Approximately 55% of American women of childbearing age are overweight or obese and approximately 5% suffer from extreme or morbid obesity. The overweight and obesity epidemic has signiﬁcantly affected risks in obstetrics and gynecology. Increased antenatal and perinatal complications in overweight and obese pregnancy women include (but are not limited to) gestational diabetes mellitus, stillbirth, fetal anomalies, fetal macrosomia, and cesarean delivery. The focus of the current review is on the implications of overweight and obesity on fertility and contraception.
Basic Researcher Perspective
By Kelle H. Moley, M.D.
Dr. Moley is the James P. Crane Professor of Obstetrics and Gynecology Vice Chair and division director of basic science research at Washington University School of Medicine, St. Louis, Mo.
Obesity is the result of a prolonged mismatch between energy intake and expenditure, leading to an excess of stored body lipids. This condition has signiﬁcant and longlasting effects on fertility. Our understanding of the possible mechanisms responsible for the reproductive sequelae come from animal studies, mostly in rodents, using both genetic and diet-induced obesity models.
Obesity results in central, gonadal, and uterine effects, impacting ovulation, oocyte quality, and implantation. This discussion supports the hypothesis that obesity affects all three sites.
Central Pathways and Neuropeptides
Hypothalamic reproductive function is regulated by neurons and their secreted neuropeptides, and these neurons can sense not only total nutritional availability but also changes in diet.1, 2 Reduced reproductive function and ovulatory dysfunction have been clearly linked to nutritional restriction in humans and animal models.3, 4 Most studies demonstrate decreased secretion of neuropeptides such as kisspeptin, galanin, leptin, and neuropeptide Y, and thus conclude that decreases in accessible energy substrates either directly or indirectly perturb signaling via the master regulator, the gonadotropin-releasing hormone neurons. Surprisingly, overnutrition in the form of obesity or chronic high-fat feeding leads to a hypothalamic hypogonadism phenotype, more similar to a low-energy balance state such as starvation. This phenomenon has been linked in high-fat fed mice to a decrease in kisspeptin-producing neurons in these neurons in the hypothalamus, resulting in a 60% reduction in pregnancy rates.5 Although these central events appear to be directly connected, genetic mouse models have emphasized the complexities of these pathways and suggest that other indirect mechanisms may be responsible for the integration of the reproductive and energy balance axes.
Mice fed a high-fat diet demonstrate decreased ovulation and fertility whereas fetuses of these mice have impaired embryonic development and growth restriction.8 Oocytes from obese mice are signiﬁcantly smaller, exhibiting delayed meiotic maturation and increased follicular apoptosis. The inciting metabolic factor is not clear; however, abnormal circulating and follicular ﬂuid levels of free fatty acids have been associated with poor oocyte quality and decreased pregnancy rates in women undergoing in vitro fertilization (IVF).
One proposed mechanism for compromised oocyte quality and poor reproductive outcomes in obese females includes altered mitochondrial activity at the oocyte stage. Oocytes have the largest number of mitochondria of any cell in the body and thus are vulnerable to many different metabolic stressors. Abnormal mitochondrial structure and function have been reported in oocytes from diet-induced obese mice resulting in poor fertilization rates and abnormal embryo development.8, 10, 11 Oocytes from high-fat fed obese mice experience uneven mitochondrial distribution, altered mitochondrial DNA copy number, and abnormal mitochondrial metabolism. These events appear to be linked to higher rates of spindle defects and chromosome misalignment in the maturing oocytes of diabetic animals.12 This higher rate of aneuploidy may be responsible for the increased miscarriage rates in obese women.
Since the fertilized zygote inherits only the maternal mitochondria, oocyte abnormalities and aberrant mitochondria carry over to the zygote stage and manifest even after transfer to non-obese recipients, thus suggesting a programming event that occurs during the periovulatory period.
