Obesity and Infertility
Course AuthorsL.J. Moran, B.N.D., and R.J. Norman, M.D. Dr. Moran is in the Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, The University of Adelaide, Australia and Dr. Norman is in CSIRO Health Sciences and Nutrition, Adelaide. Ms. Moran and Dr. Norman report no commercial conflict of interest. Estimated course time: 1 hour(s). Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.  
Learning Objectives
Upon completion of this Cyberounds®, you should be able to:
 
Overweight and obesity are serious and prevalent conditions that constitute a significant economic burden in Western countries.(1) The causes of obesity and overweight are complex, and likely involve interactions between genetic and environmental factors. Using the classification of body mass index (BMI, kg/m(2)), 54 % of the US adult population is overweight (BMI >25) and 22% is obese (BMI >30).(2) In Australia, 56 % of the adult population is overweight and 18% is obese. The proportion of Australian adults who are obese has doubled during the past 20 years.(3) This is attributed to societal change to a more sedentary lifestyle, decreases in physical activity, and changes in the energy density and composition of people's diets. This trend is spreading as more developing countries adopt Western lifestyles and diets. The increasing prevalence of obesity is a significant health issue because it is associated with many other conditions, including impaired psychosocial health, type II diabetes mellitus, cardiovascular disease (CVD), osteoarthritis, sleep apnea, and breast and uterine cancer.(4) Obesity and overweight are additionally associated with infertility and reproductive hormone abnormalities in women; 4 - 10% of women of reproductive age have polycystic ovary syndrome (PCOS), an endocrine condition with reproductive and metabolic consequences including anovulation, infertility and an increased prevalence of diabetes mellitus. PCOS in particular is associated with overweight and obesity. This Cyberounds® will briefly discuss the research linking obesity and infertility in women, assess the efficacy of weight loss on infertility in obese women, and discuss the most effective means of achieving and maintaining weight loss. Defining and Diagnosing ObesityWhile a range of research methods are available for the precise measurement of amount and localization of fat and lean mass, including skinfold thickness, underwater weighing, dual energy x-ray absorptiometry (DEXA), magnetic resonance imaging (MRI) and infrared spectroscopy,(4) a simple and reliable definition of obesity is needed for clinical use. Although it does not distinguish between lean mass and fat mass, BMI is a useful clinical tool that correlates reasonably well with adiposity (Table 1). Table 1. Classification of Overweight in Adults According to Body Mass Index.
Adapted from Seidell JC.(1) Abbreviations: BMI = body mass index Body fat distribution also plays a role in metabolic and reproductive health;(5),(6),(7) it is therefore important to identify the degree of abdominal adiposity in a clinical setting to assess the patient's risk of developing metabolic and reproductive problems. Different locations of abdominal fat may confer different risks, with evidence suggesting that abdominal visceral fat correlates more strongly with insulin resistance and markers of the metabolic syndrome than does subcutaneous fat.(8) While more sensitive imaging tools, such as computed tomography (CT) scans and MRI, are needed to accurately distinguish between fat depots, this is not practical in a clinical setting. Waist-to-hip ratios (WHR) or waist circumference measurements provide a reasonable estimate of abdominal fat without distinguishing between visceral or subcutaneous fat. Generally, a WHR >0.9 for men and >0.8 for women defines an increased risk of CVD. Waist circumference (measured midway between the lowest rib and the iliac crest) is a simpler clinical method and some research suggests this may be a more accurate determinant of health risk(9) (Table 2). Table 2. Waist Circumference Predicts Risk of Metabolic Complications Associated with Obesity.
