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Vitamin D Increases Serum Levels of the Soluble Receptor for Advanced Glycation End Products in Women With PCOS Mohamad Irani, Howard Minkoff, David B. Seifer, and Zaher Merhi Department of Obstetrics and Gynecology (M.I., H.M., D.B.S.), Maimonides Medical Center, Brooklyn, New York 11219; and Department of Obstetrics, Gynecology and Reproductive Sciences (Z.M.), Division of Reproductive Endocrinology and Infertility, University of Vermont College of Medicine, Burlington, Vermont 05401
Context: Elevation of serum proinflammatory advanced glycation end products (AGEs) is involved in the pathogenesis of polycystic ovary syndrome (PCOS). The soluble receptor for AGEs (sRAGE) acts as a decoy by binding circulating AGEs. Vitamin D supplementation attenuates the deposition of AGEs in the vascular system of diabetic animals and improves some metabolic aspects of vitamin D-deficient women with PCOS. Additionally, serum anti-Mullerian hormone (AMH) is elevated in women with PCOS, reflecting abnormal ovarian folliculogenesis. Objective: The objective of the study was to evaluate the effect of 1,25 dihydroxyvitamin D3 (vit D3) supplementation on serum sRAGE and AMH in vitamin D-deficient women with PCOS. Design, Settings, Participants, and Intervention: Sixty-seven women with (n ⫽ 22) or without (control; n ⫽ 45) PCOS who were diagnosed with vitamin D deficiency were enrolled. Fifty-one women were replaced with oral vit D3 for 8 weeks (16 with PCOS and 35 controls) and 16 women were not treated (six with PCOS and 10 controls). Serum 25-hydroxyvitamin D (25 OH-D), sRAGE, and AMH concentrations were measured at baseline and after vit D3 supplementation in the treated group and 8 weeks apart in the nontreated group. Main Outcome Measure(s): Changes in serum sRAGE and AMH concentrations after vit D3 replacement were measured. Results: In all participants, there was a negative correlation between body mass index and serum sRAGE levels (r ⫽ ⫺0.3, P ⫽ .01). In women with PCOS, but not in controls, vit D3 increased serum sRAGE (P ⫽ .03) and decreased serum AMH levels (P ⬍ .001). The increase in serum sRAGE positively correlated with the increase in serum 25 OH-D after supplementation in women with PCOS (r ⫽ 0.6, P ⫽ .01). Conclusion: In women with PCOS, vit D3 might exert a protective effect against the inflammatory action of AGEs by increasing circulating sRAGE. The normalization in serum AMH induced by vit D3 replacement suggests an improvement in folliculogenesis. (J Clin Endocrinol Metab 99: E886 –E890, 2014)
olycystic ovary syndrome (PCOS) affects up to 15% of reproductive-aged women (1). Serum anti-Mullerian hormone (AMH), produced in the ovaries by small follicles, is usually elevated in women with PCOS and corre-
P
lates with the severity of this syndrome (2, 3). AMH plays an important role in inhibiting follicular development by decreasing the sensitivity of the follicles to FSH and by inhibiting granulosa cell aromatase (4, 5). Thus, elevated
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received December 11, 2013. Accepted February 20, 2014. First Published Online February 27, 2014
Abbreviations: AGE, advanced glycation end product; AMH, anti-Mullerian hormone; BMI, body mass index; IR, insulin resistance; 25 OH-D, 25-hydroxyvitamin D; PCOS, polycystic ovary syndrome; RAGE, receptor for AGE; sRAGE, soluble receptor for AGE; vit D3, 1,25 dihydroxyvitamin D3.
