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Tuesday 1 January 2019

Is there a role for diet in ameliorating the reproductive sequelae associated with chronic low-grade inflammation in polycystic ovary syndrome and obesity?

September 1, 2016Volume 106, Issue 3, Pages 520–527

Is there a role for diet in ameliorating the reproductive sequelae associated with chronic low-grade inflammation in polycystic ovary syndrome and obesity?

Joan K. Riley, Ph.D., H.C.L.D.
,
Emily S. Jungheim, M.D., M.S.C.I.'Correspondence information about the author M.D., M.S.C.I. Emily S. Jungheim
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Washington University, St. Louis, Missouri
PlumX Metrics
DOI: https://doi.org/10.1016/j.fertnstert.2016.07.1069
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A 2013 ASRM committee opinion titled “Optimizing natural fertility” stated that “there is little evidence that dietary variations such as vegetarian diets, low-fat diets, vitamin-enriched diets, antioxidants, or herbal remedies improve fertility ….” However, there are emerging epidemiologic data demonstrating that certain components of the diet may influence reproductive health outcomes. Furthermore, translational work with human specimens and animal models lends biologic plausibility to the epidemiologic data, particularly in the context of female reproductive diseases associated with inflammation, including polycystic ovary syndrome (PCOS) and obesity. How to best apply these data clinically for improved reproductive outcomes remains to be determined. In this review, we outline a role for chronic inflammation in the reproductive sequelae of PCOS and obesity and we summarize epidemiologic and translational work demonstrating a potential role for diet in the regulation of inflammatory processes associated with these disorders. These studies identify areas for future research and potential clinical intervention in women affected by the reproductive sequelae of PCOS and obesity.

Key Words:

Inflammation, obesity, PCOS, diet, counseling

As outlined in a 2013 ASRM committee opinion titled “Optimizing natural fertility,” investigating the role of diet in reproductive health and fertility is a difficult undertaking (1). This difficulty arises from the fact that most of the existing research on this topic comes from cohort studies because randomized studies of diet are challenging. Retrospective cohort studies are often missing important data about potential confounding factors. Prospective studies take a long time to complete, and women planning to become pregnant may begin to practice more healthy eating habits. Importantly, these newly acquired habits may not truly reflect their typical long-term diets (2). Also, although diet as an exposure is difficult to assess, reproductive health outcomes such as fertility and pregnancy are complex, because they are influenced not only by physiology, but also by sociologic factors, genetic factors, and disease processes in either or both partners (3). Given these challenges, the 2013 ASRM committee opinion states, “there is little evidence that dietary variations such as vegetarian diets, low-fat diets, vitamin-enriched diets, antioxidants, or herbal remedies improve fertility …” (1). On the other hand, there is emerging evidence that focusing on mechanisms involved in a specific reproductive pathology and identifying women for whom this pathology is relevant may facilitate the identification of truly modifiable risk factors such as diet.
The present review focuses on the role that diet plays in mitigating chronic low-grade inflammation and the downstream effects on reproductive outcomes in women with polycystic ovary syndrome (PCOS) or that are obese. In addition to summarizing work investigating these relationships, evidence-based strategies for clinical application of the data and areas for future research are highlighted.

Inflammation and reproduction

Inflammation is the result of an innate immune response to infection, injury, or other irritation. The objective of an acute inflammatory response is to limit the spread of infection and eliminate the invading pathogen or insult. On removal of the originating stimuli, the inflammatory response is resolved and the tissue returns to its normal state (4). If the initial insult persists or if mechanisms important for the resolution of inflammation are impaired, the inflammatory response may become chronic, leading to tissue damage and chronic inflammatory disease progression (4). Inflammation plays a critical role in a number of normal reproductive processes including ovulation and embryo implantation as reviewed elsewhere (5, 6, 7). However, chronic low-grade inflammation may have detrimental effects on these key biologic processes, resulting in poor reproductive outcomes (7, 8).

