Fertility Dr. Fiona McCulloch 26 September 2013 Fertility - Impact of Insulin Resistance By: Fiona McCulloch BSc, ND White Lotus Naturopathic Clinic and Integrated Health 18 Greenfield Ave.,Suite #201 Toronto, ON. M2N 3C8 www.whitelotusclinic.ca Jump to: Part 1 Part 2 Part 3Part 4 Part I: About Insulin Resistance Insulin resistance is a common condition, affecting 10% of young adults and nearly 44% of adults in mid-life.(1) It is now known that genetic factors play a role in insulin resistance. Diet, body composition, and exercise levels are also major causes, explaining the growing incidence of this disorder with modern lifestyles. Interestingly, insulin resistance may also contribute to infertility, another significant modern health problem that causes great distress to the lives of 1 in every 6 couples. Insulin resistance is defined by a state where the cells in the body do not respond normally to insulin. Left unchecked over time, insulin resistance can result in what is known as metabolic syndrome, a constellation of problems including high blood pressure, high triglycerides, low HDL (good cholesterol), and abdominal obesity. Before it gets to this extreme point however, it can certainly cause a lot of disruption to health. Insulin is produced by the beta cells of the pancreas. It causes fat, liver and muscle cells to take up and store glucose from the blood. In fat cells, glucose is stored as triglycerides, and in muscle and liver cells, it is stored as glycogen. In fat cells, insulin resistance causes the breakdown of stored triglycerides. When cells do not use insulin effectively, the blood sugar levels rise. The pancreas will then try to re-establish normal blood sugar by producing extra insulin. These high levels of insulin can cause a variety of effects on female fertility including increased androgens (male hormones), hormonal imbalances, circulatory and inflammatory effects. High insulin is thought to be an underlying cause of polycystic ovarian syndrome (PCOS), and contributes to fertility concerns such as recurrent miscarriage, inflammatory implantation failure, and obesity. Diagnosis of insulin resistance Insulin resistance can be measured by several methods. The gold standard is known as the hyperinsulinemic euglycemic clamp, which measures the amount of glucose necessary to compensate for increased insulin levels. This test is rarely performed in a clinic setting. Another method for measuring insulin resistance is the HOMA-IR index.(2) The HOMA-IR index is a special calculation that compares the fasting glucose and the fasting insulin levels. Oral glucose tolerance testing and HBA1C levels can also be used as assessments for insulin resistance. Causes of Fertility Related Insulin Resistance In PCOS, it is thought that there is an underlying, possibly genetic defect within the theca cells (male hormone producing cells) of the ovary. This makes the theca cells produce excessive amounts of androgens when exposed to insulin. Patients with PCOS often carry a family history of type 2 diabetes. There may also be other women in the family with PCOS, evidenced by irregular menstrual cycles or difficulty getting pregnant. Elevated body mass index (BMI) or increased amounts of abdominal body fat is also associated with insulin resistance. Abdominal body fat is actually related to fat deposits that are around the organs and inside the abdominal cavity. Free fatty acids are released more readily from abdominal fat deposits than from other areas in the body where fat is stored. These fatty acids affect the liver, causing it to release glucose, produce LDL (bad) cholesterol, and reduce the clearance of insulin.(3) Together these contribute to insulin resistance, which can impact healthy fertility. Poor diet can also promote insulin resistance in the body. A high fat, high simple carbohydrate, and low fibre diet has been repeatedly documented to induce insulin resistance and metabolic syndrome.(4, 5) It has also been suggested that a high fructose diet (containing soda, candy, and other corn syrup products) causes the liver to make triglycerides, inducing metabolic syndrome and insulin resistance.