Diet and Men’s Reproductive Health: A Review of the Evidence

What is covered in this review:

• Human and primate studies provide strong evidence that healthful plant-based diets low in saturated fat and cholesterol play a critical role in preventing erectile dysfunction (ED), and that there is a shared etiology between vascular ED and atherosclerotic cardiovascular disease.
• Cholesterol feeding, including from fresh egg yolk has been used in thousands of experiments to successfully accelerate the development of atherosclerosis across mammals, birds, and fish of herbivorous, omnivorous, and carnivorous nature (Tables 1-6).
• Cholesterol feeding has been used to induce atherosclerosis in >20 species of nonhuman primates, including the chimpanzee, and these adverse effects have been observed even at very low intakes and in part independent of increases in LDL cholesterol (Tables 2-4).
• In primate studies, saturated fat from animal fats and tropical oils has also been extensively used to accelerate the progression of atherosclerosis and induce heart attacks (Figure 1).
• In primate studies, compared to plant protein, animal protein increases the progression of atherosclerotic plaque volume in the main blood supplies to the heart, brain, and pelvic region by up to 10-fold, and these adverse effects are in part independent of increases in LDL (Table 5).
• In primate studies, cessation of diets rich in cholesterol and saturated fat have been consistently demonstrated to induce the regression of atherosclerosis when total cholesterol is lowered to below 150 mg/dL, and this effect has been observed even when lipid-lowering is achieved by the feeding of very large quantities of refined sugar and omega 6-rich seed oils (Table 3).
• Diets naturally very rich in dietary fiber promote the regression of atherosclerosis in primates even at moderately elevated total cholesterol levels, indicating a greater benefit of minimally processed plant foods and supporting the clinical findings that whole-food plant-based diets promote the regression of atherosclerosis in humans.
• In primate studies, diets rich in cholesterol and saturated fat cause the development of atherosclerosis in the deep and superficial penile arteries followed by the inability to achieve and maintain an erection (Table 6).
• Clinical and epidemiological evidence indicates that a high intake of fruits, vegetables, legumes, and nuts, and a low intake of saturated fat reduces the risk of ED.
• A meta-analysis of epidemiological studies involving 12,845 cases of ED presented here found that a high healthful plant-based diet index score was associated with a 12% to 33% reduced risk of erectile dysfunction (Figure 2).
• The Harvard Health Professionals Follow-Up Study indicated that compared to other typically consumed foods, each ≤85 g/day serving increment in meat intake increases the risk of ED by a magnitude comparable to that observed for smoking 7 cigarettes per day, and that this effect would be greater if substituted for fruit or legumes.
• A meta-analysis of 23 double-blind, randomized, placebo-controlled trials found that antioxidants improve erectile function by a magnitude comparable to other commonly prescribed drugs, including Sildenafil (Viagra).
• Meta-analyses of randomized controlled trials found that antioxidants also have an additive effect on improving erectile function when combined with these drugs.
• A meta-analysis of 5 randomized controlled trials presented here found that compared to low-fat diets, ketogenic diets rich in saturated fat impair flow-mediated dilation (artery dilation in response to increased blood flow) by a magnitude at least comparable to that observed for cigarette smoking (Figure 3).
• A meta-analysis of 6 controlled trials presented here found that compared to low-fat diets, ketogenic diets reduce total testosterone by a magnitude that would result in hypogonadism in the average man over the age of 26 (Figure 4).
• Individuals with a ketogenic diet-induced mean LDL of 254 mg/dL were found to have a 4-fold increase in the annual rate of atherosclerotic plaque volume progression relative to individuals with otherwise similar health status who follow a Western diet.
• Hunter-gatherer Inuit and nomadic pastoralists that consumed animal-based low-carbohydrate diets had a high prevalence of atherosclerosis relative to plant-based populations (Table 7).
• Evidence from >150 randomized controlled trials and Mendelian randomization studies involving >2 million participants has established that LDL and Apolipoprotein B (ApoB) cause atherosclerotic cardiovascular disease (ACVD), and that ApoB is the primary lipid determinant of ACVD.
• Meta-analyses of randomized controlled trials and Mendelian randomization studies found that multiple LDL lowering mechanisms reduce the risk of ED.
• Evidence from >1,000 controlled dietary experiments has established that plant-based diets and the associated nutrients reduce atherogenic blood lipids, including ApoB.
• A meta-analysis of 104 controlled feeding experiments found that substituting equal parts of energy from carbohydrate, monounsaturated fat, and polyunsaturated fat with 10% of energy from saturated fat increases ApoB by 74 mg/dL, predicting 10-fold increased odds of major coronary events for a lifetime of cumulative exposure.
• A meta-analysis of 10 randomized controlled trials presented here found that reducing dietary saturated fat and cholesterol reduces the odds of cardiovascular disease by 50% per 1 mmol/L reduction in total cholesterol for 5 years of cumulative exposure (Figure 5).
• A meta-analysis of prospective cohort studies involving 756,663 participants presented here found that substituting 5% of energy from plant protein with protein from red meat, poultry, fish, dairy, and eggs were each associated with between a 17% and 52% increased risk of cardiovascular death (Figure 6).
• Clinical, genetic, and epidemiological evidence indicates that a high intake of animal-derived micronutrients, including heme iron, choline, and calcium each increase the risk of cardiovascular disease by ≥15%.
• In contrast, evidence from >100 prospective cohort studies found that a high intake of dietary fiber and plant-derived antioxidants were associated with up to a 45% reduced risk of cardiovascular disease.
• Evidence from >200 randomized controlled trials indicate that substituting processed and animal foods with healthful plant foods reduce blood pressure.
• Inpatient feeding studies demonstrate that whole-food plant-based diets reduce body fat compared to minimally processed omnivorous diets, including ketogenic and Mediterranean diets.
• Clinical and epidemiological evidence indicates that diets rich in animal foods and low in healthful plant foods may increase the risk of prostate cancer by a magnitude at least comparable to that observed for heavy smoking.
• Human and animal studies have found that a high intake of saturated fat, cholesterol, meat, and dairy are associated with decreased sperm count and quality.
• In contrast, evidence from randomized controlled trials indicates that antioxidants and nuts improve sperm count and quality, supporting the findings from epidemiological studies that healthful plant-based diets improve these same parameters.
• Clinical and epidemiological evidence indicates a shared etiology between male and female sexual dysfunction (FSD), and that the benefits of a healthful plant-based diet likely extend to FSD.
• Clinical and epidemiological evidence indicates that diets rich in animal foods and low in healthful plant foods may increase the risk of breast cancer by a magnitude at least comparable to that observed for heavy smoking.

