Assessment of Nutritional Status and Its Influence on Ovarian Reserve: A Systematic Review.

We conducted a systematic review following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework [ 22 ]. Study quality was assessed using the Cochrane Collaboration Risk of Bias tool [ 23 ] (Higgins, J. et al., 2011), which consists of seven items covering six domains of bias. Each item is classified as having a high, low, or unclear risk of bias. Electronic searches were carried out in the international databases Medline, ScienceDirect, and the Cochrane Library. Additional articles were identified by a hand search of the reference lists of identified articles. The search strategy was designed to identify full-text, published articles and included MeSH (Medical Subject Heading) terms and the terms title and abstract. The following keywords, transformed into MeSH terms, were used: “ovarian reserve”, “anti-Müllerian hormone”, “nutritional status”, and “body mass index” combined with the Boolean operators AND and OR. The search strategy used in PubMed is shown in Table 1 . Articles for full-text review were selected by screening the titles and abstracts of all publications yielded by the systematic search of Medline, ScienceDirect, and the Cochrane Library. The articles were independently reviewed by two authors, who checked the inclusion and exclusion criteria. The quality of each study was assessed by the same authors working separately using the Crombie criteria adapted by Petticrew and Roberts. Any discrepancies were resolved by a third author. For cross-sectional studies, the AXIS critical appraisal tool [ 24 ] was used to assess quality and risk of bias ( Table 2 ). The quality of cohort and case–control studies was assessed using the Newcastle–Ottawa Scale [ 25 ] ( Table 3 ). Randomized clinical trials were assessed using the PEDro tool [ 26 ] ( Table 4 ). The first and second authors (L.P.-H. and C.Á.P.-J.) independently scored each article, with discrepancies resolved by agreement with the third author (A.Z.-M.). Cohen’s kappa statistic (κ) was calculated to assess interrater reliability for risk of bias assessments. Assessment of blinding of participants or observers was not performed as all the studies were rated as high risk by both authors based on the overall items. Interrater reliability analyzed using Cohen’s κ yielded an intraclass correlation coefficient of 0.8. The inclusion criteria were (1) open-access articles with an abstract and full text, (2) articles written in English or Spanish, (3) articles published between 2011 and 2021, and (4) articles that included women aged between 18 and 46 years. The exclusion criteria were (I) protocols and articles unrelated to the topic; (II) review articles, systematic reviews, and meta-analyses; (III) conference proceedings; (IV) studies involving women undergoing ART procedures; and (V) studies of women with a serious disease or a condition that could diminish ovarian reserve. The first author extracted all relevant data from the articles, namely, year of publication (2011–2021), study design and objectives, year of study conduct, sample size, mean participant age, country of origin, study results, and conclusions. The data extracted from the texts were grouped into two blocks to analyze, including (I) the variables used to assess ovarian reserve and nutritional status and (II) the association between ovarian reserve and nutritional status.

