The growing obesity epidemic has significant impact on overall health, but it is a particular burden on reproduction. Given that two-thirds of reproductive age women and one-third of men are overweight or obese, the burden of weight on reproduction and pregnancy complications has become an increasing point of concern [1,2▪▪]. Most literature has been based on smaller studies or reviews that were fraught by heterogeneity of outcomes that range from ovulation rates, clinical pregnancy rate (CPR), live birth rate (LBR), and a variety of weight loss interventions [3▪▪]. Historically, literature on reproductive outcomes and BMI has focused on the female population, and to a lesser extent, how weight loss interventions impact reproductive outcomes. Alternatively, the impact of male obesity on fertility has been given little attention [4▪]. This review provides an assessment of current literature of how obesity affects reproduction in both males and females, as well as interventions to improve outcomes.
DEFINITIONS AND PREVALENCE
BMI, or the ratio of a patient's weight in kilograms compared to their height in meters squared, has been standardized to establish a healthy weight (BMI 18.5–24.9 kg/m2); underweight (<18.5 kg/m2); overweight (25–29.9 kg/m2); class I obesity (30–34.9 kg/m2); class II obesity (35–39.9 kg/m2); and class III obesity as (>40 kg/m2) (Table 1) . The 2016 World Health Organization estimated that 1.9 billion or 39% of adults worldwide were overweight and 650 million are obese . Data indicates that 12% of infertility is the result of abnormal BMI alone, which seems to be correlated with BMI as those with morbid obesity had a 6.9-fold risk of infertility compared to normal BMI (2.9–16.8, P < 0.0001) [6,7] Additionally, pregnancy outcomes are negatively affected with an increase in fetal anomalies, preeclampsia, gestational diabetes, and stillbirth .
FEMALE OBESITY AND REPRODUCTIVE DYSFUNCTION
Obesity is known to impact reproductive capacity at a multitude of levels, including insulin resistance, alterations of reproductive hormones, oocyte/embryo development, endometrium, increase in miscarriage rates, and adverse artificial reproductive outcomes. In fact, menstrual irregularity is three times more common in obese women than those with normal BMI, which contributes to a 15% decrease live births per year . A culmination of new research delineates the effect of obesity on reproductive capacity and often relates back to how adipose tissue acts as an endocrine organ and disrupts the hormonal milieu.
Functioning as an endocrine organ, excess adipose tissue can lead to increased insulin levels and insulin resistance, which is more prevalent in overweight women and is positively correlated with increasing BMI compared to those of normal weight (23.4% in normal weight, 36.7% in overweight; 39.9% in obese, P < 0.001) [10▪]. This causes an increase in peripheral androgens, decrease in hepatic sex hormone binding globulin (SHBG) production and hypothalamus-pituitary-gonadal (HPG) dysfunction [11▪▪,12▪▪,13]. A confounding point is the incidence of polycystic ovarian syndrome (PCOS) in the obese population, and whether insulin resistance is related to or the cause of PCOS and infertility. Some studies have shown that up to 30% of obese individuals have PCOS and there is an increased prevalence of insulin resistance in PCOS obese women (83.6 versus 46.3%, P < 0.001) [10▪,11▪▪]. Yet, not all obese individuals have PCOS, insulin resistance, or are infertile [11▪▪]. This was demonstrated by a recent prospective control study that analyzed the demographics of infertile women and found no difference in the rates of infertility with obese PCOS or non-PCOS women (20.9 versus 17.5%) [14▪]. This confounding picture supports the notion that infertility in obese women is likely multifactorial and involves other hormones.
Leptin, produced by adipose tissue, is also an important hormone that plays a vital role in communicating adipose store status and energy balance to the hypothalamus. Increased leptin, due to obesity, directly effects the hypothalamus, which then modulates the effect of luteinizing hormone (LH) on the granulosa cells, as well as impacting the secretion of gonadotropin releasing hormone (GnRH) [13,15▪▪,16▪▪]. Its constant elevation causes downregulation of leptin receptors and relative leptin resistance [16▪▪]. The high leptin levels negatively affect the secretion of kisspeptin, resulting in altered GnRH release and decreased LH secretion [15▪▪,17▪]. Rehman et al. found that there was a positive correlation between the ratio of kisspeptin to leptin and improved CPR in assisted reproductive technology (ART) cycles, reinforcing the important role of these hormones in reproduction [17▪]. In direct contrast to leptin, increasing adipose tissue is inversely correlated with adiponectin levels . Low levels of adiponectin not only affect the release of LH/GnRH, but also decreases the utilization of insulin [13,16▪▪]. Its reduced expression continues to perpetuate the cycle of abnormalities seen in the HPO axis, with decreased secretion of LH and subsequent ovulatory dysfunction [11▪▪].
