脂联素与女性身体成分和骨密度的研究进展

脂联素是参与调节糖脂代谢、能量消耗、炎症反应、免疫应答、心血管功能和生殖的内分泌因子。除此之外,脂联素还可以促进成骨细胞的增殖和分化,同时抑制破骨细胞的形成,对骨骼的发育以及维持具有积极作用。该文系统描述了从出生到更年期女性的血清脂联素波动情况及其分泌模式,讨论了脂联素在女性身体成分和骨密度方面发挥的调节作用。胎儿时期,脂联素通过母胎界面,以自分泌/旁分泌的方式在胎盘和脂肪组织中发挥作用,并促进葡萄糖代谢和胎儿发育。新生儿时期,脐带血清脂联素水平是成人的2～3倍,体重与血清脂联素水平呈正相关。幼儿时期,血清脂联素水平与体脂率呈负相关;骨量和骨密度也随体重增加而增加,与脂联素呈负相关。青年时期,血清脂联素水平似乎与雌激素分泌调节无必然关系;内脏脂肪是肥胖女性骨密度的负预测因子,与血清脂联素水平呈负相关。中年期,血清脂联素水平与体重呈负相关,肥胖的个体表现出血清脂联素水平下降,血清脂联素水平与骨密度亦呈负相关。绝经后,随着雌激素水平的降低,女性血清脂联素水平升高。总之,一生中不断增加的体脂肪总量似乎影响了女性脂联素的分泌,与雌激素水平的下降协同,导致女性老年时期发生骨质疏松的风险增加。     

Markers of insulin resistance in Polycystic ovary syndrome women: An update

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting 5%-10% of women of reproductive age. The importance of this syndrome lies in the magnitude of associated comorbidities: infertility, metabolic dysfunction, cardiovascular disease (CVD), plus psychological and oncological complications. Insulin resistance (IR) is a prominent feature of PCOS with a prevalence of 35%-80%. Without adequate management, IR with compensatory hyperinsulinemia contributes directly to reproductive dysfunction in women with PCOS. Furthermore, epidemiological data shows compelling evidence that PCOS is associated with an increased risk of impaired glucose tolerance, gestational diabetes mellitus and type 2 diabetes. In addition, metabolic dysfunction leads to a risk for CVD that increases with aging in women with PCOS. Indeed, the severity of IR in women with PCOS is associated with the amount of abdominal obesity, even in lean women with PCOS. Given these drastic implications, it is important to diagnose and treat insulin resistance as early as possible. Many markers have been proposed. However, quantitative assessment of IR in clinical practice remains a major challenge. The gold standard method for assessing insulin sensitivity is the hyperinsulinemic euglycemic glucose clamp. However, it is not used routinely because of the complexity of its procedure. Consequently, there has been an urgent need for surrogate markers of IR that are more applicable in large population-based epidemiological investigations. Despite this, many of them are either difficult to apply in routine clinical practice or useless for women with PCOS. Considering this difficulty, there is still a need for an accurate marker for easy, early detection and assessment of IR in women with PCOS. This review highlights markers of IR already used in women with PCOS, including new markers recently reported in literature, and it establishes a new classification for these markers.     

Fracture Risk Is Decreased in Women With Polycystic Ovary Syndrome: A Register‐Based and Population‐Based Cohort Study