(6, 7) Insulin resistance is a common and growing condition with a variety of causes ranging from genetics to lifestyle. High levels of insulin can cause powerful changes in our health that can create serious conditions including cardiovascular disease, infertility, diabetes and obesity. Part 2 of this article will focus on the specific ways that insulin resistance affects healthy fertility. References 1. Beck-Nielsen H. General characteristics of the insulin resistance syndrome: prevalence and heritability. EuropeanGroup for the study of Insulin Resistance (EGIR). Drugs. 1999;58Suppl 1:7-10; discussion 75-82. 2. Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study. Diabetes Care. 1997 Jul;20(7):1087-92. 3. Björntorp P. Visceral obesity: a "civilization syndrome". Obes Res. 1993 May;1(3):206-22. 4. Brøns C, Jensen CB, Storgaard H, Hiscock NJ, White A, Appel JS, Jacobsen S, Nilsson E, Larsen CM, Astrup A, Quistorff B, Vaag A. Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J Physiol. 2009 May 15;587(Pt 10):2387-97. doi: 10.1113/jphysiol.2009.169078. Epub 2009 Mar 30. 5. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes. 1988 Sep;37(9):1163-7. 6. Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. NutrMetab (Lond). 2005 Feb 21;2(1):5. 7. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ. Fructose, weight gain, and the insulin resistance syndrome. Am J ClinNutr. 2002 Nov;76(5):911-22. Fertility - Impact of Insulin Resistance Part II: How does Insulin Resistance (IR) affect Fertility? By: Fiona McCulloch BSc, ND White Lotus Naturopathic Clinic and Integrated Health 18 Greenfield Ave.,Suite #201 Toronto, ON. M2N 3C8 www.whitelotusclinic.ca Polycystic Ovarian Syndrome The most well known insulin resistant condition that affects fertility is polycystic ovarian syndrome (PCOS). PCOS is a condition that has many variations. It includes characteristics such as irregular ovulation or menstrual cycles, androgenic/male hormone related signs such as hirsutism (excessive hair growth), acne or male pattern hair loss, abdominal obesity. Some women with PCOS have multiple small follicles (cysts) from eggs that never developed fully in the ovary. There might also be blood markers for insulin resistance, hormonal abnormalities like increased LH to FSH ratio, high estrogen, and/or high androgens such as free testosterone. There are several variants of PCOS that contain different combinations of the aforementioned signs and symptoms. In PCOS, high insulin levels cause the follicles in the ovary to produce male hormones. These male hormones (androgens) slow down the development of the follicles and can even stop ovulation altogether. High amounts of insulin also cause fat cells to convert testosterone into estrogen, a process known as aromatization. High estrogen levels increase the pituitary gland’s secretion of luteinizing hormone (LH), which results in even more testosterone release from the ovary. Truly a “vicious cycle”. High estrogen also suppresses follicle-stimulating hormone (FSH), causing the eggs to develop poorly. Insulin resistance causes even more problems with hormones. It lowers sex hormone binding globulin (SHBG),(1) which normally binds up hormones and keeps them from activating tissue receptors. When SHBG is low, there are more androgens freely floating in the bloodstream, available to act on tissues and therefore produce androgenic effects. For patients with PCOS, insulin resistance is always a part of the condition, regardless of whether a woman is slim or overweight.(2) Patients with PCOS are particularly sensitive to the effects of extra weight however, when compared to control females who do not have PCOS. As more fatty tissue further aggravates insulin resistance, patients with PCOS need to aim for a lower BMI to promote optimal reproductive health. Moreover, insulin resistance in PCOS is associated with inflammation. Certain inflammatory factors have been found to be high in women with PCOS. These same markers (C - reactive protein and homocysteine) are also potential factors in miscarriage and implantation failure .(3) Women with PCOS are at an increased risk for miscarriage when compared to the general population. Obesity Insulin resistance increases sharply at a BMI level of 27 and above.(4) Obesity has well documented effects on reproduction, much of which is attributed to insulin resistance. Patients who are obese have higher miscarriage rates, and lower rates of success in assisted reproductive technologies such as IVF.