 

It is estimated that more than 320 million men worldwide experience erectile dysfunction (ED).¹ Vascular ED, the most common form of ED is characterized by poor blood flow to the penis and has been attributed to the loss of endothelial function and the buildup of atherosclerotic plaque in the arteries.² The feeding of diets rich in cholesterol and saturated fat is probably the single most replicated modifiable lifestyle factor for the induction of erectile dysfunction in laboratory animals.^{3 4 5 6} In primates, prolonged exposure to these diets promote the formation of atherosclerotic plaque in the central arteries, followed by the peripheral arteries, and ultimately in the penile arteries, leading to ED.^{7 8} A recent meta-analysis of 23 double-blind, randomized, placebo-controlled trials found that antioxidants improve erectile function by a magnitude comparable to other commonly prescribed treatments, supporting epidemiological evidence of a benefit of healthful plant-based diets and confirming the important role of diet in the pathogenesis of ED in humans.^{9 10 11 12} ED not only has a significant negative impact on the quality of life in men, but is also an early indicator of cardiovascular disease, underscoring the importance of preventative measures.^{13 14} However, many men face obstacles to reduce the intake of meat and other sources of animal protein and saturated fat which may be counterproductive in improving health.^{15 16} Therefore, it may be imperative that men are provided with the necessary knowledge to make informed dietary decisions. This review will examine the evidence of the effect of diet on men’s reproductive health with a focus on erectile function and its relationship with vascular disease.

Since the breakthrough led by Nikolai Anichkov more than a century ago, the feeding of dietary cholesterol has been recognized as a virtual sine qua non for the induction of experimental atherosclerosis and has been used in thousands of experiments to successfully accelerate the development of atherosclerosis across mammals, birds, and fish of herbivorous, omnivorous, and carnivorous nature (Tables 1-6).^{17 18 19 20 21 22 23 24} Indeed, virtually every species of vertebrate are susceptible to developing atherosclerosis in response to diet so long as atherogenic lipoproteins can be raised high enough and maintained for long enough. Cholesterol feeding in either processed form or from fresh, non-oxidized egg yolk is the single most common method used for the induction of experimental atherosclerosis, primarily due to challenges encountered inducing atherosclerosis in its absence.^{25 26 27 28}

Of relevance to the study of humans, cholesterol feeding has been used to induce atherosclerosis in over 20 species of nonhuman primates, including the chimpanzee (Table 2).^{29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46} Importantly, it was demonstrated in a primate model that even very small amounts of cholesterol, the equivalent of less than half an egg per day in a 2,000 kcal human diet can induce atherosclerosis when fed over a prolonged period and that the adverse effects are in part independent of increases in LDL cholesterol (Table 4).²⁹ This novel finding at the time was elaborated on by the researchers.