Hyperandrogenism, obesity, and hyperinsulinemia may protect against osteoporosis, whereas amenorrhea, increased cortisol, and low growth hormone may be associated with higher fracture risk in polycystic ovary syndrome (PCOS). The objective of this study was to investigate fracture risk in PCOS. In the PCOS Denmark study, women with PCOS and/or hirsutism were identified in the Danish National Patient Register (1995–2012). Each patient was assigned three age‐matched controls on the index date of PCOS diagnosis. Individuals with a previous endocrine diagnosis were excluded. Within PCOS Denmark, we embedded a well‐characterized subcohort of patients, PCOS OUH, diagnosed with PCOS at Odense University Hospital (n = 1217). We identified incident fractures by International Classification of Diseases, 10th Revision (ICD‐10) codes and used conditional Cox regression analyses to compare fracture risk. In the PCOS Denmark study, there were 19,199 women with PCOS and 57,483 controls were included, mean age 30.6 years (range, 12–60 years). Fracture rates were decreased in PCOS Denmark (10.3/1000 patient years) versus controls (13.6/1000 patient years). The adjusted ORs were 0.76 (95% CI, 0.71 to 0.80) for all fractures, 0.82 (95% CI, 0.74 to 0.92) for major osteoporotic fractures, and 0.57 (95% CI, 0.47 to 0.70) for fractures of head and face. The risk reduction was more pronounced below the age of 30 years at diagnosis. Women with PCOS had significant more hospital contacts due to strains and sprains. In the PCOS OUH subcohort, the risk reduction of fractures did not differ between PCOS women with elevated versus normal testosterone levels and the risk reduction was nominally smaller in overweight versus normal weight PCOS women. Women with PCOS had reduced risk of fractures, in particular of the appendicular skeleton. The risk reduction was greater in women with younger age at diagnosis suggesting that the skeletal effects of PCOS may be greater in women who have not yet reached peak bone mass. Reduced participation in sports activities was probably not the reason for the reduced risk of fractures. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

多囊卵巢综合征与复发性流产的研究进展

复发性流产(RSA)的发生与多种因素相关,包括年龄、遗传、内分泌与代谢障碍、免疫因素、子宫发育异常、血栓形成倾向、感染、精液质量和生活方式等。多囊卵巢综合征(PCOS)是一种以持续性无排卵、多卵泡不成熟、雄激素水平升高和胰岛素抵抗为主要特征的生殖功能障碍与糖代谢异常并存的内分泌紊乱综合征。PCOS患者RSA的发生率明显高于普通人群,30%~40%的PCOS患者存在自然流产史。目前,PCOS患者易发生RSA的具体发病机制尚不明确,可能与高黄体生成素血症、高雄激素血症、胰岛素抵抗、肥胖、高泌乳素血症、黄体功能不全、血栓形成等有关。本文从上述方面对PCOS患者发生RSA的常见原因及其预防进行综述。     

血清lncRNA MEG3的表达与多囊卵巢综合征患者胰岛素抵抗的关系

目的 探讨长链非编码RNA(lncRNA)人类母系表达基因3(MEG3)的表达与多囊卵巢综合征(PCOS)患者胰岛素抵抗(IR)的关系.方法 选取2018年7月至2020年8月本院收治的123例PCOS患者为研究对象进行前瞻性分析,根据胰岛素抵抗指数(HOMA-IR)水平分为IR组(n=54)和非IR组(n=69),另...     

Treatment of Metformin on women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) appears to be the most common endocrine disorders of women. It is associated with significant reproductive, endocrine, metabolic, and cardiovascular morbidity. Hyperinsulinemia and insulin resistance, which result in hyperandrogenemia have been documented as a central role in the pathogenesis of PCOS. Treatment with insulin sensitizer, metformin, has been shown to follow by regularization of menstrual cycle, improved response to ovulation induction and reduction of hyperandrogenism. It possibly prevents early trimester pregnancy loss and decrease the risk of developing type Ⅱ diabetes and cardiovascular disease. This article aims to review the current evidence on the use of metformin in women with PCOS.     

The Phenotypic Approach to Osteoarthritis: A Look at Metabolic Syndrome-Associated Osteoarthritis

Metabolic syndrome-associated osteoarthritis (Met-OA) is a clinical phenotype defined by the role of obesity and metabolic syndrome as risk factors and by chronic low-grade inflammation. Obesity is an established risk factor for osteoarthritis not only at the knee, but also at the hands. Metabolic syndrome is also a risk factor for osteoarthritis, and a cumulative effect of the various syndrome components combines with an independent effect of each individual component (diabetes, dyslipidemia, and/or hypertension). The higher incidence of osteoarthritis in patients with obesity is related to several factors. One is the larger fat mass, which imposes heavier loads on the joints. Another is endocrine production by the adipose tissue of proinflammatory mediators (cytokines, adipokines, fatty acids, and reactive oxygen species) that adversely affect joint tissues. Obesity-related dysbiosis and sarcopenia were more recently implicated in the association between obesity and osteoarthritis. Finally, patients who have osteoarthritis, with or without metabolic syndrome, are at increased risk for cardiovascular mortality due not only to a sedentary lifestyle, but also to shared risk factors. Among these is the low-grade inflammation seen in patients with metabolic disorders. Thus, primary prevention and appropriate management of obesity and metabolic syndrome may delay the development and slow the progression of osteoarthritis.     

