Fertility Preservation in Prepubertal Boys: An Experimental Approach

描述（由申请人提供）：目前用于治疗儿童癌症的治疗方法的不幸后果是不孕。需要考虑的一个重要问题是，儿童以后的生育状况是否可能受到治疗的影响。理想情况下，这应该在治疗开始之前进行，因为此时可能存在保留患者未来生殖潜力的机会之窗。对于处于青春期的男性来说，有一些选择，具体来说，就是通过手淫来产生精子，然后将精子冷冻起来以供以后使用。对于没有经历青春期的男孩来说，保持生育能力更具挑战性。青春期前的男孩不能通过手淫产生精液，他们的睾丸中没有成熟的精子。然而，青春期前的睾丸确实含有少量的干细胞（亲本细胞），在正确的信号和适当的条件下，这些干细胞最终会变成成熟的精子。有希望的相关动物模型研究表明，睾丸组织可以被移除，干细胞可以被提取。这些细胞可以原样移植，或者在移植前在体外成熟并增加数量。动物研究表明，这些细胞一旦重新植入体内，就会继续产生成熟的精子。这项研究的成功为人类临床实践创造了一个令人兴奋的潜力，特别是对于那些面临癌症治疗而导致不孕的患者。在理想的情况下，男孩可以在诊断时冷冻睾丸组织。然后，当他们准备好组建家庭时，可以解冻组织，取出干细胞，扩大数量，然后放回睾丸，成为成熟的精子，从而恢复年轻人的生育能力。这些细胞也可以在体外成熟，然后可以使用专门的卵子受精技术。目前，这门科学在人类身上的临床应用纯粹是实验性的。有几个关键问题，需要进一步调查之前，这可以成功地转化为人类临床实践。本研究将探讨以下几点:1)评估可行性和可接受的患者和家庭提供冻结新诊断睾丸组织的青年期男孩不孕的风险2)来评估手术的安全需要对这些患者和3)执行睾丸活检来确定什么是最好的方式来处理睾丸组织的生殖细胞,在实验室的创建细胞可以获得最大数量的精子。公共卫生相关性：该方案将研究向因癌症治疗而有不育风险的青春期前男孩（目前没有生育能力保存选择的队列）提供睾丸冷冻保存的可行性，并将推进人类精原干细胞体外扩增所需的转化实验室科学。将利用睾丸组织获取和储存的多学科基础设施，最终为未来人类睾丸组织冷冻保存方案提供基准，作为青春期前患有癌症的男性保存生育能力的标准选择。

DESCRIPTION (provided by applicant): An unfortunate consequence of the treatments currently used to treat pediatric cancers is infertility. An important issue to consider is whether a child's fertility status later in life is likely to be impacted by his treatment. Ideally, this should occur prior to the initiation of therapy, when a window of opportunity may exist to preserve the patient's future reproductive potential. For pubertal males, there are options available, specifically, producing sperm by masturbation and freezing the sperm for use later in life. For boys who have not gone through puberty, preserving fertility is more challenging. Prepubertal boys cannot produce semen by masturbation and they do not have mature sperm in their testes. The prepubertal testicle does, however, contain a small amount of the stem cells (parent cells) that, with the right signals and under the appropriate conditions, will eventually become mature sperm. Promising research with relevant animal models has shown that testicular tissue can be removed, and the stem cells can be extracted. These cells can then be reimplanted as is, or matured and increased in number outside of the body before reimplantation. Animal research has demonstrated that these cells will then go on to produce mature sperm once reimplanted in the body. The success of this research has created an exciting potential for translation to human clinical practice, particularly for patients who are facing cancer therapy that will leave them infertile. In the ideal scenario, boys could freeze testicular tissue at diagnosis. Then, when they are ready to start a family, the tissue could be thawed, the stem cells removed, expanded in number and put back into the testes to become mature sperm, thus restoring the young man's fertility. These cells could also be matured outside of the body and then specialized techniques for fertilization of an egg could be used. At this time, clinical applications of this science in humans are purely experimental. There are several key issues which require further inquiry before this can be successfully translated to human clinical practice. This study will explore the following: 1) To assess feasibility and acceptable to patients and families to offer freezing of testicular tissue for newly diagnosed prepubertal boys at risk for infertility 2) To evaluate the safety of the surgical procedure required to perform a testicular biopsy on these patients and 3) To determine what is the best way to handle the germ cells that are in the testicular tissue in the laboratory so the maximum number of sperm creating cells can be obtained. PUBLIC HEALTH RELEVANCE: This protocol will examine the feasibility of offering testicular cryopreservation to prepubertal boys who are at risk for infertility from cancer therapy (a cohort who currently have no options for fertility preservation) and will advance the translational laboratory science that is required for in vitro expansion of human spermatogonial stem cells. A multidisciplinary infrastructure for the acquisition and storage of testicular tissue will be utilized, ultimately providing a benchmark for future protocols for the cryopreservation of human testicular tissue as a standard option for fertility preservation in prepubertal males with cancer.