Adapted from Seidell JC.(1) NB: Level 1 is intended to alert clinicians to potential risk for CHD whereas level 2 should initiate therapeutic action. Obesity and Reproductive DysfunctionReproductive processes are influenced by body weight and reproductive dysfunction will occur with both positive and negative extremes of body weight.(10),(11) Menstrual disturbances including oligomenorrhea, amenorrhea and anovulation have been consistently related to obesity in women. Obesity, defined as 20 % over ideal body weight, was present in 43% of women of reproductive age with menstrual disorders (n = 100) and 48 % of women with amenorrhea (n = 60), compared with 13% of an age-matched control group (n = 201).(12) A direct relationship between menstrual irregularity and the degree of obesity in women (n = 26,638) of reproductive age was reported by Hartz et al.(13) Infertility is also associated with obesity. In women who had not previously been pregnant (n = 204), an increased relative risk (RR) for infertility with ovulatory dysfunction was observed for women over their ideal body weight (RR = 2.1).(10) Lake et al.(11) observed an increased infertility rate for obese women (33.6 %) compared with women of normal weight (18.6%). In a subset of The Nurses' Health Study, women with ovulatory disorders (n = 2, 527) were compared with controls with no history of infertility (n = 46, 718); increased BMI at age 18 was significantly associated with ovulatory infertility -- a multivariate-adjusted RR of 2.4 for a BMI of 28 -- 29.9 and a RR of 2.7 for a BMI ³ 30.(14) Furthermore, obesity presents a greater risk of complications with pregnancy, including gestational diabetes and miscarriage.(15),(16) Reduced fecundity (the probability of achieving at least one pregnancy during treatment) may additionally be observed with increased weight. In 3,586 women receiving assisted reproductive treatment (ART), there was a significant linear reduction in fecundity from non-obese to obese women.(17) Thus, there is a clear association between obesity (both in adulthood and childhood) and menstrual abnormalities and consequent infertility. Abdominal Obesity and Reproductive FunctionThe association between abdominal obesity, menstrual abnormalities and infertility is also apparent, although it has not yet been elucidated whether it is the visceral or subcutaneous depot that is related to reproductive dysfunction. Hartz et al.(18) found that for women with upper body fat predominance (WHR >0.8), the relative risks of irregular menstruation and oligomenorrhea were 1.56 and 2.29, respectively, compared with women with a lower body fat predominance. In 40,980 postmenopausal women, WHR was significantly positively associated with a history of infertility.(19) Zaadstra et al.(7) documented a 30% decrease in the probability of conception for each 0.1 increase in WHR in women of reproductive age (n = 500) presenting for ART. Android obesity is additionally associated with a low pregnancy rate after in vitro fertilization (IVF).(20) PCOS and Reproductive FunctionWomen with PCOS constitute a significant proportion of the infertile population. In the Nurses' Health Study, 22.5% of women with ovulatory infertility were diagnosed with PCOS, compared with 3.8% of controls.(14) Women with PCOS tend to have a BMI outside of the acceptable range and a central distribution of adiposity. Obesity prevalence estimates in women with PCOS range from 35 -- 63%.(21),(22) WHR measurements >0.8 have been reported in 63%(23) and 53% of women with PCOS(22) compared to 35% of Australian women.(3) Obesity and abdominal obesity worsen the clinical features of menstrual irregularity and infertility in PCOS.(24) Insulin Resistance, Androgens, Obesity and Reproductive FunctionThe link between obesity and infertility is complex. In addition to having altered gonadotrophin levels, obese women often exhibit varied reproductive hormone profiles with increased serum androgens (predominantly the ovarian androgens testosterone and androstenedione) and reduced serum sex-hormone binding globulin (SHBG). Abdominal fat is related to decreased SHBG and increased androgenicity in infertile women.(25),(26),(27) Obesity and abdominal obesity are strongly associated with insulin resistance.(28) Increased androgen production and reduced binding of androgens to SHBG contribute to hyperandrogenism, resulting in anovulation through inhibition of follicular maturation. Evidence also suggests that hyperinsulinemia increases ovarian androgen production(29) and decreases serum SHBG.(30) This is of particular significance for a considerable proportion of women with PCOS, in whom insulin resistance has been consistently documented in lean and obese women compared to weight-matched controls.(31) Obesity and abdominal obesity may, therefore, contribute to hormonal aberrations that increase the prevalence of anovulation, irregular menstruation and infertility. The impact of obesity is greater in women with an underlying metabolic abnormality such as PCOS. Treating ObesityAs a precursor to pharmacologic intervention (such as clomiphene citrate, gonadotrophins and insulin-sensitizing agents), treatment of obesity itself should be the initial therapeutic goal for obese infertile women. Reduction of fat and abdominal fat should result in improved menstrual function and fertility as well as a reduction of metabolic risks. In cases in which infertility is linked to insulin resistance, weight loss is again a logical option because weight loss and lowering of abdominal fat reduce insulin resistance.