New models for the onset of virilisation in the developing male

男性化障碍是人类最常见的发育缺陷之一，但超过一半的病例无法用我们目前的知识来解释。对这些过程的研究受到阻碍，因为在大多数哺乳动物中，男性化发生在子宫内，即胎儿早期。我们最近对有袋动物的研究表明，雄性化发生在出生后，这一过程是由5- α -雄甾二醇介导的，这是一种先前未确定生理功能的激素。我们将用袋鼠进行实验，以检验解释为什么不同的男性组织——如生殖道、前列腺和阴茎——在不同的时间开始分化的假设。我们将研究雄激素的形成途径和靶器官中激素的激活和失活，以及激素结合蛋白的作用。我们还将研究生长因子在阴茎早期发育过程中可能起到的调节作用。这些实验的结果将在接下来的几年里为我们收集的200多个男性化缺陷（假两性畸形）患者样本中相应的基因突变测试提供资金，这些样本的原因尚不清楚。我们期望这些研究的发现不仅能深入了解睾丸激素使发育中的男性男性化的途径，还能解释人类中不明原因的男性假两性现象。

Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes are hindered because in most mammals virilisation occurs in utero, in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar wallabies, to test hypotheses that explain why different male tissues - such as the reproductive ducts, prostate and penis - start to differentiate at widely different times. We will investigate pathways of androgen formation and the activation and inactivation of hormones in the target organs, and the role of hormone binding proteins. We will also investigate the role of growth factors that may mediate growth of the penis during early development. The results of these experiments will direct funding in subsequent years to test for corresponding gene mutations in our collection of over 200 specimens from patients with defects of virilization (pseudohermaphroditism) whose causes are still unknown. It is our expectation that the findings in these studies will provide insight not only into the pathways by which testicular hormones masculinize the developing male, but will also explain instances of male pseudohermaphroditism of unknown aetiology in humans.