Nutrients ability in modulating the activity of nuclear receptors mainly occurs through the regulation of signal transduction of the respective regulated pathways. For example, it is well known that fatty acids are the natural inducers of PPARs (peroxisome proliferator-activated receptors alpha, beta, and gamma), nuclear receptors that regulate the transcription of genes involved in cellular differentiation, development, metabolism, and tumorigenesis [
183,
184,
185,
186]. Like fatty acids for PPARs, other classes of nutrients may act as agonists of other transcription factors, such as glucose for liver X receptor alpha (LXRα) [
187] or amino acids for ERα [
6]. Furthermore, some pathways are greatly inter-connected, as demonstrated by different studies highlighting the relevance of the cross-talk between LXRα and PPARα for the modulation of hepatic lipogenesis [
188] or between LXRα and farnesoid X receptor (FXR), which regulates bile acids, sterols and fatty acids, which, in turn, are the activators of FXR, LXRα and PPARα, respectively [
189]. All these nuclear receptors have a pivotal role for female fertility [
190,
191,
192,
193,
194,
195,
196], thus supporting the possibility that specific class of nutrients may contribute to the coordination of energy metabolism and fertility acting as signaling molecules on these receptors.
6.1. Poly-Unsaturated Fatty Acids and Female Fertility
In women, the reproductive process and its success are affected by the trend in postponing childbearing, typical in the Western societies [
197]. In fact, over the past century, the reproductive lifespan of women has not proportionally increased with the increased woman’s life expectancy [
198], as women fertility precipitously declines after the age of 35 [
199]. The discrepancy between the overall and the reproductive lifespan of women is more pronounced today than ever before and could be partially related to the changes in the human diet over the past 100 years, most notably with regard to the type and amount of fat consumed [
200,
201].
In Western diets, the daily caloric intake of fatty acids was estimated around 30%–35%, a value that far exceeds the nutritional requirements [
202,
203]. Some specific classes of fatty acids, such as the poly-unsaturated (PUFA) omega-3 (
n-3) and omega-6 (
n-6) fats, need to be provided with the diet, as they are indispensable for different biological processes, including growth, brain development and reproduction and animals are not able to synthesize them [
204,
205,
206]. Different studies highlighted the beneficial effects exerted by PUFA on metabolic parameters when compared to other type of fatty acids, in particular
trans fatty acids (TFA) and saturated fatty acids (SFA), and to a lesser extent mono-unsaturated fatty acids (MUFA) [
207,
208,
209,
210,
211]. However, the beneficial effects exerted by PUFA in counteracting metabolic diseases could be influenced by the type of PUFA, as the optimal
n-6:
n-3 PUFA
ratio changes depending on the pathophysiological condition [
212]. Furthermore, other studies have downsized the beneficial metabolic effects of PUFA over other type of fats, in particular MUFA [
213].
In women, consumption of TFA instead of MUFA or PUFA is positively associated with ovulatory infertility, independent of age, BMI, lifestyle and hormonal levels [
4]. At the mechanistic level, it has been proposed that the detrimental effects of TFA on fertility could be due to their different ability to bind PPARγ and down-regulate its expression [
214,
215,
216]. Furthermore, the higher intake of TFA has been associated with altered metabolic parameters, such as insulin resistance [
217], risk of T2D [
218], and inflammatory markers [
219,
220], which may negatively impair ovarian functions. Replacing TFA with MUFA has been demonstrated to be associated with a lower risk of ovulatory infertility [
4], although these conclusions could be only partially ascribable to the changes in dietary fats and could be further affected by other nutritional factors, such as the source of proteins (vegetable
vs. animal), the higher intake of high-fiber, low glycemic carbohydrates, high-fat dairy products, and other micronutrients [
4].
In addition, several studies demonstrated that a higher intake of PUFA [
221,
222,
223,
224] instead of TFA [
225], SFA [
225] or MUFA [
226] has been associated with the improvement of metabolic and hormonal characteristics in women with PCOS [
221]. However, other studies performed in PCOS women failed to confirm some of these beneficial effects [
221] and have found that a diet enriched in MUFA instead of PUFA could be more useful in ameliorating the metabolic profile and consequently the fertility rate [
227].