(32) Weight Loss Improves Reproductive Function in Overweight Infertile WomenIn a study of obese women with menstrual dysfunction (n = 35), weight loss of 22.4 lbs over approximately 32 weeks reduced androgens and resulted in a 29% pregnancy rate and 80% improvement in menstrual function.(33) Several investigators have observed similar improvements in menstrual dysfunction and infertility following weight loss in obese women.(34),(35) Analogous results are seen in women with PCOS. Weight loss results in increases in SHBG,(36),(37) reductions in testosterone and androgenicity,(27),(36),(38) improved menstrual function,(39) improved conception rates and reduction in miscarriage rates.(39) These results are often observed in conjunction with improved insulin sensitivity and reduction of abdominal fat. Indeed, Huber-Buchholz et al.(40) found abdominal fat loss was critical in restoring ovulation in obese women with PCOS. How Much Weight Loss Is Needed?A small weight loss is sufficient to restore reproductive health in infertile obese women. Resumption of ovulation occurred with weight losses of 12 -- 14 lbs in anovulatory women. This amount of weight loss is generally sufficient to reduce abdominal fat and improve insulin sensitivity. A 2 -- 5% reduction in body weight was associated with restoration of ovulation, an 11% reduction in abdominal fat, a 4 cm reduction in waist circumference and a 71% increase in insulin sensitivity.(40) Furthermore, reproductive improvements occurred in women with BMIs >30 (i.e., women still classified as obese). Large reductions in weight may not be needed to restore reproductive function, and, therefore, realistic and achievable weight loss goals can be set for overweight infertile women. How Is This Weight Loss Best Achieved?Obesity and overweight can be treated with a variety of strategies, including dietary management, physical activity, behavior modification, pharmacologic treatment and surgery.(4) Dietary management should be adopted initially with pharmacologic and other interventions reserved for when dietary changes have proved unsuccessful. In situations in which short-term energy restriction results in rapid weight loss and improved reproductive and metabolic health, more than 90% of people who lose weight eventually regain their original weight.(41) Therefore, the practical question to address is how to best achieve and maintain weight loss. The National Institutes of Health (NIH) report, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults recommends a multifaceted approach to treating obesity (Table 3).)(42) Table 3. (Paraphrased from) National Institutes of Health Clinical Guidelines for Long-term Treatment of Overweight and Obesity.
Adapted from National Institutes of Health(42) Dietary TreatmentDietary treatment of obesity aims for gradual weight loss (1 -- 2lbs/week) through reduced caloric consumption and increased physical activity, with the overall goal of energy expenditure exceeding energy intake. Tailoring an intervention to a person's individual weight, and current dietary and exercise patterns, increases the chance for sustained weight loss. A dietitian may aid in evaluating dietary intake and eating patterns and in designing an effective diet. An energy deficit of 500 -- 600 kcal/day is generally well tolerated and sustainable over an extended period of time.(4) A diet low in fat (~30% of calories from total fat and ~10% of calories from saturated fat), moderate in protein (~15% of calories) and high in carbohydrates (~55%), with increased consumption of fiber, whole-grain breads and cereals, fruit and vegetables, in conjunction with moderate regular exercise (30 -- 60 minutes/day), is proposed to aid in weight loss and maintenance in both the general population and in obese infertile women with PCOS.(43) Incorporation of low glycemic-index foods into a healthful eating plan may aid in weight loss through increased satiation.(44) For patients in whom there is concern over the potential adverse effects of increased carbohydrate intake on HDL-C and triglyceride levels, a moderate substitution of monounsaturated fat for carbohydrates may alleviate this effect and be of added benefit. This is consistent with the American Diabetes Association recommendations for dietary treatment of type 2 diabetes mellitus.(45) Some PCOS support groups have additionally recommended increasing dietary protein to displace carbohydrates in the diet. These regimens may aid in increased weight and fat loss(46) as a result of the increased satiating power of dietary protein compared with carbohydrate and fat.(47) Higher protein diets may improve insulin sensitivity through maintenance of lean body mass.(48) There is, however, currently no evidence to support this strategy in obese infertile women or in those with PCOS. The success of a dietary pattern in the short-term provides no guarantee that weight will not be regained. Diets based on healthful eating principles have a better long-term outcome, which is important because weight loss maintenance requires that changes in eating habits be sustained for life. Lifestyle ModificationAddressing a number of lifestyle factors can improve long-term reproductive and metabolic health. Exercise is helpful in the management of infertility by reducing insulin resistance,(49) limiting loss of lean muscle mass during weight loss(50) and aiding in weight loss maintenance.