Evidence for pathologic inflammation affecting ovulation and implantation

Overweight and Obese

More than two-thirds of adults in the United States are overweight or obese (9). Importantly, obesity is known to negatively affect female fertility and is associated with anovulation, miscarriage, and pregnancy complications (3). Studies conducted in mice demonstrate that diet-induced obesity leads to anovulation (10), delayed oocyte maturation (11), increased oocyte aneuploidy rate (12), and decreased fertilization rates (10). Similarly, clinical studies of women undergoing assisted reproductive technology demonstrate that obesity is negatively associated with oocyte maturation and fertilization (13) and positively associated with oocyte spindle and chromosome alignment abnormalities in oocytes that failed to fertilize (14).
In addition to adverse effects on the oocyte, obesity is also associated with negative effects on embryo implantation. Although some of the adverse effects on implantation may originate from poor oocyte quality, studies suggest that obesity also negatively affects the endometrium. Recent data from a mouse model showed that diet-induced obesity negatively affects decidualization of the endometrium (15). Importantly, decidualization regulates implantation and placentation (16), and impaired decidualization leads to pregnancy failure (17, 18). Clinically, obese women receiving donor oocytes appear to have lower embryo implantation rates compared with nonobese women (19, 20) and a higher rate of euploid miscarriage (21), providing further evidence to suggest that obesity negatively affects the endometrium.
Given that the number of obese women of reproductive age is on the rise, it is critical to understand the mechanism(s) by which obesity adversely affects the reproductive process so that evidence-based interventions may be implemented. Obesity is associated with chronic low-grade inflammation. This inflammation is the source of most complications linked with obesity (22). As an endocrine organ, adipose tissue secretes chemokines and free fatty acids (FFAs) important to immune cell infiltration of intra-abdominal adipose tissue and the initiation of an inflammatory process (22). This initial inflammatory response is an important mediator of obesity-associated systemic inflammation. In the obese state, adipocytes undergo hypertrophy, hyperplasia, or both to store excess fat (23). However, adipocyte hypertrophy is associated with insulin resistance and inflammation (24, 25, 26, 27). In the obese state the ability of adipocytes to store fat is ultimately overcome and FFAs begin to accumulate in nonadipose tissues, which is characteristic of metabolic disease (28). Eventually, the cells experience a process known as lipotoxicity in which the accumulation of intracellular lipid leads to oxidative stress, endoplasmic reticulum (ER) stress, and ultimately apoptosis (29). Lipotoxicity occurs in numerous cell types, leading to obesity-related diseases such as heart disease and type II diabetes (30).
An emerging body of evidence suggests that lipotoxicity may occur in the ovarian follicle. Studies in mice demonstrate that diet-induced obesity leads to several hallmarks of lipotoxicity, including lipid accumulation in both cumulus cells and the oocyte, activation of the ER stress pathway, mitochondrial dysfunction (10), and increased apoptosis in cells of the developing ovarian follicles (10, 11). Markers of oxidative and ER stress are linked to inflammation (22) and are elevated within the ovarian follicles of obese women (10, 31). Accordingly, obese women demonstrate increased levels of inflammatory markers, including C-reactive protein (CRP) (32) and tumor necrosis factor alpha (TNF-α) (33) in ovarian follicular fluid. In mice, diet-induced obesity leads to immune cell infiltration of adipose tissue surrounding the ovary and the up-regulation of proinflammatory genes in the ovary and periovarian adipose tissue (34). Therefore, it appears that in the obese state, the ovary, similarly to other tissues, is subject to lipotoxicity and increased local inflammation. Limited data exist regarding local alterations in immune cell populations and inflammation in the endometrium of obese women. One study demonstrated that gene expression is altered in endometrium from obese women around the window of embryonic implantation, with genes involved in the regulation of the immune system being particularly dysregulated (35). Although inflammation plays an important role in normal reproductive physiology, chronic low-grade inflammation as mediated by obesity may have detrimental effects on various components of the reproductive process, leading to poor outcomes.

Polycystic Ovary Syndrome

The clinical presentation of PCOS varies in severity, but it is characterized by oligomenorrhea, hyperandrogenism, and polycystic-appearing ovaries. PCOS is associated with significant reproductive morbidity, including anovulation and endometrial cancer, and although the mechanisms driving the pathophysiology of PCOS are undetermined, chronic inflammation is emerging as one unifying factor (5, 36, 37, 38). Obesity-induced inflammation may trigger a cascade of events leading to insulin resistance, dyslipidemia, increased ovarian androgen production, and reproductive dysfunction in women with PCOS (37, 39, 40, 41, 42). Increased adiposity may not be the only driver of these inflammation-induced physiologic changes, because glucose and saturated fatty acids induce a proinflammatory phenotype in mononuclear cells and foster dyslipidemia independent from insulin resistance and obesity in PCOS (37, 39, 40). However, it is clear that obesity augments the degree of inflammation in PCOS patients, resulting in increased metabolic dysfunction (37).
Similarly to obese women, women with PCOS have elevated circulating serum FFA and CRP levels (43, 44) and their endometrium demonstrates altered expression of genes important to the immune system and inflammation (35, 45, 46). These findings are independent from obesity, although many women with PCOS are also obese (46). In vitro studies with the use of endometrial cells from women with PCOS demonstrate that progesterone-mediated decidualization is impaired (47). In addition, increased production of proinflammatory mediators and enhanced immune cell migration were observed. The authors of that study suggest that compromised decidualization and excessive inflammation may impair implantation and predispose women with PCOS to endometrial cancer, a condition that is also common among obese women.

Is there a role for diet in ameliorating the reproductive sequelae of chronic low-grade inflammation in PCOS and obesity?

A question that we raise is whether or not we can counteract the chronic low-grade inflammation associated with PCOS and obesity with the use of diet and whether or not that could help improve reproductive outcomes for women facing fertility treatments (Fig. 1).
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Figure 1