There is growing interest in the links between lifestyle, reproductive health, and fertility. Against a backdrop of social change, recent years have witnessed an increasing trend towards delayed motherhood, with many women choosing to wait until their 30s or 40s to have their first child. According to the National Statistics Institute, the average age of Spanish mothers in 2021 was 33.05 years [ 1 ], which was above the European average of 29.5 years [ 2 ]. The data collected since the start of this registry also attest to a growing trend towards delayed motherhood in Spain. Moreover, an increasing number of couples are being diagnosed with infertility or conditions that make it difficult to become pregnant [ 2 ]. The World Health Organization’s definition of infertility is a “disease of the male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse” [ 3 ]. Infertility affects between 15% and 20% of couples of reproductive age in developed countries. In Spain, one in six couples have fertility issues, which is reflected in the growing demand for assisted reproductive technology (ART) procedures in recent years [ 2 , 4 ]. Concerns about rising infertility rates have intensified research into the environmental causes of infertility, although most research to date has centered on the influence of male infertility and sperm-related issues [ 5 ]. The main causes of female infertility are anovulation, endometriosis, fallopian tube disorders, pelvic adhesions, uterine anomalies, and diminished ovarian reserve [ 6 ]. Ovarian reserve refers to the number and quality of oocytes and is an indicator of reproductive potential [ 7 ]. It is one of the most important factors for achieving natural pregnancy and a strong predictor of ART success. Ovarian reserve is inversely correlated with maternal chronological age, the main determinant of reproductive capacity and success. Reproductive aging is considered to accelerate after the age of 35 years [ 8 ]. The assessment of ovarian reserve is therefore an important step in both the evaluation and treatment of infertility. Markers of ovarian reserve include antral follicle count (AFC), assessed by transvaginal ultrasound, and serum levels of various biomarkers, such as anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) [ 6 , 8 ]. While these markers are easy to measure, few studies have investigated the causes of diminished ovarian reserve [ 9 ]. Well-known factors associated with reduced oocyte quantity and quality are genetic alterations [ 10 ]; gynecological conditions, such as endometriosis, tumors, infections, and ovarian surgery; and eating disorders, such as anorexia nervosa [ 7 , 9 ]. Recent research has also highlighted the potential effects of environmental and lifestyle factors, such as chronic stress, exposure to certain endocrine disruptors, diet, and nutritional status [ 10 , 11 , 12 , 13 ]. Nutritional status is assessed using a range of anthropometric parameters, including body mass index (BMI), body fat composition (% of fat), body perimeters, and waist circumference or waist-to-hip ratio. BMI has been used for decades to classify individuals as underweight, normal weight, overweight, or obese [ 14 ]. Obesity has been defined as the pandemic of the 21st century due to its global effects on morbidity, mortality, quality of life, and health expenditure [ 15 ]. In 2020, 61.4% of men and 46.1% of women in Spain were considered to be overweight or obese [ 1 ]. Overweight and obesity are linked to an increased prevalence of reproductive disorders and chronic diseases, such as cardiovascular disease and certain cancers [ 16 , 17 ]. Several studies have shown that a BMI outside the normal range affects female reproductive capacity. Obesity has been associated with menstrual disorders, anovulation, hirsutism, and higher miscarriage and infertility rates [ 17 ]. Impaired fertility in women with a high BMI is linked to changes in the hypothalamic–pituitary–ovarian (HPO) axis that induces endocrine and metabolic disorders, with adipose tissue acting as a key regulator [ 18 ]. In obese women, the upregulation of enzymes involved in androgen metabolism in adipose tissue can cause hyperandrogenism. The increased peripheral aromatization of androgens to estrogens, combined with the reduced production of sex-hormone-binding globulin (SHBG), exerts negative feedback on the HPO axis in obese women, inhibiting folliculogenesis [ 18 ]. Another physiological mechanism underlying the effects of obesity on reproductive capacity is the association between obesity and insulin resistance [ 19 ]. Obesity causes adipocyte hyperplasia and hypertrophy, resulting in a greater volume of adipose tissue. As an endocrine organ, adipose tissue secretes multiple proteins known as adipokines. The expansion of this tissue contributes to altered adipokine profiles, with a predominance of proinflammatory cytokines (mainly interleukin-6 and tumor necrosis factor-α), resulting in low-intensity chronic inflammation that can cause muscle and liver insulin resistance [ 19 ]. Obese women are thus prone to chronic low-grade inflammation and insulin resistance, both of which are associated with impaired reproductive function and late spontaneous abortion after ART [ 20 , 21 ]. Based on the evidence suggesting an important role for optimal nutritional status in fertility, we designed a systematic review to assess the influence of nutritional status on ovarian reserve in women of reproductive age.