(51) Furthermore, the combination of exercise and dietary intervention will increase the success of a weight loss regime. Other lifestyle factors that influence fertility include smoking and alcohol consumption. Smoking is a major risk factor for reduced fertility in women, with consequences including extended time to pregnancy, preterm birth and low birth weight in babies born to mothers who smoke.(52) High levels of alcohol intake have been associated with reduced fertility and increased risk of spontaneous abortion.(53) Cessation of smoking and reduction of alcohol intake are therefore important treatment goals. Stress is another contributing factor. Cognitive-behavior therapy and reduction of psychosocial stressors can promote both weight loss and its maintenance.(54) A weight loss program undertaken in a group environment additionally provides psychologic support.(55) The aforementioned principles were applied in the Fertility Fitness program in Adelaide, Australia, and showed remarkable success. These programs involve weekly dietetic and psychologic intervention in a group environment and use a multidisciplinary team approach, with an obstetrician/gynecologist, psychiatrist, dietitian, fitness professional and nurse. Over a 6-month period, a 13.6 lb weight loss was associated with restoration of ovulation in 12 previously anovulatory women and with pregnancy in 11 women, as well as decreased insulin and testosterone. Women continued to lose weight after the completion of the 6-month program, indicating that long-term lifestyle changes can be achieved.(37) In an additional study of 67 women,(39) participants lost an average of 22.4 lbs, with ovulation restored in 60 previously anovulatory women and pregnancy achieved in 52 women. Miscarriage rates were reduced from 75% pre-intervention to 18% post-intervention.(39) Lifestyle modification programs are non-invasive, less costly than pharmacologic treatments and frequently successful in achieving reproductive improvements. Metabolic Complications of Obesity and PCOSThe aforementioned lifestyle modification principles can also help reduce the associated metabolic morbidity and mortality risks. This is critical because obese women and women with PCOS, in particular, are at an increased risk of diabetic and cardiovascular morbidity and mortality. A lifestyle modification program involving regular exercise, a diet low in saturated and trans fat and high in cereal fiber compared overweight subjects with Impaired Glucose Tolerance (IGT) with a control group over 4 years. A weight loss of 9.2 lbs in the intervention group resulted in a 58 % reduced risk for diabetes compared with the control group, which had a 1.7 lb weight loss.(56) In a 16-year follow-up study (n = 84, 941), the incidence of diabetes mellitus was 90% lower in subjects who had the following characteristics: a BMI >(25); consumed a diet high in cereal fiber and polyunsaturated fat, low in saturated fat, trans fats and glycemic load; exercised regularly; did not smoke; and consumed alcohol in moderation.(57) A weight loss of approximately 10% can improve metabolic variables,(58) and the aforementioned dietetic principles are additionally associated with reduced risk for cardiovascular disease.(59) These principles are similar to those taught in the Fertility Fitness program and indicate that, with appropriate dietary changes, both metabolic and reproductive parameters can be improved. ConclusionObesity is a serious health issue that results in increased metabolic and reproductive morbidity. The distribution of obesity is additionally important, with reproductive dysfunction associated with increased abdominal adiposity. A clear relationship is exhibited between obesity and reproductive morbidity, including anovulation and menstrual irregularity, reduced conception rates, reduced response to fertility treatment, and miscarriage and other pregnancy complications. This is particularly dominant in a subset of infertile women with PCOS in whom insulin resistance plays a strong etiologic role. Reduction of obesity and abdominal obesity is associated with improvements in reproductive function and should be adopted as the first course of action in the treatment of obese, infertile women. Indeed, weight loss (as little as 11 lbs) consistently improves insulin resistance, menstrual dysfunction and infertility in obese women. It is, therefore, crucial to identify ways to increase the ease of achieving and maintaining weight loss. Principles identified in the general population and in obese infertile women include adoption of healthful eating plans and engaging in moderate amounts of low-intensity exercise that can be sustained as lifestyle changes. Modifying additional factors (such as alcohol consumption, smoking and psychosocial stress), as well as utilizing a group environment, can increase the long-term success and maintenance of weight loss and associated improvements in reproductive and metabolic parameters (Table 4). Table 4. Principles for Treatment of Infertility in Obese Women.
Abbreviations: BMI: body mass index, PCOS: polycystic ovary syndrome |