The relative
n-6 and
n-3 PUFA content has been significantly changed: in the Western diet, the
ratio of
n-6 to
n-3 PUFA ranges from 10:1 to 25:1, greatly diverging from the 1:1
ratio typical of the primitive diet, from which our genetic constitution was selected. This change in diet composition, over the last 100 years, has been associated to decreased fertility rates in women over the age of 35 [
228]. At the mechanistic level, the proportion of different PUFAs in the diet significantly influences prostaglandin (PG) [
229,
230,
231] synthesis and ovarian steroidogenesis, both having crucial role in the reproductive process [
232,
233].
PUFA, in particular arachidonic acid (AA) and its metabolites, influence steroidogenesis in female mammals by exerting direct effects on specific enzymes such as STAR and CYP11A1, and on the regulation of PG synthesis [
229]. PUFA may also alter the function of nuclear receptors such as LXRα [
234] and PPARs [
230], by influencing the transcription of their target genes involved in PG synthesis and ovarian steroidogenesis [
235]. Furthermore, the amount and type of dietary PUFA might affect several metabolic pathways and the consequent metabolic impairment might cause negative reproductive outcomes [
236]. The amount and the type of dietary PUFA might affect different stages of the reproduction, not only ovarian steroid synthesis [
237], but also oocyte maturation [
238], uterine activity [
239], pregnancy [
240] and labor [
241].
The association between the increased
n-6:
n-3 PUFA
ratio in Western diet and the reduced fertility lifespan in women suggests that a diet enriched in
n-3 PUFA could be useful in counteracting the relative excess of
n-6 PUFA and could thus improve the reproductive success. Although some studies seem to confirm this hypothesis [
242,
243,
244], other works do not sustain any positive effect of PUFA on female reproduction [
245,
246] or even report health problems associated to chronic treatments [
241]. This discrepancy could rely on the fact that some investigations were underpowered, lack appropriate controls or were directed only on a specific subset of PUFA [
240]. In addition, the specific mechanisms underpinning the positive impact of
n-3 PUFA on the female reproductive axis remain to be fully elucidated.
In female mammals, diets enriched in
n-3 PUFA enhance plasmatic levels of 17β-estradiol (E2) [
232,
247,
248], thereby leading to increased secretion of GnRH and triggering the LH surge. The mechanism behind the enhanced E2 synthesis is still unclear; however, several explanations have been suggested: PUFA supplementation might enhance plasma steroid concentrations by increasing the availability of lipoprotein–cholesterol, by modulating PG synthesis, or by directly stimulating ovarian steroidogenesis [
249,
250]. Conversely, other studies [
251,
252] suggested that the greater and long-lasting elevation of E2 levels in female mammals consuming
n-3 PUFA could be due to the inhibitory effects exerted by
n-3 PUFA on the metabolism of steroid hormones in the liver [
253,
254,
255].
The delay in E2 surge and in the consequent positive feedback of E2 on hypothalamus and pituitary could explain the tendency for a delay in LH peak and ovulation observed in females supplemented with PUFA [
256]. Furthermore, dietary PUFA could influence ovulation timing by acting on PG synthesis and PG-mediated changes in LHRH release [
257,
258].
Some studies showed that the content of E2 and the 17β-estradiol/progesterone (E2/P4)
ratio, a reliable indicator of follicles health [
259,
260], are increased in the pre-ovulatory follicles of females supplemented with PUFA [
261]. All these hormonal changes contribute to the increased number and size of pre-ovulatory follicles and may be beneficial for ovarian function.
In PCOS women, the supplementation of
n-3 PUFA ameliorates both the metabolic and hormonal parameters (in particular, by decreasing the levels of androgens) [
223,
226], even if others studies failed to unravel significant changes in the regulation of HPG axis [
221]. Conversely, studies done in a rat model of PCOS demonstrated that dietary
n-3 PUFA are able to increase the mean of FSH and significantly decrease the testosterone levels [
262].
6.2. Carbohydrates and Sugars and Female Fertility
The strong relationship between decreased insulin sensitivity and women infertility observed in diabetics and PCOS women [
263] suggests that the amount and quality of carbohydrates in diet might influence reproductive functions. The existence and the mechanism of the correlation between sugars and reproduction, in healthy premenopausal women, are far from being fully elucidated: in the literature, many conflicting data are present.
