Metabolic heterogeneity of follicular amino acids in polycystic ovary syndrome is affected by obesity and related to pregnancy outcome

BMC Pregnancy and Childbirth

Jie Qiao¹  Ping Liu²  Na-na Liu¹  Li Li¹  Li-ying Yan²  Yang Yu²  Rong Li¹  Yue Zhao¹  Chun-mei Zhang¹ 

[1] Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China;Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China

关键词: Follicular fluid;    Obesity;    Amino acid;    PCOS;   

Others  :  1131800
DOI  :  10.1186/1471-2393-14-11

 received in 2013-10-08, accepted in 2014-01-06,  发布年份 2014

【 摘 要 】

Background

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder frequently accompanied by obesity and by insulin resistance, and patients with this syndrome suffer from infertility and poor pregnancy outcome. Disturbances in plasma amino acid (AA) metabolism have been implicated in women with PCOS. However, direct evidence on follicular AA metabolic profiles in PCOS patients and their relationship with pregnancy outcome is sparse.

Methods

We conducted a prospective study in 63 PCOS patients and 48 controls in the Division of Reproductive Center, Peking University Third Hospital. Follicular AA levels were measured by the liquid chromatography-tandem mass spectrometric method, and the results were analyzed based on different grouping criteria.

Results

The levels of aromatic amino acid (AAA) increased in PCOS patients independent of obesity (P < 0.05), whereas the levels of branched-chain amino acid (BCAA), glutamic acid, phenylalanine, alanine, and arginine increased with body mass index irrespective of the PCOS status (all P < 0.05). In addition, compared with non insulin resistant-PCOS patients and controls, insulin resistant-PCOS group had higher levels of leucine, valine and glutamic acid (all P < 0.05). In PCOS group, aspartic acid and serine levels were elevated in pregnant patients compared with the non-pregnant subjects (both P < 0.05). Moreover, the levels of BCAA and valine were higher in the non-pregnant group than in the pregnant group (both P < 0.05). The pregnancy rate (45.00%) of subjects with elevated BCAA level was significantly lower than that (66.67%) in control subjects (P = 0.036) at a BCAA cutoff value of 239.10 μM, while the abortion rate was much higher (33.33% versus 2.78%, P = 0.004).

Conclusions

Both PCOS and obesity were accompanied by follicular AA metabolic disturbances, with obesity exerting a more pronounced effect on AA metabolic profiles. The disruptions in specific AAs in the follicular fluid might account for the inferior pregnancy outcome in obese patients and increased risk of abortion in PCOS patients.