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doi: 10.1210/jc.2013-4374
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AMH in PCOS increases intrafollicular androgen level and the selection of a dominant follicle, subsequently reflecting abnormal ovarian folliculogenesis. Advanced glycation end products (AGEs) are the products of nonenzymatic modification of proteins, lipids, and nucleic acids by glucose (6). AGEs are highly reactive proinflammatory molecules and are formed slowly under physiological conditions (6). Diabetes, insulin resistance (IR), and aging accelerate their generation of AGEs that ultimately deposit throughout the body, including the ovaries (6). Serum AGEs have been shown to be elevated in women with PCOS and have been implicated in the pathogenesis of PCOS (7, 8). In women with PCOS, with or without IR, AGEs accumulate in ovarian granulosa and theca layers (9). Thus, the accumulation of AGEs might contribute to worsening of ovarian function in PCOS. AGEs act by binding to the extracellular matrix (receptor independent) or by binding to a cellular receptor called receptor for AGE (RAGE; receptor dependent) (6). The AGE-RAGE interaction activates signaling pathways that in turn activate nuclear factor-B, promoting the development of a proinflammatory state, cellular toxicity, and damage (10). An extracellular form of RAGE circulates in the blood and follicular fluid and is called soluble receptor for AGEs (sRAGE) (10). In contrast to RAGE, sRAGE acts as decoy because it binds circulating AGEs and prevents the adverse intracellular events of the AGE-RAGE binding (10). We have recently shown that elevation in follicular fluid sRAGE correlates with elevated measures of ovarian reserve (as reflected by AMH), hence reflecting a better reproductive environment (11). Vitamin D deficiency is common among reproductiveaged women, especially those with PCOS (12). Vitamin D deficiency contributes to several aspects of PCOS, such as IR, obesity, and metabolic syndrome (13, 14). 1,25-Dihydroxy-vitamin D3 (vit D3) supplementation to vitamin D-deficient women with PCOS improves some clinical and laboratory parameters of PCOS, such as androgen levels and the IR index (15, 16). Interestingly, vitamin D supplementation (such as cholecalciferol and calcitriol) attenuates the deposition of AGEs in the vascular system of diabetic rats (17) and increases serum sRAGE in hemodialysis patients (18). This suggests that vit D3 treatment could play an antiinflammatory role by altering the AGERAGE system. Little is known about the effect of vit D3 on circulating sRAGE and AMH in women with PCOS. Therefore, we hypothesize that vit D3 attenuates the effect of the AGE-RAGE system in vitamin D-deficient with PCOS by increasing the antiinflammatory serum sRAGE levels. We also hypothesize that vit D3 improves folliculogenesis in these women, as reflected by lowering the
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abnormally elevated serum AMH observed in these patients.
Materials and Methods Subjects and oral vit D3 supplementation Two hundred reproductive-aged women, with or without PCOS, presenting to women’s primary care center at the Maimonides Medical Center for an annual regular check-up between July 2012 and September 2013 were screened for vitamin D deficiency [defined as serum 25-hydroxyvitamin D (25 OH-D) levels ⬍ 20 ng/mL]. One hundred fifty-five women were found to have vitamin D deficiency. To increase participation, we used Rotterdam criteria (19) for the diagnosis of PCOS, but we used serum AMH of greater than 4 ng/mL instead of the sonographic criterion (ie, polycystic ovary looking ovaries). Of note, serum AMH level reflects typical sonographic features found in women with PCOS, and it can reliably substitute sonogram for the diagnosis of PCOS (2, 20 –23). Of the 155 vitamin D-deficient participants, 67 completed the study: 22 women were diagnosed with PCOS and 45 women did not have PCOS (controls). Sixteen of the 22 women with PCOS and 35 of the 45 controls were treated with 50 000 IU of vit D3 orally once weekly for 8 weeks (Supplemental Figure 1). The dose and timing of vit D3 replacement regimen were extracted from The Endocrine Society guidelines (24). To ensure compliance with vit D3 intake, each participant was called weekly and reminded to take the pill. Exclusion criteria included women who were: 1) pregnant, postpartum, or breast-feeding, 2) taking any kind of exogenous hormones, 3) receiving any form of oral vit D3 replacement, and 4) had poor ovarian reserve (defined as serum AMH ⬍ 1 ng/mL). All participants were consented, and the study was approved by the Institutional Review Board of the Maimonides Medical Center.
Serum 25 OH-D, AMH, and sRAGE measurements Measurement of serum sRAGE and AMH concentrations were obtained at baseline and after vit D3 supplementation in the treated group and 8 weeks after baseline in the nontreated group. 25 OH-D levels were repeated for all participants at the end of the 8-week period and were measured using the ADVIA Centaur vitamin D assay (Siemens Healthcare Diagnostics). AMH and sRAGE were measured using commercially available ELISA kits (AMH Gen II ELISA; Beckman Coulter and R&D Systems Inc, respectively). The inter- and intraassay coefficients of variation for all assays were less than 10%.
Statistics Data were tested for normality. All values were expressed as mean ⫾ SEM. A paired t test, Wilcoxon signed-rank test, oneway ANOVA, 2 test, linear regression, and Pearson correlation were used as appropriate. All statistical procedures were run on SigmaPlot 12.0.
