Undoubtedly, both the amount and the type of carbohydrates are essential in the context of a pro-fertility diet among women with lipid and glucose metabolism disturbances. However, this aspect is also essential in the diet of reproductive-aged women planning to become pregnant.
Fats constitute a vital dietary compound affecting fertility. Hohos and Skaznik-Wikiel (38) suggested that a high-fat diet can be associated with changes in the reproductive functions, including menstrual cycle length, reproductive hormone concentrations [e.g., luteinizing hormone (LH)], and embryo quality in the ART cycles.
Furthermore, it seems that the quality of fat is more important than its amount. The Chavarro et al. study (39) comprising 18,555 women planning a pregnancy or who became pregnant during the study demonstrated that increasing the intake of TFAs by even 2% resulted in a significant increase in infertility risk due to ovulation disorders. In contrast, Mumford et al. (40) did not observe associations between TFAs, SFAs, and the relative risk of anovulation in the BioCycle Study. It is worth bearing in mind that the Chavarro et al. study was conducted in the United States between 1991 and 1995, and the first cohort study indicating the harmfulness of TFAs appeared only in 1993 (41). On the other hand, the BioCycle Study was conducted between 2005 and 2007, when the United States already had mandatory labeling of the TFA content in foods containing ≥0.5 g TFAs/serving (42). Furthermore, in another study, the negative influence of TFA intake on fertility was observed among 1290 American women planning a pregnancy. However, this association was not observed among the Danish women and, as the authors suggested, may be associated with a low consumption of TFAs among this cohort due to the 2003 Danish law requiring a limit of TFAs in fats and oils to 2% of the total fatty acids (FAs) (42, 43).
TFAs have proinflammatory properties and may increase insulin resistance, increasing the risk of developing type 2 diabetes or other metabolic disturbances, including PCOS, which can negatively affect fertility (39, 44–47). It has been assumed that the direct negative effect of TFAs is associated with their influence on and a decreased expression of peroxisome proliferator–activated receptor γ (PPAR-γ). Moreover, the intake of TFAs was associated with the incidence of endometriosis (48). According to the Global Burden of Diseases Study, differences in TFA consumption between countries in 2010 range from 0.2% to 6.5% of energy intake, whereas the mean global TFA intake is 1.4% of the total energy intake (39). The highest intake of TFAs is observed in Egypt, Pakistan, Canada, Mexico, and Bahrain, although the WHO recommends limiting consumption of TFAs to <1% of total energy intake (40). Some countries, following the example of Denmark, have taken action to limit the amount of TFAs in food by introducing TFA limits in food or by compulsory labeling of products containing TFAs. It seems that prohibiting TFAs is the most effective approach to reduce the amount of TFAs in the food supply (49). In countries where there are no limits on the amount of TFAs in food, products high in TFAs can still be found in supermarkets and are often cheaper than their TFA-free counterparts. Therefore, it seems that it is necessary to continuously increase the nutritional awareness of the public, as well as to learn how to read labels in order to make proper nutritional choices (44).
On the other hand, ɷ-3 FAs can positively affect fertility, as they play an essential role in steroidogenesis and have significant anti-inflammatory properties (50, 51). Currently, the available studies indicate that ɷ-3 FAs from oily fish or supplements have a beneficial effect on the growth and maturation of oocytes, decrease the risk of anovulation, and improve embryo morphology, and are associated with higher concentrations of progesterone (40, 51, 52). However, the results of the association between ɷ-3 FAs and fertility are contradictory. In numerous studies, no association, or insufficient evidence, has been observed (39, 43, 53–56). It seems, however, that ɷ-3 FAs—by increasing insulin sensitivity and improving the lipid profile—may be helpful in the treatment of PCOS, although more studies are required (57). The supplementation of ɷ-3 FAs decreases follicle-stimulating hormone (FSH) among women with normal weight, which has not been observed in women with obesity. On the basis of this study, it is possible to suggest that ɷ-3 FAs extend the reproductive lifespan (58). Nevertheless, further investigations among women with a diminished ovarian reserve are critical. Nassan et al. (59) demonstrated that the consumption of fish, which is a good source of ɷ-3 FA, was associated with a higher probability of live birth following ART. On the other hand, according to the study by Stanhiser et al. (60), no association was observed between concentration of ɷ-3 FAs and the probability of becoming pregnant naturally. Additionally, the consumption of seafood increases sexual intercourse frequency and provides greater fecundity (61).
Conversely, MUFAs can bind with the PPAR-γ receptor, thus decreasing inflammation and positively affecting fertility. In fact, studies have presented a positive correlation between the consumption (62) and concentration in plasma (53) of MUFAs, fertility, and the time to achieve pregnancy.