(5) Obese women with PCOS have even more problems with fertility when compared to lean PCOS women. This is because high BMI greatly aggravates the underlying insulin resistant state that is already present in PCOS. A high BMI is also associated with increased blood and follicular leptin concentrations.(6) Leptin is a hormone that inhibits appetite and regulates calorie expenditure. Leptin typically is higher in overweight people, and lower in those who are lean. It inhibits appetite by acting on the hypothalamus of the brain. In cases of obesity however, it is thought that the cells become resistant to leptin. High levels of leptin without the corresponding reduction in appetite contribute to even more weight gain. Leptin also acts on the granulosa cells in the ovary, inhibiting the production of hormones by the ovary, and affecting the function and quality of the follicles.(7) High BMI is also associated with lower serum adiponectin levels.(8) Adiponectin is a fat specific protein that prevents arterial plaques and is anti-inflammatory. Adiponectin is lower in patients with obesity, type 2 diabetes and cardiovascular disease. Low adiponectin(8) levels in obese women also decrease Sex Hormone Binding Globulin (SHBG), and thereby increase free male hormones in a similar fashion to PCOS. High free androgens disrupt the normal ovarian cycle, and impair egg quality. Obesity also produces chronic low-grade inflammation. Inflammation has been associated with different fertility conditions such as implantation failure and recurrent miscarriage. A study on mouse models of obesity found elevated inflammatory markers interleukin-6, TNF-alpha and CRP, all of which have been associated with infertility.(9) Miscarriage: Insulin resistance has also been implicated in recurrent miscarriage. A study on 74 women with recurrent pregnancy loss (rpl) found that 27% had insulin resistance, compared to 9.5% of matched controls.(10) Another large study suggested that insulin resistance was an independent risk factor for recurrent miscarriages, even when controlled for PCOS.(11) References 1. Jayagopal V, Kilpatrick ES, Jennings PE, Hepburn DA, Atkin SL. The biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: implications for SHBG as a surrogate marker of insulin resistance. J ClinEndocrinolMetab. 2003 Apr;88(4):1528-33. 2. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, Teede HJ. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum Reprod. 2013 Mar;28(3):777-84. Epub 2013 Jan 12. 3. Tarkun I, Arslan BC, Cantürk Z, Türemen E, Sahin T, Duman C. Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. J ClinEndocrinolMetab. 2004 Nov;89(11):5592-6. 4. Campbell PJ, Gerich JE. Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity. J ClinEndocrinolMetab. 1990 Apr;70(4):1114-8. 5. Moragianni VA, Jones SM, Ryley DA. The effect of body mass index on the outcomes of first assisted reproductive technology cycles. FertilSteril. 2012 Jul;98(1):102-8. 6. Metwally M, Li TC, Ledger WL. The impact of obesity on female reproductive function. Obesity Rev.2007;8:515–23 7. Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: A review. FertilSteril. 2002;77:433–44 8. Gil-Campos M, Canete RR, Gil A. Adiponectin, the missing link in insulin resistance and obesity. ClinNutr. 2004;23:963–74. 9. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003 Dec;112(12):1821-30. 10. LaTasha B Craig, Raymond W Ke, William H Kutteh, Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss, Fertility and Sterility, Volume 78, Issue 3, September 2002, Pages 487-490, 11. Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Hum Reprod. 2004 Jul;19(7):1644-6 Fertility - Impact of Insulin Resistance Part III: Diet and Exercise Interventions for Insulin Resistant Fertility Concerns By: Fiona McCulloch BSc, ND White Lotus Naturopathic Clinic and Integrated Health 18 Greenfield Ave.,Suite #201 Toronto, ON. M2N 3C8 www.whitelotusclinic.ca It has been found that each 1kg increase in body weight is associated with a 2.84 day increase in time to pregnancy. Therefore, losing additional weight may significantly reduce the time to successful conception. Diet A carbohydrate-restricted diet can improve insulin resistance. In one study, insulin response to an oral glucose load was reduced significantly for patients following a low carbohydrate diet.(1) When compared to a low fat diet, a very low carbohydrate diet significantly improved both insulin sensitivity and weight loss in overweight or obese women. A Duke University study on a very low carbohydrate ketogenic diet caused improvements in American women with PCOS.