Genetic Etiologies of Nonobstructive Azoospermia 非阻塞性无精症的遗传病因

Genetic factors causing nonobstructive azoospermia include chromosomal abnormalities, Y-chromosome microdeletions, and individual gene mutations. The workup for these genetic causes includes karyotype testing, Y-chromosome microdeletion analysis, various chromosomal structural abnormalities, and specific gene mutation studies. However, clinicians and patients alike must be aware that there may be additional unidentified or unknown genetic factors contributing to nonobstructive azoospermia that will not be detected with currently available genetic tests.

导致非阻塞性无精症的遗传病因包括染色体异常，Y染色体缺失和单基因突变，相关检查包括核型检查，Y染色体微缺失检查，各种染色体结构异常和特定基因突变分析。除此之外，临床医生和患者需要知道可能有其他无法判定或未知的遗传因素导致非阻塞性无精症，而目前的检测技术暂时还不能检查出这些异常。

Y-Chromosome Microdeletions

Y染色体微缺失

Y-chromosome microdeletions are commonly diagnosed genetic disorders causing male infertility, with a prevalence of 10-15 percent in men with severe oligospermia or azoospermia (1).

Y染色体微缺失是导致男性不育的常见遗传疾病，在患有严重少精症或无精症的男性中患病率为10-15%(1)。

The Y-chromosome is the smallest human chromosome with 60 million bases, and it consists of a short arm and a long arm. The short arm carries the SRY gene which is responsible for male differentiation. The long arm houses many genes that code for spermatogenesis. The missing areas on the long arm of the Y-chromosome in azoospermic men were discovered by Tiepolo and Zuffardi in 1976, and they were named “microdeletions” because the areas were too small to be seen on a routine karyotype (2).

Y染色体是人类最小的染色体，有6000万个碱基对。Y染色体由短臂和长臂组成。短臂携带的SRY基因表达男性性别，长臂上有许多跟精子生成有关的基因。Tiepolo和Zuffardi于1976年发现无精症男性患者的Y染色体长臂上有缺失区域，因为这些缺失太小无法在常规核型检查上观察到而被称为“微缺失”(2)。

Further investigation led to the description of the 3 different areas called AZFa, AZFb and AZFc. Microdeletions in these segments lead to varying degrees of decreased spermatogenic activity (3). More specifically, men with complete AZFa, AZFb, AZFb/c and AZFabc deletions typically have either Sertoli cell only or maturation arrest histological patterns and a poor prognosis for sperm retrieval (4). The AZFc microdeletion can be seen in 6 percent of men with severe oligozoospermia as well as up to 13 percent of those with nonobstructive azoospermia, with successful sperm retrieval rates typically > 50 percent (4).

更进一步的研究发现了微缺失所在的三个不同区域，分别被称为AZFa，AZFb和AZFc。它们的缺失会在不同程度上降低生精能力(3)。具体来说，具有完全AZFa，AZFb，AZFb/c和AZFabc缺失的男性通常仅具有支持细胞或成熟障碍的组织学模式，并且取出精子预后性较差(4)。 AZFc微缺失在严重少精症男性患者中的发生率为6%，在非阻塞性无精症男性患者中可高达13%，成功取出精子的机率>50%(4)。

Klinefelter’s Syndrome

Klinefelter综合征

Klinefelter’s syndrome is a chromosomal genetic disorder characterized by an extra X-chromosome (47, XXY), although this condition is occasionally found in its mosaic form (46, XY/47, XXY). The syndrome has a reported incidence of 1 in 660 men but may represent up to 3.1 percent of the infertile male population and 10 percent of men with nonobstructive azoospermia (5).

Klinefleter综合征是一种染色体遗传性疾病，患者染色体核型增加了一条X染色体(47，XXY)，不过有些情况下是以嵌合体出现的(46，XY/47，XXY)。研究发现，该综合征的发病率大概是1/660，在不育男性和非阻塞性无精症男性中发病率可能分别为3.1%和10%(5)。

Semen analysis typically reveals azoospermia or severe oligospermia. Laboratory testing usually detects hypergonadotropic hypogonadism with elevated FSH and LH levels, and low to normal testosterone. Many patients with Klinefelter’s syndrome also exhibit an abnormally low testosterone-to-estradiol ratio. Because of the endocrinopathy typically associated with this genetic disorder, it is important to consider medical therapy for men with Klinefelter’s syndrome in advance of sperm retrieval procedures.

Klinefelter综合征患者的精液分析结果通常显示无精症或严重的少精症。实验室检查通常会发现患者有高促性腺激素性促腺功能减退症，表现为FSH和LH水平升高，而睾酮水平低于或等于正常值。许多Klinefelter综合征患者的睾酮与雌二醇比值异常低。由于这种遗传疾病通常与内分泌疾病相关，因此必须在取精手术前考虑对Klinefelter综合征患者进行药物治疗。

Ramasamy et al. reported that increasing serum testosterone to >= 250 ng/dL before microsurgical testicular sperm extraction yielded a 77 percent retrieval rate for men with Klinefelter’s syndrome compared to 55 percent for those men with testosterone levels < 250 ng/dL (6). After a median duration of medical therapy of 163 days before micro-TESE, the overall sperm retrieval rate was 66 percent, clinical pregnancy rate 57 percent and live birth rate 45 percent with IVF. This study highlights the benefit of medical optimization of this subpopulation of men with nonobstructive azoospermia.

根据Ramasamy等人的报告，在显微手术取精前，将血清睾酮水平提高至>=250ng/dL可使患有Klinefelter综合征的男性取精成功率达到77%，而血清睾酮水平<250ng/dL的男性患者取精成功率则为55%(6)。在进行睾丸显微取精手术前对患者进行中位持续时间163天的药物治疗后，取出精子的患者比例为66%，试管临床妊娠率为57%，活产率为45%。这项研究强调了对非阻塞性无精症男性亚群体进行医学治疗的益处。

Reference

参考文献

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3. Reijo R, Alagappan RK, Patrizio P, et al. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y-chromosome. Lancet 1996;337:1290-3.

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5. Bojesen A, Gravholt C. Klinefelter syndrome in clinical practice. Nat Clinic Pract Urol 2007;4:192-204.

5. Male Infertility Best Practice Policy Committee of the American Urological Association and Practice Committee of the American Society for Reproductive Medicine: Report on optimal evaluation of the infertile male. Fertil Steril, suppl 2006;86:S202-9.

6. Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, Schlegel PN. Successful fertility treatment for Klinefelter’s syndrome. J Urol 2009;182:1108-13.