Studies investigating the influence of dairy-derived fats on fertility are interesting, although the results are often contradictory. On the one hand, according to the study by Chavarro et al. (63), the consumption of low-fat dairy—including low-fat milk, yogurt, and cottage cheese—increased the risk of infertility due to anovulation, whereas high-fat dairy increased fertility. This may possibly be associated with a higher content of estrogen and fat-soluble vitamins in high-fat dairy. Moreover, it could also be assumed that the beneficial effect of dairy-derived fat may be associated with the presence of the trans-palmitoleic acid, which seems to improve insulin sensitivity (64, 65). On the other hand, Wise et al. (66) did not confirm that the consumption of high-fat dairy is correlated with increased fecundity, and they did confirm that consuming lactose and low-fat dairy did not negatively affect fertility.
It is vital to note that the consumption of >3 portions of dairy/d decreases the risk of endometriosis diagnosis by 18%, when compared with the consumption of 2 servings (67). Additionally, women consuming >4 portions of dairy daily during adolescence presented a 32% lower risk of endometriosis during adulthood than women consuming ≤1 portion (68). Moreover, the total dairy intake was positively associated with live birth among women aged ≥35 y (69).
Taking the abovementioned facts into consideration, a high consumption of MUFAs and PUFAs (including a high consumption of É·-3 from oily fish or from supplementation) with a low consumption of TFAs and SFAs should be recommended to childbearing-age women trying to become pregnant. Moreover, the evidence for a positive influence of reduced-fat dairy and an increased consumption of high-fat dairy is scarce; thus, it should not be recommended. However, more studies are necessary.
The next element of a fertility diet is protein. Chavarro et al. (70) suggested that animal protein consumption has been associated with a higher risk of infertility due to a lack of ovulation. In turn, the intake of plant protein increases fertility among women >32 y. The difference may stem from the disparate impact of plant and animal protein on insulin and IGF-I secretion. Insulin response is lower after plant protein consumption than following animal protein.
According to Mumford et al. (71), protein intake—in particular animal protein—correlated negatively with testosterone concentrations among healthy women. It seems that androgens, i.e., testosterone, play an important role in regulation of the ovarian function and female fertility. However, excessive androgen signaling seems to be a major factor in androgen-related reproductive disorders, since it disturbs the pathways regulating ovarian follicular dynamics (72). However, protein intake was not associated with estradiol, progesterone, LH, and FSH concentrations. Additionally, the study showed a lack of association between the total, plant, and animal (without protein from dairy products) protein intake and the amount of antral follicles among women experiencing infertility (71). On the other hand, a high protein intake from dairy products was connected with a decreased number of antral follicles, which is a biomarker predicting ovarian primordial follicle numbers (73).
Furthermore, increasing protein intake may improve carbohydrate-insulin balance, which seems to be important in treating infertility due to a lack of ovulation. It is vital to notice that protein presents the highest satiety properties, affects diet-induced thermogenesis, and protects muscle mass (74).
Future studies on protein's role in the diet of women attempting pregnancy are necessary. In fact, protein should be included in the diet in the amount recommended for the rest of the population, based on such elements as the level of physical activity. Additionally, the diet ought to contain especially plant protein sources.
It is possible that folic acid, vitamin B-12, and vitamin B-6 affect fertility. Studies indicate that the supplementation of folic acid (particularly in a dose higher than the recommended one for the prevention of congenital defects and combined with vitamin B-12) in the period prior to pregnancy may increase the chances of becoming pregnant and ART success. However, there is no randomized controlled trial on the impact of a high dose of folic acid associated with a positive response in observational studies (75).
In fact, fortification of cereals with folic acid increased the number of twin births in the United States. However, this possibly results from an increasing number of women using the ovulation-inducing drugs and not the increased folic acid intake (76). It is vital to note that folic acid supplementation has been negatively associated with a shorter length of the menstrual cycle (77). Murto et al. (78) showed that women with unexplained infertility supplemented more folic acid than fertile women. Additionally, women experiencing infertility had higher concentrations of folic acid and lower concentrations of homocysteine when compared with the control group. On the other hand, the intake of synthetic folic acid was associated with an increase in progesterone and a decreased risk of sporadic anovulation (79).
Additionally, women with methylenetetrahydrofolate reductase (MTHFR) mutation achieved a lower percentage of in vitro fertilizations than subjects without a mutation. On the other hand, the prevalence of implantation and clinical pregnancy was similar in both groups (80). Moreover, the concentration of vitamin B-12 and folic acid was not associated with in vitro fertilization probability (81).