(2) Over a 24-week period, patients showed significant improvement in free testosterone, LH/FSH ratios, weight loss and fasting insulin. Interestingly, the Paleolithic diet is showing great promise in treating insulin resistance. The “Paleo” diet includes vegetables, lean meats, fish, fruits, nuts and seeds, and excludes grains, dairy, salt, sugar, and legumes. A 2009 study on a group of type 2 diabetics found that the Paleolithic diet improved glycemic control and reduced HBA1C, triglycerides, insulin and glucose when compared to a traditional diabetes diet.(3) Exercise Exercise is thought to improve fertility for women with PCOS mostly through waist circumference reduction and weight loss (even if modest), which can greatly improve insulin sensitivity. A study on 40 obese women with anovulatory PCOS found that structured exercise improved menstrual regularity, insulin sensitivity, fertility, and androgen levels.(4) The structured exercise program, consisting of three 30-minute stationary bicycle sessions per week, reduced waist circumference (WC) significantly even when only smaller amounts of total body weight were lost. Reduced WC is a result of losing intra-abdominal fat (as opposed to subcutaneous fat, which is often present on other areas such as the hips and thighs). Abdominal fat is a strong sign of insulin resistance and excess androgens. Women with PCOS are also known to have poor micro vascular uterine function, which may cause implantation failure. Exercise training may improve micro vascular function in PCOS women by enhancing nitric oxide vasodilation.(5) References 1. Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS, Szapary PO, Rader DJ, Edman JS, Klein S. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med. 2003 May 22;348(21):2082-90. 2. Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. NutrMetab (Lond). 2005 Dec 16;2:35. 3. Klonoff DC. The beneficial effects of a Paleolithic diet on type 2 diabetes and other risk factors for cardiovascular disease. J Diabetes Sci Technol. 2009 Nov 1;3(6):1229-32 4. Palomba S, Giallauria F, Falbo A, Russo T, Oppedisano R, Tolino A, Colao A, Vigorito C, Zullo F, Orio F. Structured exercise training programme versus hypocalorichyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study. Hum Reprod. 2008 Mar;23(3):642-50. 5. Sprung VS, Cuthbertson DJ, Pugh CJ, Daousi C, Atkinson G, Aziz N, Kemp GJ, Green DJ, Cable T, Jones H. Nitric Oxide-mediated cutaneous micro vascular function is impaired in PCOS but can be improved by exercise training. J Physiol. 2013 Jan 14. Fertility - Impact of Insulin Resistance Part IV: Supplements for Insulin Resistance and Fertility By: Fiona McCulloch BSc, ND White Lotus Naturopathic Clinic and Integrated Health 18 Greenfield Ave.,Suite #201 Toronto, ON. M2N 3C8 www.whitelotusclinic.ca Myo-inositol Myo-inositol as an insulin-sensitizing supplement that is useful in polycystic ovarian syndrome and other insulin resistant fertility concerns. At a dose of 4 grams per day, myo-inositol improves ovarian activity, insulin sensitivity and fertility in patients with PCOS.(1) Myo-inositol also decreases testosterone(2) and is a marker of good egg quality.(3) N-Acetyl Cysteine A study on 37 women with PCOS found that 1.8 grams daily of NAC improved insulin resistance by reducing insulin levels and increasing insulin sensitivity.(4) Another study on 100 women with PCOS found that 600mg of NAC three times daily had effects comparable to metformin on lowering insulin, male hormones, and improving menstrual cyclicity.(5) A study on 180 patients with PCOS taking 1.2 grams of NAC daily along with the ovulation inducer Clomid had improved ovulation and pregnancy rates when compared to Clomid alone.(6) Fish Oil Fish oil may decrease insulin resistance. In a study of 12 overweight men and women who had insulin resistance, 70% of the participants taking fish oil decreased insulin resistance.(7) EPA and DHA from fish oil also increase adiponectin,(8) which improves insulin resistance. Omega 3 fatty acids from fish oil also lower the inflammatory markers(9) secreted by the fatty tissue in patients with insulin resistance. This improves implantation in patients suffering with infertility.(10) EPA and DHA also prevent fatty acid oxidation and reduce inflammation in adipose tissue, favouring insulin sensitivity.