The search yielded 103 articles. Five duplicate studies were removed before the selection process. Of the remaining 98 articles, 23 were excluded due to duplication and 55 due to exclusion criteria. Twenty studies were thus included in the systematic review ( Figure 1 ). The characteristics of the articles included in this systematic review are summarized in Table 5 . Six articles were conducted in the USA [ 28 , 29 , 30 , 31 , 32 , 38 ], two in France [ 42 , 44 ], two in China [ 34 , 43 ], and one each in Taiwan [ 21 ], Australia [ 33 ], Scotland [ 41 ], Turkey [ 45 ], the United Arab Emirates [ 40 ], Israel [ 46 ], India [ 35 ], Brazil [ 36 ], Denmark [ 37 ], and the Philippines [ 39 ]. The mean age of the study participants was 32.3 years. There were eight cross-sectional studies [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], seven cohort studies [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ], four case–control studies [ 42 , 43 , 44 , 45 ], and one randomized clinical trial [ 46 ]. The total number of participants analyzed in the 20 studies was 5929. The study variables used to assess nutritional status and ovarian reserve are summarized in Table 6 . BMI was used to assess nutritional status in all the studies. Five studies also measured weight and height [ 32 , 33 , 34 , 43 , 45 ], and one assessed waist circumference [ 31 ]. AMH was used exclusively to assess ovarian reserve in seven studies [ 30 , 31 , 32 , 33 , 38 , 39 , 46 ]. Six studies used a combination of AMH and other serum biomarkers, namely FSH and LH [ 34 , 37 , 41 , 42 , 43 , 45 ]. Eleven studies used serum markers and AFC assessed by transvaginal ultrasound [ 27 , 28 , 29 , 35 , 36 , 37 , 40 , 42 , 43 , 44 , 45 ]. Three studies evaluated biochemical parameters (cholesterol, high-density lipoprotein (HDL), and triglycerides) [ 31 , 32 , 41 ], and five included smoking as a confounder [ 28 , 29 , 30 , 37 , 38 ]. Table 7 shows the relationship between BMI and AMH, together with the results and conclusions of each study. Five of the studies concluded that a high BMI was associated with diminished ovarian reserve based on below-normal serum AMH levels or AFC [ 27 , 28 , 35 , 41 , 44 ]. One of these studies [ 41 ], which divided the sample into three subgroups based on cardiometabolic, psychological, and reproductive profiles, concluded that low ovarian reserve was associated with cardiovascular and psychological factors. Another [ 29 ] found correlations between a high BMI and diminished ovarian reserve, particularly in Caucasian women. Finally, one study reported that a high BMI had a negative effect on inhibin B levels [ 35 ]. Two studies [ 31 , 32 ] indicated a possible positive relationship between a healthy cardiometabolic profile and AMH levels. Bleil et al., who investigated the association between variations in reproductive aging and cardiovascular risk factors, also determined that low and medium AMH levels were associated with a larger waist circumference and higher cholesterol, indicating the need for longitudinal studies to determine whether this association is mediated by BMI [ 31 ]. The same group, in a later study of ovarian reserve, reported that infertile women had a larger waist circumference than fertile women [ 28 ]. Two studies of women with polycystic ovarian syndrome (PCOS) reported differences in ovarian reserve between women with a high and a normal BMI [ 27 , 44 ]. Both detected significant differences and found that women with PCOS and a BMI > 25 had lower AMH levels than those with a BMI within the normal range. Yang et al. also investigated associations between iron levels, obesity, and ovarian reserve in women with PCOS, finding evidence of diminished ovarian reserve and higher iron levels. These variables correlated with insulin resistance and reduced menstrual period frequency. Another study investigating the association between AMH and metabolic syndrome in women with PCOS concluded that AMH was positively correlated with HDL cholesterol and SHBG and negatively correlated with glucose, insulin, blood glucose, BMI, and blood pressure [ 32 ]. Table 8 shows a summary of the relationships between BMI, AMH, and AFC.