The process of implantation and uterine receptivity is adversely affected by obesity and a high-fat diet in mice. This phenomenon may be associated with inﬂammation and abnormal lipid metabolism. First, global transcriptome proﬁling of a rat uterus following a high-fat diet reveals distinct signatures for genes regulating inﬂammation and lipid metabolism. Gene-set enrichment and pathway analysis suggest upregulation of uterine nuclear factor–kB and c-Jun-N-terminal kinase signaling. This induction is accompanied by a pattern of increased cytokines and other inﬂammatory process regulators.12 Second, high-fat feeding may result in morphological evidence of abnormal lipid accumulation in the uterine endometrium of rats.12 This ectopic localization of stored lipids has been linked to increased mRNA expression of several lipid metabolism genes such as FABP4, CD36, and lipoprotein lipase. Lipid accumulation in the uterine endometrium has also been described in the genetic obesity models, db/db and ob/ob.13 Although the data suggest that extensive pro-inﬂammatory gene expression together with uterine lipid accumulation occur in maternal obesity at the time of implantation, it is not clear how these observations affect uterine receptivity. Recent studies show that adiponectin and its receptors have distinct expression patterns during the peri-implantation and decidualization processes.14 Such events may interfere with attachment of the blastocyst or differentiation of the endometrial stroma leading to decidualization. Implications of these studies remain unexplored.
Health Disparities from an Animal Perspective
Although a seemingly odd pairing, two recent basic science studies in mice have informed clinical studies related to women’s health. These studies tested the hypothesis that the observed social and ethnic disparities in breast cancer incidence and mortality might be related to higher levels of social stress in vulnerable populations.9, 10 Both types of studies examined social isolation as a biological stressor in a female mouse model predisposed to develop mammary tumors. Peri-pubertal female mice were caged either individually or group-housed in the usual fashion of ﬁve mice to a cage, with all other parameters controlled. In the ﬁrst study, 14 weeks of social isolation was associated with up-regulation of lipid synthesis and glycolytic pathway gene expression, which led to the development of a signiﬁcantly larger mammary gland tumor burden than in group-housed mice.10 This study identiﬁed putative biomarkers and targets for preventive intervention in breast cancer. Although the second study did not show a difference in tumor growth, the investigators determined that social isolation resulted in hypothalamic differences in kisspeptin expression associated with reduced duration of estrous cycles.9 Both studies modeled a potential cause of health disparity, namely social isolation, to inform the mechanism of disease. The same type of approach could be adapted to studies in obesity, because social and ethnic disparities play a key role.
Clinical Practitioner Perspective
By Samantha F. Butts, M.D., M.S.C.E.
Dr. Butts is the assistant professor of obstetrics and gynecology, Division of Infertility and Reproductive Endocrinology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia.
A growing body of research has emerged acknowledging the presence of differences in reproductive outcomes across racial and ethnic groups, with a goal of isolating basic determinants to improve outcomes for women at risk. One of the prevailing, modiﬁable correlates of reproductive risk that has high prevalence in ethnic and racial minorities (African Americans and Latinas compared to women of European descent) is the presence of obesity.1 Obesity is linked to many reproductive problems that are disparate between racial and ethnic groups including early puberty, infertility, assisted reproductive technology (ART) outcomes, and perinatal risks (i.e., stillbirth and preeclampsia). Although it has been hypothesized that racial and ethnic reproductive disparities have numerous environmental and genetic underpinnings, obesity as a link between disparities and reproductive challenges will be the focus of this review.
Overweight, Obesity, and Diminished Fecundity: Anovulation and Beyond
Multiple reports demonstrate that risk of early pregnancy loss increases both after unassisted conception and after conception with infertility treatments in overweight and obese women.2 Mechanisms of impaired fecundity in obese women are unclear, but Study of Women’s Health Across the Nation (SWAN) investigators found that women with a BMI greater than 25 kg/m2 have decreased luteinizing hormone (LH) amplitude and mean serum LH levels, with a longer follicular phase and a shortened luteal phase.3,4 LH alterations likely have an impact on follicular development and ovulation, with implications for endometrial development and embryo implantation. Several reports of large cohorts have noted an adverse impact of obesity on ART outcomes, with respect to attenuated response to gonadotropins, increased cycle cancellation rates, diminished clinical pregnancy rates, and diminished live birth rates.5,6 In contrast, the majority of reports suggest that donor egg IVF pregnancy rates are not affected when the donor egg recipient is obese.