The regimen for group 1 was originally designed to demonstrate a null point of the effect of dietary cholesterol on the arterial intima. However, such a point was not found; no threshold for dietary cholesterol was established with respect to a putatively adverse effect on arteries.

In the primate model, saturated fat from animal fats and tropical oils has also been extensively used to accelerate the progression of atherosclerosis and induce heart attacks (Figure 1).^{26 30 32 33 35 36 37 39 42 45 47 48} The substitution of plant protein with animal protein has also been consistently demonstrated to accelerate the progression of atherosclerotic plaque volume in the main blood supplies to the heart, brain, and pelvic region by up to 10-fold, and these adverse effects are in part independent of increases in LDL (Table 5).^{49 50 51 52 53}

Of particular interest to the study of vascular disease, experiments dating back more than half a century have consistently demonstrated that the cessation of an atherogenic diet can induce the regression of atherosclerosis in primates, generally so long as total cholesterol is lowered to below 150 mg/dL.^{54 55 56} Limited or no benefit has often been observed at higher cholesterol levels typical in experiments where sources of cholesterol were maintained at levels considered realistic to Western populations.^{54 57} Interestingly, significant regression has been observed when blood cholesterol was lowered by substituting sources of cholesterol and saturated fat used to induce atherosclerosis, including egg yolk, butter, beef tallow, lard, and coconut oil with very large quantities of refined sugar and omega 6-rich seed oils (Table 3).^{58 59} These findings greatly contrast the expectations of the hypotheses commonly proposed by proponents of animal-based diets. Nevertheless, the feeding of very high intakes of dietary fiber in the form of alfalfa meal was found to promote the regression of atherosclerosis in primates even when total cholesterol was maintained at 170 mg/dL, indicating a greater benefit of minimally processed plant foods.⁶⁰ These lines of evidence are consistent with that from clinical trials demonstrating that the regression of atherosclerosis in humans generally occurs when LDL is lowered to below 70 mg/dL.⁶¹ However, it is important to recognize that this magnitude of LDL lowering in humans through lifestyle changes alone is generally only reliably achievable with a minimally processed plant-based diet.^{62 63 64} Taken together with the evidence of a benefit of substituting sources of cholesterol and animal protein with fiber rich plant foods over and above that predicted by reductions in LDL, these findings support and compliment that from randomized and non-randomized studies that whole-food plant-based diets promote the regression of atherosclerosis in humans.^{65 66 67}

Within 5 years of exposure to diets rich in cholesterol and saturated fat, primates develop atherosclerosis in the internal iliac, internal pudendal, and deep and superficial penile arteries.⁸ This atherosclerotic arterial obstruction is followed by the inability to achieve and maintain erection to ejaculation (Table 6). These atherogenic diets also promote endothelial dysfunction in primates which may contribute to this increased prevalence of ED.⁶⁸ Importantly, experiments have found that alongside the regression of atherosclerosis, cessation of these diets promote the restoration of endothelial function in primates, indicating that dietary improvements may significantly improve or even reverse ED.^{69 70} 

Table 1. Select species found to develop atherosclerosis in response to dietary cholesterol feeding, either alone or with sources of saturated fat.

  

Table 2. Select species of nonhuman primates found to develop atherosclerosis in response to dietary cholesterol feeding, either alone or with sources of saturated fat.

Table 3. Atherosclerosis induction and regression diets in select experiments in nonhuman primates.

Table 4. Arterial atherosclerosis in normocholesterolemic rhesus macaques fed low supplements of dietary cholesterol. Derived from Armstrong 1974.

Table 5. Arterial atherosclerosis and testicular weight in male crab-eating macaques fed whey and casein or soy protein with (+) or without (-) isoflavones. Derived from Anthony 1997.

Table 6. Iliac, pudendal, and penile artery atherosclerosis and behavior in male crab-eating macaques after 5 years on an atherogenic diet with 43% of energy from lard and egg yolk. Derived from Adams 1984.