The impact of folic acid, vitamin B-12, and vitamin B-6 on fertility is possibly associated with homocysteine metabolism. A lack of vitamin B-12 disturbs the remethylation process, whereas vitamin B-6 deficiency directly leads to an accumulation of homocysteine due to the induction of an enzyme called cystathione b-synthase. Consequently, the transsulfuration process, through which histamine is converted to cysteine, decelerates (82). Clinical studies show that hyperhomocysteinemia combined with a low concentration of folic acid constitutes a risk factor for recurrent miscarriage. Additionally, a higher homocysteine concentration has been associated with a faulty vascularity of chorion among women with a recurrent early pregnancy loss (83). In fact, it is homocysteine that induces trophoblast apoptosis and decreases chorionic gonadotropin (84), whereas a high concentration of homocysteine causes endothelial inflammation through increased expression of proinflammatory cytokines (85). Moreover, an increased homocysteine concentration in the ovarian follicle liquid may affect the interaction between the ovarian follicle and the spermatozoon, decreasing the chances of fertilization (86). Additionally, hyperhomocysteinemia increases oxidative stress, which affects women's fertility (87).
A cohort study including 259 women who were regularly menstruating and not using hormonal contraceptives and diet supplements showed a connection between a higher homocysteine concentration and an increased risk of a lack of ovulation by 33%. Furthermore, a higher folic acid to homocysteine ratio decreased the risk of anovulation by 10% (88). In fact, mild homocysteinemia is often observed in mothers of children with neural tube defects (89). It is vital to note that women experiencing PCOS present homocysteine metabolism disorders and a higher concentration of homocysteine in comparison to healthy women (90). The supplementation of folic acid is recommended for women with PCOS (91).
According to the recommendations, women should supplement with folic acid in the period prior to pregnancy, since supplementation is safe and does not cause side effects. Nevertheless, there is a further need for randomized trials confirming the impact of folic acid supplementation on fertility, as well as in doses higher than recommended for preventing neural tube defects (88).
Dr EliranVitamin D likely participates in the modulation of female reproductive functions. Studies have demonstrated that vitamin D receptors are expressed in numerous tissues of the reproductive organs, such as ovaries, endometrium, placenta, pituitary gland, and hypothalamus (92–95). Additionally, vitamin D affects various endocrine processes and the steroidogenesis of sex hormones (96, 97). A study indicated that serum concentration of vitamin D may be associated with PCOS and endometriosis and affects the success of ART (98). On the other hand, there was no association between vitamin D and fertility among healthy subjects (99). The deficiency of vitamin D affects calcium balance, increases the production and secretion of proinflammatory cytokines, as well as participates in glucose metabolism through stimulating the synthesis and secretion of insulin. Therefore, many studies discuss the impact of vitamin D on inflammatory diseases, including diabetes and cardiovascular disease (100). Moreover, vitamin D may be an essential component of PCOS development by means of regulating glucose metabolism (92). In fact, insulin resistance and hyperinsulinemia are associated with enhanced androgen synthesis in the ovaries and a lower concentration of SHGB (101).
The meta-analysis by He et al. (102) showed a lack of significant differences in vitamin D concentration between women with PCOS and healthy individuals. Nevertheless, the authors emphasized a significantly varied prevalence of vitamin D deficiency among women with PCOS that was associated with comorbidities. In fact, women with PCOS with vitamin D deficiency more frequently presented endocrine and metabolic disorders than women with the normal vitamin D concentrations. It is vital to note that vitamin D has anti-inflammatory and immunomodulating properties, and its deficiency may be associated with endometriosis, which is one of the causes of infertility (103, 104). In vitro animal studies (105–108) showed that vitamin D has beneficial effects on endometrial tissues, although clinical studies on the role of vitamin D in the diagnosis and treatment of endometriosis provide inconclusive evidence (109–111).
Furthermore, in a meta-analysis, Chu et al. (112) suggest that there is an association between vitamin D status and ART results. Additionally, the authors highlighted that vitamin D deficiency may be an essential factor in infertility treatment using ART. On the other hand, Abadia et al. (113) reported that vitamin D may be linked to a higher rate of fertilization in women undergoing ART. Nevertheless, this was not associated with a higher probability of live birth, or pregnancy.
Future studies are necessary to assess the association between vitamin D and PCOS, endometriosis, and with women's fertility. It is vital to note that a deficiency of vitamin D is common. Individuals presenting too-low concentrations of this vitamin should supplement vitamin D in doses of ≥1500–2000 IU/d (114).
The proper concentration of minerals is essential for many physiological processes, including maintaining the normal quality of oocytes and embryo fertilization, maturation, and implantation (115). A deficiency of minerals may disturb fertility; therefore, women should pay attention to the proper intake of minerals and supplement the elements that could be deficient. One study showed that many women fail to meet nutrient needs—particularly in terms of folic acid, calcium, iodine, iron, selenium, vitamin D, and vitamin B-12—and thus have lower blood concentrations (116). Calcium, iron, zinc, magnesium, iodine, and selenium are especially essential with regard to fertility.
