Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany.
Endocrinology. 2019 May 1;160(5):1323-1332. doi: 10.1210/en.2019-00038.
Hyperprolactinemia causes infertility, but the specific mechanism is unknown. It is clear that elevated prolactin levels suppress pulsatile release of GnRH from the hypothalamus, with a consequent reduction in pulsatile LH secretion from the pituitary. Only a few GnRH neurons express prolactin receptors (Prlrs), however, and thus prolactin must act indirectly in the underlying neural circuitry. Here, we have tested the hypothesis that prolactin-induced inhibition of LH secretion is mediated by kisspeptin neurons, which provide major excitatory inputs to GnRH neurons. To evaluate pulsatile LH secretion, we collected serial blood samples from diestrous mice and measured LH levels by ultrasensitive ELISA. Acute prolactin administration decreased LH pulses in wild-type mice. Kisspeptin neurons in the arcuate nucleus and in the rostral periventricular area of the third ventricle (RP3V) acutely responded to prolactin, but prolactin-induced signaling in kisspeptin neurons was up to fourfold higher in the arcuate nucleus when compared with the RP3V. Consistent with this, conditional knockout of Prlr specifically in arcuate nucleus kisspeptin neurons prevented prolactin-induced suppression of LH secretion. Our data establish that during hyperprolactinemia, suppression of pulsatile LH secretion is mediated by Prlr on arcuate kisspeptin neurons.
高泌乳素血症可导致不孕，但具体机制尚不清楚。很明显，泌乳素水平升高会抑制下丘脑 GnRH 的脉冲式释放，导致垂体 LH 的脉冲式分泌减少。然而，只有少数 GnRH 神经元表达泌乳素受体（Prlrs），因此泌乳素必须在潜在的神经回路中发挥间接作用。在这里，我们检验了这样一种假设，即泌乳素诱导的 LH 分泌抑制是由 kisspeptin 神经元介导的，这些神经元为 GnRH 神经元提供主要的兴奋性输入。为了评估 LH 的脉冲式分泌，我们从动情期小鼠中采集连续的血液样本，并通过超灵敏 ELISA 测量 LH 水平。急性给予泌乳素会降低野生型小鼠的 LH 脉冲。弓状核和第三脑室前室周区（RP3V）的 kisspeptin 神经元对泌乳素有急性反应，但与 RP3V 相比，弓状核中泌乳素诱导的信号转导要高出四倍。与此一致的是，特异性敲除弓状核 kisspeptin 神经元中的 Prlr 可防止泌乳素诱导的 LH 分泌抑制。我们的数据表明，在高泌乳素血症期间，LH 脉冲式分泌的抑制是由弓状核 kisspeptin 神经元上的 Prlr 介导的。