On the one hand, some studies demonstrated that the quality of quantity of dietary carbohydrates might be associated with ovulatory infertility among nulliparous women [
264]. The mechanism could be mainly ascribable to reduced insulin sensitivity that leads to increased free IGF-I and androgen levels [
265], thus reproducing some clinical features typical of PCOS [
78]. The impact of carbohydrates on the HPG axis has been suggested in a longitudinal study done in women, where a low-fat, high-carbohydrate diet decreased significantly the blood levels of E2 and P4 and increased the levels of FSH and the ratio FSH:E2, independent of age and weight [
266]. The lower E2 levels and the longer menstrual cycles observed in women subjected to this diet partly reflect the changes in the years that precede the menopause [
267]. On the other hand other studies did not found any significant association between dietary intake of these macronutrients and plasma sex steroid levels [
268,
269]. These discrepancies could rely on the different protocol adopted (intake and sources of carbohydrates, length of the treatment) and on the magnitude of the study. The main effects of high intake of carbohydrates could be mainly mediated by insulin and its signalling pathway, thereby affecting the HPG axis (see also
Section 5.1). A captivating explanation suggests that the impairment of the ovulatory process is not due to the increased carbohydrate intake
per se, but could rather be linked to the fact that the increasing carbohydrate intake is at the expense of natural fats, which exert a beneficial effect on ovulatory function [
270].
Even if the consumption of carbohydrates and sugars—particularly fructose in liquids, such as in sugar-sweetened beverage (SSB)—is decreasing [
271], mean intakes among premenopausal women continue to exceed recommendations and might affect the reproductive process. Diets high in carbohydrates/sugars lead to dyslipidemia and insulin resistance, thereby causing hormonal and ovulatory disorders, however very few studies have assessed the effects of energy containing beverages on hormonal levels and ovulatory function in premenopausal women. One study showed that high carbohydrate intake is associated with an increased risk of anovulatory infertility: dietary glycemic index is positively related to this condition in a cohort of apparently healthy women [
264]. However, other studies did not found any association between SSB and premenopausal reproductive hormones [
272,
273] or, even if they showed an association between sugars intake and elevated follicular free and total estradiol, these altered hormone levels do not interfere with ovulation among healthy premenopausal women without ovulatory disorders [
274,
275].
This discrepancy might, once again, be due to limitations in the studies, such as small sample sizes and/or inadequate assessment of nutritional and hormonal variables.
6.3. Proteins, Amino Acids and Female Reproduction
Few studies done in overweight women with PCOS [
276,
277] showed that diet enriched in proteins (30%
vs. 15% of total energy) improved menstrual cyclicity by reducing circulating androgens levels and improving insulin sensitivity as a consequence of weight loss. In these studies, the increased protein intake had no effect on reproductive function
per se indeed, the small improvements in menstrual cyclicity seems to be ascribable to a greater insulin sensitivity associated to a reduced carbohydrates intake (replaced by proteins) rather than an increased dietary protein intake.
The Nurses’ Health Study II (NHS II) highlighted the association between animal proteins intake and increased risk of ovulatory infertility in a cohort of healthy women [
278]; conversely, the consumption of proteins from vegetable sources instead of carbohydrates or animal protein was associated with a substantially lower risk of ovulatory infertility, at least among women older than 32 years [
278], thus suggesting that protein intake may differently affect female fertility depending on the protein source. Although the biological mechanisms responsible for this association have not been identified, evidence indicates that the benefits associated to a diet enriched in proteins from vegetable instead of animal sources might rely on the increased insulin sensitivity [
279,
280] and might be associated to changes in circulating free IGF-I levels [
281].
These evidences seem to contradict other studies showing an association between vegetarian/vegan diets and menstrual disturbances [
282,
283,
284,
285,
286,
287]. However, most of the studies showing a correlation between these diets and menstrual disturbances were performed in athletes, in which the elevated energy expenditure consequent to physical activity may be the main cause leading to reproductive alterations. Similarly, the menstrual disturbances observed in vegetarian women, who are generally leaner and lighter than non-vegetarian ones [
288,
289,
290], may be due to reduced energy availability and increased physical activity [
290] rather than a deficiency in dietary protein intake.
The reproductive effects of vegetarian/vegan diets have not been fully elucidated. Very few studies showed impairments in the reproductive parameters among vegetarian women in comparison to non-vegetarians [
285]. Others did not support any vegetarian diet dependent difference related to the reproductive process [
291]. Similarly, although some studies showed altered reproductive outcomes [
292,
293,
294,
295,
296], others did not support any significant differences between vegetarian and non-vegetarian diet in relation to pregnancy outcomes [
297,
298,
299]. These discrepancies may be due to the paucity and limitations of the studies; indeed, they often did not take into account the possible effects dependent upon changes in others macronutrient classes such as fat and fiber and the lifestyle of vegetarian
vs. non-vegetarian women. Additionally, in these studies, the number of observations is often restricted to 1–2 menstrual cycles. Furthermore, some studies lack of significance because they considered underpowered and not randomized groups. Finally, others studies performed in larger populations could be affected by peculiar lifestyles (such as abstention from drugs, alcohol, tobacco, and caffeine-containing beverages) [
293], thus making impossible to elucidate the specific role of the vegetarian/vegan diet.