Results Correlations with age and body mass index (BMI) The demographics and clinical profiles of the 67 participants who completed the study are presented in Sup-
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J Clin Endocrinol Metab, May 2014, 99(5):E886 –E890
plemental Table 1. At baseline, there was a negative correlation between age and serum AMH levels among all participants (r ⫽ ⫺0.34, P ⫽ .002). There was also a significant negative correlation between BMI and serum sRAGE levels (r ⫽ ⫺0.3, P ⫽ .01) (Figure 1). Among women who received oral vit D3, 25 OH-D levels were compared between baseline and 8 weeks after vit D3 replacement. After replacement, there was a significant increase in serum 25 OH-D in women without (from 13.31 ⫾ 0.37 to 42.32 ⫾ 3.67; P ⬍ .0001) and with PCOS (from 13.73 ⫾ 0.96 to 52.60 ⫾ 8.57; P ⬍ .0001). There was a progressively smaller elevation in serum 25 OH-D as BMI increased (r ⫽ ⫺0.46, P ⬍ .05). Changes in serum sRAGE and AMH levels after oral vit D3 replacement Compared with women without PCOS, women with PCOS did not differ in age (Supplemental Table 1) and had significantly higher serum AMH levels (5.3 ⫾ 0.6 vs 3.9 ⫾ 0.5 ng/mL; P ⬍ .001). After vit D3 replacement, AMH concentrations in women with PCOS dropped significantly (P ⫽ .003; Figure 2A). There was no significant change in AMH levels after vit D3 replacement among women without PCOS (P ⫽ .6) (Figure 2A). Contrary to what happened in AMH after vit D3 replacement, there was a significant increase in serum sRAGE levels in women with PCOS (P ⫽ .03) but not in women without PCOS (P ⫽ .5) (Figure 2B). Additionally, the increase in serum 25 OH-D after supplementation positively correlated with the increase in serum sRAGE levels in women with PCOS (r ⫽ 0.6, P ⫽ .01).
Discussion This study evaluated the effect of vit D3 supplementation on serum sRAGE and AMH levels in vitamin D-deficient women with or without PCOS. We found a negative cor-
Figure 1. Correlation between serum sRAGE and BMI at baseline. Serum sRAGE concentrations were measured by ELISA in all participants. There was a significant negative correlation between BMI and serum sRAGE levels.
Figure 2. Changes in serum AMH (A) and sRAGE (B) after oral vit D3 replacement. Serum sRAGE and AMH levels were measured by ELISA before and after vit D3 replacement in vitamin D-deficient women with or without PCOS. A, In women with PCOS (n ⫽ 16), AMH concentrations significantly dropped to normal levels. There was no significant change in AMH levels in women without PCOS (n ⫽ 35). B, There was a significant increase in serum sRAGE levels in women with PCOS (n ⫽ 16). Serum sRAGE levels did not significantly change in women without PCOS (n ⫽ 35). *, P ⬍ .05, baseline vs after vit D3 replacement in the PCOS group; **, P ⬍ .05, controls vs PCOS (at baseline).
relation between age and serum AMH levels. We also found that the increase in serum 25 OH-D following vit D3 replacement was negatively correlated with BMI and that baseline serum sRAGE levels were negatively correlated with BMI. Finally, among women with PCOS, vit D3 supplementation significantly increased serum sRAGE levels but decreased the abnormally elevated serum AMH levels; these changes were not observed in women without PCOS. There is an inverse relationship between adiposity and vitamin D deficiency (24). Consistent with other data (25, 26), our results indicated that obese women needed higher doses of oral vit D3 when compared with normal-weight women because the rise in serum 25 OH-D after vit D3 treatment was inversely correlated with BMI. A potential explanation for this relationship is the sequestration of the lipophilic vitamin D molecules by fat cells (26). In line with other data (27), we also found that serum sRAGE was
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inversely correlated with BMI. Interestingly, sRAGE significantly increases after diet-induced weight loss in obese women (28). Due to the beneficial role of sRAGE, low circulating sRAGE levels seen in obese women supports the fact that obesity is a state of elevated inflammatory processes. Additionally, studies have shown that AGEs are directly involved in adipogenesis (29) and production of inflammatory mediators in adipocytes, leading to complications related to obesity (30). Taken together, these findings suggested a potential role of the AGE-RAGE system in obesity-related comorbid conditions. Several studies have shown that vit D3 replacement improves some of the clinical and metabolic parameters in women with PCOS (15, 16). In our current study, normalization in AMH levels could, in part, represent a mechanism by which vit D3 improves ovulatory dysfunction in women with PCOS. Indeed, higher serum AMH levels in PCOS are correlated with a more severe phenotype of PCOS (3, 31).Thus, lowering serum AMH in PCOS might allow enhanced activity of FSH, thus promoting follicular development and ultimately ovulation. This might potentially improve the menstrual irregularities and infertility associated with PCOS. Because AMH also inhibits aromatase (5), lower serum AMH in PCOS might be associated with more physiological intrafollicular concentration of androgens, leading to healthier folliculogenesis. There is accumulating evidence suggesting that the AGE-RAGE system could be implicated in the pathophysiology of PCOS (8, 9) and systemic inflammation (32, 33). Moreover, activation of the AGE-RAGE system correlates with IR, a significant contributor to the pathophysiology of PCOS (34). At the cellular level, ovaries of women with PCOS have increased the expression of AGEs and RAGE proteins in theca and granulosa cell layers (9). Furthermore, AGEs have been shown to interfere with LH and insulin actions on granulosa cells (35, 36). These alterations could, in part, explain the AGEs-induced abnormal folliculogenesis in women with PCOS. In our study, the significant increase in serum sRAGE after vit D3 supplementation constitutes a potential mechanism by which vit D3 acts as antiinflammatory therapeutic agent for women with PCOS. The rise in serum sRAGE can inhibit the deleterious effect of circulating AGEs by subsequently improving follicular growth and decreasing insulin resistance at granulosa cell level. Our study has several limitations including the following: 1) a relatively high dropout rate, 2) no evaluation of other clinical and biochemical parameters of PCOS such as menstrual irregularity, anovulation, hirsutism, and IR index, 3) no adjustment for seasonal changes in serum 25 OH-D and AMH levels (37), and 4) although we did not measure any of the serum AGEs (more than 20 members),
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sRAGE binds most them and has been shown to be a good marker for the systemic effect of AGEs (8, 10). In conclusion, this study supports the beneficial effect of vit D3 supplementation in vitamin D-deficient women with PCOS on follicular development, as reflected by normalization of serum AMH levels. Interestingly, it provides a novel molecular explanation of its antiinflammatory effect by increasing serum sRAGE. Understanding the role of the AGE-RAGE system in the ovary may offer opportunities for innovative therapeutic options for the treatment of ovulatory dysfunction associated with PCOS.
