Abstract
This chapter considers the effect of paternal age on semen analysis, sperm function and DNA damage, as well as age-related impact on male fertility, both natural conception (time to conception (TTC)) and assisted reproduction technology (ART) outcomes, including intrauterine insemination (IUI), in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI). The effects of advanced paternal age (APA) on health of offspring, including congenital birth defects, paternal age effect (PAE) disorders, and psychiatric spectrum disorders (schizophrenia, autism and dyslexia) are also discussed. Increasing male age results in a steady decline in semen quality, reduced sperm function, including acrosome reaction, proteomic and genomic expression and increase in sperm nuclear DNA damage. However, lack of a clear definition of advanced paternal age, and a variable impact on relevant endpoints (conception, miscarriage, live birth, child health) make discussions challenging for healthcare professionals when counselling patients regarding specific male age-related risks.
5.1 Introduction
Sperm counts have decreased by 50–60% between 1973 and 2011 across North America, Europe, Australia and New Zealand [1]. This decline has been predominantly attributed to lifestyle factors, which include poor-quality diets, increased rates of obesity and sedentary lifestyles. This chapter will examine the role of these factors in sperm quality and subfertility, making recommendations based on the available evidence (see Table 5.1 and Table 5.2).
| Nutrient | Sources |
|---|---|
| Zinc | Oysters, beef*, lamb*, cashew nuts, almonds, pumpkin seeds, oats, chickpeas, kidney beans, peas, shiitake mushrooms |
| Selenium | Brazil nuts, tuna, salmon, white fish, shellfish, beef*, lamb*, chicken, eggs, sunflower seeds |
| Iron | Oysters, organ meats*, red meat*, tofu, oats, pumpkin seeds, lentils, beans, chickpeas |
| Copper | Oysters, kale, shiitake mushroom, sesame seeds, chickpeas, cashew nuts, soybeans or tofu, spinach |
| Vitamin C | Red and yellow peppers, guava, papaya, kiwi, oranges, strawberries, pineapple, broccoli, red cabbage |
| Vitamin E | Almonds, almond butter, sunflower seeds, hazelnuts, peanut butter, egg, avocado, spinach, chard |
| Omega-3 | Anchovies, sardines, salmon, mackerel, trout, halibut |
| Folic Acid | Edamame beans, spinach, artichoke, asparagus, lentils, beans, chickpeas, liver*, fortified cereals |
| Vitamin D | Sunshine, salmon, mackerel, albacore tuna, trout, fortified dairy, fortified bread, eggs |
*Limit sources of red meat
Table 5.2 Lifestyle factors affecting sperm quality
| Include and increase | Decrease | Avoid | |
|---|---|---|---|
| Fruits and vegetables |
| Red meat, processed meats |
|
| Fish |
| Biscuits, cakes, pastries, some fried foods and ready meals |
|
| Pulses: lentils, beans, peas |
| High sugar foods, sugar sweetened beverages |
|
| Nuts and seeds |
| Excess heat |
|
| Exercise |
| Smoking |
|
| Sleep |
| ||
5.2 Nutrition and Male Fertility: Limitations of Research
The research on the effects of nutrition on sperm is growing, although there are a number of limitations. First, observational studies can give us information on dietary patterns that are associated with better semen parameters or increased pregnancy rates but causality cannot be proven. However, with repeated confirmation of these associations through several different studies, it is prudent to take valuable information from this.
The second limitation is that many studies focus on improvement of parameters of a semen analysis but may not include follow-up data regarding increased pregnancy rates or live birth rates. While this information would be useful, there are many variables that contribute to a healthy and viable pregnancy, not least the female’s reproductive health. In cohorts undergoing assisted reproduction, there are additional variables and often concomitant conditions. The WHO methodology of semen analysis has a proven association with fecundity. It is therefore logical to extrapolate and suggest that improving semen analyses will increase fecundity.
A significant limitation to almost all dietary and nutrition research is control and measurement of food intake. The development of new apps and tracking monitors may improve recall and accuracy but there is currently no ideal solution. The inability to accurately measure dietary intake makes it difficult to control for confounding factors.
Estimating dietary intake also does not account for absorption of nutrients. Digestive complaints are extremely common, some associated with poor diet and lifestyle factors themselves, such as gastro-intestinal reflux disease (GERD), hyper- or hypochloridria and irritable bowel syndrome (IBS), which can lead to malabsorption. Measuring blood levels of nutrients is often a better way of monitoring recent nutrient intake and absorption but is not frequently performed.