In some studies performed in female mammals, the impact of dietary proteins was associated with changes in HPG axis regulation: in particular, a higher intake of proteins was shown to enhance GnRH-induced LH release [
300,
301]. Conversely, in other studies, diets deficient in proteins delay puberty in female ruminants but does not impair the synthesis and processing of LHRH in the brain neurons and synthesis of LH in pituitary cells [
302]. Furthermore, most studies done in female ruminants showed that higher intake of proteins increases ovarian activity by non LH-mediated pathways, but acting at a local level, through changes in insulin [
303] or IGF system, by enhancing the sensitivity of follicles toward FSH and regulating oocyte quality [
304]. According to this data, we demonstrated that a diet enriched in amino acids is able to partly counteract the block of estrous cycle progression in mouse females subjected to 40% calorie restriction: this effect is mediated by changes in IGF-1 levels that we showed to be dependent on the hepatic activity of estrogen receptor alpha (ERα) [
10].
Dietary intake of proteins may affect the circulating levels of P4, although different studies led to opposite results and others showed no changes [
305,
306,
307]. The discrepancy could be related to the different protein-enriched diets adopted in these studies (different percentage of proteins or different source of proteins). Another explanation for these conflicting responses could be ascribable to the difference in the lactation status: high dietary proteins reduced plasma P4 concentrations in lactating [
305,
306,
308], but not in non-lactating female mammals [
308,
309,
310,
311].
In women under physiological conditions, amino acids levels fluctuate during the menstrual cycle and, in particular, decrease in the luteal phase [
312,
313,
314]. It has been suggested that the decreased plasma amino acid levels reflect an increased utilization and could be due to the raised levels of P4 and E2 [
312,
315,
316]. Although the dietary intake of proteins has not been evaluated during the menstrual cycle progression, the decreased in plasma amino acid levels measured during the luteal phase could be the consequence of the increased physiological demands of metabolic intermediates for steroid synthesis by the corpus luteum as well as glycogenesis [
317,
318], protein synthesis and secretion by the endometrium [
319]. This fascinating suggestion might further explain the association between the reduced fertility in women observed nowadays and the decrease in protein intake in the industrialized societies compared to the nutritional environment for which our genetic constitution was selected [
200,
320].
6.4. Food-Associated Endocrine Disrupting Chemicals and Female Fertility
Some naturally-occurring or industrial-derived food components can have adverse effects
per se and could interfere and impair the signaling pathways regulating the reproductive process. It has been shown that very high doses of genistein, a phytoestrogen present in food in particular in soy milk, could have adverse effects on female reproductive physiology [
321] and on pregnancy outcomes [
322,
323,
324]. Similarly, endocrine disrupting chemicals (EDCs) present in food as additives or contaminants [
325] were proposed to be associated with altered reproductive functions both in males and females [
326,
327,
328,
329,
330,
331].
Some substances, for their chemical structures, could accumulate in tissues and, once mobilized under energetic imbalance, could exert their action in the whole organism. For example, it has been reported that genistein might accumulate in placenta [
332] or in body depots [
333], where, once mobilized during fasting, might reach the fetus through the maternal-fetal transfer [
334,
335,
336].
In females, EDCs affect steroidogenesis by acting on the HPG axis [
325,
337,
338,
339], impair ovarian development and function [
340,
341,
342,
343,
344,
345,
346,
347] and cause uterine and ovarian alterations such as endometriosis [
348,
349,
350,
351], premature ovarian failure (POF) [
352] and PCOS [
353].
Although the mechanisms of action of ECDs are difficult to unravel given the complexity of the endocrine system, ECDs were demonstrated to interfere with the ER or the androgen receptor (AR) signaling resulting in synergistic or antagonistic outcomes [
354]. Furthermore, ECDs can modify hormones bioavailability by interfering with their synthesis, secretion, transport and metabolism [
355,
356,
357,
358,
359,
360,
361].