Acknowledgments Address all correspondence and requests for reprints to: Zaher Merhi, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Reproductive and Endocrinology and Infertility, University of Vermont College of Medicine, 111 Colchester Avenue, Burlington, VT 05401. E-mail: [email protected]. This work was supported by grants from the American Society for Reproductive Medicine (to Z.M.), Ferring Pharmaceuticals (to Z.M.) and Maimonides Research and Development Foundation (to M.I. and D.B.S.). Disclosure Summary: D.B.S. received royalties from a licensing agreement between Rutgers Medical School/Massachusetts General Hospital and Beckman Coulter for the use of AMH in determining ovarian reserve.
References 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. Sahmay S, Atakul N, Aydogan B, Aydin Y, Imamoglu M, Seyisoglu H Elevated serum levels of anti-Mullerian hormone can be introduced as a new diagnostic marker for polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2013;92(12):1369 –1374. 3. Piouka A, Farmakiotis D, Katsikis I, Macut D, Gerou S, Panidis D. Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab. 2009;296(2): E238 –E243. 4. Visser J. [Role of anti-Mullerian hormone in follicle recruitment and maturation]. J Gynecol Obstet Biol Reprod (Paris). 2006;35(5 Pt 2): 2S30 –2S34. 5. Chang HM, Klausen C, Leung PC. Antimullerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells. Fertil Steril. 2013;100(2):585–592. 6. Piperi C, Adamopoulos C, Dalagiorgou G, Diamanti-Kandarakis E, Papavassiliou AG. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. J Clin Endocrinol Metab. 2012;97(7):2231–2242. 7. Diamanti-Kandarakis E, Katsikis I, Piperi C, et al. Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf). 2008;69(4):634 – 641.
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8. Merhi Z. Advanced glycation end products and their relevance in female reproduction. Hum Reprod. 2014;29(1):135–145. 9. Diamanti-Kandarakis E, Piperi C, Patsouris E, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol. 2007;127(6):581–589. 10. Kalea AZ, Schmidt AM, Hudson BI. RAGE: a novel biological and genetic marker for vascular disease. Clin Sci (Lond). 2009;116(8): 621– 637. 11. Merhi Z, Irani M, Doswell AD, Ambroggio J. Follicular fluid soluble receptor for advanced glycation end-products (sRAGE): a potential indicator of ovarian reserve. J Clin Endocrinol Metab. 2014;99(2): E226 –E233. 12. Mahmoudi T, Gourabi H, Ashrafi M, Yazdi RS, Ezabadi Z. Calciotropic hormones, insulin resistance, and the polycystic ovary syndrome. Fertil Steril. 2010;93(4):1208 –1214. 13. Hahn S, Haselhorst U, Tan S, et al. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006;114(10):577–583. 14. Yildizhan R, Kurdoglu M, Adali E, et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet. 2009;280(4):559 –563. 15. Pal L, Berry A, Coraluzzi L, et al. Therapeutic implications of vitamin D and calcium in overweight women with polycystic ovary syndrome. Gynecol Endocrinol. 2012;28(12):965–968. 16. Selimoglu H, Duran C, Kiyici S, et al. The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010; 33(4):234 –238. 17. Salum E, Kals J, Kampus P, et al. Vitamin D reduces deposition of advanced glycation end-products in the aortic wall and systemic oxidative stress in diabetic rats. Diabetes Res Clin Pract. 2013; 100(2):243–249. 18. Sung JY, Chung W, Kim AJ, et al. Calcitriol treatment increases serum levels of the soluble receptor of advanced glycation end products in hemodialysis patients with secondary hyperparathyroidism. Tohoku J Exp Med. 2013;230(1):59 – 66. 19. 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. 20. Iliodromiti S, Kelsey TW, Anderson RA, Nelson SM. Can anti-Mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data. J Clin Endocrinol Metab. 2013;98(8):3332–3340. 21. Casadei L, Madrigale A, Puca F, et al. The role of serum anti-Mullerian hormone (AMH) in the hormonal diagnosis of polycystic ovary syndrome. Gynecol Endocrinol. 2013;29:545–550. 22. Pawelczak M, Kenigsberg L, Milla S, Liu YH, Shah B. Elevated serum anti-Mullerian hormone in adolescents with polycystic ovary
