目的:在多囊卵巢综合征(PCOS)样疾病中,过度活跃的kisspeptin神经元是否会导致异常高LH分泌和下游高雄激素血症,并且抑制kisspeptin神经元可以挽救这种内分泌损伤?
背景:PCOS是一种以高雄激素血症为特征的生殖障碍,无排卵,和/或多囊卵巢,伴随着异常LH过度搏动的标志性特征,但内分泌损伤的潜在机制仍不清楚.慢性来曲唑(LET;芳香化酶抑制剂)小鼠模型概括了PCOS表型,包括多囊卵巢,无排卵,高睾酮,和过度活跃的LH脉冲。LETPCOS样女性也有增加的下丘脑kisspeptin神经元激活,这可能驱动他们的高活性LH分泌和高雄激素血症,但这还没有经过测试。
方法:用安慰剂治疗转基因KissCRE+/hM4Di雌性小鼠或同窝Cret-对照组,或慢性LET(50µg/天)诱导PCOS样表型,随后急性(一次)或慢性(2周)氯氮平-N-氧化物(CNO)暴露于化学抑制kisspeptin细胞(n=6至10只小鼠/组)。
方法:主要内分泌措施,包括体内LH脉冲分泌模式和循环睾酮水平,在选择性kisspeptin神经元抑制之前和之后进行评估,并在PCOS组和健康对照组之间进行比较。测量体重变化,并通过qRT-PCR测定垂体和卵巢基因表达。
结果:急性靶向抑制PCOS小鼠kisspeptin神经元成功地降低了异常活跃的LH脉冲分泌(P<0.05)。同样,对kisspeptin神经元活性的慢性选择性抑制将先前的高LH和睾丸激素水平(P<0.05)逆转至健康对照水平,并挽救了生殖基因表达(P<0。05).
方法:不适用。
结论:本研究未评估卵巢形态。此外,小鼠模型可以提供对PCOS样疾病中神经内分泌过程的机制见解,但可能不能完全反映女性的PCOS。
结论:这些数据支持过度活跃的kisspeptin神经元可以驱动神经内分泌PCOS样损伤的假设,这可能发生在PCOS女性身上。我们的发现补充了最近使用NKB受体拮抗剂降低PCOS女性LH的临床研究,并表明kisspeptin神经元活性的药理学剂量依赖性调节可能是临床治疗高雄激素血症和降低PCOS女性LH升高的有价值的未来治疗目标。
背景:这项研究得到了NIH授予R01HD111650,R01HD090161,R01HD100580,P50HD012303,R01AG078185和NIHR24HD102061的支持,并获得了英国神经内分泌学学会的试点项目奖。没有竞争的利益。
OBJECTIVE: Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments?
CONCLUSIONS: Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels.
BACKGROUND: PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses. LET PCOS-like females also have increased hypothalamic kisspeptin neuronal activation which may drive their hyperactive LH secretion and hyperandrogenemia, but this has not been tested.
METHODS: Transgenic KissCRE+/hM4Di female mice or littermates Cre- controls were treated with placebo, or chronic LET (50 µg/day) to induce a PCOS-like phenotype, followed by acute (once) or chronic (2 weeks) clozapine-N-oxide (CNO) exposure to chemogenetically inhibit kisspeptin cells (n = 6 to 10 mice/group).
METHODS: Key endocrine measures, including in vivo LH pulse secretion patterns and circulating testosterone levels, were assessed before and after selective kisspeptin neuron inhibition and compared between PCOS groups and healthy controls. Alterations in body weights were measured and pituitary and ovarian gene expression was determined by qRT-PCR.
RESULTS: Acute targeted inhibition of kisspeptin neurons in PCOS mice successfully lowered the abnormally hyperactive LH pulse secretion (P < 0.05). Likewise, chronic selective suppression of kisspeptin neuron activity reversed the previously high LH and testosterone levels (P < 0.05) down to healthy control levels and rescued reproductive gene expression (P < 0. 05).
METHODS: N/A.
CONCLUSIONS: Ovarian morphology was not assessed in this study. Additionally, mouse models can offer mechanistic insights into neuroendocrine processes in PCOS-like conditions but may not perfectly mirror PCOS in women.
CONCLUSIONS: These data support the hypothesis that overactive kisspeptin neurons can drive neuroendocrine PCOS-like impairments, and this may occur in PCOS women. Our findings complement recent clinical investigations using NKB receptor antagonists to lower LH in PCOS women and suggest that pharmacological dose-dependent modulation of kisspeptin neuron activity may be a valuable future therapeutic target to clinically treat hyperandrogenism and lower elevated LH in PCOS women.
BACKGROUND: This research was supported by NIH grants R01 HD111650, R01 HD090161, R01 HD100580, P50 HD012303, R01 AG078185, and NIH R24 HD102061, and a pilot project award from the British Society for Neuroendocrinology. There are no competing interests.