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<p>Brain-derived serotonin (5-HT) is a key neurotransmitter that regulates diverse central and peripheral physiological processes, including endocrine function, mood, and circadian rhythms. Patients with anxiety and depression often exhibit reduced brain 5-HT levels, which contribute significantly to female infertility. However, the role of brain-derived 5-HT in maintaining ovarian reserve function remains unclear. We generated brain-specific <i>Tph2</i> conditional knockout (<i>Tph2</i>-CKO) mice lacking 5-HT and observed reduced follicle numbers and anti-Müllerian hormone (AMH) levels, indicating diminished ovarian reserve (DOR). Mechanistically, Brain-derived 5-HT deficiency suppressed ovarian mTOR signaling, triggering excessive autophagy, mitochondrial dysfunction, and apoptosis. In the hypothalamus, reduced central 5-HT levels downregulated 5-HT receptor 7 (HTR7)-cAMP/PKA signaling, disrupted circadian rhythms, and decreased gonadotropin-releasing hormone (GnRH) expression, impairing hypothalamic-pituitary-ovarian (HPO) axis function. Ovarian follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) levels decreased, ultimately leading to DOR. Thus, 5-HT deficiency in the dorsal raphe nucleus disrupts the HPO axis <i>via</i> HTR7, leading to DOR.</p>

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Brain Serotonin Deficiency Impairs Ovarian Reserve Function via the Hypothalamic-Pituitary-Ovarian Axis

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Shuang-Shuang Cui,
  • Zhuo-Nan Yang,
  • Jin Xiao,
  • Jin-Ping Qiao,
  • Yue-Ming Zhang,
  • Ling-Ge Shi,
  • Hui-Ru Cheng,
  • Si-Min Ding,
  • Meng-Yao Wang,
  • Dong-Mei Ji,
  • Tao Zhang,
  • Dan Liang,
  • Peng Chen,
  • Yun-Xia Cao,
  • Jiang-Ning Zhou,
  • Ya-Jing Liu

摘要

Brain-derived serotonin (5-HT) is a key neurotransmitter that regulates diverse central and peripheral physiological processes, including endocrine function, mood, and circadian rhythms. Patients with anxiety and depression often exhibit reduced brain 5-HT levels, which contribute significantly to female infertility. However, the role of brain-derived 5-HT in maintaining ovarian reserve function remains unclear. We generated brain-specific Tph2 conditional knockout (Tph2-CKO) mice lacking 5-HT and observed reduced follicle numbers and anti-Müllerian hormone (AMH) levels, indicating diminished ovarian reserve (DOR). Mechanistically, Brain-derived 5-HT deficiency suppressed ovarian mTOR signaling, triggering excessive autophagy, mitochondrial dysfunction, and apoptosis. In the hypothalamus, reduced central 5-HT levels downregulated 5-HT receptor 7 (HTR7)-cAMP/PKA signaling, disrupted circadian rhythms, and decreased gonadotropin-releasing hormone (GnRH) expression, impairing hypothalamic-pituitary-ovarian (HPO) axis function. Ovarian follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) levels decreased, ultimately leading to DOR. Thus, 5-HT deficiency in the dorsal raphe nucleus disrupts the HPO axis via HTR7, leading to DOR.