Figure 1. Correlation between total cholesterol and aortic atherosclerotic lesions in Chimpanzees. Derived from Andrus 1968.

Evidence from epidemiological studies has found that a higher intake of fruits, vegetables, legumes, nuts, and ratio of monounsaturated to saturated fat are associated with a decreased risk of ED.^{10 71 72} A recent meta-analysis found that plant-based diets, diets rich in nuts, and low-fat diets were associated with between 29% and 73% reduced odds of erectile dysfunction compared to usual diet.⁷¹ However, only a single study was included for each of these diets, limiting the implications of these findings. For this review, an expanded meta-analysis was carried out to examine the effect of the healthful plant-based diet index (hPDI) on the risk of ED. When estimates were reported per point increase in the hPDI score, it was rescaled to represent a 25-point increase as this was the mean difference in scores between extreme quintiles of hPDI in the remaining studies. In a meta-analysis of 3 studies involving 24,675 men, a high hPDI score was associated with 33% reduced odds and a 12% reduced risk of erectile dysfunction in case-control and prospective cohort studies, respectively.^{10 11 12} Importantly, there was a linear trend between quintiles of hPDI and ED observed across studies implicating that even greater increases in healthful plant food intake may associate with a greater reduction in risk.

Among the individual foods examined in the Harvard Health Professionals Follow-Up Study, including sugary and other unhealthful plant-foods, meat was associated with the greatest increase in risk of ED, with each ≤85 g/day serving increment corresponding to an approximate 10% increased risk compared to other typically consumed foods.¹⁰ This increase in risk alone is comparable to that observed for smoking 7 cigarettes per day.⁷³ Moreover, a high intake of fruits and legumes were each associated with a 10% decreased risk of ED, indicating that if included in a substitution analysis with these foods, the risk for meat intake would be even higher. Compared with median intake, men with the lowest intakes of eggs and dairy also had a lower risk of ED. Interestingly, tea and coffee intake and fruit juice intake were associated with an increased and decreased risk of ED, respectively, a finding that would have attenuated the benefit observed for the hPDI score in this study. 

Figure 2. Effect of a high healthful plant-based dietary index (hPDI) score and risk of erectile dysfunction in a meta-analysis of 3 epidemiological studies involving 24,675 men and 12,845 cases.

 

In a randomized controlled trial testing the effects of a Mediterranean diet, it was found that men in the experimental group consumed more fruits, vegetables, nuts, whole grains, and olive oil and had a significantly improved International Index of Erectile Function (IIEF) score, considered the gold standard for assessing male sexual function.⁷⁴ Within the intervention group, improvements in the IIEF score were associated with a higher intake of fruits, vegetables, nuts, legumes, and ratio of polyunsaturated to saturated fat. Another randomized, controlled feeding trial found that 60 g/day mixed nut intake improved the orgasmic function and sexual desire domains of the IIEF in the background of a Western diet.⁷⁵ A single-arm trial also found that 100 g/day pistachio intake improved all 5 domains of the IIEF.⁷⁶ Nevertheless, the non-blindable nature of diet and individual foods remains a challenge for the study of diet in the pathogenesis of ED given the possible susceptibility to the placebo effect, a phenomenon established in clinical trials of phosphodiesterase type 5 (PDE5) inhibitors.⁷⁷

Research into antioxidants provides perhaps the strongest evidence of a causal, placebo-independent effect of diet on ED in humans. A meta-analysis of 23 double-blind, randomized, placebo-controlled trials found that antioxidants improved the erectile function domain of the IIEF by 5.5 points.⁹ This is comparable or moderately lower than the 4 to 8 point improvement found for common PDE5 inhibitors, including the 6 point improvement found for Sildenafil (Viagra), but without the off-target adverse drug effects.⁷⁸ Importantly, evidence from clinical trials have demonstrated an additive benefit of antioxidants on erectile function when combined with PDE5 inhibitors.^{79 80} Evidence of a benefit of antioxidant intake directly from diet is supported by the findings from epidemiological studies that a high intake of lycopene, flavanones, and a high composite dietary antioxidant index score were associated with a 75%, 11%, and 34% reduced risk of ED, respectively.^{81 82 83} There are more than 25,000 known bioactive food constituents, of which the vast majority are antioxidants derived from plants.⁸⁴ Given the established benefits of the oxidative stress-reducing and arterial blood flow-promoting properties of many antioxidants it is reasonable to expect that many of these less well-studied antioxidants found almost exclusively in minimally processed plant foods may have combined additive or synergistic effects on improving erectile function, explaining evidence of a benefit of healthful plant-based diets.