Obesity has also been shown to impact oocytes at multiple levels, including molecular dysfunction, which results in smaller oocytes that are less mature/competent, and higher rates of apoptosis [11▪▪,18▪]. At the organelle level, meiotic spindles in obese mice have been noted to be disorganized, and changes were seen in mitochondria and endoplasmic reticulum, such as an increased number of vacuoles, abnormal distribution within the cell, decreased cristae, and an increase in stress markers [11▪▪]. A case–control study reported that obese women had statistically significant reduction in oocyte size (157.9 versus 164.3 μm, P < 0.0001) and number of mature oocytes (15.1 versus 9.7, P < 0.001) [18▪]. Higher degrees of inflammation were noted in follicular fluid, as indicated by higher levels of C-reactive protein, interleukin-6, tumor necrosis-alpha, insulin, lactate, and leptin. Additionally, there are lower levels of anti-inflammatory markers, including adipokine or glutathione, which impact oocyte maturation. It has been suggested that this may result in lipotoxicity that occurs when the amount of fatty acids overwhelms the storage system, leading to an increase in reactive oxygen species (ROS), and a decrease in ovarian development and survival [11▪▪,15▪▪]. Abnormalities in lipid or cholesterol synthesis may also lead to changes in ovarian development [18▪].
BMI has a significant negative impact on ART, requiring higher doses of gonadotropins, longer stimulation cycles, and a lower oocyte yield [12▪▪,16▪▪]. A retrospective cohort study of over 50 000 cycles in the United States showed a dose-related response with more cycles canceled [adjusted odds ratio (OR) 1.5, P < 0.001], less oocytes retrieved (adjusted incidence ratio 0.93, P < 0.001), and less usable embryos (adjusted incidence ratio 0.95, P < 0.001) that was most notable in individuals with worsening obesity [19▪].
Leptin and insulin are also vital for embryo formation and changes lead to improper embryologic development [20▪]. Former literature has demonstrated that BMI has no impact on the rate of aneuploidy, which has not been duplicated in recent years, but rather has focused on the potential for inadequate insulin/glucose pathways and alterations seen in leptin suggests an impact on embryo development [21,22]. Some studies suggest blastocyst formation may be impaired, with a statistically significant decrease in normal blastocyst development in the overweight/obese population (57.2 versus 43.6%, P < 0.007) . In contrast, other studies showed no difference in quality of embryos; however, the primary outcome was not embryo development [18▪].
The donor egg model allows one to discern the impact of the oocyte versus the endometrial environment. Cardozo et al. divided donors into quartiles by BMI, and as BMI increased CPR and LBR decreased – even after controlling for donor and recipient age/BMI . This indicates that there is an impact of BMI prior to implantation. This information was also supported by a retrospective review of 4600 fresh autologous cycles that had a decrease in implantation rates with increasing BMIs [24▪]. In contrast, other reviews suggest no differences in outcomes of obese individuals. One systematic review showed equivocal results of implantation rates with variable recipient BMI and donor eggs/embryos, as did a large retrospective cohort study of over 450 women utilizing autologous gametes that found no effect on LBR with increasing maternal BMI [11▪▪,24▪]. Additionally, an older study utilizing gestational carriers, exhibited no difference in outcomes of LBR with normal weight, overweight, or obese individuals (75, 83, or 78%) . These data support the theory that infertility is related to the HPG axis or ovarian dysfunction rather than on implantation.
Utilizing nearly 500 000 cycles from United States’ ART surveillance system, an increase in miscarriage rate was noted with obesity [adjusted risk ratio (aRR) 1.23; 95% confidence interval (CI) 1.20–1.26] . The rate of miscarriage also seems to be dose dependent; one systematic review showing that the OR in overweight individuals to be 1.15 (95% CI 1.05–1.26) versus obese at 1.52 (95% CI 1.28–1.81), and another showing the lowest intrauterine pregnancy rate (38.8%) in those with class III obesity [3▪▪,26]. A lower LBR was seen in the overweight population (pooled OR 0.90, aRR 0.87, 95% CI 0.86–0.88), which took a significant impact in individuals with a BMI more than 40 with a 50% reduction in LBR [11▪▪,26]. This was corroborated by an older Danish study of more than 12 000 women which showed a 12% reduction in LBR in overweight women and a 25% reduction in the obese population. However, this was not seen when in vitro fertilization (IVF) was combined with intracytoplasmic insemination (ICSI) . Overall, there is clearly a linear correlation between increasing BMI and rising rates of infertility.