Women with polycystic ovary syndrome or that are obese seeking fertility treatment may benefit from lifestyle interventions. Alterations in dietary intake of fats, carbohydrates, and proteins may mitigate the low-grade chronic inflammation associated with these disorders and improve fertility.
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We are particularly interested in fatty acids because a number of studies suggest that dietary fats have distinct effects on inflammatory pathways. Saturated fatty acids are thought to foster an inflammatory state, whereas certain polyunsaturated fatty acids (PUFAs) may facilitate the resolution of inflammation and perhaps confer a protective effect (48). PUFAs play an important role in reproductive processes, and cellular levels of these fatty acids are affected by diet (49). Essential PUFAs are fatty acids that are not synthesized by the body and must be obtained from the diet. These include linoleic acid (LA), an omega-6 fatty acid, and α-linolenic acid (ALA), an omega-3 fatty acid. Long-chain omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can be synthesized from ALA, but the process is inefficient and therefore the diet is the best source of these fatty acids as well (50). Long-chain omega-3 fatty acids have antiinflammatory effects, and there are data to support that dietary supplementation of these fatty acids reduce the risk of cardiovascular disease (51). Mechanistically, omega-3 PUFAs have been shown in vitro to decrease activity of the NLRP3 inflammasome and to attenuate inflammatory pathways mediated by adipocyte-macrophage interactions (52). Moreover, they have been shown to inhibit the production of proinflammatory cytokines and other mediators of inflammation (53). Genetic polymorphisms in the enzymes involved in fatty acid metabolism may also provide insight into the mechanisms by which these fatty acids modify disease risk (54, 55).
Importantly, the effects of altered PUFA concentrations or omega-6:omega-3 PUFA ratios on normal reproductive processes must be more fully understood before recommending dietary interventions to patients. In a study investigating serum PUFAs in women undergoing IVF, we found that women with an increased linoleic:α-linolenic ratio had a higher chance of pregnancy compared with women with a lower linoleic:α-linolenic ratio (relative risk [RR] 1.52, 95% confidence interval [CI] 1.09–2.13) (56). Embryo implantation rates were also weakly associated with higher serum linoleic:α-linolenic ratios (r = 0.21; P=.003). This finding may reflect the fact that normal implantation occurs in a proinflammatory environment (57). Eicosanoids derived from arachidonic acid (omega-6 fatty acid) are generally proinflammatory, whereas those derived from eicosapentaenoic acid (omega-3 fatty acid) are largely antiinflammatory. We hypothesized that an increased omega-6:omega-3 PUFA ratio facilitates the inflammatory process required for proper implantation (57, 58). Similarly, a recent study demonstrated that among overweight and obese women undergoing IVF, women with higher intake of omega-6 PUFAs and linoleic acid had greater pregnancy rates (P=.03 and P=.045, respectively) (59). In short, understanding the effects of PUFAs on normal reproductive processes and how concentrations of these fatty acids and their relative ratios are altered in pathogenic states warrants further study before clinical recommendations can be made.

Evidence-based recommendations in lifestyle counseling for obese women and women with PCOS undergoing fertility treatment