The aim of this systematic review was to evaluate the association between nutritional status and ovarian reserve in women of reproductive age. Eleven of the twenty studies analyzed showed lower AMH levels in obese women [ 27 , 28 , 29 , 32 , 34 , 35 , 36 , 41 , 44 ]. Five studies included BMI as a confounder [ 30 , 33 , 40 , 43 , 46 ], and the other six found no evidence that nutritional status influenced ovarian reserve [ 31 , 38 , 39 , 40 , 41 , 46 ]. The above findings are consistent with previous reports. Vitek et al. studied the relationship between BMI, AMH, and oocyte yield in women undergoing in vitro fertilization; of the 29,895 women studied, 16,579 were obese, and 13,316 had a normal BMI. Compared to normal-weight women, women with a high BMI had lower AMH levels (1.8 ± 2.0 vs. 2.1 ± 2.0, p < 0.001) and a lower oocyte yield (11.9 ± 7.3 vs. 12.8 ± 7.7, p < 0.001) [ 47 ]. Several publications have reported a negative correlation between BMI and AMH in women of late reproductive age [ 48 , 49 ]. Freeman et al., in a study of 122 women with a mean age of 45.8 ± 5.2 years, found that AMH levels were 65% lower in obese women than in non-obese women [ 48 ]. Steiner et al., who investigated the effects of oral contraceptive use and AMH levels in obese and normal-weight women, observed a 34% reduction in AMH levels in the former [ 50 ]. Another study observed a correlation between obesity and biochemical and ultrasound markers of ovarian reserve, showing lower AMH levels in obese women compared to normal-weight women of a similar age. AFC, by contrast, was similar in both groups [ 51 ]. Marca et al. found that AMH levels decreased with increasing BMI [ 52 ]. Ovarian reserve can also be assessed by AFC. We observed lower oocyte quality and AFC in overweight and obese women, confirming previous findings [ 29 , 35 , 44 , 53 , 54 , 55 ]. Chronic inflammation caused by obesity induces ovarian oxidative stress, which affects the different stages of folliculogenesis (development, maturation, and ovulation). Some authors have indicated that obesity might affect oocyte quality via lipotoxicity, a mechanism marked by the persistent, unregulated release of cytokines from adipose tissue which have even been detected in follicular fluid [ 35 , 56 , 57 ]. Several authors have suggested that ART could improve the chances of pregnancy in obese women, albeit with an increased risk of spontaneous abortion [ 56 , 58 ] and implantation failure [ 54 ]. These risks could be reduced by using oocytes from lean donors [ 59 , 60 ]. This systematic review confirms previous findings showing that metabolic syndrome, understood as a combination of central obesity, elevated blood pressure, elevated triglycerides, elevated fasting glucose, and reduced HDL-cholesterol, has an important role in female fertility. Cardozo et al. suggested that metabolic syndrome might also affect endometrial receptivity as it appears to influence both oocyte and embryo quality [ 61 ]. Similarly, Snider et al. found that obesity-dependent changes in the gut microbiome contributed to lower oocyte quality [ 57 ]. Several studies have reported contrasting findings on the link between nutritional status and ovarian reserve [ 39 , 53 , 62 , 63 , 64 , 65 ], possibly because of the use of small samples with few obese women. Dolleman et al., for instance, in a study of 2320 women of reproductive age, found that AMH levels were lower in oral contraceptive users and did not correlate with BMI [ 53 ]. Sahmay et al. suggested that reduced fertility rates in obese women are more likely to be due to impaired endometrial receptivity [ 62 ]. This systematic review has some limitations. First, we may have missed some evidence as we only analyzed studies published in English and Spanish. Second, we searched just three databases: Medline, Science Direct, and the Cochrane Library. Future studies could target additional databases such as Web of Science and Embase. Third, we excluded studies of women undergoing ART procedures as low ovarian reserve is not the only reason for the use of these treatments. The main strength of this study is that it is one of the few systematic reviews to evaluate the influence of nutritional status on ovarian reserve in women of reproductive age.

Nutritional status can influence ovarian reserve in women of reproductive age. Overweight and obesity have a negative impact on ovarian function as women with a high BMI had significantly lower AMH levels and AFC than those with a normal BMI. Overweight and obesity can also affect oocyte quality, leading to higher rates of subfertility and infertility and a greater demand for ART procedures. Suboptimal nutritional status, however, can jeopardize the chances of ART success by inducing a detrimental inflammatory environment in the ovaries. Future studies are needed to inform the design of prevention and health promotion strategies to improve the nutritional status of women of reproductive age.