FEMALE OBESITY INTERVENTIONS
Weight loss has been a proposed management for the reproductive problems seen with obesity, due to improvement of HgA1c, lipid profiles, and diabetes risk. However, previous literature has provided little evidence to support that this improves ART outcomes [27▪▪]. Importantly, some studies have shown that spontaneous pregnancy rate was improved in those with weight loss (10.5 versus 2.6%, P = 0.009), thus showing some benefit and cost effectiveness with the avoidance of IVF in these individuals [28▪▪].
This improvement in ovulation rate has been shown when analyzing the impact of weight loss and ovulatory dysfunction. In a systematic review of anovulatory overweight/obese individuals, 30–60 min of vigorous exercise per day improved ovulation rate [29▪]. The main confounding factor was whether the restoration of ovulation was due to exercise or weight loss. Also, they did not address obese ovulatory individuals. Additionally, excessive vigorous exercise (>60 min), was seen to have a decrease in reproductive outcomes [29▪]. Exercise has been known to improve insulin resistance by decreasing adipose tissue, increasing the use of glucose at musculoskeletal level, and increasing SHBG, even without weight reduction [29▪]. It has been a common practice to encourage exercise, particularly in obese individuals; however, exercise may also impact energy expenditure and increase stress hormones that negatively impact reproduction, making recommendations difficult [29▪]. Therefore, more information is needed to determine if exercise assists anovulatory individuals of a normal BMI or overweight ovulatory women.
When specifically evaluating IVF outcomes, the largest study to date was the Dutch Lifestyle study, which randomized patients to weight loss prior to IVF to immediate IVF. Although there was a statistically significant weight loss in the delayed group, the vaginal birth after 2 years was higher in the those randomized to immediate treatment (35.2 versus 27.1%, rate ratio 0.77, 95% CI 0.6–0.99) . Of note, nearly 20% of those randomized to weight loss (delayed treatment) dropped out of the study ultimately limiting the power of the study. In a recent small randomized multicenter trial utilized an intense weight loss program with a substantial weight loss (−9.44 kg versus +1.19 kg) also had no improvement in IVF outcomes [27▪▪,28▪▪].
Recently, several systematic reviews have analyzed weight loss and exercise in obese individuals. They noted significant heterogeneity between studies yet concluded that there was no improvement in IVF outcomes and LBR with weight reduction but did observe improvement in spontaneous ovulation and natural pregnancy rate [12▪▪,27▪▪,28▪▪,31▪]. A confounder that is difficult to account for is the time required to obtain optimal weight that may reduce reproductive outcomes through advanced age alone.
MALE OBESITY AND REPRODUCTIVE DYSFUNCTION
Similar to women, increasing male obesity has been negatively correlated with fertility, with a 12% increased risk of infertility for every three units of BMI more than 25 [2▪▪,13]. This is likely due to changes in normal hormones and inflammation that causes dysregulation of the HPG axis, insulin, changes in SHBG and leptin, and subsequent spermatogenesis [2▪▪,32▪–34▪]. Obesity has also been shown to affect spermatogenesis at a molecular level with potential modifications of histones, methylation, and hydroxylation as well as several others [33▪]. It is difficult to know where this dysregulation begins; however, most literature suggests it is due to excess adipose tissue. Adipose tissue releases numerous factors and has several comorbid conditions that lead to poor overall health and reduction in reproductive capacity.
A decrease in SHBG leads to an increase in free testosterone that is aromatized to estrogen peripherally by adipose tissue. The elevated estrogen acts as negative feedback on the HPG axis, preventing appropriate levels of LH/FSH that are needed for spermatogenesis [2▪▪,35▪,36▪]. Additionally, leptin acts at the hypothalamus, testes, and even spermatozoa, and is vital in puberty and reproduction [2▪▪,37▪]. Its constant elevated presence causes downregulation of receptors, leading to the inability of leptin to exert is central effects. It is unknown if this is due to indirect stimulation of GnRH receptors via kisspeptin neurons or through direct stimulation of premamillary nucleus, which acts on GnRH and kisspeptin [2▪▪,37▪]. Furthermore, elevated estrogen levels may also directly impact kisspeptin and lower GnRH release [2▪▪]. However, considering that not all obese men are infertile, other mechanisms must be impacting fertility outside of the HPG axis.