As summarized in the preceding, inflammation is required for normal ovulation and embryo implantation. Obesity and PCOS may offset the balance to a proinflammatory state that may negatively affect reproductive health. There is evidence that diet and other lifestyle interventions may be beneficial. In reviewing these interventions, it is important to offer evidence-based recommendations (60, 61). In our practice we highlight the following when counseling patients.
1) We review body mass index (BMI) and body weight with women who are overweight or obese. Knowledge of BMI and the effect of being overweight or obese on reproductive health is poor among the general population, and this also applies to women seeking fertility treatment (62, 63). In general, weight loss in the setting of obesity is associated with decreased circulating levels of inflammatory markers. However, what drives that decrease, whether dietary changes, exercise, weight loss, or all three, remains to be determined (64, 65, 66). In working with patients, we discuss that in the case of PCOS there are good data that as little as a 5% loss of body weight is associated with improved ovulatory function, although at higher BMIs more weight loss may be required (67, 68). In the case of obese women without ovulatory dysfunction, advice on weight loss goals are more complicated, because there are very little data demonstrating that weight loss improves live birth rates. In fact, recent data from a trial of a lifestyle intervention for women with a BMI of ≥29 kg/m2 showed no benefit of a lifestyle intervention in improving the chance of a healthy singleton delivery (69). For women undergoing IVF, a 2012 prospective cohort study of short-term weight change found no improvements in clinical outcomes. Furthermore, deferring fertility treatment for weight loss may be prohibitive because the time required to lose weight may reduce a woman's time for conception and family building, particularly if she is older (70). Given this, we strive to identify long-term family-building goals, discuss the effect of being overweight or obese on long-term morbidity and mortality, and work with the patient to determine what strategy works best for their individual goals.
2) We review dietary patterns with the patient and outline evidence for specific food choices in improving reproductive outcomes. We encourage all of our patients with PCOS and obesity to consider consultation with a nutrition specialist (71). As an introduction to discussions of diet, we ask every new patient to review what she eats in a typical day. We then review these dietary patterns with the patient and compare them with patterns associated with lower risk of ovulatory infertility as identified by Dr. Jorge Chavarro et al. with the use of data from the Nurses’ Health Study II (NHS II) (72). These patterns are particularly relevant to obese women and those with PCOS, because many demonstrate ovulatory dysfunction. The NHS II dataset includes 18,555 married premenopausal women who attempted pregnancy from 1991 to 1999. There are limitations to the data because it is a cohort study, but the principles identified are corroborated by a number of randomized controlled trials investigating dietary interventions to reduce the risk of other chronic diseases associated with inflammation and obesity (73). Furthermore, NHS II was not a study of women undergoing fertility treatment, so how these recommendations specifically improve fertility treatment outcomes warrants further study. Our general discussion with patients on nutrition and the rationale is as follows.
  • a)
    Carbohydrates: We provide a brief explanation of dietary carbohydrates and why carbohydrate intake may be particularly important for women with insulin resistance—a condition that is not uncommon among women with PCOS or obesity. We emphasize the importance of carbohydrate quantity and quality in accordance with previously published work (74). Data from the NHS II suggested that women with higher total carbohydrate intake and a higher dietary glycemic load are at an increased risk of ovulatory infertility. This association is independent from BMI, physical activity, and total energy intake. We also introduce the concept of glycemic index to patients, a measure of how rapidly food causes a rise in blood glucose values, and help them to identify foods with a low glycemic load (75). Diets with a lower glycemic index are associated with lower serum concentrations of inflammatory markers such as CRP (76, 77). One specific recommendation would be to increase whole grain intake and to avoid refined carbohydrates. Examples of whole grain foods include steel cut oats, brown rice, and quinoa. Encouragingly for women undergoing IVF, recent work by Gaskins et al. shows that higher pretreatment whole grain intake is associated with a higher live birth rate (78).
  • b)
    Fats: We outline the different types of fats and sources of these fats. Again in NHS II, the data demonstrate a role for fat intake in ovulatory infertility. It was determined that higher intake of trans fats is associated with an increased risk of ovulatory infertility (79). These findings are corroborated by randomized controlled trials investigating diet and the risk of developing chronic diseases (73). Given findings from studies like these, in 2013 the Food and Drug Administration (FDA) declared that partially hydrogenated oil is not generally recognized as safe (GRAS) and took action to remove artificial trans fat from processed foods (80, 81). Because the compliance period extends through 2018, counseling women to avoid trans fat is currently relevant and important. Determining the amount of trans fat in food can be difficult, because currently the FDA requires that nutrition labels quantify trans fat only if a serving contains >0.5 g per serving. Many people consume more than one serving, so we discuss with women how to read food labels and how to identify different types of fats contained in food. We advise patients to avoid foods containing hydrogenated oils in their listed ingredients, because these are trans fats. Dietary consumption of trans fat is associated with insulin resistance (82) and a proinflammatory state (83, 84). Finally, we discuss that although there are not a lot of data on omega-3 fatty acid intake and fertility, there are data to suggest that omega-3 fatty acid intake is associated with lower risk of coronary heart disease, another condition associated with chronic inflammation (51). In addition, studies demonstrate that long-chain omega-3 supplementation improves metabolic and hormonal profiles in women with PCOS (85, 86).
  • c)
    Proteins: In addition to looking at the effect of carbohydrate and fat quality on ovulatory infertility, Chavarro et al. used NHS II data to look at protein quality as well (87). Replacing animal protein with protein from vegetable sources was associated with a lower risk of ovulatory infertility. The biologic mechanism underlying the protein finding is less clear, but again the principles are corroborated by large randomized controlled trials investigating dietary patterns and chronic diseases associated with inflammation (73). Perhaps in addition to protein, beef and chicken are also a source of high levels of arachidonic acid, a proinflammatory fatty acid (88). We review nonmeat protein choices that patients may not have previously considered. In addition, we encourage women who eat beef and chicken to consider replacing it at times with fatty fish like salmon, because it is a good source of protein as well as contains potentially beneficial omega-3 fatty acids.
  • d)
    Micronutrients: We review the data on folic acid and discuss that women may want to take an over-the-counter supplement or use a prescription prenatal vitamin. We discuss the amount of folic acid contained in an over-the-counter prenatal vitamin (up to 800 μg) versus the amount in a typical prescription prenatal vitamin (1 mg). Data show that higher dietary folate intake is associated with higher fertilization rates and lower cycle failure before embryo transfer in women undergoing IVF (89). Also, follicular fluid levels of homocysteine, an amino acid whose metabolism is facilitated by folic acid and other B vitamins (90, 91, 92), are negatively associated with embryo quality (93, 94). Ultimately, the association between folic acid supplementation and improvements in these intermediate outcomes may translate into higher live birth rates among women undergoing IVF, because a recent report, again from Gaskins et al., showed that women with higher serum concentrations of folate and vitamin B12 were more likely to have a live birth after IVF than women with lower serum levels of these micronutrients (95).

3) Exercise: Finally, in discussing how patients with PCOS or obesity may improve their reproductive outcomes, we discuss exercise. Data on the benefits of exercise in PCOS and reproductive outcomes are unclear. In work from NHS II, no level of exercise was associated with an increased or decreased risk of ovulatory infertility (72). Furthermore, a Cochrane review in 2011 found no literature assessing clinical reproductive outcomes among women with PCOS who undertook a lifestyle intervention (59). However, in the setting of obesity, there are data from two large prospective cohort studies totaling >5,000 women and demonstrating that any form of exercise is beneficial (96, 97).

Important considerations for future research and for current counseling

As discussed in this review, there are data to suggest that chronic inflammation is important to the pathophysiology involved in the reproductive sequelae of PCOS and obesity. We believe that existing data on diet and reproductive physiology suggest that specific dietary modifications may be beneficial in counteracting the chronic low-grade inflammatory processes in these conditions and perhaps lead to improved reproductive outcomes for these patients. It is currently unclear whether or not the dietary and lifestyle counseling outlined above positively influence patient reproductive outcomes. Prospective studies in women undergoing IVF may be the best avenue to address this question, because there are opportunities to obtain biologic samples at distinct time points during the reproductive process. Serum and follicular fluid may be obtained as women go through IVF treatment, allowing for analysis of metabolites or proteins of interest. The oocytes collected from these patients and their resulting embryos can be directly visualized, and there is often an opportunity to sample the endometrium. Further translational research and the ability to capture nutritional information from patients seeking fertility treatment will offer important insight into the potential role of dietary modifications in improving reproductive outcomes in women with PCOS and obesity.
Overall, reproductive-age women with PCOS and obesity represent an important opportunity for interventions to improve long-term health outcomes (70, 98). Emerging data support a role for chronic low-grade inflammation in the morbidity associated with these conditions. Dietary intervention may, in part, ameliorate the inflammatory processes associated with these disorders. Given the privileged access that fertility specialists hold with these women, it is important that fertility specialists begin this counseling and/or provide resources for this counseling.

