Corpus luteum as a novel target of weight changes that contribute to impaired female reproductive physiology and function

Obesity and malnutrition are associated with decreased fecundity in women. Impaired reproductive capacity in obese women is often attributed to anovulation. However, obese women with ovulatory cycles also have reduced fertility, but the etiology of their impaired reproduction is only partially understood. Accumulating evidence suggests that obesity directly impairs oocyte and embryo quality as well as endometrial receptivity. In obese women, urinary progesterone metabolite excretion is decreased, but in excess of what can be explained by suppressed gonadotropin secretion, suggesting that apart from its central effect obesity may directly affect progesterone (P4) production. These observations have led to the novel hypothesis that obesity directly affects corpus luteum (CL) function. Similarly, we hypothesize that weight loss may contribute to luteal dysfunction. Here, we propose a non-human primate model, the vervet monkey, to examine the effect of weight gain and loss on menstrual cycle parameters and CL gene expression. In this model, weight gain and loss did not significantly alter menstrual cyclicity; however, both induced alterations in the CL transcriptome. In the weight gain monkey, we observed that impaired mid-luteal P4 secretion was associated with downregulation of steroidogenic pathways in CL. Collectively, these preliminary findings support our hypothesis that weight gain and loss may contribute to CL dysfunction. The vervet model described and preliminary observations provide a basis for a larger study to address this important question. Understanding the mechanisms by which weight gain and loss contribute to reproductive dysfunction can assist in the development of targeted treatments to enhance women’s reproductive capability when it is desired. Abbreviations: CL: corpus luteum; P4: progesterone; E2: estradiol; PDG: pregnanediol 3-glucoronide; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin releasing hormone; BMI: body mass index; qrtPCR: quantitative real-time PCR; PGR: progesterone receptor; ART: assisted reproductive technology; IVF: in vitro fertilization; HPO: hypothalamic-pituitary-ovarian axis; MMPs: matrix metalloproteinases Gene symbols: LH receptor (LHGCR); cholesterol side-chain cleavage enzyme (CYP11A1); 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2); steroidogenic acute regulatory protein (STAR); LDL receptor (LDLR); scavenger receptor B1 (SCARB1); ATP-binding cassette sub-family A member 1 (ABCA1); ATP-binding cassette sub-family G member 1 (ABCG1); apolipoprotein A (APOA1); 24 dehydrocholesterol reductase (DHCR24); 3-hydroxy-3-methylglytaryl-CoA reductase (HMGCR); vascular endothelial growth factor A (VEGFA); vascular endothelial growth factor C (VEGFC); vascular endothelial growth factor receptor 1 (VEGFR1); and TIMP metallopeptidase inhibitor 1 (TIMP1); amphiregulin (AREG); epiregulin (EREG); CCAAT/enhancer binding protein alpha (CEBPBA); cAMP responsive element binding protein 3-like 1 (CREB3L1); ADAM metallopeptidase with thrombospodin type 1 motif 1 (ADAMTS1); matrix metallopeptidase 9 (MMP9); cytochrome b-245 beta polypeptide (CYBB or NOX2); NADH oxidase (NCF2 or NOXA2); Fc fragment of IgG receptor IIb (FCGR2B); Fc fragment of IgG receptor IIb (FCGR2C); ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1); RAB27A member RAS oncofamily (RAB27A); hydroxyprostaglandin dehydrogenase (HPGD); prostaglandin-endoperoxidase synthase 1 (PTGS1); integrin B2 (ITGB2); leukotriene A4 hydrolase (LTA4H); radixin (RDX); ezrin (EZR); nuclear receptor subfamily 5 group A member 2 (NR5A2)

肥胖与营养不良均与女性生育力下降相关。肥胖女性的生殖能力受损通常归因于无排卵。然而，存在排卵周期的肥胖女性仍存在生育力降低的情况，但其生殖功能受损的病因仅部分明确。越来越多的证据表明，肥胖会直接损害卵母细胞与胚胎质量，以及子宫内膜容受性。
在肥胖女性中，尿孕酮代谢产物排泄量减少，且减少幅度超过了促性腺激素分泌受抑制所能解释的范围，这提示除中枢效应外，肥胖可能直接影响孕酮（progesterone, P4）的生成。上述观察结果催生了一项全新的假说：肥胖可直接影响黄体（corpus luteum, CL）功能。同理，我们提出假说认为体重减轻可能也会导致黄体功能异常。
本研究拟采用非人灵长类动物模型——黑长尾猴（vervet monkey），以探究体重增减对月经周期参数及黄体基因表达的影响。在该模型中，体重增减并未显著改变月经周期节律，但二者均可诱导黄体转录组发生改变。在体重增加的黑长尾猴中，我们观察到黄体中期孕酮分泌受损与黄体类固醇生成通路的下调相关。综上，这些初步研究结果支持我们的假说：体重增减可能会导致黄体功能异常。
本研究所描述的黑长尾猴模型及初步观察结果，为开展更大规模的相关研究奠定了基础，以解答这一重要科学问题。阐明体重增减导致生殖功能受损的具体机制，可为开发针对性治疗手段提供依据，从而在女性有生育需求时提升其生殖能力。