Multiple studies have supported the changes in semen profiles seen in obesity, although there are inconsistencies in the parameters affected [36▪]. The most consistent abnormalities noted are oligospermia (OR 1.11–3.3, 95% CI 1.01–1.21), azoospermia, sperm morphology, DNA fragmentation index (OR 2.5, 95% CI 1.2–5.1), and alteration of the mitochondrial action membrane potential [4▪,33▪–36▪,38▪]. One study displayed a positive correlation with the rate of oligospermia with increasing BMI [34▪]. Other reviews have shown an increased OR of fewer total motile sperm (OR 3.4, 95% CI 1.12–10.60) and asthenospermia in obese males (OR 1.82, 95% CI 1.20–2.77) [2▪▪,35▪]. These changes in sperm parameters may be due to irregularities in sperm genetic modifications, such as noncoding RNA, DNA methylation, and histones [2▪▪,35▪,36▪]. Another possible etiology could be due to the increase in inflammation, ROS, and adipokines from adipose tissue that impact both primordial germ cells and differentiation of sperm [33▪,36▪,37▪].
There has been a void of data on embryo quality when considering male obesity. Building evidence has suggested that sperm have roles beyond donating paternal chromosomes and are essential in the formation of a healthy embryo [2▪▪]. This was supported by a decrease in LBR (OR 0.65, 95% CI 0.44–0.97) in ART cycles among obese males [2▪▪,36▪]. However, a recent retrospective chart review of nearly 1000 embryo transfers found no difference in LBR when controlling for obesity, age, or abnormal sperm [39▪]. This suggests that male factor can be overcome with ART. A Danish study of more than 12 000 men also showed no change in LBR with BMI more than 25 with either IVF or IVF with ICSI . Notably, these studies are in ART and do not reflect natural pregnancy rates.
MALE OBESITY AND INTERVENTIONS
Recent information has focused on male obesity and interventions to reduce adverse reproductive outcomes. Weight loss via diet and exercise has been shown to improve hormone levels such as SHBG, testosterone, inhibin B, and estrogen, as well as promote improvement in epigenetic changes and sperm parameters [2▪▪,33▪,35▪]. Additionally, a reduction in weight was thought to assist with potential external mechanisms of infertility including changes in thermoregulation of the testicles, sleep apnea that alters nocturnal LH pulses or chronic hypoxia, erectile dysfunction, and diabetes. There is limited to no information regarding the effects of medicinal induced weight loss or bariatric surgery, but one could extrapolate that any form of weight loss may improve hormonal and sperm outcome [33▪]. One review did support the improvement of free and total testosterone after bariatric surgery, with an associated decrease in leptin and CRH [38▪]. However, it is vital to note that an improvement in these parameters does not directly associate with the couple's primary outcome: a live birth.
The literature surrounding reproduction and elevated BMI reinforce its detrimental impact in both men and women due to alteration of the HPG axis, gametogenesis, and poor IVF outcomes. However, the research surrounding this topic has been exceedingly heterogeneous, making it difficult to draw conclusions without a high degree of bias. Further studies with human models utilizing a standard approach would assist in determining a better causative relationship between infertility and BMI. Moreover, it is vital as obstetricians and gynecologists that we target couples prior to attempting pregnancy about the detrimental impacts weight may have on future family planning and pregnancy outcomes.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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Review that outlines male infertility from genetic, extrinsic, and hormonal aspects. Also incorporates various weight loss methods and potential implications on infertility.
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Systemic review from over 50 years of data and pooled outcomes from numerous sources concerning obesity and clinical pregnancy, live birth, miscarriage rates, as well as IVF outcomes. They highlighted areas with high heterogeneity between studies.
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Cross sectional study analyzing infertile women with and without PCOS and the rate of the different phenotypes of PCOS, obesity, and insulin resistance. There was an association between PCOS and insulin resistance, as well as obesity and insulin resistance; however, obese and nonobese PCOS women had equivalent rates of insulin resistance.
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Extensive review on female infertility and the aggregated literature concerning mechanisms behind HPG axis, ovarian, embryo, and endometrial dysfunction.
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Systematic review concerning both male and female obesity and adverse reproductive outcomes, specifically integrating sources concerning weight loss via exercise and/or diet with pregnancy/live birth rate, and so on. Reinforced the lack of quality studies in males and the extreme heterogeneity between different methods of weight loss and/or definitions of exercise as well as the reproductive outcome of interest.
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Extensive summary on initially various mechanisms of infertility, then comprehensively covers how obesity impacts hormonal/endocrinologic function and therefore the HPG axis, oocytes/embryo development, and pregnancy outcomes. Last, it briefly discusses positive effects of weight loss compared to the time it requires.