多囊卵巢综合征与脂肪因子相关性的研究进展

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是育龄期妇女最常见的一种内分泌及代谢紊乱性疾病,其主要特征为肥胖、胰岛素抵抗、高雄激素表现、持续性无排卵以及卵巢多囊样改变等。近年来发现肥胖与PCOS的发生有着密切的联系,随着对脂肪细胞的内分泌作用进一步了解,逐渐认识到脂肪所产生的脂肪细胞因子可能是导致PCOS发生的重要因素之一。现就国内外这一方面的研究进展做一综述。     

Relationship between treatments with insulin and oral hypoglycemic agents versus the presence of vertebral fractures in type 2 diabetes mellitus

Although previous studies indicated that hypoglycemic agents could affect bone metabolism, little is known about whether these agents are associated with the risks of osteoporotic fracture in Japanese patents with type 2 diabetes. We examined whether treatments of diabetes, such as insulin administration, sulfonylurea, thiazolidinedione, and metformin, were associated with the presence of vertebral fractures in 494 men and 344 postmenopausal women with type 2 diabetes. We analyzed the relationships between each treatment versus bone turnover markers, bone mineral density (BMD), and the presence of prevalent vertebral fractures. Multiple logistic regression analysis adjusted for age, duration of diabetes, body mass index, serum creatinine, serum C-peptide, and HbA_1c showed that, in postmenopausal women, treatments with insulin administration or thiazolidinedione were significantly and positively associated with the presence of vertebral fractures [odds ratio (OR) = 2.27, P = 0.012 and OR = 3.38, P = 0.038, respectively], whereas treatment with sulfonylurea was significantly and inversely associated with vertebral fractures (OR = 0.48, P = 0.018). These relationships were still significant after additional adjustment for lumbar BMD. In contrast, no significant relationships between treatments with any agent and the presence of vertebral fractures were found in men. These findings suggest that postmenopausal women treated with insulin or thiazolidinedione have a high risk of vertebral fractures independent of age, body stature, blood glucose level, insulin secretion, or BMD whereas treatment with sulfonylurea is associated with a decreased risk.     

Bone metabolism in anorexia nervosa: molecular pathways and current treatment modalities

Eating disorders are associated with a multitude of metabolic abnormalities which are known to adversely affect bone metabolism and structure. We aimed to comprehensively review the literature on the effects of eating disorders, particularly anorexia nervosa (AN), on bone metabolism, bone mineral density (BMD), and fracture incidence. Furthermore, we aimed to highlight the risk factors and potential management strategies for patients with eating disorders and low BMD. We searched the MEDLINE/OVID (1950–July 2011) and EMBASE (1980–July 2011) databases, focussing on in vitro and in vivo studies of the effects of eating disorders on bone metabolism, bone mineral density, and fracture incidence. Low levels of estrogen, testosterone, dehydroepiandrosterone, insulin-like growth factor-1 (IGF-1), and leptin, and high levels of cortisol, ghrelin, and peptide YY (PYY) are thought to contribute to the ‘uncoupling’ of bone turnover in patients with active AN, leading to increased bone resorption in comparison to bone formation. Over time, this results in a high prevalence and profound degree of site-specific BMD loss in women with AN, thereby increasing fracture risk. Weight recovery and increasing BMI positively correlate with levels of IGF-1 and leptin, normalisation in the levels of cortisol, as well as markers of bone formation and resorption in both adolescent and adult patients with AN. The only treatments which have shown promise in reversing the BMD loss associated with AN include: physiologic dose transdermal and oral estrogen, recombinant human IGF-1 alone or in combination with the oral contraceptive pill, and bisphosphonate therapy.     

