National Institutes of Health (NIH) define erectile dysfunction (ED) as a persistent difficulty achieving and maintaining an erection sufficient for satisfactory sexual intercourse [1
]. The prevalence of ED ranged from 2% in men younger than 40 years old, around 52% in men aged 40–70 years, and more than 85% in men with 80 years and older [2
]. Although significant advances in the field were made, primary prevention research on this condition is very preliminary. Lifestyle risk factors for ED include smoking, excessive alcohol consumption, lack of physical activity, psychological stress, overweight or obesity, and adherence to unhealthy diets, among others [4
Lifestyle factors may influence ED through the vascular and nervous system. Because adequate arterial supply is critical for erection, any disorder that impairs blood flow may be implicated in the etiology of erectile failure. However, a wide variety of psychological problems can influence the male erectile response because, in a vascular event initiated by neuronal action, it is maintained by a complex interplay between vascular, neurological events and other comorbidities [7
]. Moreover, it is generally accepted that nitric oxide (NO) is the principal agent responsible for relaxation/erection of penile smooth muscle.
Mediterranean diet and some components of the Mediterranean diet have been inversely related to erectile and sexual dysfunction [9
] but also a better endothelial function [10
]. This is the case of nuts that its consumption has consistently demonstrated beneficial effects on endothelial function [11
]. In fact, in a recent study, it has demonstrated that pistachio consumption improves erectile function, probably because it contains (as other types of nuts [12
]) several antioxidants, and arginine, a precursor of nitric oxide (NO), a powerful compound that increases vasodilatation [13
To demonstrate that a dietary pattern or a food group can not only modulate the erectile function, but also the sperm function increasing the chances of fertility is of great interest mainly in developed countries where male infertility seems to have fallen drastically [14
], and the psychological stress seems to be more prevalent [15
Therefore, in order to elucidate the possible role of nut consumption in the primary prevention of ED, we explored using a randomized controlled trial (RCT), the effects of nuts supplementation on erectile function determined by the International Index of Erectile Function, but also the endothelial function by measuring peripheral concentrations of NO and E-selectin.
In the FERTINUTS trial, we assessed 244 subjects for eligibility. Of these, 57 subjects declined to participate and 68 did not meet the inclusion criteria. Thus, 119 participants were included in the trial and were randomly assigned to one of the two intervention groups: 61 in the nuts group and 58 in the control group. A total 98 participants successfully completed the study, and finally, 83 participants were included in this secondary analysis (those subjects who fulfilled the International Index of Erectile Function questionnaire): 43 in the nuts supplemented group and 40 in the control group (Figure 1
Baseline characteristics (age, weight, height, BMI, waist circumference, systolic and diastolic blood pressure, fasting glucose, serum total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, insulin, C-reactive protein and folate, and main sperm parameters) are detailed in Table 1
. No significant differences were observed in these baseline parameters agreeing to the sequence of randomization. Participants in the two groups reported similar adherence to the Western-style diet at baseline according to the 15-item dietary screener.
Compliance with the intervention, as assessed by counting the empty sachets of nuts returned by the participants, was high (>95% of empty sachets returned). According to the 3DDR data, significant between-group differences in nut intake was shown through the study. This was associated with an increase in the intake total fat (p
-value < 0.001), MUFA (p
-value<0.001), PUFA (p
-value < 0.001), magnesium (p
-value < 0.001), vitamin E (p
-value = 0.014), omega-3 fatty acids (p
-value < 0.001), α-Linolenic acid (ALA) (p
-value < 0.001), and omega-6 fatty acids (p
-value = 0.016) in the nut-supplemented group. The intake of energy (p
-value = 0.029) and fiber (p
-value = 0.002) experienced a smaller decrease in the nut-supplemented group compared with the control group (Table 2
No significant between-group differences were observed in erectile function parameters at baseline. However, compared to the control group, a significant increase in the orgasmic function (OF; p
-value = 0.037) and sexual desire (SD; p
-value = 0.040) was observed in the nut-supplemented group during the intervention. No significant between-group differences in changes during the intervention were found in erectile function (EF; p
-value = 0.192), intercourse satisfaction (IS; p
-value = 0.473), and overall satisfaction (OS; p
-value = 0.333) (Figure 2
). No significant correlations were found between changes in ED parameters and changes in biochemical parameters during the intervention.
Moreover, no significant differences in changes between intervention groups were shown in peripheral concentrations of NO (p
-value = 0.737) (Figure 3
A) or E-selectin (p
-value = 0.347) (Figure 3
Herein we report that adding 60 g/d of mixed raw nuts to a Western-style diet for 14-wk improved the auto-reported orgasmic function and sexual desire parameters in a group of healthy reproductive-aged participants compared with an age-matched control group. In the present study, none of the possible mechanisms explored (NO and E-selectin as surrogated markers of endothelial function) seem to explain the beneficial effects observed on orgasmic function and sexual desire.