When looking at specific nutrients or supplements, the major limitation in many studies is that the background diet or indeed starting measurements of the nutrient is not taken into account. If a cohort takes zinc supplements for example, and 60% of this cohort is already replete, then the effects of case versus control will be diluted significantly, and more importantly the true effect will be unknown.
Looking at whole dietary patterns and whole foods or meals as we eat them in the real world lends to better overall recommendations that can be used on a large scale. Individual requirements may be more accurately assessed by using blood testing and then tailoring dietary or supplement recommendations accordingly. This could be conserved for more severe cases where general dietary improvements could be recommended for anyone considering conception.
5.3 Dietary Patterns Associated with Improved Sperm Quality and Quantity
There are now a number of studies, which taken together, can define a “healthy diet” for men, which is associated with normal semen parameters and increased fecundity. This is a diet high in fish, fruits, vegetables, nuts and pulses and low in red meat, saturated fat, trans fats, processed foods and sugary snacks or sugar sweetened beverages [2]. Despite differences across study design, food intake measurement tools and dietary classifications, the association is clear. Improving the general diet of men, either before conception or when attending fertility clinics, is a simple recommendation to make and carries no risk.
5.3.1 Dietary Food Groups
5.3.1.1 Fruits and Vegetables
Brightly coloured fruits and vegetables are particularly high in antioxidant vitamins including vitamin C, vitamin E and beta-carotene and a wide range of polyphenols. Antioxidants neutralise reactive oxygen species (ROS) and thus may prevent damage to sperm from high levels of oxidative stress which may cause reduced concentration, motility, morphology and higher levels of DNA fragmentation [3].
Fruits and vegetables are excellent sources of fibre. High fibre diets are associated with reduction in weight which will be discussed later in (see Section 5.5, Overweight and Obesity). Fibre also binds to oestrogen in the digestive tract, which may support a healthy testosterone/oestrogen ratio necessary for spermatogenesis. Brassica vegetables in particular (cabbage, kale, cauliflower, broccoli, bok choi) are high in indole-3-carbinol, a phytochemical that may inhibit aromatase.
5.3.1.2 Fish
Fish is very low in saturated fat which may contribute to a reduction in weight and risk factors associated with the metabolic syndrome. This includes insulin resistance which is a risk for sperm abnormalities, high DNA fragmentation and infertility [4]. A diet high in fish is also by default likely to be lower in meat so there is a reduction in overall saturated fat intake.
Oily fish, such as salmon, mackerel, herring, sardines and anchovies, are an excellent source of omega-3 polyunsaturated fats (see Section 5.4.5, Omega-3).
5.3.1.3 Meat, Processed Meats and Saturated Fats
Red meat is high in saturated fat and omega-6 arachidonic acid. A dose–response association between increased intake of saturated fat and a lower total sperm count and sperm concentration has been observed [5]. Arachidonic acid can be metabolised to pro-inflammatory prostaglandins and leukotrienes, promoting the inflammatory cascade and ultimately oxidative stress. A balanced diet that includes more fish and less meat will have greater overall anti-inflammatory potential.
Beyond the above mechanisms, it is not well understood why processed meats in particular are detrimental to male fertility, though higher intakes have been shown to correlate with significantly reduced fertilisation rates in IVF [6]. It may be that soy-containing additives have oestrogenic activity and there may be other unknown effects of artificial preservatives, colourings or flavourings.
5.3.1.4 Pulses
Pulses or legumes such as beans, lentils and peas are high fibre, low fat foods. They are often part of vegetarian meals as a source of protein and replace higher fat, pro-inflammatory foods such as meat or processed meats. Again, by default, a diet higher in pulses and fish is likely to be low in meat, but also may be high in vegetables due to their incorporation into vegetable-based meals.
5.3.1.5 Trans Fats
Trans fats are known to be pro-inflammatory and may increase markers of oxidation. In an intervention study, increased intake of trans fats in young men caused a marked decrease in sperm concentration [5]. Trans fats are also found in foods high in saturated fat, omega-6 oils and sugar such as confectionary, pastries, biscuits, cakes and processed foods. Therefore trans fat intake could also be seen as a marker for a high-fat, high-sugar, high processed food diet.
5.3.1.6 High Sugar Foods and Sugar Sweetened Beverages
High sugar diets contribute to weight gain, obesity, insulin resistance, inflammation and other hallmarks of the metabolic syndrome (see Section 5.5, Overweight and Obesity). Sugar sweetened beverages (SSB) in particular have been highlighted as a source of additional calories that has largely been blamed for the over-consumption of sugar by the consumer. Many European countries have singled out SSB by adding additional taxation or by promoting their exclusion from schools.
