Fertility Preservation in Childhood Cancer: Endocrine Activity in Prepubertal Human Testis Xenografts Exposed to a Pubertal Hormone Environment.
Fertility Preservation in Childhood Cancer: Endocrine Activity in Prepubertal Human Testis Xenografts Exposed to a Pubertal Hormone Environment.
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儿童癌症中的生育保护：暴露在青春期激素环境中的青春期前人类睾丸移植物的内分泌活动。
DOI：
10.3390/cancers12102830
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发表时间：
2020-09-30
期刊：
影响因子：
5.2
通讯作者：
Mitchell RT
中科院分区：
文献类型：
--
作者：
Hutka M;Kadam P;Van Saen D;Homer NZM;Onofre J;Wallace WHB;Smith LB;Stukenborg JB;Goossens E;Mitchell RT
在治疗儿童癌症方面取得了长足进展;然而，由于化疗和放疗，年轻男性会受到长期副作用，包括生育能力受损。虽然青春期前的睾丸组织可以在性腺毒性治疗前冷冻保存，但如何从未成熟的人类睾丸组织中产生成熟的配子仍有待确定。未成熟的生殖细胞发育成精子是一个复杂的过程，这是由成熟的支持细胞和睾丸间质细胞产生的睾酮支持的。我们使用一个已建立的睾丸异种移植模型来研究青春期激素（促性腺激素）对精原干细胞（SSC）小生境功能成熟的影响。有限的睾酮生产和部分成熟的Sertoli细胞发生在青春期前睾丸移植，这表明需要更长时间的移植和/或识别的其他因素，以发展睾丸移植作为一种模式，在男性幸存者的生育能力保存儿童癌症。儿童癌症的幸存者有长期治疗引起的健康后遗症的风险，包括性腺毒性和医源性不孕症。目前，对于青春期前的男孩，没有可行的临床选择来保留未来的生殖潜力。我们研究了促性腺激素青春期诱导方案对青春期前人睾丸异种移植物发育的影响。人睾丸组织获自患有癌症和非恶性血液病的患者（n = 6;年龄1-14岁），这些患者经历睾丸组织冷冻保存以保存生育力。将新鲜和冻融的睾丸碎片皮下或睾丸内移植到免疫功能低下的小鼠体内。移植荷瘤小鼠接受载体或外源性促性腺激素、人绒毛膜促性腺激素（hCG，20 IU）和促卵泡激素（FSH，12.5 IU）注射，每周3次，持续12周。两个移植部位的溶媒和促性腺激素暴露移植物的大体形态相似。暴露于外源性促性腺激素的青春期前人睾丸组织异种移植物导致移植物的内分泌功能有限，如类固醇生成胆固醇侧链裂解酶（CYP 11 A1）的偶尔表达所示。促性腺激素暴露受体小鼠的血浆睾酮浓度（0.13 vs. 0.25 ng/mL; p = 0.594）和精囊重量（10.02 vs. 13.93 mg; p = 0.431）与溶剂暴露对照相当。无论移植部位和治疗，雄激素受体（AR）的表达的启动和维持观察支持细胞，表明致力于更分化的状态。然而，无论是外源性促性腺激素（在阉割的宿主小鼠）或内源性睾酮（在完整的宿主小鼠）都不足以抑制与未成熟的支持细胞相关的标志物的表达，如抗苗勒管激素（AMH）和Ki 67，或诱导连接蛋白（连接蛋白43，CX 43; claudin 11，CLDN 11）重新分布到邻近基底膜的区域。精原细胞没有发展，但仍然是最先进的生殖细胞类型的睾丸异种移植。总之，这些研究结果表明，外源性促性腺激素促进部分激活和成熟的体细胞环境在青春期前睾丸异种移植。然而，替代激素方案或额外的因素，青春期诱导完成精原干细胞（SSC）生态位的功能成熟是必需的。
Substantial strides have been made in treating childhood cancers; however, as a result of chemotherapy and radiotherapy, young males experience long-term side effects, including impaired fertility. Whilst prepubertal testicular tissue can be cryopreserved prior to gonadotoxic treatments, it remains to be determined how to generate mature gametes from the immature human testis tissue. Development of immature germ cells into sperm is a complex process, which is supported by mature Sertoli cells and testosterone produced from Leydig cells. We used an established testicular xenotransplantation model to investigate the effect of puberty hormones, known as gonadotrophins, on functional maturation of the spermatogonial stem cell (SSC) niche. Limited testosterone production and partial maturation of Sertoli cells occurred in prepubertal testis grafts, suggesting that longer periods of grafting and/or identification of additional factors are required to develop testicular transplantation as a model for fertility preservation in male survivors of childhood cancer. Survivors of childhood cancer are at risk for long-term treatment-induced health sequelae, including gonadotoxicity