Department of Gynecology and Obstetrics, Medical School, Federal University of Mato Grosso; and Tropical Institute of Reproductive Medicine,Cuiabá, MT, Brazil.
Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia, Australia.
Hum Reprod Update. 2021 Jun 22;27(4):771-796. doi: 10.1093/humupd/dmab004.
Metabolic and endocrine alterations in women with polycystic ovary syndrome (PCOS) affect adipose tissue mass and distribution. PCOS is characterised by hyperandrogenism, obesity and adipocyte dysfunction. Hyperandrogenism in PCOS drives dysfunctional adipocyte secretion of potentially harmful adipocytokines. Glucocorticoids and sex-steroids modulate adipocyte development and function. For their part, adipocyte products interact with adrenal and ovarian steroidogenic cells. Currently, the relationship between adipocyte and steroidogenic cells is not clear, and for these reasons, it is important to elucidate the interrelationship between these cells in women with and without PCOS.
This comprehensive review aims to assess current knowledge regarding the interrelationship between adipocytes and adrenal and ovarian steroidogenic cells in animal models and humans with or without PCOS.
We searched for articles published in English and Portuguese in PubMed. Keywords were as follows: polycystic ovary syndrome, steroidogenesis, adrenal glands, theca cells, granulosa cells, adipocytes, adipocytokines, obesity, enzyme activation, and cytochrome P450 enzymes. We expanded the search into the references from the retrieved articles.
Glucocorticoids and sex-steroids modulate adipocyte differentiation and function. Dysfunctional adipocyte products play important roles in the metabolic and endocrine pathways in animals and women with PCOS. Most adipokines participate in the regulation of the hypothalamic-pituitary-adrenal and ovarian axes. In animal models of PCOS, hyperinsulinemia and poor fertility are common; various adipokines modulate ovarian steroidogenesis, depending on the species. Women with PCOS secrete unbalanced levels of adipocyte products, characterised by higher levels of leptin and lower levels of adiponectin. Leptin expression positively correlates with body mass index, waist/hip ratio and levels of total cholesterol, triglyceride, luteinising hormone, oestradiol and androgens. Leptin inhibits the production of oestradiol and, in granulosa cells, may modulate 17-hydroxylase and aromatase enzyme activities. Adiponectin levels negatively correlate with fat mass, body mass index, waist-hip ratio, glucose, insulin and triglycerides, and decrease androgen production by altering expression of luteinising hormone receptor, steroidogenic acute regulatory protein, cholesterol-side-chain cleavage enzyme and 17-hydroxylase. Resistin expression positively correlates with body mass index and testosterone, and promotes the expression of 17-hydroxylase enzyme in theca cells. The potential benefits of adipokines in the treatment of women with PCOS require more investigation.
The current data regarding the relationship between adipocyte products and steroidogenic cells are conflicting in animals and humans. Polycystic ovary syndrome is an excellent model to investigate the interrelationship among adipocyte and steroidogenic cells. Women with PCOS manifest some pathological conditions associated with hyperandrogenism and adipocyte products. In animals, cross-talk between cells may vary according to species, and the current review suggests opportunities to test new medications to prevent or even reverse several harmful sequelae of PCOS in humans. Further studies are required to investigate the possible therapeutic application of adipokines in women with obese and non-obese PCOS. Meanwhile, when appropriate, metformin use alone, or associated with flutamide, may be considered for therapeutic purposes.
多囊卵巢综合征（PCOS）女性的代谢和内分泌改变会影响脂肪组织的质量和分布。PCOS 的特征是高雄激素血症、肥胖和脂肪细胞功能障碍。PCOS 中的高雄激素血症导致脂肪细胞分泌潜在有害的脂肪细胞因子功能失调。糖皮质激素和性激素调节脂肪细胞的发育和功能。就其本身而言，脂肪细胞产物与肾上腺和卵巢类固醇生成细胞相互作用。目前，脂肪细胞和类固醇生成细胞之间的关系尚不清楚，因此，阐明这些细胞之间的相互关系对于患有和不患有 PCOS 的女性来说非常重要。
本综述旨在评估目前关于动物模型和患有或不患有 PCOS 的女性中脂肪细胞与肾上腺和卵巢类固醇生成细胞之间相互关系的知识。
我们在 PubMed 中以英文和葡萄牙文搜索了已发表的文章。关键词如下：多囊卵巢综合征、类固醇生成、肾上腺、卵泡膜细胞、颗粒细胞、脂肪细胞、脂肪细胞因子、肥胖、酶激活、细胞色素 P450 酶。我们从检索到的文章的参考文献中扩展了搜索范围。
糖皮质激素和性激素调节脂肪细胞的分化和功能。功能失调的脂肪细胞产物在动物和患有 PCOS 的女性的代谢和内分泌途径中发挥重要作用。大多数脂肪细胞因子参与调节下丘脑-垂体-肾上腺和卵巢轴。在 PCOS 的动物模型中，通常会出现高胰岛素血症和生育力低下；各种脂肪细胞因子根据物种调节卵巢类固醇生成。患有 PCOS 的女性会分泌失衡的脂肪细胞产物，其特征是瘦素水平升高和脂联素水平降低。瘦素表达与体重指数、腰臀比和总胆固醇、甘油三酯、黄体生成素、雌二醇和雄激素水平呈正相关。瘦素抑制雌二醇的产生，并且在颗粒细胞中，可能通过调节 17-羟化酶和芳香化酶的活性来调节。脂联素水平与脂肪质量、体重指数、腰臀比、葡萄糖、胰岛素和甘油三酯呈负相关，并通过改变黄体生成素受体、类固醇急性调节蛋白、胆固醇侧链裂解酶和 17-羟化酶的表达来降低雄激素的产生。抵抗素的表达与体重指数和睾酮呈正相关，并促进卵泡膜细胞中 17-羟化酶的表达。脂肪细胞因子在治疗患有 PCOS 的女性中的潜在益处需要进一步研究。
目前关于脂肪细胞产物和类固醇生成细胞之间关系的数据在动物和人类中存在矛盾。多囊卵巢综合征是研究脂肪细胞和类固醇生成细胞之间相互关系的极佳模型。患有 PCOS 的女性表现出一些与高雄激素血症和脂肪细胞产物相关的病理状况。在动物中，细胞之间的串扰可能因物种而异，本综述提出了测试新药物的机会，以预防甚至逆转人类 PCOS 的一些有害后果。需要进一步研究以调查肥胖和非肥胖 PCOS 女性中脂肪细胞因子的可能治疗应用。同时，单独使用二甲双胍或与氟他胺联合使用，可考虑用于治疗目的。