Interestingly, our findings in healthy young males are pretty consistent with the only previous clinical study reporting an increase of all the five IIEF-15 domains after 100 g/day pistachio consumption for 3 weeks [13
], although this study was conducted in patients with erectile dysfunction at baseline. Therefore, our study extends the findings to a healthy population without erectile dysfunction supplemented with a mixture of nuts like hazelnuts, almonds, and walnuts.
Nuts are nutrient-dense foods with a special nutrient content, a key component of several healthy dietary patterns and recommendations, and its consumption is associated with improvements in some cardiovascular disease risk factors [30
]. Specifically, hazelnuts, almonds and walnuts contain high amounts of vegetable protein and fat (mainly unsaturated fatty acids), are dense in antioxidants and vitamins (e.g., folic acid, niacin, tocopherols, and vitamin B6, among others) and some minerals (e.g., calcium, magnesium, phosphorous and potassium), and also rich = in dietary fiber and many other bioactive constituents (e.g., phytosterols and phenolic compounds) (Supplementary Materials Table S1
In addition, nuts had a relatively high amount of the nonessential amino acid arginine, a precursor of NO, that is a potent vasoactive neurovascular, nonadrenergic, noncholinergic (NANC) neurotransmitter that plays an important role in erectile action through the corpora cavernosa [34
]. The results from our study do not demonstrate that Arginine-NO pathway act as the unique player modulating erectile function. However, we cannot discard a lack of statistical power to demonstrate differences between intervention groups in relation to these subrogated markers of endothelial function, because the sample size of the present sub-analysis was estimated using the IIEF as the main outcome.
Another promising serum biomarker for erectile function is serum E-selectin [35
]. In that case, E-selectin, because it is an endothelial dysfunction marker, seems more useful in patients diagnosed with diabetes mellitus [36
]. E-selectin is a cell adhesion molecule activated by cytokines that plays an important role in inflammation. Because consuming between 60 and 90 g of nuts has proven effective improving inflammation [37
] it could have been reasonable to detect some differences in this marker due to the nut’s supplementation. Nonetheless, our study does also not confirm any effect on this endothelial marker. This lack of effect could be explained not only because of a lack of power but also because our participants were healthy and therefore without having type 2 diabetes.
Because we detected an improvement in the auto-reported orgasmic function and sexual desire parameters, maybe other mechanisms beyond those mentioned above may be implicated. It is interesting to mention that erectile (dys)function and atherogenesis share common pathways [38
]. For that reason, several antioxidants (e.g., polyphenols) and vitamins, that are present in nuts, have been suggested to be effective treatments for ED and at the same time are beneficial for the cardiovascular system [38
]. Previous studies reported that chronic consumption of nuts has proven effective for lowering LDL cholesterol [32
] and improving glucose metabolism [39
], among other cardiovascular risk factors, decreasing the incidence of major cardiovascular events [17
]. Therefore, we strongly believe in the necessity to develop similar trials with participants at high cardiovascular risk and erectile dysfunction to accurately establish an effect of nut consumption on erectile function and cardiovascular risk.
Our study has several strengths. This is the largest and unique RCT to date analyzing the effect of nut supplementation on erectile and sexual function in healthy participants. Moreover, the present analysis has theoretically enough statistical power to detect effects on erectile function measured by a validated International Index of Erectile Function. Although several questionnaires have been developed to objectively evaluate EDs, the validated International Index of Erectile Function (IIEF) questionnaire is considered a valuable tool for defining the area of sexual dysfunction that may be incorporated as part of the clinical history to document the degree of dysfunction and gauge response to therapy [25
]. Moreover, having detailed information on medical and reproductive history allowed us to reduce bias by excluding participants with chronic and reproductive diseases that may influence diet, seminogram or erectile function. The main strength of the present study is the design because RCTs represent the cornerstone of evidence-based medicine.
However, the following limitations need to be highlighted. The present study is based on a secondary outcome analysis of the FERTINUTS trial. Second, our study was conducted in apparently healthy and fertile participants limiting the extrapolation of the results to other populations, for example with erectile dysfunction, the inclusion of a group of subjects suffering from erectile dysfunction could help us to extend the results obtained. Third, reproductive hormonal (e.g., testosterone, prolactin, FSH, estradiol) values, which could affect erectile and sexual function are not reported. Finally, our study did not provide enough evidence to support the main mechanism for these improvements, however, an absence of evidence does not mean evidence of no effect [40
]. Only equivalence trials are properly suited to demonstrate the equality of effects. For that reason, other RCT focused on markers of erectile endothelial function as possible mechanisms of the effect as main outcomes, are warranted in the future to increase the scientific evidence in the field.