Studies directly linking the intake of SSB with male fertility are limited. Analysis of the Rochester Young Men’s Study showed that a higher intake of SSB was related to significantly decreased motility in lean men only but not in those overweight or obese, where other factors may be involved [7]. Intakes of cola of over one litre per day also showed association with significantly lower sperm count and concentration [8]. In terms of pregnancy outcome, the Pregnancy Study Online (PRESTO) in North America including 1,045 men showed that higher SSB intake was related to a decreased fecundability ratio of 0.67 with daily consumption of one SSB [9]. This ratio declined further to 0.42 for energy drinks regardless of caffeine content. It is known that lifestyle habits often co-exist and PRESTO participants who drank more SSBs were more likely to smoke, have a higher BMI, lower physical activity, lower Healthy Eating Index scores and higher caloric intake; all factors contributing to inflammation and ROS which can affect sperm health.
5.4 Individual Nutrients
As mentioned previously, it is important to note that studies investigating individual nutrients rarely take into account the baseline status or even the likely dietary intake of the cohort. In the case of antioxidants, a negative effect may be seen with over-supplementation. Pro-oxidant reactions play an essential role in the body and sperm produce small amounts of ROS in order to fuel reactions involved in capacitation, binding to the zona pellucida and the acrosome reaction and thus, ultimately, fertilisation. The balance of pro-oxidant reactions is closely regulated by antioxidants. Over-supplementation is not advised, which may inhibit essential reactions or even cause chromatin instability [10].
5.4.1 Zinc
Zinc plays a number of diverse roles in the body, acting as a co-factor for hundreds of enzymatic reactions. Zinc fingers represent an abundant binding motif of DNA-binding proteins, protamines involved in chromatin remodelling and transcription factors to name a few. Zinc is found in high concentrations in the male reproductive tissues and seminal fluid has a zinc concentration of approximately 100 times higher than that of plasma. Infertile men have significantly lower seminal zinc than normal controls [11].
Zinc is involved in regulating lipid flexibility and thus motility, and membrane integrity during capacitation and the acrosome reaction [12]. Zinc is also critical to chromatin unpacking in the sperm head after fertilisation within the oocyte and deficiency may inhibit this, even in the cases of intracytoplasmic sperm injection (ICSI) [13]. Zinc is also an essential component of the abundant antioxidant compound copper/zinc superoxide dismutase (Cu/Zn SOD or SOD1), found at high concentration in seminal fluid. Zinc prevents lipid peroxidation by copper and iron. Lastly, zinc is essential for the production of thyroid hormones which in turn regulate sex hormone production and balance. Zinc deficiency correlates with testosterone deficiency.
Good sources of zinc include lamb, beef and dark chicken meat, although red meat should be limited in a “healthy diet” for male fertility. Good plant sources of zinc include cashew nuts, almonds, pumpkin seeds, oats, chickpeas, kidney beans, peas and some mushrooms. Oysters contain 10 times more zinc than the next highest food but are unlikely to be consumed regularly.
Zinc deficiency is common worldwide. Zinc absorption is negatively affected by hypochloridria which may be a pre-existing condition or induced by medications such as proton pump inhibitors (PPI) or H2 blockers. PPIs are among the most commonly used medications in the world and are easily available over the counter. Zinc absorption is also decreased in a high phytate diet such as a vegetarian or vegan diet high in pulses or wholegrains. Thus the advantages of an anti-inflammatory diet versus possible inhibition of mineral absorption should be considered. Some efforts can be made to reduce the phytate content of a meal such as pre-soaking foods such as pulses, brown rice or oats.
Analysing seminal zinc is uncommon in routine testing but testing blood serum zinc is economic and relatively accessible. Though zinc is higher in seminal plasma, blood levels may indicate overall deficiency. Blood levels also do not reflect long-term stores but may be a good indicator for recent dietary intake and absorption. Blood samples for assaying should be collected after fasting, as high protein intake before sampling will falsely reduce serum zinc.
Zinc is commonly found in supplement formulations targeted at men and male fertility. A number of studies include zinc as a component of a multivitamin and mineral, which may improve semen parameters and DNA fragmentation. A Cochrane review identified a marked increase in pregnancy rates in males using these formulations (OR 4.5) but rated the evidence as low due to poor design and heterogeneity of studies [14]. As a single supplement, meta-analysis has shown a positive role in improving morphology, motility and semen volume [11]. Supplement dosage varies in studies, with some giving high doses, for example 440 mg zinc sulphate daily; however, bioavailability of zinc from zinc sulphate may be as low as 10%. Zinc glycinate or zinc citrate have markedly higher bioavailability (as high as 60%) where zinc oxide may be poorly absorbed in hypochloridria or conditions of elevated gastric pH. The WHO/FAO assigned a Daily Recommended Value (DRV) of zinc for men with low bioavailability diets (e.g. high in phytates) at 14 mg per day. On a low meat, high fibre diet as described herein, a supplement of zinc glycinate or zinc citrate containing approximately 23 mg of zinc glycinate/citrate would provide the DRV for a male.