A recent experiment found that very-low-carbohydrate high-protein diets cause erectile dysfunction with vascular endothelial dysfunction in rats.⁸⁵ Human studies have also raised concerns of an adverse effect of ketogenic and other saturated fat-rich diets on endothelial function. Flow-mediated dilation (FMD), which measures the dilation of an artery in response to increased blood flow is considered a gold standard for measuring vascular endothelial function, with each 1% reduction in FMD observationally associated with a 14% increased risk of future cardiovascular events.⁸⁶ A meta-analysis of 90 controlled dietary experiments found that a single high fat meal reduced postprandial FMD, and that meals with greater than 80% fat reduced FMD by 2.77% after 3 hours.⁸⁷ This is comparable to the 2.86% lower FMD observed in patients with erectile dysfunction.⁸⁸ Separately, a randomized, crossover trial found that a very-low-carbohydrate Atkins diet reduced fasting FMD compared to a very-low-fat Ornish diet after 4 weeks and that the reduction was associated with saturated fat intake.⁸⁹ Moreover, a randomized, crossover, controlled feeding trial found that substituting the equivalent energy from a combination of refined and unrefined sources of carbohydrate, monounsaturated fat, or polyunsaturated fat with 50 g/day butter reduced fasting FMD by 5.41% after 3 weeks.⁹⁰ This is an effect that would predict a 2-fold increased risk of future cardiovascular events. In contrast, evidence from over 50 randomized controlled trials found that plant-derived antioxidants improve FMD.^{91 92 93}

An earlier meta-analysis of randomized controlled trials of at least 3 weeks found that low-carbohydrate high-fat diets reduced FMD compared to low-fat diets.⁹⁴ For this review an updated meta-analysis was carried out to examine this effect for ketogenic diets (≤10% carbohydrate) that did not limit saturated fat intake. Change-from-baseline standard deviation was calculated using the formula described in the Cochrane Handbook and assumed a correlation coefficient of 0.50.⁹⁵ Based on 5 randomized controlled trials, ketogenic diets rich in saturated fat reduced FMD by 2.61% compared to low-fat diets (Figure 3).^{96 97 98 99 100} In a subgroup analysis in which all food was provided to maximize compliance, ketogenic diets reduced FMD by 3.65%, a reduction that is at least comparable to that observed for cigarette smoking.¹⁰¹

Ketogenic diets may also adversely affect erectile function by reducing total testosterone (TT) and causing depression and atherosclerotic obstruction.^{102 103} A meta-analysis found that in the absence of significant weight loss, low-carbohydrate diets reduce TT compared to higher carbohydrate diets of non-specific quality.¹⁰⁴ However, this study did not specifically examine ketogenic diets. For this review, the data was reanalyzed here to examine this effect compared to low-fat diets (≤30% fat). Based on 6 controlled trials, ketogenic diets reduced TT by 3.75 nmol/L compared to low-fat diets (Figure 4). This magnitude of TT reduction would result in hypogonadism (TT of <10.4 nmol/L) in the average man over the age of 26.^{105 106}

A randomized controlled trial found that compared to a fiber-rich, low-fat diet, a calorie-matched, minimally processed, animal-based, ketogenic diet increased anger, confusion, depression, and the total mood disturbance score after one year.¹⁰⁷ In contrast, evidence from over 20 randomized controlled trials found that plant-derived antioxidants improve depressive symptoms.^{108 109 110}

A recent study found that individuals with a ketogenic diet-induced mean LDL of 254 mg/dL, but otherwise near optimal risk factors experienced a 4-fold increase in the annual rate of atherosclerotic plaque volume progression than observed in mostly healthy individuals with a mean LDL of 112 mg/dL who mainly consume a Western diet.^{111 112} This finding is compatible with the high prevalence of atherosclerosis observed in the hunter-gatherer Inuit and other populations that consumed animal-based low-carbohydrate diets relative to plant-based populations despite often similar levels of total cholesterol (Table 7).^{113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132}

Figure 3. Effect of ketogenic diets high in saturated fat on flow-mediated dilation (%) compared to low-fat diets in a meta-analysis of 5 randomized controlled trials.

 

Figure 4. Effect of ketogenic diets on total testosterone (nmol/L) compared to low-fat diets in a meta-analysis of 6 randomized and non-randomized controlled trials.

