vitro as has been described in the case of ovaries. however, none of these technologies have actually been performed successfully in humans at this point. Testicular tissue cryopreservation at this point has the greatest potential for fertility preservation in prepubertal children, as has been mentioned previously, it is an investigational protocol. It specifically involves the harvesting of immature testicular tissue prior to the initiation of treatment and it's cryopreservation with slow freezing techniques. We use very similar techniques that have been previously described for ovarian testicular cryopreservation. And again, I want to emphasize that testicular tissue cryopreservation relies on the future development of technologies in order to allow for the maturation of spermatogonial stem cells into mature sperm that can be used for fertilization and eventual pregnancy. Um, as Doctor Hopkin mentioned, the eligibility at institutions vary based on their individual IRBs. I thought I would share our eligibility criteria here at Cincinnati Children's. Um, so we include, uh, pediatric male patients between the ages of 6 months and 17 years who are in the high risk category which is defined as. than 80% risk of long term azospermia, which is based on the risk assessment that's provided by our oncology colleagues. We also include adult male patients between the ages of 18 and 25 years in either the high or intermediate risk categories, which is defined as 21 to 79% risk of long-term azospermia, and then patients undergoing surgery, chemotherapy, drug treatment, and or radiation for the treatment or prevention of a medical condition or malignancy with the risk of causing permanent. And complete loss of fertility in the future. We also include patients who have a medical condition or malignancy that requires a removal of all or part of one of both testicles, which are primarily be testicular cancers, or unable to provide a semen by other means, as I mentioned previously. We also include patients with newly diagnosed or recurrent disease unless their initial treatment was viewed as likely to result in a complete and permanent loss of fertility. And then lastly, patients must have two testicles if they're going to be undergoing elective removal of part or one testicle for fertility preservation only. The excisional biopsy is coordinated with other surgical procedures to minimize the anesthetic risk and expedite the initiation of treatment whenever possible. We perform the biopsy through a transscrotal approach. The amount of tissue that's removed depends on the size of the testicle, similar to what Doctor Hopkins mentioned in terms of the size of the ovary. We have built into our protocol that we can remove an entire testicle if necessary, but we try to preserve it at all costs and have not needed to do that at this point. 75% of our tissue stored at Repertech for later use for the patient and then the remaining 25% is designated for research at McGee Women's Research Institute which we're working in collaboration with. Several studies have recently been published, and as with OTC, they've demonstrated a high satisfaction and acceptance of risk for both patients and families. However, we have to remember that there are a number of limitations of this technology. One is the cost, which can be significant and prohibitive for certain families. The cost includes not only the cost of the procedure and storage of tissue, but also potential costs in the future when they're using assisted reprotective technologies. There's also obvious ethical considerations associated with testicular tissue cryopreservation, which our colleague is going to be discussing next. And then lastly we have to remember that this is an experimental technology. No successful retrieval of mature sperm or pregnancies have been reported to date. As such, we should be discussing this with families in the context of an IRB approved study. Um, so if you have any questions or um want me to elaborate on anything further, I certainly can just post it, um, on the elaborate on something, OK, we have some postings. So, uh, Jody, thank you for these questions. These are great. So she wants to know how do you define intermittent and high risk. So that's based on the chemotherapy regimen that is planned to be given to them and that might be better elaborated on by your oncology colleague. Yeah, um, so, um, we work with the oncologist, the treating oncologist, um, to develop the treatment plan, and, um, basically it's the risk categories based on whether or not they're gonna receive radiation therapy as well as the specific chemotherapy that, um, they're gonna receive and the cumulative dosing of that chemo. Therapy. So based on that, using the cyclophosphamide equivalent dosing that Dan Green published back in 2014, we come up with the risk category using standardized guidelines by the Live Strong Foundation, Fertile Hope, um, and Uncle Fertility Consortium to put them in one of the categories. They're pretty broad categories, so um it does help to quantify it, but it still leaves a little bit of of indecision too. And then, is there a role for vitrification? Um, in terms of the testicular tissue cryopreservation, I don't think there's a lot of research to suggest one versus the other. Um, in some instances we've been following what they've been doing in OTC because I think the technology is obviously further in terms of, um, successfully being able to perform that. Think. Awesome. That's all I got, right, I think, uh, you know, I, I think when we get to the panel discussion there are several more questions that have been posted and we are reassured the participants will engage those then I think the other opportunity then is to engage you a little bit on your expertise and the team's newfound expertise on talking about acquiring a semens specimen in young patients and talking with either their parents or the patient about how we get the specimen. How that whole interaction goes so you can save up with that and then maybe during Michelle's presentation I can talk to Todd about posting a few poll questions as well. Awesome.