Calcium affects blood vessels, muscle contractions, nerve conduction, and hormone secretion. Additionally, the fetus uses the mother's skeletal calcium for bone growth. Therefore, the recommended dose of calcium constitutes a crucial element in the diet of women of childbearing age (117). Additionally, calcium deficiency may decrease vitamin D concentrations and increase the risk of hypertension, and pre-eclampsia. However, no studies refer to the validity of the supplementation of or fortification with calcium in the period before pregnancy to prevent pregnancy complications (118, 119).
Few studies have reported on the association between serum iron concentration and fertility. However, both excess and deficiency of iron may negatively affect fertility (120). According to Hahn et al. (121), total or heme iron intake was poorly associated with fecundity, particularly among women with a potential risk of iron deficiency, e.g., women with frequent and heavy periods. On the other hand, a prospective study showed that the supplementation of total and nonheme iron may decrease the risk of infertility due to disorders of ovulation (122).
Another key element is iodine, affecting thyroid gland function, which is essential for proper fertility. In a study conducted in 501 women experiencing moderate or severe iodine deficiency, pregnancy was delayed, and the chances of becoming pregnant in each cycle decreased by 46% when compared with women who were not iodine deficient. Among women with mild iodine deficiency, this association was minimal (123, 124). It is vital to note that mild and moderate iodine deficiency is common among women of reproductive age around the world (125–127).
Grieger et al. (128) reported that low serum concentrations of zinc and selenium were associated with a 1-mo longer period before achieving pregnancy. Additionally, a deficiency of selenium and copper, but not zinc, was linked to a higher risk of infertility. On the basis of limited studies, the impact of zinc and copper concentration on women's fertility remains unclear, and future research is required (128).
Selenium also affects thyroid gland function. Additionally, it is an antioxidant participating in the reduction of oxidative stress. In fact, selenium possibly influences the growth and maturation of oocytes. Therefore, an adequate supply of selenium is necessary (129).
The impact of phytoestrogens on fertility has been a highly controversial topic for years. Phytoestrogens are compounds of plant origin, including isoflavones found in soy products; lignans found in nuts, seeds, and cruciferous vegetables; as well as coumestans found in sprouts, peas, and beans (104).
On one hand, numerous scientific studies indicate the preventive effect of phytoestrogen consumption on the development of breast and endometrial cancer, fibroids, osteoporosis, cardiovascular diseases, inflammation, metabolic syndrome, and obesity (104–109). In fact, soy isoflavone supplementation was associated with an increase in the number of live births following clomiphene therapy, increased endometrial thickness, pregnancy rates following insemination, and in vitro fertilization. Furthermore, soy consumption was associated with an increased chance of live birth using ART (134–137).
On the other hand, certain studies point to endocrine system disorders as negative effects of phytoestrogen consumption. In the Adventist Health Study, women who consumed a greater amount of isoflavones were at an increased risk of never becoming pregnant and being childless (138). In contrast, a cohort study by Mumford et al. (139) found no association between soy intake and fertility.
In an analysis of 2 cohorts comprising women planning a pregnancy in North America and Denmark, which included 4880 and 2898 women, respectively, no strong association was observed between dietary phytoestrogen intake and the chances of becoming pregnant (140). At the same time, it is worth considering that, in Western countries, the average intake of phytoestrogen is <2 mg, and in European countries, the intake is even lower than 1 mg compared with the ∼50 mg consumed in Asian countries (141).
Among women struggling with infertility, a discussion of the negative influence of gluten on fertility is relatively common—for instance, the study by Harper and Bold (143) asked subjects about their motivations for eliminating gluten from their diet. However, according to the recommendations, the exclusion of gluten from the diet is not recommended for the general population, and there is no evidence that it is beneficial in non-celiac individuals (144).
Castaño et al. (145) conducted a meta-analysis that included a total of 23 research studies, and aimed to assess the prevalence of celiac disease seroprevalence in women with fertility disorders. The study group consisted of women with overall infertility, women with idiopathic infertility, and women with recurrent spontaneous abortions. The studies included in the meta-analysis did not comprise women with a diagnosed celiac disease or allergy to wheat proteins. The meta-analysis demonstrated that celiac disease seroprevalence among women with infertility amounted to ∼1.3–1.6%, which allows estimating that women experiencing such disorders are 3 times more likely to develop celiac disease. However, due to the small number of respondents, it is impossible to precisely calculate the total incidence of the association between celiac disease and fertility disorders.
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