Table 7. Prevalence of atherosclerosis in the Inuit, nomadic pastoral societies, Papua New Guineans, and Okinawans.

Atherosclerotic cardiovascular disease (ACVD), and in-turn hyperlipidemia, are likely major risk factors that mediate the effect of lifestyle factors on ED.¹³³ Evidence from over 150 randomized controlled trials and Mendelian randomization (MR) studies involving more than two million participants has unequivocally established that lowering LDL and Apolipoprotein B (ApoB) reduces the risk of ACVD in a log-linear manner, independent of the lipid-lowering mechanism, and without indication of a threshold at which a further decrease in LDL or ApoB does not confer greater benefit.^{61 134 135 136 137 138 139} It has also been established that ApoB which represents the total number of circulating atherogenic lipoprotein particles is the primary lipid determinant of ACVD.^{140 141 142 143} Lipid-lowering may also have a direct effect on reducing the risk of ED. Meta-analyses of randomized controlled trials found that statins reduce the risk of ED.^{144 145} In addition, a meta-analysis of MR studies found that multiple other LDL lowering mechanisms also reduce the risk of ED.¹⁴⁶

Evidence from over 1,000 controlled dietary experiments has also unequivocally established that plant-based diets and the associated nutrients reduce atherogenic blood lipids.^{62 63 64 147 148 149 150 151 152 153 154} Specifically, the substitution of animal protein with plant protein,^{155 156} reducing the intake of dietary cholesterol,^{157 158} and increasing the intake of soluble fiber¹⁵⁹ and plant sterols¹⁶⁰ each reduce ApoB by up to 5 to 10 mg/dL. Importantly, based on evidence from 104 controlled feeding experiments,¹⁶¹ substituting equal parts of energy from carbohydrate, monounsaturated fat, and polyunsaturated fat with 10% of energy from saturated fat would increase ApoB by 74 mg/dL, predicting a 156% increased risk of major adverse cardiovascular events for 4.7 years of cumulative exposure,¹⁴⁰ and a 10-fold increased odds of major coronary events for a lifetime of exposure.¹⁶²

A meta-analysis of prospective cohort studies commissioned by the World Health Organization found that substituting dietary saturated fat with either slowly digestible carbohydrates, plant-derived monounsaturated fat, or polyunsaturated fat was associated with a decreased risk of coronary heart disease.¹⁶³ More importantly, a Cochrane review of randomized controlled trials found that reducing dietary saturated fat reduced the risk of cardiovascular disease directly proportional to the absolute reduction in total cholesterol.¹⁶⁴ However, estimates of risk were not provided per unit reduction in total cholesterol. Therefore, the data was reanalyzed here to determine this effect using the adjusted odds ratio based on methods described elsewhere.¹⁶⁵ In a meta-analysis of 10 randomized controlled trials involving 53,390 participants, reducing dietary saturated fat reduced the odds of cardiovascular disease by 50% per 1 mmol/L reduction in total cholesterol for 5 years of cumulative exposure (Figure 5).

A reduction in dietary cholesterol may explain up to 20% of the reduction in total cholesterol found in the saturated fat reduction trials, and therefore likely contributed to the reduction in cardiovascular disease.¹⁶⁶ Importantly, even if it is assumed that almost all of the reduction in total cholesterol observed in these dietary trials was from LDL, this would still indicate a two-fold greater reduction in cardiovascular events per unit lower LDL than observed in statin trials with a similar median follow-up.^{61 167}

Figure 5. Effect of reducing dietary saturated fat and odds of cardiovascular disease per 1 mmol/L reduction in total cholesterol in a meta-analysis of 10 randomized controlled trials involving 53,390 participants and 4,528 cases. RR=0.64 CI, 0.44-0.91 (data not shown). Differences in cardiovascular events and total cholesterol were derived from Analysis 1.35 and Analysis 3.1, respectively, from Hooper 2020.