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A small multicenter cross-sectional study that analyzed the association between the relationship between Kisspeptin and Leptin in infertile individuals, categorizing by BMI. One of the first studies that demonstrated a correlation between the ratio of the two levels to CPR, which was seen more often in those of normal weight.
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Case-controlled, single-site study that compared oocyte size and maturity to BMI, determining a correlation between smaller and less mature oocytes with increasing BMI. They proposed the lower implantation and higher miscarriage rate is due to oocyte quality.
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A large retrospective cohort study of more than 50 000 cycles that analyzed underweight, normal BMI, and obese individuals with respect to reproductive outcomes (CPR, LBR, usable embryos, oocytes retrieved). They demonstrated statistically significant decreased OR of all outcomes in overweight individuals, that positively correlated with increasing BMI. Data was less strong for those with low BMI.
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Murine study demonstrating that obese and underweight mass had abnormal response to follicle stimulating hormone, with increase in progesterone that perpetuates abnormalities seen in the hormonal cycle.
21. Goldman KN, Hodes-Wertz B, McCulloh DH, et al. Association of body mass index with embryonic aneuploidy. Fertil Steril
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Single-site retrospective cohort study that stratified women by BMI (including underweight), who had same ART, with primary outcome of implantation rate. They found no difference in adjusted OR, but were underpowered for those with low BMI or obese.
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Literature review and commentary on the lack of quality information concerning the relationship between effective weight loss and improved reproductive outcomes. Highlights that this may be more targeted to specific patient populations, such as those who are anovulatory.
28▪▪. Einarsson S, Bergh C, Friberg B, et al. Weight reduction intervention for obese infertile women prior to IVF: a randomized controlled trial. Human Reprod
Multicenter randomized control trial analyzed intense weight loss regiment prior to initiating ART versus those who undergo ART without intervention. Powered to determine a 13% difference in LBR. They determined no difference in ART outcomes; however, an increase in spontaneous pregnancy in individuals who achieved weight loss.
29▪. Hakimi O, Cameron LC. Effect of exercise on ovulation: a systematic review. Sports Medicine (Auckland, NZ)
Retrospective review analyzing all studies concerning exercise and its intensity on ovulation. They found an association of improved ovulation with moderate exercise and a decrease in intense exercise; however, noted several gaps in literature especially concerning anovulation with normal weight individuals.
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Systematic review covering articles that looked at interventions to improve weight in females prior to attempting pregnancy and fertility outcomes. They did see an increase in natural pregnancy rate; however, noted that studies all had different methods of preconception interventions and measurable outcomes.
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Short statement concerning the imbalanced ratio of literature of infertility and obesity in females versus males. Discussed potential harms of rapid weight loss prior to reproduction and encouraged lifestyle changes many months prior to attempting pregnancy.
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Review concerning how male obesity reduces fertility through its impact on the HPG axis, hormonal changes, medical comorbidities, and epigenetic changes. Last briefly covers mechanisms of weight loss with its limited data on improvement of hormonal parameters but not necessarily reproductive outcomes.
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Review of patients from both infertility clinics and general population, stratifying by BMI, and correlating with fertility parameters. They determined an increasing OR for abnormal semen parameters and vital hormones (lutenizing hormone, follicle stimulating hormone, AMH), with rising BMI.
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Retrospective cohort of semen parameters and the association between BMI. Comprehensive list of a variety of semen parameters, notably elevated BMI was associated with lower volume, sperm count, concentration, motility, oligospermia, and asthemospermia. They used a cutoff of a BMI more than 25 as obese and class II obesity more than 30.
36▪. Raad G, Hazzouri M, Bottini S, et al. Paternal obesity
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Review covering the change in metabolism, reproductive cells, and semen parameters with male obesity, while highlighting the lack of information on the quality of embryos with male obesity.
37▪. Malik IA, Durairajanayagam D, Singh HJ. Leptin and its actions on reproduction in males. Asian J Androl
Review specifically analyzing on the effects of leptin throughout puberty and then reproductive life in males through previous human and murine research. Also identifies the limited information on how leptin interacts through the HPG axis.
38▪. Di Vincenzo A, Busetto L, Vettor R, Rossato M. Obesity
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Review that features the insufficient knowledge of reproductive outcomes after bariatric surgery in men. They found improvement in some parameters such as testosterone; however, conflicting information on semen parameters, and they question whether the nutritional deficiencies seen after bariatric surgery could had a negative impact on reproduction.
39▪. Capelouto SM, Nagy ZP, Shapiro DB, et al. Impact of male
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Retrospective chart review that analyzed the impact of abnormal semen parameters, age, and male BMI on donor oocyte cycles with IVF/ICSI. They found no difference in the primary outcome of LBR.