【 授权许可】

   
2014 Zhang et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R: Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011, 7(4):219-231.
• [2]de Groot PC, Dekkers OM, Romijn JA, Dieben SW, Helmerhorst FM: PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum Reprod Update 2011, 17(4):495-500.
• [3]Franks S: Polycystic ovary syndrome. N Engl J Med 1995, 333(13):853-861.
• [4]Sahu B, Ozturk O, Ranierri M, Serhal P: Comparison of oocyte quality and intracytoplasmic sperm injection outcome in women with isolated polycystic ovaries or polycystic ovarian syndrome. Arch Gynecol Obstet 2008, 277(3):239-244.
• [5]Zhao Y, Fu L, Li R, Wang LN, Yang Y, Liu NN, Zhang CM, Wang Y, Liu P, Tu BB, et al.: Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis. BMC Med 2012, 10:153. BioMed Central Full Text
• [6]Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, et al.: Metabolite profiles and the risk of developing diabetes. Nat Med 2011, 17(4):448-453.
• [7]Garcia-Macedo R, Sanchez-Munoz F, Almanza-Perez JC, Duran-Reyes G, Alarcon-Aguilar F, Cruz M: Glycine increases mRNA adiponectin and diminishes pro-inflammatory adipokines expression in 3 T3-L1 cells. Eur J Pharmacol 2008, 587(1–3):317-321.
• [8]Gonzalez IM, Martin PM, Burdsal C, Sloan JL, Mager S, Harris T, Sutherland AE: Leucine and arginine regulate trophoblast motility through mTOR-dependent and independent pathways in the preimplantation mouse embryo. Dev Biol 2012, 361(2):286-300.
• [9]Escobar-Morreale HF, Samino S, Insenser M, Vinaixa M, Luque-Ramirez M, Lasuncion MA, Correig X: Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS. Clin Chem 2012, 58(6):999-1009.
• [10]Sun L, Hu W, Liu Q, Hao Q, Sun B, Zhang Q, Mao S, Qiao J, Yan X: Metabonomics reveals plasma metabolic changes and inflammatory marker in polycystic ovary syndrome patients. J Proteome Res 2012, 11(5):2937-2946.
• [11]Arya BK, Haq AU, Chaudhury K: Oocyte quality reflected by follicular fluid analysis in poly cystic ovary syndrome (PCOS): a hypothesis based on intermediates of energy metabolism. Med Hypotheses 2012, 78(4):475-478.
• [12]Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004, 81(1):19-25.
• [13]Hemmings KE, Maruthini D, Vyjayanthi S, Hogg JE, Balen AH, Campbell BK, Leese HJ, Picton HM: Amino acid turnover by human oocytes is influenced by gamete developmental competence, patient characteristics and gonadotrophin treatment. Hum Reprod 2013, 28(4):1031-1044.
• [14]Xing XY, Yang WY, Yang ZJ: The diagnostic significance of homeostasis model assessment of insulin resistance in metabolic syndrome among subjects with different glucose tolerance. Chin J Diabetes 2004, 12(3):182-186.
• [15]Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults Am J Clin Nutr 1998, 68(4):899-917.
• [16]Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang JX: Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 2004, 10(3):267-280.
• [17]Pantasri T, Norman RJ: The effects of being overweight and obese on female reproduction: a review. Gynecol Endocrinol 2013. Epub ahead of print
• [18]Newgard CB: Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 2012, 15(5):606-614.
• [19]Tremblay F, Marette A: Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 2001, 276(41):38052-38060.
• [20]Xiao F, Huang Z, Li H, Yu J, Wang C, Chen S, Meng Q, Cheng Y, Gao X, Li J, et al.: Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes 2011, 60(3):746-756.
• [21]Qiao J, Feng HL: Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update 2011, 17(1):17-33.
• [22]Rice S, Christoforidis N, Gadd C, Nikolaou D, Seyani L, Donaldson A, Margara R, Hardy K, Franks S: Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod 2005, 20(2):373-381.
• [23]Purcell SH, Chi MM, Lanzendorf S, Moley KH: Insulin-stimulated glucose uptake occurs in specialized cells within the cumulus oocyte complex. Endocrinology 2012, 153(5):2444-2454.
• [24]D’Aniello G, Grieco N, Di Filippo MA, Cappiello F, Topo E, D’Aniello E, Ronsini S: Reproductive implication of D-aspartic acid in human pre-ovulatory follicular fluid. Hum Reprod 2007, 22(12):3178-3183.
• [25]Topo E, Soricelli A, D’Aniello A, Ronsini S, D’Aniello G: The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. Reprod Biol Endocrinol 2009, 7:120. BioMed Central Full Text
• [26]Macchia G, Topo E, Mangano N, D’Aniello E, Boni R: DL-Aspartic acid administration improves semen quality in rabbit bucks. Anim Reprod Sci 2010, 118(2–4):337-343.
• [27]Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N: Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001, 86(6):2453-2455.
• [28]Amato G, Conte M, Mazziotti G, Lalli E, Vitolo G, Tucker AT, Bellastella A, Carella C, Izzo A: Serum and follicular fluid cytokines in polycystic ovary syndrome during stimulated cycles. Obstet Gynecol 2003, 101(6):1177-1182.
• [29]Spittler A, Reissner CM, Oehler R, Gornikiewicz A, Gruenberger T, Manhart N, Brodowicz T, Mittlboeck M, Boltz-Nitulescu G, Roth E: Immunomodulatory effects of glycine on LPS-treated monocytes: reduced TNF-alpha production and accelerated IL-10 expression. FASEB J 1999, 13(3):563-571.
• [30]Alarcon-Aguilar FJ, Almanza-Perez J, Blancas G, Angeles S, Garcia-Macedo R, Roman R, Cruz M: Glycine regulates the production of pro-inflammatory cytokines in lean and monosodium glutamate-obese mice. Eur J Pharmacol 2008, 599(1–3):152-158.
• [31]Montgomery Rice V, Limback SD, Roby KF, Terranova PF: Differential responses of granulosa cells from small and large follicles to follicle stimulating hormone (FSH) during the menstrual cycle and acyclicity: effects of tumour necrosis factor-alpha. Hum Reprod 1998, 13(5):1285-1291.
• [32]Vural P, Degirmencioglu S, Saral NY, Akgul C: Tumor necrosis factor alpha (-308), interleukin-6 (-174) and interleukin-10 (-1082) gene polymorphisms in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2010, 150(1):61-65.
• [33]Cruz M, Maldonado-Bernal C, Mondragon-Gonzalez R, Sanchez-Barrera R, Wacher NH, Carvajal-Sandoval G, Kumate J: Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes. J Endocrinol Invest 2008, 31(8):694-699.
• [34]Sekhar RV, McKay SV, Patel SG, Guthikonda AP, Reddy VT, Balasubramanyam A, Jahoor F: Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care 2011, 34(1):162-167.
• [35]Kikuchi G, Hiraga K: The mitochondrial glycine cleavage system. Unique features of the glycine decarboxylation. Mol Cell Biochem 1982, 45(3):137-149.
• [36]Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC: A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006, 12(1):13-21.