 

Several prospective cohort studies found that substituting plant protein with animal protein was associated with an increased risk of cardiovascular death.^{168 169 170 171} For this review, a meta-analysis was carried out to examine this effect. Based on data involving 756,663 participants with 12.7 million person-years of follow-up from 5 prospective cohort studies, substituting 5% of energy from plant protein with protein from red meat, poultry, fish, dairy, and eggs were each associated with between a 17% and 52% increased risk of cardiovascular disease mortality (Figure 6). This is consistent with the findings from another meta-analysis that substituting unprocessed red meat, poultry, dairy, and eggs with nuts and legumes was associated with a decreased risk of cardiovascular disease.¹⁷²

Several animal-derived micronutrients have also been implicated as a cause of cardiovascular disease. A meta-analysis of 19 prospective cohort studies found that each 1 mg/day increment in heme iron intake was associated with a 25% increased risk of cardiovascular death.¹⁷³ Similarly, a meta-analysis of 6 prospective cohort studies found that each 100 mg/day increment in choline intake was associated with an 11% increased risk of cardiovascular death, consistent with the findings from a MR study that high choline levels are causally associated with 25% increased odds of heart attack.^{174 175} Moreover, evidence from randomized controlled trials and MR studies has found that a high intake of calcium increases the risk of cardiovascular disease by 11% to 15%.^{176 177} In contrast, evidence from over 100 prospective cohort studies has found that a high intake of dietary fiber and plant-derived antioxidants, which are surrogate markers of healthful plant food intake were associated with up to a 45% reduced risk of cardiovascular disease.^{178 179 180 181}

Figure 6. Effect of substituting 5% of energy from plant protein with animal protein and relative risk of cardiovascular disease mortality in a meta-analysis of 5 prospective cohort studies involving 756,663 participants with 12.7 million person-years of follow-up.

 

High blood pressure and adiposity may also mediate the effect of diet on ED.^{103 182} A randomized, crossover, inpatient feeding study found that a minimally processed, very-low-fat, vegan diet reduced systolic blood pressure (SBP) by 3.6 mmHg compared to a vegetable and nut-rich but otherwise minimally processed, animal-based, ketogenic diet.⁶² This is consistent with the findings from a MR study involving 613,783 individuals that a higher total energy-adjusted relative carbohydrate intake is causally associated with 71% reduced odds of hypertension, and that this benefit is in part independent of the causal association between a higher carbohydrate intake and lower adiposity and improved psychological well-being.¹⁸³ A recent meta-analysis of 5 randomized controlled trials found that substituting 2 cups per day of low fat dairy milk with ultra-processed or unsweetened soy milk reduced SBP by 8.00 mmHg.¹⁸⁴ This adverse effect of dairy milk on SBP alone would predict a 71% increased odds of major coronary events for a lifetime of cumulative exposure.¹⁶² The findings of a benefit of healthful plant foods are further corroborated by the evidence from over 190 randomized controlled trials establishing that soluble fiber and plant-derived antioxidants reduce blood pressure.^{91 185 186 187 188 189}

A review of 51 randomized controlled trials of at least 6 weeks found that plant-based diets reduced BMI, body weight, and waist circumference compared to usual diet.¹⁹⁰ A randomized, crossover, inpatient feeding study with no intention to induce weight loss found that a minimally processed, very-low-fat, vegan diet reduced body fat by 0.48 kg after 2 weeks compared to a minimally processed, animal-based, ketogenic diet.⁶² Another randomized, inpatient feeding study found that a low-fat, macrobiotic vegan diet reduced BMI (1 kg/m²), body weight (2.7 kg), and waist (1.9 cm) and hip (1.6 cm) circumference after 3 weeks compared to a calorie-matched, but higher protein, healthy Mediterranean diet.⁶³ Similarly, a crossover, partial feeding trial with no intention to induce weight loss found that among identical twins, a healthy vegan diet reduced body weight by 1.9 kg after 4 weeks compared to a healthy omnivorous diet.¹⁴⁷ These findings are further corroborated by a meta-analysis of 10 randomized, placebo-controlled trials without energy-restriction protocols that found that soluble fiber meaningfully reduces BMI, body weight, and body fat percentage.¹⁹¹

Diet likely also plays a critical role in prostate cancer, a major risk factor for death and sexual dysfunction.¹⁹² The Health Professionals Follow-Up Study found that greater plant-based consumption was associated with a 19% decreased risk of prostate cancer, and that a high healthful plant-based diet index score was associated with improved quality-of-life and sexual functionality among prostate cancer survivors.^{193 194} These findings are compatible with those from meta-analyses of epidemiological studies that a high intake of cruciferous vegetables, legumes, and several plant-derived antioxidants, and a low intake of meat, eggs, and dairy were each associated with up to a 19% and 26% decreased risk of prostate cancer and aggressive prostate cancer, respectively.^{195 196 197 198 199 200 201 202 203 204} These findings indicate that diets rich in animal foods and low in healthful plant foods may increase the risk of prostate cancer by a magnitude at least comparable to that observed for heavy smoking.²⁰⁵