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syndrome: relationship to ultrasound features. J Pediatr Endocrinol Metab. 2012;25:983–989. 23. Eilertsen TB, Vanky E, Carlsen SM. Anti-Mullerian hormone in the diagnosis of polycystic ovary syndrome: can morphologic description be replaced? Human Reprod. 2012;27:2494 –2502. 24. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96:1911–1930. 25. Zhou JC, Zhu YM, Guo P, et al. Serum 25(OH)D and lipid levels in Chinese obese and normal weight males before and after oral vitamin D supplementation. Biomed Environ Sci. 2013;26:801– 807. 26. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72: 690 – 693. 27. Koyama H, Shoji T, Yokoyama H, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25:2587–2593. 28. Vazzana N, Guagnano MT, Cuccurullo C, et al. Endogenous secretory RAGE in obese women: association with platelet activation and oxidative stress. J Clin Endocrinol Metab. 2012;97:E1726 –E1730. 29. Jia X, Chang T, Wilson TW, Wu L. Methylglyoxal mediates adipocyte proliferation by increasing phosphorylation of Akt1. PLoS One. 2012;7:e36610. 30. Gaens KH, Stehouwer CD, Schalkwijk CG. Advanced glycation endproducts and its receptor for advanced glycation endproducts in obesity. Curr Opin Lipidol. 2013;24:4 –11. 31. Lin YH, Chiu WC, Wu CH, Tzeng CR, Hsu CS, Hsu MI. Antimullerian hormone and polycystic ovary syndrome. Fertil Steril. 2011; 96:230 –235. 32. Uribarri J, Cai W, Peppa M, et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol A Biol Sci Med Sci. 2007;62:427– 433. 33. Cheng C, Tsuneyama K, Kominami R, et al. Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs. Mod Pathol. 2005;18:1385–1396. 34. Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. Curr Pharm Des. 2008;14:987–989. 35. Diamanti-Kandarakis E, Piperi C, Livadas S, Kandaraki E, Papageorgiou E, Koutsilieris M. Interference of AGE-RAGE Signaling with Steroidogenic Enzyme Action in Human Ovarian Cells. San Francisco, CA: Endocrine Society; 2013. 36. Piperi C, Papageorgiou E, Koutsilieris M, Diamanti-Kandarakis E. Advanced Glycation End-Products Inhibit Insulin Signaling in Human Granulosa Cells: A Causative Link to PCOS Pathogenesis. San Francisco, CA: Endocrine Society; 2013. 37. Dennis NA, Houghton LA, Jones GT, van Rij AM, Morgan K, McLennan IS. The level of serum anti-Mullerian hormone correlates with vitamin D status in men and women but not in boys. J Clin Endocrinol Metab. 2012;97:2450 –2455.
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O N L I N E
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Vitamin D Increases Serum Levels of the Soluble Receptor for Advanced Glycation End Products in Women With PCOS Mohamad Irani, Howard Minkoff, David B. Seifer, and Zaher Merhi Department of Obstetrics and Gynecology (M.I., H.M., D.B.S.), Maimonides Medical Center, Brooklyn, New York 11219; and Department of Obstetrics, Gynecology and Reproductive Sciences (Z.M.), Division of Reproductive Endocrinology and Infertility, University of Vermont College of Medicine, Burlington, Vermont 05401
Context: Elevation of serum proinflammatory advanced glycation end products (AGEs) is involved in the pathogenesis of polycystic ovary syndrome (PCOS). The soluble receptor for AGEs (sRAGE) acts as a decoy by binding circulating AGEs. Vitamin D supplementation attenuates the deposition of AGEs in the vascular system of diabetic animals and improves some metabolic aspects of vitamin D-deficient women with PCOS. Additionally, serum anti-Mullerian hormone (AMH) is elevated in women with PCOS, reflecting abnormal ovarian folliculogenesis. Objective: The objective of the study was to evaluate the effect of 1,25 dihydroxyvitamin D3 (vit D3) supplementation on serum sRAGE and AMH in vitamin D-deficient women with PCOS. Design, Settings, Participants, and Intervention: Sixty-seven women with (n ⫽ 22) or without (control; n ⫽ 45) PCOS who were diagnosed with vitamin D deficiency were enrolled. Fifty-one women were replaced with oral vit D3 for 8 weeks (16 with PCOS and 35 controls) and 16 women were not treated (six with PCOS and 10 controls). Serum 25-hydroxyvitamin D (25 OH-D), sRAGE, and AMH concentrations were measured at baseline and after vit D3 supplementation in the treated group and 8 weeks apart in the nontreated group. Main Outcome Measure(s): Changes in serum sRAGE and AMH concentrations after vit D3 replacement were measured. Results: In all participants, there was a negative correlation between body mass index and serum sRAGE levels (r ⫽ ⫺0.3, P ⫽ .01). In women with PCOS, but not in controls, vit D3 increased serum sRAGE (P ⫽ .03) and decreased serum AMH levels (P ⬍ .001). The increase in serum sRAGE positively correlated with the increase in serum 25 OH-D after supplementation in women with PCOS (r ⫽ 0.6, P ⫽ .01). Conclusion: In women with PCOS, vit D3 might exert a protective effect against the inflammatory action of AGEs by increasing circulating sRAGE. The normalization in serum AMH induced by vit D3 replacement suggests an improvement in folliculogenesis. (J Clin Endocrinol Metab 99: E886 –E890, 2014)
