Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, UK.
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
Eur J Endocrinol. 2018 Sep;179(3):R143-R150. doi: 10.1530/EJE-18-0396. Epub 2018 Jun 29.
The two pituitary gonadotrophins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and in particular LH-stimulated high intratesticular testosterone (ITT) concentration, are considered crucial for spermatogenesis. We have revisited these concepts in genetically modified mice, one being the ()-knockout mouse (LuRKO), the other a transgenic mouse expressing in Sertoli cells a highly constitutively active mutated (Fshr-CAM). It was found that full spermatogenesis was induced by exogenous testosterone treatment in LuRKO mice at doses that restored ITT concentration to a level corresponding to the normal circulating testosterone level in WT mice, ≈5 nmol/L, which is 1.4% of the normal high ITT concentration. When hypogonadal LuRKO and Fshr-CAM mice were crossed, the double-mutant mice with strong FSH signaling, but minimal testosterone production, showed near-normal spermatogenesis, even when their residual androgen action was blocked with the strong antiandrogen flutamide. In conclusion, our findings challenge two dogmas of the hormonal regulation of male fertility: (1) high ITT concentration is not necessary for spermatogenesis and (2) strong FSH stimulation can maintain spermatogenesis without testosterone. These findings have clinical relevance for the development of hormonal male contraception and for the treatment of idiopathic oligozoospermia.
两种垂体促性腺激素，黄体生成素（LH）和卵泡刺激素（FSH），尤其是 LH 刺激的高睾丸内睾酮（ITT）浓度，被认为对精子发生至关重要。我们在基因修饰小鼠中重新研究了这些概念，一种是（）-敲除小鼠（LuRKO），另一种是在支持细胞中表达高度组成性激活突变的 Fshr-CAM 的转基因小鼠。研究发现，在外源性睾酮处理下，LuRKO 小鼠的精子发生可以完全被诱导，其剂量足以将 ITT 浓度恢复到与 WT 小鼠正常循环睾酮水平相当的水平，即 ≈5nmol/L，这相当于正常高 ITT 浓度的 1.4%。当低促性腺激素 LuRKO 和 Fshr-CAM 小鼠杂交时，具有强烈 FSH 信号但极少产生睾酮的双突变小鼠表现出接近正常的精子发生，即使它们的残余雄激素作用被强抗雄激素氟他胺阻断。总之，我们的发现挑战了男性生育力激素调节的两个教条：（1）高 ITT 浓度对于精子发生不是必需的；（2）强烈的 FSH 刺激可以维持精子发生而无需睾酮。这些发现对激素男性避孕的发展和特发性少精子症的治疗具有临床意义。