References

  1. Practice Committee of American Society for Reproductive Medicine, Society for Reproductive Endocrinology and Infertility. Optimizing natural fertility: a committee opinion. Fertil Steril. 2013; 100: 631–637
  2. Chavarro, J., Cardozo, E., and Afeiche, M. Nutrition in human fertility. in: E. Jungheim (Ed.) Obesity and fertility. Springer, New York; 2015: 31–72
  3. Jungheim, E.S., Travieso, J.L., Carson, K.R., and Moley, K.H. Obesity and reproductive function. Obstet Gynecol Clin North Am. 2012; 39: 479–493
  4. Nathan, C. and Ding, A. Nonresolving inflammation. Cell. 2010; 140: 871–882
  5. Boots, C.E. and Jungheim, E.S. Inflammation and Human Ovarian Follicular Dynamics. Semin Reprod Med. 2015; 33: 270–275
  6. Mor, G., Cardenas, I., Abrahams, V., and Guller, S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011; 1221: 80–87
  7. Weiss, G., Goldsmith, L.T., Taylor, R.N., Bellet, D., and Taylor, H.S. Inflammation in reproductive disorders. Reprod Sci. 2009; 16: 216–229
  8. Vannuccini, S., Clifton, V.L., Fraser, I.S., Taylor, H.S., Critchley, H., Giudice, L.C. et al. Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome. Hum Reprod Update. 2016; 22: 104–115
  9. National Institute of Diabetes and Digestive and Kidney Diseases. 2016. overweight and obesity statistics. Available at: http://www.niddk.nih.gov/health-information/health-statistics/Pages/overweight-obesity-statistics.aspx. Accessed July 27, 2016.
  10. Wu, L.L., Dunning, K.R., Yang, X., Russell, D.L., Lane, M., Norman, R.J. et al. High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology. 2010; 151: 5438–5445
  11. Jungheim, E.S., Schoeller, E.L., Marquard, K.L., Louden, E.D., Schaffer, J.E., and Moley, K.H. Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology. 2010; 151: 4039–4046
  12. Luzzo, K.M., Wang, Q., Purcell, S.H., Chi, M., Jimenez, P.T., Grindler, N. et al. High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One. 2012; 7: e49217
  13. Shah, D.K., Missmer, S.A., Berry, K.F., Racowsky, C., and Ginsburg, E.S. Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization. Obstetrics and gynecology. 2011; 118: 63–70
  14. Machtinger, R., Combelles, C.M., Missmer, S.A., Correia, K.F., Fox, J.H., and Racowsky, C. The association between severe obesity and characteristics of failed fertilized oocytes. Hum Reprod. 2012; 27: 3198–3207
  15. Rhee, J.S., Saben, J.L., Mayer, A.L., Schulte, M.B., Asghar, Z., Stephens, C. et al. Diet-induced obesity impairs endometrial stromal cell decidualization: a potential role for impaired autophagy. Hum Reprod. 2016; 31: 1315–1326
  16. Aplin, J. Maternal influences on placental development. Semin Cell Dev Biol. 2000; 11: 115–125
  17. Robb, L., Li, R., Hartley, L., Nandurkar, H.H., Koentgen, F., and Begley, C.G. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med. 1998; 4: 303–308
  18. Lydon, J.P., DeMayo, F.J., Conneely, O.M., and O’Malley, B.W. Reproductive phenotpes of the progesterone receptor null mutant mouse. J Steroid Biochem Mol Biol. 1996; 56: 67–77
  19. Bellver, J., Pellicer, A., Garcia-Velasco, J.A., Ballesteros, A., Remohi, J., and Meseguer, M. Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovum donation with normal weight donors. Fertil Steril. 2013; 100: 1050–1058
  20. DeUgarte, D.A., DeUgarte, C.M., and Sahakian, V. Surrogate obesity negatively impacts pregnancy rates in third-party reproduction. Fertil Steril. 2010; 93: 1008–1010
  21. Boots, C.E., Bernardi, L.A., and Stephenson, M.D. Frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss. Fertil Steril. 2014; 102: 455–459
  22. Gregor, M.F. and Hotamisligil, G.S. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011; 29: 415–445
  23. Jo, J., Gavrilova, O., Pack, S., Jou, W., Mullen, S., Sumner, A.E. et al. Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Comput Biol. 2009; 5: e1000324
  24. Arner, E., Westermark, P.O., Spalding, K.L., Britton, T., Ryden, M., Frisen, J. et al. Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes. 2010; 59: 105–109
  25. Lundgren, M., Svensson, M., Lindmark, S., Renstrom, F., Ruge, T., and Eriksson, J.W. Fat cell enlargement is an independent marker of insulin resistance and “hyperleptinaemia”. Diabetologia. 2007; 50: 625–633
  26. Jernas, M., Palming, J., Sjoholm, K., Jennische, E., Svensson, P.A., Gabrielsson, B.G. et al. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. FASEB J. 2006; 20: 1540–1542
  27. Skurk, T., Alberti-Huber, C., Herder, C., and Hauner, H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007; 92: 1023–1033