olycystic ovary syndrome (PCOS) affects up to 15% of reproductive-aged women (1). Serum anti-Mullerian hormone (AMH), produced in the ovaries by small follicles, is usually elevated in women with PCOS and corre-
P
lates with the severity of this syndrome (2, 3). AMH plays an important role in inhibiting follicular development by decreasing the sensitivity of the follicles to FSH and by inhibiting granulosa cell aromatase (4, 5). Thus, elevated
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received December 11, 2013. Accepted February 20, 2014. First Published Online February 27, 2014
Abbreviations: AGE, advanced glycation end product; AMH, anti-Mullerian hormone; BMI, body mass index; IR, insulin resistance; 25 OH-D, 25-hydroxyvitamin D; PCOS, polycystic ovary syndrome; RAGE, receptor for AGE; sRAGE, soluble receptor for AGE; vit D3, 1,25 dihydroxyvitamin D3.
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doi: 10.1210/jc.2013-4374
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doi: 10.1210/jc.2013-4374
AMH in PCOS increases intrafollicular androgen level and the selection of a dominant follicle, subsequently reflecting abnormal ovarian folliculogenesis. Advanced glycation end products (AGEs) are the products of nonenzymatic modification of proteins, lipids, and nucleic acids by glucose (6). AGEs are highly reactive proinflammatory molecules and are formed slowly under physiological conditions (6). Diabetes, insulin resistance (IR), and aging accelerate their generation of AGEs that ultimately deposit throughout the body, including the ovaries (6). Serum AGEs have been shown to be elevated in women with PCOS and have been implicated in the pathogenesis of PCOS (7, 8). In women with PCOS, with or without IR, AGEs accumulate in ovarian granulosa and theca layers (9). Thus, the accumulation of AGEs might contribute to worsening of ovarian function in PCOS. AGEs act by binding to the extracellular matrix (receptor independent) or by binding to a cellular receptor called receptor for AGE (RAGE; receptor dependent) (6). The AGE-RAGE interaction activates signaling pathways that in turn activate nuclear factor-B, promoting the development of a proinflammatory state, cellular toxicity, and damage (10). An extracellular form of RAGE circulates in the blood and follicular fluid and is called soluble receptor for AGEs (sRAGE) (10). In contrast to RAGE, sRAGE acts as decoy because it binds circulating AGEs and prevents the adverse intracellular events of the AGE-RAGE binding (10). We have recently shown that elevation in follicular fluid sRAGE correlates with elevated measures of ovarian reserve (as reflected by AMH), hence reflecting a better reproductive environment (11). Vitamin D deficiency is common among reproductiveaged women, especially those with PCOS (12). Vitamin D deficiency contributes to several aspects of PCOS, such as IR, obesity, and metabolic syndrome (13, 14). 1,25-Dihydroxy-vitamin D3 (vit D3) supplementation to vitamin D-deficient women with PCOS improves some clinical and laboratory parameters of PCOS, such as androgen levels and the IR index (15, 16). Interestingly, vitamin D supplementation (such as cholecalciferol and calcitriol) attenuates the deposition of AGEs in the vascular system of diabetic rats (17) and increases serum sRAGE in hemodialysis patients (18). This suggests that vit D3 treatment could play an antiinflammatory role by altering the AGERAGE system. Little is known about the effect of vit D3 on circulating sRAGE and AMH in women with PCOS. Therefore, we hypothesize that vit D3 attenuates the effect of the AGE-RAGE system in vitamin D-deficient with PCOS by increasing the antiinflammatory serum sRAGE levels. We also hypothesize that vit D3 improves folliculogenesis in these women, as reflected by lowering the
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abnormally elevated serum AMH observed in these patients.
