In our field of work, like many others, we need to apply some level of critical analysis to the evidence base we work with. A couple of years ago I was asked to critically review the impact of nutrition on infertility (which is also sometimes referred to as sub fertility). After this review had served its purpose I didn’t like the idea of it collecting dust (or whatever they do when in cyberspace) so thought I’d share it with you.
We start with a brief overview of the causes of infertility and then take a closer look at genetics and the impact that nutrition has on:
1) Polycystic Ovary Syndrome (PCOS)
2) Premature Ovarian Failure (POF)
3) Recurrent Pregnancy Loss (RPL)
It is widely recognised that diet plays a pivotal role in PCOS, whereas less is known about POF. There are direct correlations between RPL and oxidative stress; however altering inflammatory markers via nutritional modification may be an area for future research. Assessing genetic inheritance and how nutrients may alter their expression as well as a short discussion on environmental toxins is included under the prevention of infertility.
Amelioration and treatment are discussed together with the primary focus on diet and nutrients and critically evaluating the evidence for using nutrition to improve or treat fertility outcomes, as many of the epidemiological studies have been based around the Nurses’ Health Study II, which could be criticised for biased research.
The Department of Health (UK) define infertility as: “Failure to conceive after frequent unprotected sexual intercourse for two years in couples in the reproductive age group in the absence of known pre-existing causes of infertility. This definition is different from the treatment criteria in the NICE clinical guideline, because the guideline’s aim is to define the point at which treatment should be offered” (Department of Health, 2009).
Of all couples classified as infertile, female infertility accounts for around 40-50% with ovulatory failure including PCOS accounting for 20%, tubal damage 15% and endometriosis 5%. Male infertility is around 30-40% and unexplained is 10-30% (Department of Health, 2009).
Concerns regarding decline in human fertility have been increasing over recent years (Carlsen et al., 1992; Irvine et al., 1996; Swan et al., 2000) and research suggests that testicle size and sperm production have been steadily decreasing for generations with sperm count currently in men being less than half of that compared to men in the 1940’s (Dindyal, 2004).
These studies have recently been criticised for selection bias as semen quality and quantity is not as seriously affected in men living in developing countries that are “non-westernised” (Deonandan & Jaleel, 2012).
Maternal nutrition is thought to underpin a variety of pregnancy outcomes and the established literature is rapidly growing. Nutrition influences ovulation, fertilization, implantation and early foetal development (ESHRE, 2006).
Causes of infertility
There are multiple factors to consider when discussing the causes of infertility, these include our genes and health, reproductive and medical history to nutrition, lifestyle and environmental issues. The extent nutrition plays towards the cause of infertility is a well-researched and much discussed subject.
Overall poor health status also significantly contributes to the cause of infertility, with obesity and diabetes being the most recognised, and stress being a contributory factor. All three are modifiable by lifestyle changes.
The British Fertility Society published guidelines in order to manage the effects of obesity on female reproduction, (Balen & Anderson, 2007) stating that a weight loss “as little as 5-10% may be able to restore fertility in those significantly overweight” (Kay & Barratt, 2009). Hyperglycemia increases Reactive Oxygen Species (ROS) and affects spermatic parameters (Salma et al., 2011) and stress reduces semen quality (Fenster et al., 1997) increases ROS generation (Eskiocak et al., 2006) affects testosterone levels and spermatogenesis (Hall & Burt, 2012).
Is it all in the genes?
In about 15% of infertile men, genetic abnormalities may be found. Chromosome abnormalities are known to be around 10-15% higher in infertile men than in the general population, the higher the rate of abnormalities the lower the sperm count (Kara & Simoni, 2010). Gene Mutations, include INSL3 (Insulin-like factor 3). Most recognised are Y chromosomal haplogroups or micro-deletions representing genetic causes for spermatogenetic failures and include MTHFR the enzyme 5-methylenetetrahydrofloate reductase involved in conversion of homocysteine to methionine. As well as Follicle Stimulating Hormone Receptor (FSHR) the interaction between the FSH and the FSH receptor is essential for oogenesis and spermatogenesis, and further studies are needed in men to see which populations may be affected as currently it is unclear (Ferlin et al., 2006). There are a wide range of studies demonstrating the impact of the environment and nutrition on these genes and some are discussed below.
In females around 10% of genetic abnormalities may be found (Ferlin et al., 2006) and the major underlying causes of female infertility are PCOS, POF and RPL. POF is thought to be genetically determined and is defined by absence of menstruation before the age of 40. Even though many genes are found none are common. In RPL the genetic mechanisms are still poorly understood although immunological based aetiology has been recognised it has been suggested that up to 51% of miscarriages in women with RPL are associated with chromosome abnormalities (Kara & Simoni, 2010).