缩写说明：CL：黄体（corpus luteum）；P4：孕酮（progesterone）；E2：雌二醇（estradiol）；PDG：孕二醇3-葡萄糖醛酸苷（pregnanediol 3-glucoronide）；LH：黄体生成素（luteinizing hormone）；FSH：卵泡刺激素（follicle-stimulating hormone）；GnRH：促性腺激素释放激素（gonadotropin releasing hormone）；BMI：体质量指数（body mass index）；qrtPCR：实时定量聚合酶链反应（quantitative real-time PCR）；PGR：孕酮受体（progesterone receptor）；ART：辅助生殖技术（assisted reproductive technology）；IVF：体外受精（in vitro fertilization）；HPO：下丘脑-垂体-卵巢轴（hypothalamic-pituitary-ovarian axis）；MMPs：基质金属蛋白酶（matrix metalloproteinases）

基因符号：黄体生成素受体（LH receptor, LHGCR）；胆固醇侧链裂解酶（cholesterol side-chain cleavage enzyme, CYP11A1）；3β-羟类固醇脱氢酶II型（3 beta-hydroxysteroid dehydrogenase type II, HSD3B2）；类固醇生成急性调节蛋白（steroidogenic acute regulatory protein, STAR）；低密度脂蛋白受体（LDL receptor, LDLR）；清道夫受体B1（scavenger receptor B1, SCARB1）；ATP结合盒转运蛋白亚家族A成员1（ATP-binding cassette sub-family A member 1, ABCA1）；ATP结合盒转运蛋白亚家族G成员1（ATP-binding cassette sub-family G member 1, ABCG1）；载脂蛋白A（apolipoprotein A, APOA1）；24-脱氢胆固醇还原酶（24 dehydrocholesterol reductase, DHCR24）；3-羟基-3-甲基戊二酰辅酶A还原酶（3-hydroxy-3-methylglytaryl-CoA reductase, HMGCR）；血管内皮生长因子A（vascular endothelial growth factor A, VEGFA）；血管内皮生长因子C（vascular endothelial growth factor C, VEGFC）；血管内皮生长因子受体1（vascular endothelial growth factor receptor 1, VEGFR1）；金属蛋白酶组织抑制剂1（TIMP metallopeptidase inhibitor 1, TIMP1）；双调蛋白（amphiregulin, AREG）；表皮调节素（epiregulin, EREG）；CCAAT/增强子结合蛋白α（CCAAT/enhancer binding protein alpha, CEBPBA）；cAMP应答元件结合蛋白3样蛋白1（cAMP responsive element binding protein 3-like 1, CREB3L1）；含血小板反应蛋白1型基序的ADAM金属蛋白酶1（ADAM metallopeptidase with thrombospodin type 1 motif 1, ADAMTS1）；基质金属蛋白酶9（matrix metallopeptidase 9, MMP9）；细胞色素b-245 β多肽（cytochrome b-245 beta polypeptide, CYBB或NOX2）；NADH氧化酶（NADH oxidase, NCF2或NOXA2）；IgG Fc片段受体IIb（Fc fragment of IgG receptor IIb, FCGR2B）；IgG Fc片段受体IIc（Fc fragment of IgG receptor IIc, FCGR2C）；胞外核苷酸焦磷酸酶/磷酸二酯酶1（ectonucleotide pyrophosphatase/phosphodiesterase 1, ENPP1）；RAS癌基因家族成员RAB27A（RAB27A member RAS oncofamily, RAB27A）；羟基前列腺素脱氢酶（hydroxyprostaglandin dehydrogenase, HPGD）；前列腺素内过氧化物合酶1（prostaglandin-endoperoxidase synthase 1, PTGS1）；整合素β2（integrin B2, ITGB2）；白三烯A4水解酶（leukotriene A4 hydrolase, LTA4H）；根蛋白（radixin, RDX）；埃兹蛋白（ezrin, EZR）；核受体亚家族5A组A成员2（nuclear receptor subfamily 5 group A member 2, NR5A2）