  28. van Herpen, N.A. and Schrauwen-Hinderling, V.B. Lipid accumulation in nonadipose tissue and lipotoxicity. Physiol Behav. 2008; 94: 231–241
  29. Robker, R.L., Wu, L.L., and Yang, X. Inflammatory pathways linking obesity and ovarian dysfunction. J Reprod Immunol. 2011; 88: 142–148
  30. Schaffer, J.E. Lipotoxicity: when tissues overeat. Curr Opin Lipidol. 2003; 14: 281–287
  31. Bausenwein, J., Serke, H., Eberle, K., Hirrlinger, J., Jogschies, P., Hmeidan, F.A. et al. Elevated levels of oxidized low-density lipoprotein and of catalase activity in follicular fluid of obese women. Mol Hum Reprod. 2010; 16: 117–124
  32. Robker, R.L., Akison, L.K., Bennett, B.D., Thrupp, P.N., Chura, L.R., Russell, D.L. et al. Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women. J Clin Endocrinol Metab. 2009; 94: 1533–1540
  33. la Vignera, S., Condorelli, R., Bellanca, S., la Rosa, B., Mousavi, A., Busa, B. et al. Obesity is associated with a higher level of pro-inflammatory cytokines in follicular fluid of women undergoing medically assisted procreation (PMA) programs. Eur Rev Med Pharmacol Sci. 2011; 15: 267–273
  34. Nteeba, J., Ortinau, L.C., Perfield, J.W. 2nd, and Keating, A.F. Diet-induced obesity alters immune cell infiltration and expression of inflammatory cytokine genes in mouse ovarian and peri-ovarian adipose depot tissues. Mol Reprod Dev. 2013; 80: 948–958
  35. Bellver, J., Martinez-Conejero, J.A., Labarta, E., Alama, P., Melo, M.A., Remohi, J. et al. Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome. (41.e1–8)Fertil Steril. 2011; 95: 2335–2341
  36. Spritzer, P.M., Lecke, S.B., Satler, F., and Morsch, D.M. Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction. 2015; 149: R219–R227
  37. Gonzalez, F. Nutrient-induced inflammation in polycystic ovary syndrome: role in the development of metabolic aberration and ovarian dysfunction. Semin Reprod Med. 2015; 33: 276–286
  38. Duleba, A.J. and Dokras, A. Is PCOS an inflammatory process?. Fertil Steril. 2012; 97: 7–12
  39. Gonzalez, F., Rote, N.S., Minium, J., and Kirwan, J.P. Increased activation of nuclear factor kappaB triggers inflammation and insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006; 91: 1508–1512
  40. Gonzalez, F., Rote, N.S., Minium, J., and Kirwan, J.P. Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006; 91: 336–340
  41. Gonzalez, F., Rote, N.S., Minium, J., and Kirwan, J.P. Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism: clinical and experimental. 2009; 58: 954–962
  42. Malin, S.K., Kirwan, J.P., Sia, C.L., and Gonzalez, F. Pancreatic beta-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-kappaB activation and systemic inflammation. Am J Physiol Endocrinol Metab. 2015; 308: E770–E777
  43. Escobar-Morreale, H.F., Luque-Ramirez, M., and Gonzalez, F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. (e1–2)Fertil Steril. 2011; 95: 1048–1058
  44. Holte, J., Bergh, T., Berne, C., and Lithell, H. Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables. Clin Endocrinol. 1994; 41: 463–471
  45. Piltonen, T.T., Chen, J., Erikson, D.W., Spitzer, T.L., Barragan, F., Rabban, J.T. et al. Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential. J Clin Endocrinol Metab. 2013; 98: 3765–3775
  46. Piltonen, T.T. Polycystic ovary syndrome: endometrial markers. Best Pract Res Clin Obstet Gynaecol. 2016;
  47. Piltonen, T.T., Chen, J.C., Khatun, M., Kangasniemi, M., Liakka, A., Spitzer, T. et al. Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro. Hum Reprod. 2015; 30: 1203–1215
  48. Calder, P.C. Long chain fatty acids and gene expression in inflammation and immunity. Curr Opin Clin Nutr Metab Care. 2013; 16: 425–433
  49. Wathes, D.C., Abayasekara, D.R., and Aitken, R.J. Polyunsaturated fatty acids in male and female reproduction. Biol Reprod. 2007; 77: 190–201
  50. Arterburn, L.M., Hall, E.B., and Oken, H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr. 2006; 83: 1467S–1476S
  51. Wall, R., Ross, R.P., Fitzgerald, G.F., and Stanton, C. Fatty acids from fish: the antiinflammatory potential of long-chain omega-3 fatty acids. Nutrition reviews. 2010; 68: 280–289
  52. De Boer, A.A., Monk, J.M., Liddle, D.M., Hutchinson, A.L., Power, K.A., Ma, D.W. et al. Fish-oil-derived n-3 polyunsaturated fatty acids reduce NLRP3 inflammasome activity and obesity-related inflammatory cross-talk between adipocytes and CD11b macrophages. J Nutr Biochem. 2016; 34: 61–72
  53. Wang, Y. and Huang, F. N-3 polyunsaturated fatty acids and inflammation in obesity: local effect and systemic benefit. Biomed Res Int. 2015; 2015: 581469