(11) Vitamin D Vitamin D is also crucial for treating insulin resistance in patients with fertility concerns. Vitamin D has been found to improve insulin resistance and lower androgen levels in women with PCOS.(12) Low levels of vitamin D are associated with increased insulin resistance markers in PCOS women.(13) Alpha Lipoic Acid (ALA) Numerous studies exist supporting the use of alpha lipoic acid in insulin resistant and diabetic conditions.(14) ALA has been found to increase peripheral insulin sensitivity,(15) decrease waist circumference(16) and act as an antioxidant.(17) all of which benefit insulin resistance and infertility. A 2010 study administered 600mg bid of controlled release ALA to PCOS patients. At the end of the treatment, there was a 13.5% improvement in insulin sensitivity, an improvement in menstrual cyclicity, and a reduction in triglycerides. Insulin resistance is one of the most common factors in fertility concerns. It affects the entire reproductive cycle, from egg development and quality, to the implantation and maintenance of a pregnancy. Fortunately, there are effective ways to reduce insulin resistance with diet, lifestyle changes and supplement therapies, allowing conception to happen with greater ease and even better, significantly improved underlying health. References 1. Unfer V, Carlomagno G, Dante G, Facchinetti F. Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. GynecolEndocrinol. 2012 Jul;28(7):509-15. doi: 10.3109/09513590.2011.650660. Epub 2012 Feb 1. 2. Ciotta L, Stracquadanio M, Pagano I, Carbonaro A, Palumbo M, Gulino F. Effects of myo-inositol supplementation on oocyte's quality in PCOS patients: a double blind trial. Eur Rev Med Pharmacol Sci. 2011 May;15(5):509-14 3. Chiu TT, Rogers MS, Law EL, Briton-Jones CM, Cheung LP, Haines CJ. Follicular fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality. Hum Reprod. 2002 Jun;17(6):1591-6. 4. Anna Maria Fulghesu, Mario Ciampelli, Giuseppe Muzj, Chiara Belosi, Luigi Selvaggi, Gian Franco Ayala, Antonio Lanzone, N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome, Fertility and Sterility, Volume 77, Issue 6, June 2002, Pages 1128-1135 5. Oner G, Muderris II. Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome. Eur J ObstetGynecolReprod Biol. 2011 Nov;159(1):127-31 6. Salehpour S, Sene AA, Saharkhiz N, Sohrabi MR, Moghimian F. N-Acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. J ObstetGynaecol Res. 2012 Sep;38(9):1182-6. 7. Denkins, Y, Experimental Biology 2002 Conference, April 20-24 2002 8. NalinSiriwardhana, Nishan S. Kalupahana, NaimaMoustaid-Moussa, Chapter 13 - Health Benefits of n-3 Polyunsaturated Fatty Acids: Eicosapentaenoic Acid and Docosahexaenoic Acid, In: Se-Kwon Kim, Editor(s), Advances in Food and Nutrition Research, Academic Press, 2012, Volume 65, Pages 211-222, 9. Kalupahana NS, Claycombe KJ, Moustaid-Moussa N. (n-3) Fatty acids alleviate adipose tissue inflammation and insulin resistance: mechanistic insights. AdvNutr. 2011 Jul;2(4):304-16. 10. Ng SC, Gilman-Sachs A, Thaker P, Beaman KD, Beer AE, Kwak-Kim J. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J ReprodImmunol. 2002 Aug;48(2):77-86. 11. Kalupahana NS, Claycombe KJ, Moustaid-Moussa N. (n-3) Fatty acids alleviate adipose tissue inflammation and insulin resistance: mechanistic insights. AdvNutr. 2011 Jul;2(4):304-16 12. Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E, Erturk E, Imamoglu S. The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010 Apr;33(4):234-8. 13. Wehr E et al, Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol. 2009 Jul 23. 14. S Jacob, P Ruus, R Hermann, H.J Tritschler, E Maerker, W Renn, H.J Augustin, G.J Dietze, K Rett, Oral administration of rac-α-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial, Free Radical Biology and Medicine, Volume 27, Issues 3–4, August 1999, Pages 309-314, 15. Kamenova P. Improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration of alpha-lipoic acid. Hormones (Athens). 2006 Oct-Dec;5(4):251-8. 16. Udupa AS, Nahar PS, Shah SH, Kshirsagar MJ, Ghongane BB. Study of comparative effects of antioxidants on insulin sensitivity in type 2 diabetes mellitus. J ClinDiagn Res. 2012 Nov;6(9):1469-73. 17. Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C. Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential. MolNutr Food Res. 2013 Jan;57(1):114-25.