罗格列酮治疗多囊卵巢综合征对改善内分泌、代谢及排卵功能的疗效

目的　探讨罗格列酮 (Rosiglitazone)对多囊卵巢综合征 (PCOS)合并胰岛素抵抗患者内分泌、代谢及排卵功能的影响。　方法　 2 5例PCOS合并胰岛素抵抗患者于自然月经或撤退性出血第 5天服用罗格列酮 12周 ,观察治疗前后血清生殖激素、胰岛素、血糖、血脂水平及排卵功能的变化。　结果　治疗后 ,患者各时相胰岛素 (INS)水平显著下降 (P <0 .0 1)。高密度脂蛋白胆固醇 (HDL C)显著升高 (P <0 .0 1) ,低密度脂蛋白胆固醇 (LDL C)显著降低 (P <0 .0 5 )。患者血清黄体生成素(LH)、黄体生成素 /促卵泡生成素比值 (LH/FSH)、睾酮 (T)和雄烯二酮 (A)水平均显著下降 (P <0 .0 1) ;性激素结合蛋白 (SHBG)水平显著升高 (P <0 .0 1) ;治疗后克罗米酚促排卵成功率为 72 % ,明显高于治疗前 2 0 % (P <0 .0 1)。　结论　罗格列酮通过改善胰岛素抵抗 ,降低胰岛素水平 ,使PCOS患者异常的血激素、血脂及排卵功能得到明显改善。     

Genetics of the polycystic ovarian syndrome and therapeutic perspectives

PCOS is the most frequent endocrine disorder of premenopausal women. The common clinical signs of PCOS are hirsutism, menstrual irregularities with chronic anovulation and a trend toward overweight or obesity. Diagnosis is based upon high plasma levels of androgens and the ultrasound image of polycystic ovaries. The high prevalence of PCOS at first degree female relatives suggest an important genetic component of this syndrome. Linking studies in sisters presenting phenotypical traits of PCOS and in their parents allowed the investigation of certain candidate genes presumed to be involved in the physiopathology of PCOS. The genes encoding enzymes involved in androgen synthesis, protein transducers of insulin signals and the paracrine regulating factors of gonadotrophins and ovarian function have been analysed. To date, no determinant gene mutation was reported. However, several loci were detected, especially a locus within the insulin receptor. Mutations or gene polymorphisms and their function remain to be identified. These research attempts should explain the physiopathology of PCOS and open new therapeutic perspectives. The usage of medication increasing the sensitivity to insulin action is an example of applying these particular aspects.     

Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome

Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). In patients with type 2 diabetes, insulin resistance in skeletal muscle is associated with abnormalities in insulin signaling, fatty acid metabolism, and mitochondrial oxidative phosphorylation (OXPHOS). In PCOS patients, the molecular mechanisms of insulin resistance are, however, less well characterized. To identify biological pathways of importance for the pathogenesis of insulin resistance in PCOS, we compared gene expression in skeletal muscle of metabolically characterized PCOS patients (n = 16) and healthy control subjects (n = 13) using two different approaches for global pathway analysis: gene set enrichment analysis (GSEA 1.0) and gene map annotator and pathway profiler (GenMAPP 2.0). We demonstrate that impaired insulin-stimulated total, oxidative and nonoxidative glucose disposal in PCOS patients are associated with a consistent downregulation of OXPHOS gene expression using GSEA and GenMAPP analysis. Quantitative real-time PCR analysis validated these findings and showed that reduced levels of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha) could play a role in the downregulation of OXPHOS genes in PCOS. In these women with PCOS, the decrease in OXPHOS gene expression in skeletal muscle cannot be ascribed to obesity and diabetes. This supports the hypothesis of an early association between insulin resistance and impaired mitochondrial oxidative metabolism, which is, in part, mediated by reduced PGC-1alpha levels. These abnormalities may contribute to the increased risk of type 2 diabetes observed in women with PCOS.     