The Prostate Cancer Lifestyle Trial which involved 92 men with early-stage prostate cancer found that only 5% of the experimental group that were advised to adopt a plant-based diet supplemented with 40 g/day soy protein isolate in addition to exercise and stress management had undergone conventional prostate cancer treatment, compared to 27% of the control group receiving usual care.²⁰⁶ Similarly, a short-term randomized, placebo-controlled trial which involved 58 high risk men found that prostate cancer developed in only 6% of men provided with 40 g/day soy protein isolate, compared to 38% provided 40 g/day milk protein isolate.²⁰⁷ While these studies were modest in size, they are consistent with the experimental findings from a xenograft human prostate cancer model that 20% plant protein from soy protein isolate, wheat gluten, and corn gluten inhibits tumor weight by 37% compared to 20% dairy protein.²⁰⁸ Taken together with the evidence from a meta-analysis of 38 clinical trials that neither soy nor soy isoflavones effect testosterone or estrogen levels in men, these findings help establish the safety of modest soy food consumption in male reproductive health.²⁰⁹

Diet has also been implicated as an important determinant of other measures of male reproductive success. A meta-analysis of 52 animal studies involving multiple breeds of mice, rats, and rabbits found that high fat diets, typically rich in cholesterol and saturated fat adversely affect more than a dozen measures of male reproductive success, including mating success, fertilization success, relative testes mass, DNA damage, sperm count, and sperm motility.²¹⁰ Consistent with these findings, epidemiological studies have found that a high intake of cholesterol, saturated fat, meat, and dairy are associated with a lower sperm count and sperm quality.^{211 212 213 214 215 216} In contrast, evidence from randomized controlled trials indicate that antioxidants and mixed nuts improve sperm count and quality, supporting the findings from epidemiological studies that healthful plant-based dietary patterns improve these same parameters.^{217 218 219 220 221 222}

In 400 BCE, Hippocrates was possibly the first to describe the shared etiology between male (MSD) and female sexual dysfunction (FSD), attributing obesity to the high prevalence of MSD and FSD observed in the nomadic Scythian who subsisted chiefly on grass-fed meat, raw milk, and cheese.²²³ This observation is compatible with modern evidence implicating obesity and other cardiovascular risk factors, and in-turn, unhealthful diets as a cause of both MSD and FSD.^{224 225 226} Indeed, a randomized controlled trial found that a Mediterranean diet had a similar effect on reducing deterioration of sexual function in men and women.²²⁷

There is also likely a shared etiology between male and female hormonal cancers, including breast cancer, a major cause of death and FSD.^{228 229} As with prostate cancer, high healthful plant-based diet score has been associated with up to a 45% decreased odds of breast cancer.^{230 231 232} Similarly, meta-analyses of epidemiological studies have found that a high intake of fruits, vegetables, dietary fiber, and several plant-derived antioxidants, and a low intake of red meat were each associated with up to a 30% reduced risk of breast cancer.^{233 234 235 236 237 238 239 240} In the Adventist Health Study-2, it was found that substituting median intakes of soy milk with dairy milk was associated with a 67% increased risk of breast cancer, with no evidence of a threshold in which a further decrease in dairy milk did not confer greater benefit down to zero intake.²⁴¹ Moreover, in the Women’s Health Initiative randomized controlled trial involving 48,835 postmenopausal women, it was found that a low-fat diet reduced death following breast cancer by 35% during the 8.5 years of dietary intervention, and breast cancer death by 21% after 19.6 years of cumulative follow-up, despite only very modest increases in fruit, vegetable, and whole grain intake, and a significant increase in sugar intake.^{242 243 244} These findings indicate that diets rich in animal foods and low in healthful plant foods may increase the risk of breast cancer by a magnitude at least comparable to that observed for heavy smoking.²⁴⁵

The overwhelming evidence from clinical, genetic, epidemiological, and primate studies strongly indicate that whole-food plant-based diets are a virtual sine qua non for optimal long-term male sexual function, and that the benefits on erectile function are at least comparable and additive to commonly prescribed ED treatments. Importantly, these diets likely also play a critical role in reversing atherosclerotic cardiovascular disease and vascular ED. Comparatively, long-term adherence to animal-based ketogenic, carnivore, and other popular diets rich in penile-artery-clogging saturated fat may increase the risk of erectile dysfunction, hormonal cancers, and atherosclerotic cardiovascular disease by a magnitude at least comparable to that observed for heavy smoking.