Nutrition and exercise effect PCOS by improving endocrine features and reproductive function; studies show that fat should be restricted to ≤30% of total calories with a low proportion of saturated fat (Farshchi et al., 2007). Marsh (2009) reported in “Diagnosis and Management of PCOS” as the majority of women with PCOS, regardless of weight, have a form of insulin resistance “dietary and lifestyle changes that improve insulin sensitivity should be the first line of treatment”. A small study of 92 obese women following a low GI diet found improvement in symptoms of PCOS and menstrual cyclicity (Marsh et al., 2010). Another small study with 131 women with PCOS showed that they snacked on sweets more frequently than women in the National Diet and Nutrition Survey. Even though both of these studies are small, and it is well documented that people who completed food frequency questionnaires as well as the NDNS survey under report food consumption (Wylie et al., 2009), the science appears solid that nutrition has an impact on PCOS. A 2012 paper supported this view by saying “diet emerges as the major environmental determinant of PCOS”. They went on to explain, “AGEs and BPA may act as endocrine disruptors in the pathogenesis of the syndrome”. The fact that this paper is published in “Current Pharmaceutical Design” (Diamanti-Kandarakis et al., 2012) indicates the significance and acceptance that diet, lifestyle and environment have on the impact of PCOS.
Women with POF have significantly reduced lifetime oestrogen levels and may be exposed to lower oestrogen for around 10 years longer than normal postmenopausal women. As this effects bone health and cardiovascular disease, women with POF are usually advised to undergo HRT until the normal age of menopause, as well as increase physical exercise, eating a diet rich in calcium and vitamin D and avoiding risk factors such as smoking and high alcohol intake (Shelling, 2010). Dietary advice appears to focus on the side effects rather than prevention of POF. The largest and most recent study into POF was a cross sectional study in the Japan Nurses Health Study, this analysed data from 21,452 pre and postmenopausal women. They identified many factors however in this study only unilateral oophorectomy was associated with POF (Yasui et al., 2012). This paper was published in July 2012, and it would be beneficial for more research in regards to diet and nutrition to come from this population group.
RPL has many etiologies, including endocrine; anatomic, genetic, hematological and immunological yet, over half of the cases remain unexplained (Kwak-Kim et al., 2009). There appears to be sound science supporting the correlation between RPL and oxidative stress (Sekhon et al., 2010) however data on how diet and nutrition specifically affect RPL is limited. Using the functional medicine model it would seem appropriate for researchers to continue research in utilising diet to modify immunological markers and inflammatory pathways in those with RPL. The European Prospective Investigation into Cancer and Nutrition (EPIC) prospective cohort study looked at 11,518 women, and found those who have RPL have a higher risk of cardiovascular disease in later life (Kharazmi et al, 2011). A recent study from India showed that those with MTHFR gene had 6-fold increase in risk of pregnancy loss (Nair et al., 2012). Measuring homocysteine may be advisable. Gluten free diets have shown a positive outcome in those with celiac disease and RPL (Tursi et al., 2008).
A recent study from India showed that those with MTHFR gene had 6-fold increase in risk of pregnancy loss (Nair et al., 2012).
Soya consumption is a topical subject and there is not scope within this document for it to be discussed in depth. It has been reported that in obese men consumption of soy lowers sperm concentrations (Chavarro et al., 2008) this study was with 99 men for 3 months, it did not state if the soya was GM or not, and the results may not be replicable due to variances in gut bacteria. The other two male studies did not support these findings (Song et al., 2006; Mitchell et al., 2011). There are wide disparities amongst the results of the impacts of soya on human reproduction, which is partly due to small sample sizes. Animal trials were popular, yet animals and humans metabolise isoflavones differently. Dosage, protein type and study design have also been inconsistent. It may take many years before ill effects are shown (Cederroth et al., 2011). Small quantities of non-genetically modified soya, either fermented, or in its natural form are likely to be beneficial.
Small quantities of non-genetically modified soya, either fermented, or in its natural form are likely to be beneficial.
Prevention of infertility
Epigenetics refers to changes in gene function that is not explained by changes in DNA sequencing, with DNA methylation being an important contributor (Kaati et al., 2007). The response to nutrition is trans-generational with nutrition from the grandmother during pregnancy not only affecting mothers nutrition during fetal life but also the grandchild’s (Lumey & Stein, 1997). Three genes implicated in male and female infertility are MTHFR, INSL3 and FSHR.