血清催产素浓度与绝经后女性骨密度相关性研究

目的探讨催产素与绝经后妇女骨代谢指标以及腰椎和髋部骨密度之间相关性。方法检测185例骨密度正常和132例患骨质疏松症女性的血清催产素、瘦素、雌激素和骨代谢指标浓度。腰椎和股骨颈的BMD通过双能X线吸收法测量。结果患骨质疏松症女性的血清催产素浓度低于骨密度正常的女性(P0.05)。骨质疏松症组中血清催产素浓度与年龄、绝经年限、体质量指数(body mass index,BMI)和血清PINP、BLAP和CTX浓度呈负相关;与瘦素和雌激素具有明显正相关性;在正常骨密度组中,血清催产素浓度和各种指标未发现明显的相关性。调整年龄和BMI后,腰椎和股骨颈骨密度仍然与绝经年限以及血清PINP、BLAP和CTX浓度呈负相关,与雌激素、瘦素和催产素浓度呈正相关。对年龄和BMI进行调整后,进行多元回归分析显示绝经年限、血清催产素、PINP和CTX是腰椎和股骨颈骨密度的显著预测因子。结论绝经后女性患者较高的血清催产素水平与较高的腰椎和股骨颈骨密度有关。     

唑来膦酸对乳腺癌治疗相关骨流失保护作用的研究进展

乳腺癌是女性最为常见的恶性肿瘤之一。化疗及内分泌治疗显著改善了早期乳腺癌患者的预后,然而肿瘤治疗带来的骨流失问题值得关注。内分泌治疗通过降低雌激素水平发挥治疗作用;化疗可导致绝经前女性卵巢功能衰竭,同样使体内雌激素水平显著下降。而低雌激素水平减少骨生成、增加骨吸收,使骨质流失和骨质疏松症的发病率增加、骨折风险升高。第三代双膦酸盐唑来膦酸是一种特异性地作用于骨的二磷酸化合物,已被证实通过抑制破骨细胞活性和诱导破骨细胞凋亡来抑制骨吸收。本文将对唑来膦酸防治女性乳腺癌患者相关骨流失的临床研究进展进行综述。     

Bone disorders associated with diabetes mellitus and its treatments

Both type 1 and type 2 diabetes mellitus are associated with bone disorders, albeit via different mechanisms. Early studies in patients with type 1 diabetes suggested a 10-fold increase in the hip fracture risk compared to non-diabetic controls. Meta-analyses published more recently indicate a somewhat smaller risk increase, with odds ratios of 6 to 7. Diminished bone mineral density is among the contributors to the increased fracture risk. Both types of diabetes are associated with decreased bone strength related to low bone turnover. The multiple and interconnected pathophysiological mechanisms underlying the bone disorders seen in type 1 diabetes include insulin deficiency, accumulation of advanced glycation end products, bone microarchitecture alterations, changes in bone marrow fat content, low-grade inflammation, and osteocyte dysfunction. The bone alterations are less severe in type 2 diabetes. Odds ratios for hip fractures have ranged across studies from 1.2 to 1.7, and bone mineral density is higher than in non-diabetic controls. The odds ratio is about 1.2 for all bone fragility fractures combined. The pathophysiological mechanisms are complex, particularly as obesity is very common in patients with type 2 diabetes and is itself associated with an increased risk of fractures at specific sites (humerus, tibia, and ankle). The main mechanisms underlying the bone fragility are an increase in the risk of falls, sarcopenia, disorders of carbohydrate metabolism, vitamin D deficiency, and alterations in cortical bone microarchitecture and bone matrix. The medications used to treat both types of diabetes do not seem to play a major role. Nevertheless, thiazolidinediones and, to a lesser extent, sodium-glucose cotransporter inhibitors may have adverse effects on bone, whereas metformin may have beneficial effects. For the most part, the standard management of bone fragility applies to patients with diabetes. However, emphasis should be placed on preventing falls, which are particularly common in this population. Finally, there is some evidence to suggest that anti-fracture treatments are similarly effective in patients with and without diabetes.     