Polycystic ovary syndrome (PCOS) affects 5%–10% of reproductive-age women.6 Overweight and obesity are most notably associated with disordered ovulation and menstrual cycle irregularity, in women with this disorder. Anovulation is the primary defect leading to infertility in obese women with PCOS. The Cooperative Multicenter Reproductive Medicine Network Trial of Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome demonstrated that independent of assigned treatment (clomiphene citrate, metformin, or the treatments combined), subjects with a body mass index (BMI) greater than 30 kg/m2 had a signiﬁcantly lower rate of live birth than those with BMI less than 30 kg/m2.
Overweight, Obesity, and Contraceptive Efficacy
Oral contraceptive pill (OCP) failure rates in the general population are higher than in clinical trials, which tend to enroll subjects who are close to ideal body weight.8 This discrepancy has led to a concern that hormonal contraceptive failures in general are increased in overweight and obese women compared to normal weight women. Proposed mechanisms for diminished effectiveness of hormonal contraception in overweight and obese women include rapid hepatic drug metabolism/clearance and sequestration of lipophilic drugs in fat stores.9 Observational studies have reported an increased risk of OCP failures in overweight and obese women—even when restricting the analysis to consistent users—who had greater than double the risk of pregnancy compared to normal weight women.9 Conversely, a randomized trial comparing ovarian suppression in normal weight and obese women who were consistent OCP users found no difference in ovarian suppression between groups.8 The results of several current studies have been contradictory, making the ﬁnal answer to this question elusive. A Cochrane Review has addressed the issue of hormonal contraceptive efﬁcacy in obese and non-obese women across drug delivery types. At present, and based on only one trial referenced, it is possible that Depo-Provera has comparable efﬁcacy in normal weight and overweight women. However, the authors conclude that a limited number of heterogenous studies using varied anthropomorphic measures, some excluding women over a certain body-size category, limits a deﬁnitive conclusion regarding whether hormonal contraception is less effective in overweight and obese women.
Impact of Weight Loss on Fertility in Overweight and Obese Women
Weight loss should be a ﬁrst-line approach to addressing infertility in overweight and obese women who are anovulatory.6 A number of short-term clinical trials have demonstrated that weight loss in the range of 2%–10% of starting body weight restores menstrual cyclicity and/or ovulation in 44%–72% of anovulatory subjects.6, 11 Medical and surgical therapies for weight loss are recommended when obesity is associated with comorbidities or when lifestyle approaches have not been successful.
Bariatric Surgery and Reproductive Outcomes
Bariatric surgery results in the most profound and long-lasting weight loss of any method currently available. Weight loss for patients with a starting BMI of 40 kg/m2 or greater averages 20–40 kg over 2 years, with weight loss maintenance described for up to 10 years.6 Such weight loss has been demonstrated to confer signiﬁcant improvement in ovulatory dysfunction in obese women with PCOS. In one series of obese women with PCOS, menstrual regularity was noted in all participants between 6 and 12 months after weight loss surgery and was associated with reduced hyperandrogenism and improved insulin sensitivity.
Pregnancy is not recommended for at least 1 year after bariatric surgery—when weight loss is the most rapid. No signiﬁcant pattern of adverse perinatal outcomes has been associated with pregnancies occurring after bariatric surgery. However, patients who conceive after bariatric surgery should be followed by a nutritionist and those with adjustable laparoscopic gastric bands should consult with their surgeon during pregnancy if new onset gastrointestinal symptoms arise.