5.4.2 Selenium
Selenium is also found in high concentrations in the male reproductive tract, mostly as part of the selenoproteins glutathione peroxidases [10]. Glutathione peroxidases (GPX) are a family of antioxidant proteins which are abundant in the testes, specifically GPX5 and GPX4, which is found in higher concentrations in the testis than any other tissue. GPX4 proteins are critical to the regulation of pro-oxidant and antioxidant reactions involved in chromatid compaction during sperm maturation. Later in development, inactive GPX4 is a structural protein of the mitochondria in mature spermatozoa.
Selenium status in a population can be related to the selenium in the soil with notable exceptions. Selenium accumulates in plants which are then consumed by people or by animals which enter the food chain. Selenium content is higher for example in the west of the UK than the east but can vary. This may also depend on intensive farming techniques which may deplete minerals more rapidly, or whether food is imported from other areas. Animals that are not grass-fed and are fed a formulated feed will have standardised levels of selenium. Another exception is where high quantities of Brazil nuts are consumed. There is much advice in the public domain to consume Brazil nuts to support male fertility and it is recommended to question patients on this. Brazil nuts are markedly higher than other foods in selenium and just one Brazil nut could provide up to 80 µg of selenium, where the recommended daily intake set by the WHO/FAO is just 34 µg for men. Due to risk of excess selenium, Brazil nuts should not be consumed daily but could be part of a well-balanced diet. Other good sources of selenium include meat, chicken, fish, shellfish and eggs. Selenium status varies widely, with the measurement in a number of EU countries finding suboptimal levels to support sufficient activity of GPX proteins [15].
Selenium is often found in supplement formulations targeted at male fertility and may be present as the organic form selenomethionine or selenium derived from yeast, or the more poorly absorbed selenite. There are only a small number of studies examining selenium supplementation as a single nutrient and no meta-analyses [16]. One small Scottish study measured the effect of supplementation on men with suboptimal selenium status and showed an improvement in motility but no significant increase in sperm count. Another well-designed larger randomised controlled trial in Iran included an infertile population with sub-optimal selenium status. Selenium status was optimal post-treatment and lead to a significant improvement in sperm count, concentration, motility and normal morphology. Notably, a study of selenium supplementation in North America which was carried out on participants that were not only selenium replete, but at the upper end of the normal range, showed no effect. Studies also varied in types of supplement used and whether the cohorts were healthy men or infertile men. As with other nutrients, we propose that the effect is more likely to be seen in males with suboptimal status and serum selenium should be measured before supplementation.
5.4.3 Iron and Copper
Iron deficiency or excess may have implications for male fertility. Ferritin in Sertoli and Leydig cells represents a source of iron for maturing spermatids and may play a number of functions in sperm development [17]. Iron deficiency can reduce oxygen availability in the testes and may correlate with suboptimal semen parameters. Copper is also critical for iron transport as the ferroxidase enzyme ceruloplasmin and thus copper deficiency could manifest as decreased iron availability in the testes also.
Iron overload or haemochromatosis is a common genetic condition, particularly in Northern Europe and highest in Ireland. Iron toxicity along with hypogonadism may lead to atrophied testes, reduced sperm quality and quantity and increased DNA fragmentation.
Copper and iron both have antioxidant roles. Copper is a component of Cu/Zn SOD. SOD converts reactive O2− to form oxygen (O2) and hydrogen peroxide. Catalase (CAT), with four iron-containing haem groups, converts hydrogen peroxide into harmless O2 and water.
Given that iron deficiency is simple to restore and iron overload is relatively common, measuring iron studies including ferritin, transferrin saturation and TIBC (Total Iron Binding Capacity) is recommended in an initial assessment of the male patient. Foods rich in haem iron include red meat. Plant sources on a low-meat diet include lentils, beans and leafy green vegetables. It is important to note that non-haem iron is poorly absorbed but this can be improved by consuming vitamin C-rich fruits or vegetables with a meal. Hypochloridria may also affect this, including use of PPIs, as the reaction to convert ferric acid to the absorbable ferrous state involves HCl and is facilitated by ascorbic acid.
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