  54. Ruiz-Narvaez, E.A., Kraft, P., and Campos, H. Ala12 variant of the peroxisome proliferator-activated receptor-gamma gene (PPARG) is associated with higher polyunsaturated fat in adipose tissue and attenuates the protective effect of polyunsaturated fat intake on the risk of myocardial infarction. Am J Clin Nutr. 2007; 86: 1238–1242
  55. Baylin, A., Ruiz-Narvaez, E., Kraft, P., and Campos, H. Alpha-linolenic acid, delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction. Am J Clin Nutr. 2007; 85: 554–560
  56. Jungheim, E.S., Frolova, A.I., Jiang, H., and Riley, J.K. Relationship between serum polyunsaturated fatty acids and pregnancy in women undergoing in vitro fertilization. J Clin Endocrinol Metab. 2013; 98: E1364–E1368
  57. Granot, I., Gnainsky, Y., and Dekel, N. Endometrial inflammation and effect on implantation improvement and pregnancy outcome. Reproduction. 2012; 144: 661–668
  58. Calder, P.C. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010; 2: 355–374
  59. Moran, L.J., Tsagareli, V., Noakes, M., and Norman, R. Altered preconception fatty acid intake is associated with improved pregnancy rates in overweight and obese women undertaking in vitro fertilisation. Nutrients. 2016; 8: 1–7
  60. Armstrong, E., Harris, L.H., Kukla, R., Kuppermenn, M., Little, M.O., Lyerly, A.D. et al. Maternal caffeine consumption during pregnancy and the risk of miscarriage. (author reply e14)Am J Obstet Gynecol. 2008; 199: e13
  61. McCall, C.A., Grimes, D.A., and Lyerly, A.D. “Therapeutic” bed rest in pregnancy: unethical and unsupported by data. Obstet Gynecol. 2013; 121: 1305–1308
  62. Cardozo, E.R., Neff, L.M., Brocks, M.E., Ekpo, G.E., Dune, T.J., Barnes, R.B. et al. Infertility patients’ knowledge of the effects of obesity on reproductive health outcomes. Am J Obstet Gynecol. 2012; 207: 509.e1–509.e10
  63. Post, R.E., Mendiratta, M., Haggerty, T., Bozek, A., Doyle, G., Xiang, J. et al. Patient understanding of body mass index (BMI) in primary care practices: a two-state practice-based research (PBR) collaboration. J Am Board Fam Med. 2015; 28: 475–480
  64. Forsythe, L.K., Wallace, J.M., and Livingstone, M.B. Obesity and inflammation: the effects of weight loss. Nutr Res Rev. 2008; 21: 117–133
  65. Christiansen, T., Paulsen, S.K., Bruun, J.M., Pedersen, S.B., and Richelsen, B. Exercise training versus diet-induced weight-loss on metabolic risk factors and inflammatory markers in obese subjects: a 12-week randomized intervention study. Am J Physiol Endocrinol Metab. 2010; 298: E824–E831
  66. Compher, C. and Badellino, K.O. Obesity and inflammation: lessons from bariatric surgery. JPEN J Parenter Enteral Nutr. 2008; 32: 645–647
  67. Teitelman, M., Grotegut, C.A., Williams, N.N., and Lewis, J.D. The impact of bariatric surgery on menstrual patterns. Obes Surg. 2006; 16: 1457–1463
  68. Thessaloniki ESHRE/ASRM–Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008; 89: 505–522
  69. Mutsaerts, M.A., van Oers, A.M., Groen, H., Burggraaff, J.M., Kuchenbecker, W.K., Perquin, D.A. et al. Randomized trial of a lifestyle program in obese infertile women. N Engl J Med. 2016; 374: 1942–1953
  70. Sabounchi, N.S., Hovmand, P.S., Osgood, N.D., Dyck, R.F., and Jungheim, E.S. A novel system dynamics model of female obesity and fertility. Am J Public Health. 2014; 104: 1240–1246
  71. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 549: obesity in pregnancy. Obstet Gynecol. 2013; 121: 213–217
  72. Chavarro, J.E., Rich-Edwards, J.W., Rosner, B.A., and Willett, W.C. Diet and lifestyle in the prevention of ovulatory disorder infertility. Obstet Gynecol. 2007; 110: 1050–1058
  73. Mente, A., de Koning, L., Shannon, H.S., and Anand, S.S. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009; 169: 659–669
  74. Chavarro, J.E., Rich-Edwards, J.W., Rosner, B.A., and Willett, W.C. A prospective study of dietary carbohydrate quantity and quality in relation to risk of ovulatory infertility. Eur J Clin Nutr. 2009; 63: 78–86
  75. American Diabetes Association. Glycemic index and diabetes. Available at: http://www.diabetes.org/food-and-fitness/food/what-can-i-eat/understanding-carbohydrates/glycemic-index-and-diabetes.html. Accessed July 27, 2016.
  76. Buyken, A.E., Goletzke, J., Joslowski, G., Felbick, A., Cheng, G., Herder, C. et al. Association between carbohydrate quality and inflammatory markers: systematic review of observational and interventional studies. Am J Clin Nutr. 2014; 99: 813–833