Approximately 55% of American women of childbearing age are overweight or obese and approximately 5% suffer from extreme or morbid obesity.13 This epidemic has signiﬁcantly impacted risks in obstetrics and gynecology especially in African American and Latina women in whom obesity is most prevalent. It is recommended that women who are overweight or obese be extensively counseled by providers about associated early pregnancy, antenatal, and perinatal risks and that this counseling occur prior to conception (if feasible) or early in pregnancy. Supervised weight loss is critical for reducing obesity-related reproductive risks. Whether or not obesity is deﬁnitively associated with hormonal contraceptive failure remains a matter of ongoing investigation. Although the results of future reports are forthcoming, it is critical to reinforce the basic principles of contraceptive efﬁcacy to our patients and to select approaches that minimize their risk.
Clinical Researcher Perspective
By Alex J. Polotsky, M.D., M.Sc.
Dr. Polotsky is an assistant professor, Department of Obstetrics and Gynecology at the University of Colorado Denver, Anschutz Medical Campus, Aurora.
The obesity pandemic is predicted to precipitate a decline in life expectancy in the 21st century. Over 32% of all U.S. adults are now obese as deﬁned by a BMI of greater than 30 kg/m2.1 By 2015, 75% of all US adults are projected to be overweight or obese with BMI of greater than 25 kg/m2.2 The reproductive consequences of female obesity are manifested by a variety of disturbances, including menstrual cycle irregularities, oligo-ovulation, higher risk of miscarriage and subfertility, decreased chances of success after fertility treatments, and higher risk of failure with some methods of contraception. On a population level, a compounded loss of fertility is likely, because obese women with an overweight or obese male partner have up to a two-fold further loss in fertility than their obese counterparts with normal weight partners. This report will concentrate on published clinical research studies devoted to the impact of female obesity on reproduction.
Impact of Female Obesity on Reproduction Should be Considered Distinctly from Evaluating Polycystic Ovary Syndrome
Traditionally, reproductive effects of female adult obesity were attributed to increases in anovulation, amenorrhea, and hyperandrogenism. Most of the existing body of literature concerning obesity and reproduction involves women with PCOS, a condition characterized by androgen excess and irregular menses and, frequently, accompanying obesity. This is understandable, because PCOS is regarded as one of the most common endocrinopathies in the general population, with an estimated 5%–8% prevalence among reproductive age women. However, simple obesity (also referred to as non-syndromic or “garden variety”) is considerably more prevalent than PCOS and affects every third woman in the United States. Importantly, several pathophysiologic features distinguish PCOS from obesity, most notably the opposing associations with indices of LH pulsatility. PCOS is characterized by increased serum LH, whereas simple obesity is generally associated with decreased overall serum LH and decreased LH pulse amplitude (see Table 1). Thus, it is imperative to avoid indiscriminate grouping of women in clinical studies of obesity and reproduction because inadequate characterization of research subjects could lead to misinterpreting the impact of adiposity per se.
Subfertility in Ovulatory Obese Women
Non-obstetric effects of female adult obesity on fertility are largely attributed to increased prevalence of anovulation. The impact of adiposity on reproductive outcomes in ovulatory obese women with preserved menstrual regularity is only recently coming to the forefront of investigative attention. Large body mass prolongs the time to pregnancy and is associated with sub-fecundity in women with regular menstrual cycles. An increase in waist-hip ratio by as little as 0.1 unit was associated with a 30% decrease in the per-cycle probability of conception in a study of 500 fertile women undergoing donor sperm insemination.3 In a cohort of over 3,000 subfertile couples in whom the female partner was conﬁrmed to be ovulatory, the probability of spontaneous conception declined with a BMI over 29 kg/m2.4 Multivariate analysis from the same study indicated that an increase in BMI by one unit resulted in a 4% reduction in the likelihood of conception. Data from SWAN, which included mostly ovulatory women, indicated that adolescent obesity was associated with a 3-fold increased risk of lifetime nulliparity and a 4-fold increased risk of lifetime nulligravidity, further underscoring the impact of obesity on lifetime childbearing potential.5 Although association of obesity with subfertility is well documented in population studies, our understanding of the pathophysiological phenomena underpinning these observations is limited.