Materials and Methods Subjects and oral vit D3 supplementation Two hundred reproductive-aged women, with or without PCOS, presenting to women’s primary care center at the Maimonides Medical Center for an annual regular check-up between July 2012 and September 2013 were screened for vitamin D deficiency [defined as serum 25-hydroxyvitamin D (25 OH-D) levels ⬍ 20 ng/mL]. One hundred fifty-five women were found to have vitamin D deficiency. To increase participation, we used Rotterdam criteria (19) for the diagnosis of PCOS, but we used serum AMH of greater than 4 ng/mL instead of the sonographic criterion (ie, polycystic ovary looking ovaries). Of note, serum AMH level reflects typical sonographic features found in women with PCOS, and it can reliably substitute sonogram for the diagnosis of PCOS (2, 20 –23). Of the 155 vitamin D-deficient participants, 67 completed the study: 22 women were diagnosed with PCOS and 45 women did not have PCOS (controls). Sixteen of the 22 women with PCOS and 35 of the 45 controls were treated with 50 000 IU of vit D3 orally once weekly for 8 weeks (Supplemental Figure 1). The dose and timing of vit D3 replacement regimen were extracted from The Endocrine Society guidelines (24). To ensure compliance with vit D3 intake, each participant was called weekly and reminded to take the pill. Exclusion criteria included women who were: 1) pregnant, postpartum, or breast-feeding, 2) taking any kind of exogenous hormones, 3) receiving any form of oral vit D3 replacement, and 4) had poor ovarian reserve (defined as serum AMH ⬍ 1 ng/mL). All participants were consented, and the study was approved by the Institutional Review Board of the Maimonides Medical Center.
Serum 25 OH-D, AMH, and sRAGE measurements Measurement of serum sRAGE and AMH concentrations were obtained at baseline and after vit D3 supplementation in the treated group and 8 weeks after baseline in the nontreated group. 25 OH-D levels were repeated for all participants at the end of the 8-week period and were measured using the ADVIA Centaur vitamin D assay (Siemens Healthcare Diagnostics). AMH and sRAGE were measured using commercially available ELISA kits (AMH Gen II ELISA; Beckman Coulter and R&D Systems Inc, respectively). The inter- and intraassay coefficients of variation for all assays were less than 10%.
Statistics Data were tested for normality. All values were expressed as mean ⫾ SEM. A paired t test, Wilcoxon signed-rank test, oneway ANOVA, 2 test, linear regression, and Pearson correlation were used as appropriate. All statistical procedures were run on SigmaPlot 12.0.
Results Correlations with age and body mass index (BMI) The demographics and clinical profiles of the 67 participants who completed the study are presented in Sup-
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plemental Table 1. At baseline, there was a negative correlation between age and serum AMH levels among all participants (r ⫽ ⫺0.34, P ⫽ .002). There was also a significant negative correlation between BMI and serum sRAGE levels (r ⫽ ⫺0.3, P ⫽ .01) (Figure 1). Among women who received oral vit D3, 25 OH-D levels were compared between baseline and 8 weeks after vit D3 replacement. After replacement, there was a significant increase in serum 25 OH-D in women without (from 13.31 ⫾ 0.37 to 42.32 ⫾ 3.67; P ⬍ .0001) and with PCOS (from 13.73 ⫾ 0.96 to 52.60 ⫾ 8.57; P ⬍ .0001). There was a progressively smaller elevation in serum 25 OH-D as BMI increased (r ⫽ ⫺0.46, P ⬍ .05). Changes in serum sRAGE and AMH levels after oral vit D3 replacement Compared with women without PCOS, women with PCOS did not differ in age (Supplemental Table 1) and had significantly higher serum AMH levels (5.3 ⫾ 0.6 vs 3.9 ⫾ 0.5 ng/mL; P ⬍ .001). After vit D3 replacement, AMH concentrations in women with PCOS dropped significantly (P ⫽ .003; Figure 2A). There was no significant change in AMH levels after vit D3 replacement among women without PCOS (P ⫽ .6) (Figure 2A). Contrary to what happened in AMH after vit D3 replacement, there was a significant increase in serum sRAGE levels in women with PCOS (P ⫽ .03) but not in women without PCOS (P ⫽ .5) (Figure 2B). Additionally, the increase in serum 25 OH-D after supplementation positively correlated with the increase in serum sRAGE levels in women with PCOS (r ⫽ 0.6, P ⫽ .01).
Discussion This study evaluated the effect of vit D3 supplementation on serum sRAGE and AMH levels in vitamin D-deficient women with or without PCOS. We found a negative cor-
Figure 1. Correlation between serum sRAGE and BMI at baseline. Serum sRAGE concentrations were measured by ELISA in all participants. There was a significant negative correlation between BMI and serum sRAGE levels.