  77. Gaskins, A.J., Mumford, S.L., Rovner, A.J., Zhang, C., Chen, L., Wactawski-Wende, J. et al. Whole grains are associated with serum concentrations of high sensitivity C-reactive protein among premenopausal women. J Nutr. 2010; 140: 1669–1676
  78. Gaskins, A.J., Chiu, Y.H., Williams, P.L., Keller, M.G., Toth, T.L., Hauser, R. et al. Maternal whole grain intake and outcomes of in vitro fertilization. Fertil Steril. 2016; 105: 1503–1510.e4
  79. Chavarro, J.E., Rich-Edwards, J.W., Rosner, B.A., and Willett, W.C. Dietary fatty acid intakes and the risk of ovulatory infertility. Am J Clin Nutr. 2007; 85: 231–237
  80. Food and Drug Administration. The FDA takes step to remove artificial trans fats in processed foods. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm451237.htm. Accessed July 1, 2016.
  81. Food and Drug Administration. FDA cuts trans fat in processed foods. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm372915.htm. Accessed July 1, 2016.
  82. Lefevre, M., Lovejoy, J.C., Smith, S.R., Delany, J.P., Champagne, C., Most, M.M. et al. Comparison of the acute response to meals enriched with cis- or trans-fatty acids on glucose and lipids in overweight individuals with differing FABP2 genotypes. Metabolism. 2005; 54: 1652–1658
  83. Baer, D.J., Judd, J.T., Clevidence, B.A., and Tracy, R.P. Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study. Am J Clin Nutr. 2004; 79: 969–973
  84. Mozaffarian, D., Pischon, T., Hankinson, S.E., Rifai, N., Joshipura, K., Willett, W.C. et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004; 79: 606–612
  85. Phelan, N., O’Connor, A., Kyaw Tun, T., Correia, N., Boran, G., Roche, H.M. et al. Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomized, placebo-controlled, crossover trial. Am J Clin Nutr. 2011; 93: 652–662
  86. Kasim-Karakas, S.E., Almario, R.U., Gregory, L., Wong, R., Todd, H., and Lasley, B.L. Metabolic and endocrine effects of a polyunsaturated fatty acid-rich diet in polycystic ovary syndrome. J Clin Endocrinol Metab. 2004; 89: 615–620
  87. Chavarro, J.E., Rich-Edwards, J.W., Rosner, B.A., and Willett, W.C. Protein intake and ovulatory infertility. Am J Obstet Gynecol. 2008; 198: 210.e1–210.e7
  88. Taber, L., Chiu, C.H., and Whelan, J. Assessment of the arachidonic acid content in foods commonly consumed in the American diet. Lipids. 1998; 33: 1151–1157
  89. Gaskins, A.J., Afeiche, M.C., Wright, D.L., Toth, T.L., Williams, P.L., Gillman, M.W. et al. Dietary folate and reproductive success among women undergoing assisted reproduction. Obstet Gynecol. 2014; 124: 801–809
  90. Blom, H.J. and Smulders, Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011; 34: 75–81
  91. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ. 1998; 316: 894–898
  92. Forges, T., Monnier-Barbarino, P., Alberto, J.M., Gueant-Rodriguez, R.M., Daval, J.L., and Gueant, J.L. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007; 13: 225–238
  93. Ebisch, I.M., Peters, W.H., Thomas, C.M., Wetzels, A.M., Peer, P.G., and Steegers-Theunissen, R.P. Homocysteine, glutathione and related thiols affect fertility parameters in the (sub)fertile couple. Hum Reprod. 2006; 21: 1725–1733
  94. Boxmeer, J.C., Macklon, N.S., Lindemans, J., Beckers, N.G., Eijkemans, M.J., Laven, J.S. et al. IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Hum Reprod. 2009; 24: 1059–1066
  95. Gaskins, A.J., Chiu, Y.H., Williams, P.L., Ford, J.B., Toth, T.L., Hauser, R. et al. Association between serum folate and vitamin B-12 and outcomes of assisted reproductive technologies. Am J Clin Nutr. 2015; 102: 943–950
  96. McKinnon, C.J., Hatch, E.E., Rothman, K.J., Mikkelsen, E.M., Wesselink, A.K., Hahn, K.A. et al. Body mass index, physical activity and fecundability in a North American preconception cohort study. Fertil Steril. 2016;
  97. Wise, L.A., Rothman, K.J., Mikkelsen, E.M., Sorensen, H.T., Riis, A.H., and Hatch, E.E. A prospective cohort study of physical activity and time to pregnancy. (e1–4)Fertil Steril. 2012; 97: 1136–1142
  98. Zera C, McGirr S, Oken E. Screening for obesity in reproductive-aged women. Prev Chronic Dis 2011;8:A125. Available at: http://www.cdc.gov/pcd/issues/2011/nov/11_0032.htm. Accessed July 27, 2016.
J.K.R. has nothing to disclose. E.S.J. has nothing to disclose.
Copyright ©2016 American Society for Reproductive Medicine, Published by Elsevier Inc.
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September 1, 2016Volume 106, Issue 3, Pages 520–527 
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