The response to nutrition is trans-generational with nutrition from the grandmother during pregnancy not only affecting mothers nutrition during fetal life but also the grandchild’s.
MTHFR gene expression is altered by diet, alcohol consumption, hormone replacement therapy and environmental toxins (Rodenhiser & Mann, 2006). Changes, predominantly deficiencies, in folate status negatively impact human reproduction (Eloulid et al., 2012) and clinical implications of the MTHFR C677T polymorphism include increased risk for several fertility and pregnancy issues. Alcohol alters folate metabolism and lowers MTHFR activity (Chiuve et al., 2005) as well as reducing absorption of zinc and impacting liver function, which may also affect sex hormone binding globulin, further exacerbating hormonal imbalances.
Alcohol alters folate metabolism and lowers MTHFR activity.
INSL3 is substantially lower in adolescent obese boys than normal weight controls and affects Leydig cell function (Taneli et al., 2010) a sign of testicular dysgenesis. Circulating amounts are higher in women with PCOS and it naturally declines consistently when aging (Ivell & Anand, 2009). Studies currently show that adiposity controls INSL3 over glycemic control (Ermetici et al, 2009), however with its links with diabetes, obesity and PCOS it would make sense that there are further studies into glycemic control.
Currently there is limited available data on diet and FSHR however in murine models low folate not only affects MTHFR gene but also inhibits FSHR gene transcription (Twigt et al., 2011). It could be assumed that nutrients, which affect FSH may also have an impact on the expression of this gene.
Sadeu et al., (2010) found smoking to be strongly associated with infertility, this is supported by studies showing smoking increases miscarriage rate and decreases sperm quality (Youngli, 2005) as well as interacting with the MTHFR gene and increasing homocysteine (Brown, 2004). There is a plethora of studies demonstrating exposure to chemicals; metals, pharmaceuticals and agricultural pesticides affect fertility, sperm quality, motility, development and maturation in men. In women these toxins disrupt reproductive development and increase the risk of foetal loss (Chapin et al., 2004; Heudorf et al., 2007; Crinnion, 2010).
There is a plethora of studies demonstrating exposure to chemicals; metals, pharmaceuticals and agricultural pesticides affect fertility, sperm quality, motility, development and maturation in men. In women these toxins disrupt reproductive development and increase the risk of foetal loss.
Amelioration and Treatment
Micronutrient deficiencies have been associated with infertility, structural defects and long-term diseases and the essential nutrients for fertility and conception include antioxidants, folate, vitamin B12, B6, vitamin A, iron, zinc and copper (Cetin et al., 2009). This list is not exhaustive and these nutrients are not all discussed within this document.
In 2006 Chevarro et al., published their research on “Iron intake and risk of Ovulatory Infertility” using data extracted from The Nurses’ Health Study II looking at 18,555 women over 8 years. This paper appears to be the first in a series of studies documenting evidence relating diet, nutrients and lifestyle to fertility. A key paper subsequently published in 2007 was again based on The Nurses’ Health Study II, a prospective cohort study, which included more than 116,000 women aged 24-42 years. This demonstrated that a diet low in trans-fats, greater intake in monounsaturated fats, lower intake of animal protein but higher in vegetable protein, high intake of high-fibre and low glycemic carbohydrates, a preference for full-fat dairy and non-heme iron all scored high for a fertility diet (Chavarro et al., 2007). Additional papers looked more closely at carbohydrate intake (2007), dairy foods (2007), soy isoflavones (2007), protein intake (2008), use of multivitamins and B vitamins (2008), caffeinated and alcoholic beverages (2009) and dietary fats (2007). The data from these studies provides a valuable resource for clinicians and in 2008 “The Fertility Diet” was popularised and is now included in many books aimed at the general public.
It could be argued that the evidence for diet, nutrition and lifestyle in relation to infertility has selection bias and this may be valid. The Nurses’ Health study is a cohort study of women, who may be a healthier group to study or at least more aware of diet and lifestyle but conversely may work shift patterns affecting circadian rhythms and may have higher stress levels than the average woman. Their working conditions are likely to be similar, such as access to canteen foods, vending machines and activity levels. The results of these papers may be biased for these reasons and others. Food Frequency Questionnaires (FFQ) were used throughout, and even though validated by Willett et al., (1985) who say they are useful to monitor nutrient intake over a one-year period, these studies use a FFQ over a two-year period, this is likely to increase the degree of error. Overestimation of consumption of vegetables has been documented and in one study was almost double that assessed from weighed records (Bingham et al., 1994).