and iatrogenic infertility. At present, for prepubertal boys there are no viable clinical options to preserve future reproductive potential. We investigated the effect of a pubertal induction regimen with gonadotrophins on prepubertal human testis xenograft development. Human testis tissue was obtained from patients with cancer and non-malignant haematological disorders (n = 6; aged 1–14 years) who underwent testis tissue cryopreservation for fertility preservation. Fresh and frozen-thawed testis fragments were transplanted subcutaneously or intratesticularly into immunocompromised mice. Graft-bearing mice received injections of vehicle or exogenous gonadotrophins, human chorionic gonadotrophin (hCG, 20 IU), and follicle-stimulating hormone (FSH, 12.5 IU) three times a week for 12 weeks. The gross morphology of vehicle and gonadotrophin-exposed grafts was similar for both transplantation sites. Exposure of prepubertal human testis tissue xenografts to exogenous gonadotrophins resulted in limited endocrine function of grafts, as demonstrated by the occasional expression of the steroidogenic cholesterol side-chain cleavage enzyme (CYP11A1). Plasma testosterone concentrations (0.13 vs. 0.25 ng/mL; p = 0.594) and seminal vesicle weights (10.02 vs. 13.93 mg; p = 0.431) in gonadotrophin-exposed recipient mice were comparable to vehicle-exposed controls. Regardless of the transplantation site and treatment, initiation and maintenance of androgen receptor (AR) expression were observed in Sertoli cells, indicating commitment towards a more differentiated status. However, neither exogenous gonadotrophins (in castrated host mice) nor endogenous testosterone (in intact host mice) were sufficient to repress the expression of markers associated with immature Sertoli cells, such as anti-Müllerian hormone (AMH) and Ki67, or to induce the redistribution of junctional proteins (connexin 43, CX43; claudin 11, CLDN11) to areas adjacent to the basement membrane. Spermatogonia did not progress developmentally but remained the most advanced germ cell type in testis xenografts. Overall, these findings demonstrate that exogenous gonadotrophins promote partial activation and maturation of the somatic environment in prepubertal testis xenografts. However, alternative hormone regimens or additional factors for pubertal induction are required to complete the functional maturation of the spermatogonial stem cell (SSC) niche.
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影响因子：
8.3
作者：
Goossens, E.;Jahnukainen, K.;Stukenborg, J. B.
通讯作者：
Stukenborg, J. B.
影响因子：
4.8
作者：
De Gendt, K;Atanassova, N;Verhoeven, G
通讯作者：
Verhoeven, G
影响因子：
1.9
作者：
Nistal, Manuel;Paniagua, Ricardo;Reyes-Mugica, Miguel
通讯作者：
Reyes-Mugica, Miguel
影响因子：
3.5
作者：
Abney, TO;Zhai, J
通讯作者：
Zhai, J
DOI：
10.1073/pnas.0308114100
发表时间：
2004-02-03
影响因子：
11.1
作者：
De Gendt, K;Swinnen, JV;Verhoeven, G
通讯作者：
Verhoeven, G