Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California 90095, USA.
Endocrinology. 2023 Jan 9;164(3). doi: 10.1210/endocr/bqad015.
Androgens are steroid hormones crucial for sexual differentiation of the brain and reproductive function. In excess, however, androgens may decrease fertility as observed in polycystic ovary syndrome, a common endocrine disorder characterized by oligo/anovulation and/or polycystic ovaries. Hyperandrogenism may also disrupt energy homeostasis, inducing higher central adiposity, insulin resistance, and glucose intolerance, which may exacerbate reproductive dysfunction. Androgens bind to androgen receptors (ARs), which are expressed in many reproductive and metabolic tissues, including brain sites that regulate the hypothalamo-pituitary-gonadal axis and energy homeostasis. The neuronal populations affected by androgen excess, however, have not been defined. We and others have shown that, in mice, AR is highly expressed in leptin receptor (LepRb) neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). Here, we assessed if LepRb neurons, which are critical in the central regulation of energy homeostasis and exert permissive actions on puberty and fertility, have a role in the pathogenesis of female hyperandrogenism. Prenatally androgenized (PNA) mice lacking AR in LepRb cells (LepRbΔAR) show no changes in body mass, body composition, glucose homeostasis, or sexual maturation. They do show, however, a remarkable improvement of estrous cycles combined with normalization of ovary morphology compared to PNA controls. Our findings indicate that the prenatal androgenization effects on adult reproductive physiology (ie, anestrus and anovulation) are mediated by a subpopulation of LepRb neurons directly sensitive to androgens. They also suggest that the effects of hyperandrogenism on sexual maturation and reproductive function in adult females are controlled by distinct neural circuits.
雄激素是对大脑的性分化和生殖功能至关重要的类固醇激素。然而,过多的雄激素可能会降低生育能力,如多囊卵巢综合征(PCOS)中观察到的那样,PCOS 是一种常见的内分泌紊乱,其特征为少/无排卵和/或多囊卵巢。高雄激素血症也可能破坏能量稳态,导致更高的中枢性肥胖、胰岛素抵抗和葡萄糖耐量受损,这可能会加重生殖功能障碍。雄激素与雄激素受体(AR)结合,AR 在许多生殖和代谢组织中表达,包括调节下丘脑-垂体-性腺轴和能量稳态的脑区。然而,雄激素过多影响的神经元群体尚未确定。我们和其他人已经表明,在小鼠中,AR 在瘦素受体(LepRb)神经元中高度表达,特别是在弓状核(ARH)和腹侧前乳头上核(PMv)中。在这里,我们评估了 LepRb 神经元是否在能量稳态的中枢调节中起关键作用,并对青春期和生育能力起许可作用,它们是否在女性高雄激素血症的发病机制中起作用。在 LepRb 细胞中缺乏 AR 的产前雄激素化(PNA)小鼠(LepRbΔAR)在体重、身体成分、葡萄糖稳态或性成熟方面没有变化。然而,与 PNA 对照相比,它们表现出明显的发情周期改善,同时卵巢形态正常化。我们的发现表明,雄激素对成年生殖生理(即无发情和无排卵)的产前作用是由直接对雄激素敏感的 LepRb 神经元亚群介导的。它们还表明,高雄激素血症对成年雌性的性成熟和生殖功能的影响是由不同的神经回路控制的。