Insulin Resistance and Bone Strength: Findings From the Study of Midlife in the United States

Although several studies have noted increased fracture risk in individuals with type 2 diabetes mellitus (T2DM), the pathophysiologic mechanisms underlying this association are not known. We hypothesize that insulin resistance (the key pathology in T2DM) negatively influences bone remodeling and leads to reduced bone strength. Data for this study came from 717 participants in the Biomarker Project of the Midlife in the United States Study (MIDUS II). The homeostasis model assessment of insulin resistance (HOMA‐IR) was calculated from fasting morning blood glucose and insulin levels. Projected 2D (areal) bone mineral density (BMD) was measured in the lumbar spine and left hip using dual‐energy X‐ray absorptiometry (DXA). Femoral neck axis length and width were measured from the hip DXA scans, and combined with BMD and body weight and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. We used multiple linear regressions to examine the relationship between HOMA‐IR and bone strength, adjusted for age, gender, race/ethnicity, menopausal transition stage (in women), and study site. Greater HOMA‐IR was associated with lower values of all three composite indices of femoral neck strength relative to load, but was not associated with BMD in the femoral neck. Every doubling of HOMA‐IR was associated with a 0.34 to 0.40 SD decrement in the strength indices (p < 0.001). On their own, higher levels of fasting insulin (but not of glucose) were independently associated with lower bone strength. Our study confirms that greater insulin resistance is related to lower femoral neck strength relative to load. Further, we note that hyperinsulinemia, rather than hyperglycemia, underlies this relationship. Although cross‐sectional associations do not prove causality, our findings do suggest that insulin resistance and in particular, hyperinsulinemia, may negatively affect bone strength relative to load. © 2014 American Society for Bone and Mineral Research.     

胰岛素抵抗与多囊卵巢综合征

多囊卵巢综合征(PCOS)是妇科常见的内分泌疾病,其发病机理可能涉及下丘脑、垂体、肾上腺、胰岛素抵抗、肥胖等多种因素。国外对胰岛素抵抗的研究较多,现就胰岛素抵抗与PCOS进行综述。     

多囊卵巢综合征伴胰岛素抵抗患者肠道菌群分析

目的 基于16SrRNA高通量测序技术对多囊卵巢综合征(PCOS)伴胰岛素抵抗(IR)患者肠道菌群的结构特征进行分析.方法 选择2019年7月至2020年6月期间就诊于青岛大学附属烟台毓璜顶医院的新发PCOS女性,根据稳态模型胰岛素抵抗指数(HOMA-IR)分为IR-PCOS组(n=11)和NIR-PCOS组(n=10...     

Women With Polycystic Ovary Syndrome Have Comparable Hip Bone Geometry to Age-Matched Control Women

Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting women of reproductive age manifesting with polycystic ovaries, menstrual irregularities, hyperandrogenism, hirsutism, and insulin resistance. The oligomenorrhea and amenorrhea characteristic to PCOS are associated with low bone mineral density (BMD); conversely, the hyperandrogenism and hyperinsulinemia may elicit a protective effect on BMD. As bone geometric properties provide additional information about bone strength, the objective of this study was to compare measures of hip geometry in women with PCOS to a healthy female population. Using dual-energy X-ray absorptiometry, BMD and measures of hip geometry were determined in women with PCOS (n?=?60) and healthy controls (n?=?60) aged 18–35 years. Clinical biochemical measures were also determined in women with PCOS. Measures of hip geometry, including cross-sectional area, cross-sectional moment of inertia, subperiosteal width (SPW), and section modulus, were similar between groups following correction for body mass index (BMI) (all p?>?0.05) with intertrochanter SPW significantly lower in women with PCOS (p?<?0.05). BMI-corrected whole body BMD as well as the lumbar spine and regions of proximal femur were also comparable between groups. In women with PCOS, BMI-corrected correlations were found between insulin and femoral shaft SPW (r?=?0.322, p?<?0.05), glucose and femoral neck (r?=?0.301, p?<?0.05), and trochanter BMD (0.348, p?<?0.05), as well as between testosterone and femoral neck BMD (0.376, p?<?0.05) and narrow neck cross-sectional area (0.306, p?<?0.05). This study demonstrates that women with PCOS may have compromised intertrochanter SPW while oligomenorrhea appears to have no detrimental effect on bone density or geometry in women with PCOS.