Human GnRH deficiency, both clinically and genetically, is a heterogeneous disorder comprising of congenital GnRH deficiency with anosmia (Kallmann syndrome), or with normal olfaction [normosmic idiopathic hypogonadotropic hypogonadism (IHH)], and adult-onset hypogonadotropic hypogonadism. Our understanding of the neural mechanisms underlying GnRH secretion and GnRH signaling continues to increase at a rapid rate and strikingly, the heterotrimeric guanine nucleotide–binding protein (G protein)-coupled receptors (GPCRs) continue to emerge as essential players in these processes. GPCRs were once viewed as binary on-off switches, where in the “on” state they are bound to their Gα protein, but now we understand that view is overly simplistic and does not adequately characterize GPCRs. Instead, GPCRs have emerged as masterful signaling molecules exploiting different physical conformational states of itself to elicit an array of downstream signaling events via their G proteins and the β-arrestins. The “one receptor-multiple signaling conformations” model is likely an evolved strategy that can be used to our advantage as researchers have shown that targeting specific receptor conformations via biased ligands is proving to be a powerful tool in the effective treatment of human diseases. Can biased ligands be used to selectively modulate signaling by GPCR regulators of the neuroendocrine axis in the treatment of IHH? As discussed in this review, the grand possibility exists. However, while we are still very far from developing these treatments, this exciting likelihood can happen through a much greater mechanistic understanding of how GPCRs signal within the cell.

人类GnRH缺乏症在临床和遗传上都是一种异质性疾病，包括先天性GnRH缺乏症伴有失眠症（Kallmann综合征）或嗅觉正常[正常性特发性促性腺激素性腺功能减退症（IHH）]和成人发作性促性腺激素性腺功能减退症。我们对GnRH分泌和GnRH信号转导的神经机制的理解继续迅速增加，而且引人注目的是，异三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）偶联受体（GPCR）继续在这些过程中扮演重要角色。GPCR曾经被视为二进制开关，在“开”状态下它们与Gα蛋白结合，但现在我们知道这种观点过于简单，不能充分表征GPCR。代替，GPCR已成为熟练的信号分子，利用自身的不同物理构象状态通过其G蛋白和β-arrestin引发一系列下游信号事件。“一个受体-多种信号构象”模型可能是一种进化的策略，可用于我们的优势，因为研究人员已证明，通过偏向配体靶向特定受体构象已被证明是有效治疗人类疾病的强大工具。在IHH的治疗中，是否可以使用有偏向的配体通过神经内分泌轴的GPCR调节剂选择性地调节信号传导？如本评论所述，存在很大的可能性。但是，尽管我们距离开发这些疗法还很遥远，