>Relative Hypogonadotropic Hypogonadism and Corpus Luteum Insufficiency Are Potential Mechanisms to Explain Obesity-Related Reproductive Phenotype
Since the 1970s, obesity has been associated with longer follicular phases and decreased serum gonadotropins and luteal progesterone. More recently, a detailed evaluation of daily hormones from 836 ovulatory cycles indicated that women with BMI over 25 kg/m2 excreted signiﬁcantly less urinary LH, FSH, and progesterone metabolites.6 This relative hypogonadotropic hypogonadism of obesity could conceivably be explained by either central (hypothalamic or pituitary) or peripheral defects within the hypothalamic-pituitary-ovarian (HPO) axis. Several distinct lines of evidence implicate a defect in the central part of the HPO axis in obesity, speciﬁcally, a selective deﬁciency in the LH pulse amplitude. Notably, decreased LH pulse amplitude but unaffected LH pulse frequency has been reported in obese men. Studies from ovulatory morbidly obese women indicate a signiﬁcant reduction in LH pulse amplitude, yet no change in LH pulse frequency compared to normal weight controls.7 One of the potential pathophysiologic mechanisms for this association is altered or exaggerated sensitivity to estrogen negative feedback in obesity, a hypothesis that is being actively investigated in clinical studies.
Female Obesity Is Not Associated with Decreased Sexual Activity
Reduced exposure to sexual encounters either by decreased likelihood of ﬁnding a partner or by rare sexual intercourse may potentially explain the association of female obesity with subfertility. Research on frequency of sexual intercourse among women with large body mass yielded conﬂicting results. A study from 101 German adults suggested a signiﬁcant negative correlation between the body size and frequency of vaginal intercourse.8 However, several recent reports from larger studies demonstrated no differences in frequency of sexual activity by BMI. A report of 626 women in a Reproductive Medicine Network trial, found no difference by body mass in the frequency of timed sexual intercourse when instructed to do so for conception.9 Similar results were observed by the investigators from the 2002 National Survey of Family Growth.10 The analytic sample included 6,690 women aged 15–44 years who were surveyed about a variety of health outcomes. The study found that for most of the parameters describing sexual behavior, there was no appreciable difference in frequency of sexual activity by body mass. Compared to normal weight women, both obese and overweight women had signiﬁcantly higher likelihood of ever having had a heterosexual intercourse (77% and 56%, respectively). The main conclusion of this large study should not be ignored: Obese and overweight women do not report decreased frequency of sexual encounters compared to their leaner counterparts, and thus are in need of related contraceptive, sexually transmitted diseases prevention, and preconception services. This ﬁnding may be underappreciated by providers.
Obesity, Fertility, and Contraception: Disparities among Women
There are considerable gender and ethnic differences in regard to prevalence of obesity in the United States. The prominent paradigm of considerably higher female vis-à-vis male obesity in many countries has not been adequately explained. In the United States, African American women are reported to have the highest prevalence of high BMI. The latest National Health and Nutrition Examination Survey data reported a drastic disparity as age-adjusted prevalence of obesity was found to be 58.6% for non-Hispanic black women as compared with 32.2% for non-Hispanic white women.11 Data on health disparities among women in regard to obesity and fertility are sparse, but female obesity and its link with subfertility are beginning to be cited as a problem in the developing world. Of note, obesity is thought to inﬂuence the data on ethnic differences in epidemiology of PCOS, as illustrated by a recent report from South China where a relatively small 2.2% prevalence was reported among 915 women presenting for their annual physical.12 More studies are needed to explain why nations ﬂuctuate in the male-female obesity gap and why vast ethnic differences exist in prevalence of obesity in U.S. women and the impact of these disparities on fertility studies.