However Chavarro et al., led the way for further research and the majority of papers investigating other population groups support these epidemiological studies as can be seen below, with the exception of alcohol and caffeinated beverages.
Essential Fatty Acids (EFA’s)
EFA’s are essential for many bodily functions including fertility (Dobryniewski et al., 2007) and crucial for healthy hormone function in women, as well as sperm production, motility and sperm count in men (Wathes et al., 2007; Safarinejad & Safarinejad, 2012). Essential fats help prevent blood clotting and are useful for those who have recurrent miscarriage due to clotting issues (Sekhon et al, 2010) and have been shown to improve embryo morphology in IVF treatment (Attaman et al., 2012).
Oxidative stress has been implicated in female infertility (Agarwal et al., 2005) as well as cyclical changes in endometrium, in some cases leading to endometriosis, PCOS and RPL (Sekhon et al., 2010). OS also mediates EFA alterations in infertile women (Mehendale et al., 2009).
Low dietary antioxidant intake has been strongly correlated with male infertility, Eskenazi et al., (2005) found those with a higher antioxidant intake had higher sperm numbers and better motility, with Vitamin C being associated with sperm number, vitamin E with sperm motility and beta carotene with higher sperm concentration. In human studies there has been strong correlations between low levels of seminal plasma carnitine and male infertility (Gurbuz & Yalti, 2003). Carnitine is present in high quantities in spermatozoa and epididymis, and in animal studies improved sperm quality and quantity (Blackman, 2004). A review paper in 2010 suggests that in men, carnitines, vitamin C and vitamin E should now be considered as first line therapy with glutathione, selenium and coenzyme Q10 being considered as second line therapy (Agarwal & Sekhon, 2010). Antioxidants reduce DNA damage to sperm, which may occur during semen processing used in IVF, studies have been carried out on Vit C, E, Zn, Se, b-carotene, beta-glucans (Zini et al., 2009).
As far back as 1981 a study (Netter et al.,) with 22 men and zinc showed that supplementing with 24mg of zinc sulphate for 50 days raised sperm count from 8 to 20 million per milliliter, this study further resulted in nine pregnancies for the subjects. Wong et al., (2002) showed that zinc supplementation increased normal sperm count by 74% in fertile and sub-fertile men.
In infertile men, where no genetic screening had been carried out, 15mg folate was given to 65 men daily for 3 months resulting in increased sperm density and motility, in this study 65 couples conceived after 6 months and they had previously been trying for an average of 3.2 years.
In a randomised placebo controlled trial, 99 (94 in the control group) men were supplemented with a mix of folate, placebo, zinc or both, and the results showed that men supplemented daily with folate (5mg) and zinc (66mg) had a 74% increase in sperm density compared to the men who had only folate, whose sperm density increased by 40%. It is important to remember the synergy of nutrients as zinc deficiency affects folate intestinal absorption. With genetic screening however the MTHFR 677CC carriers had a significant increase, with no affect on the TT mutations – it has been suggested that higher folate status may still support TT mutations (Forge et al., 2007).
In an IVF study involving 292 couples it was found that women who used folate supplements had better embryo quality (Boxmeer et al., 2009).
Body weight, stress and IVF.
In data extracted from the OMEGA study (involving 19,840 women undergoing IVF between 1983-1995) women with a normal BMI or overweight had higher birth rates per IVF cycle than women with a BMI above 27kg/m2 (Linsten et al., 2005). A recent report looking at the effects of stress reduction in women, found intervention groups which included health and behaviour modification, had the highest rates of IVF success (Domar et al., 2011).
BMI affects every stage of fertility and infertility and its effects on reproductive health are paramount. The science evidently supports the use of nutrition in all stages of infertility, from the causes such as obesity and PCOS, to intervention with nutrients from an epigenetic aspect with particular focus on the MTHFR gene. There is a plethora of literature in regards to amelioration and treatment from well-respected peer reviewed journals, not only with data from The Nurses’ Health Study II, but also from many other smaller studies or trials with different population groups. This research suggests that changes in diet and lifestyle should be primary care for couples that have been trying for some time and yet are unable to conceive.
This research suggests that changes in diet and lifestyle should be primary care for couples that have been trying for some time and yet are unable to conceive.
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Agarwal & Sekhon (2010) The role of antioxidant therapy in the treatment of male infertility. Human Fertility 13:4:217-225.
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