Figure 2. Changes in serum AMH (A) and sRAGE (B) after oral vit D3 replacement. Serum sRAGE and AMH levels were measured by ELISA before and after vit D3 replacement in vitamin D-deficient women with or without PCOS. A, In women with PCOS (n ⫽ 16), AMH concentrations significantly dropped to normal levels. There was no significant change in AMH levels in women without PCOS (n ⫽ 35). B, There was a significant increase in serum sRAGE levels in women with PCOS (n ⫽ 16). Serum sRAGE levels did not significantly change in women without PCOS (n ⫽ 35). *, P ⬍ .05, baseline vs after vit D3 replacement in the PCOS group; **, P ⬍ .05, controls vs PCOS (at baseline).
relation between age and serum AMH levels. We also found that the increase in serum 25 OH-D following vit D3 replacement was negatively correlated with BMI and that baseline serum sRAGE levels were negatively correlated with BMI. Finally, among women with PCOS, vit D3 supplementation significantly increased serum sRAGE levels but decreased the abnormally elevated serum AMH levels; these changes were not observed in women without PCOS. There is an inverse relationship between adiposity and vitamin D deficiency (24). Consistent with other data (25, 26), our results indicated that obese women needed higher doses of oral vit D3 when compared with normal-weight women because the rise in serum 25 OH-D after vit D3 treatment was inversely correlated with BMI. A potential explanation for this relationship is the sequestration of the lipophilic vitamin D molecules by fat cells (26). In line with other data (27), we also found that serum sRAGE was
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doi: 10.1210/jc.2013-4374
inversely correlated with BMI. Interestingly, sRAGE significantly increases after diet-induced weight loss in obese women (28). Due to the beneficial role of sRAGE, low circulating sRAGE levels seen in obese women supports the fact that obesity is a state of elevated inflammatory processes. Additionally, studies have shown that AGEs are directly involved in adipogenesis (29) and production of inflammatory mediators in adipocytes, leading to complications related to obesity (30). Taken together, these findings suggested a potential role of the AGE-RAGE system in obesity-related comorbid conditions. Several studies have shown that vit D3 replacement improves some of the clinical and metabolic parameters in women with PCOS (15, 16). In our current study, normalization in AMH levels could, in part, represent a mechanism by which vit D3 improves ovulatory dysfunction in women with PCOS. Indeed, higher serum AMH levels in PCOS are correlated with a more severe phenotype of PCOS (3, 31).Thus, lowering serum AMH in PCOS might allow enhanced activity of FSH, thus promoting follicular development and ultimately ovulation. This might potentially improve the menstrual irregularities and infertility associated with PCOS. Because AMH also inhibits aromatase (5), lower serum AMH in PCOS might be associated with more physiological intrafollicular concentration of androgens, leading to healthier folliculogenesis. There is accumulating evidence suggesting that the AGE-RAGE system could be implicated in the pathophysiology of PCOS (8, 9) and systemic inflammation (32, 33). Moreover, activation of the AGE-RAGE system correlates with IR, a significant contributor to the pathophysiology of PCOS (34). At the cellular level, ovaries of women with PCOS have increased the expression of AGEs and RAGE proteins in theca and granulosa cell layers (9). Furthermore, AGEs have been shown to interfere with LH and insulin actions on granulosa cells (35, 36). These alterations could, in part, explain the AGEs-induced abnormal folliculogenesis in women with PCOS. In our study, the significant increase in serum sRAGE after vit D3 supplementation constitutes a potential mechanism by which vit D3 acts as antiinflammatory therapeutic agent for women with PCOS. The rise in serum sRAGE can inhibit the deleterious effect of circulating AGEs by subsequently improving follicular growth and decreasing insulin resistance at granulosa cell level. Our study has several limitations including the following: 1) a relatively high dropout rate, 2) no evaluation of other clinical and biochemical parameters of PCOS such as menstrual irregularity, anovulation, hirsutism, and IR index, 3) no adjustment for seasonal changes in serum 25 OH-D and AMH levels (37), and 4) although we did not measure any of the serum AGEs (more than 20 members),
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sRAGE binds most them and has been shown to be a good marker for the systemic effect of AGEs (8, 10). In conclusion, this study supports the beneficial effect of vit D3 supplementation in vitamin D-deficient women with PCOS on follicular development, as reflected by normalization of serum AMH levels. Interestingly, it provides a novel molecular explanation of its antiinflammatory effect by increasing serum sRAGE. Understanding the role of the AGE-RAGE system in the ovary may offer opportunities for innovative therapeutic options for the treatment of ovulatory dysfunction associated with PCOS.
Acknowledgments Address all correspondence and requests for reprints to: Zaher Merhi, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Reproductive and Endocrinology and Infertility, University of Vermont College of Medicine, 111 Colchester Avenue, Burlington, VT 05401. E-mail: [email protected]. This work was supported by grants from the American Society for Reproductive Medicine (to Z.M.), Ferring Pharmaceuticals (to Z.M.) and Maimonides Research and Development Foundation (to M.I. and D.B.S.). Disclosure Summary: D.B.S. received royalties from a licensing agreement between Rutgers Medical School/Massachusetts General Hospital and Beckman Coulter for the use of AMH in determining ovarian reserve.
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