Women’s Nutrition Considerations Over the Life-course

In Sigma Statements by Alan FlanaganLeave a Comment

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Introduction

In this Sigma Statement, we intend to provide a lifespan overview of nutritional considerations for females. It is not intended that every single condition affecting females will be covered, as the scope would be too broad. Rather, we intend to cover the most prevalent conditions, for example iron-deficiency anaemia, and PCOS, together with nutrition considerations for the peri-menopausal lifestage. It also includes discussion of certain relevant sex-dimorphic factors, namely that of adipose tissue distribution.

There is a need for accurate, evidence-based information on this topic, given that women are unfortunately often provided with poor or incorrect information about nutrition and health. In the ‘Quack Asylum’ segment of a past podcast episode (see 63:09 of episode #352), we discussed this problem of pseudoscience communicated toward women about nutrition. The genesis for the discussion was the comments of an Irish medical doctor discussing (with another medical doctor) how women need to limit bread to two slices per day, need to eat little and often because of differences in metabolism, and need to avoid root vegetables during the week in favour of limiting such ‘indulgent' foods as carrots to weekends only. 

Not only do such claims lack any scientific basis, the fact that these claims were proffered as female-specific nutrition advice amounts to disempowering misinformation, which women may take as authoritative given the source. However, it is also commonplace to hear such sex-specific claims made about diets, foods and nutrients, or specific physiological factors.

So it is hoped this statement serves as a useful overview of the evidence in this area so that women (and those advising women) can make more informed choices about their nutrition.

This Sigma Statement will cover female nutrition in relation to:

  • Infancy, Childhood & Adolescence 
  • Nutrients of Emphasis in Adulthood
  • Sex Dimorphism in Adipose Tissue & Cardiometabolic Risk
  • Pregnancy & Lactation
  • Polycystic Ovarian Syndrome (PCOS)
  • Perimenopause: CVD, Breast Cancer & Osteoporosis Risk

Infancy, Childhood & Adolescence

Nutritional considerations in infancy do not differ by sex, however, there is advice for vitamin D to be supplemented to in all children from 6-months (recommendations for maternal supplemental will be discussed under Pregnancy & Lactation, below). With regard to childhood (defined as 1-10 years), while differences in nutrient intake have been observed in pre-school aged (i.e. 2-5 years old) girls compared to boys, this largely reflects differences in overall energy intake, with minimal differences once nutrient intake is adjusted for energy. 

Independent of energy-adjusted nutrient requirements and intake, inadequate intake of vitamin D remains prevalent in pre-school aged children of both sexes. It is noteworthy that dietary characteristics in this age group may resemble adult patterns in typical Western countries, with children often consuming excess total fat, saturated fat, added sugars, and sodium, while also falling short of recommendations of polyunsaturated fat, vitamin D, and potentially other nutrients like calcium and iron. This generally reflects transition from infancy feeding and weaning to adopting the general family diet.

Iron deficiency is a concern in both sexes, occurring in up to 16% of children under the age of 5 in the UK population, with diagnosed iron deficiency anaemia in 8%. The fact that in pre-school aged children, prevalence of iron deficiency may be similar in boys and girls reflects the fact that, prior to the onset of puberty, childhood nutritional considerations remain largely equivocal. Nevertheless, the cause for concern in relation to iron deficiency is warranted, given the associations between iron deficiency and impaired growth, development, and cognition. 

However, the onset of puberty spurs developmental differences with important implications for nutrition during adolescence (defined as ages 10-24), and cardiometabolic risk across the lifespan. With regard to nutritional consideration, the onset of the menstrual cycle is an additional factor to increased blood volume through adolescence which increases risk for iron deficiency in females. Globally, iron deficiency and iron deficiency anemia is the most significant micronutrient deficiency in females at all stages of adolescents, i.e., early adolescence (ages 10-14), late adolescence (ages 15-19), and early adulthood (ages 20-24). The recommended daily intakes for iron in the UK for adolescent girls (11-18yrs) is 14.8mg/d, and 11.3mg/d in same-aged boys. National Diet and Nutrition Survey (NDNS) data in the UK indicates that ~8% of girls in this age group have iron deficiency, compared to only 1.8% of boys. 46% of girls had iron levels below the lower reference nutrient intake level. Both diet, and if warranted supplementation, may assist achieving nutritional adequacy for iron. 

A relevant consideration for iron status is the source of iron, as heme iron from meat, fish, and poultry, is more readily absorbed than non-heme iron found in plant foods. However, there are factors which enhance non-heme absorption, in particular ascorbate (vitamin C). In females with iron deficiency and a low bioavailability diet (i.e., majority non-heme sources), the addition of ascorbate (from citrus fruit) to each meal resulted in a significant increase in absorption rate to 23% (from 18%).

Predicted nonheme-iron absorption from diets containing enhancers in individuals with different iron statuses. From: Collings et al., 2013

Diagnosis of iron deficiency anaemia is treated with supplementation of 65mg elemental iron (200mg ferrous sulfate) three times per day, and this should be overseen by an individuals' medical and nutrition professional advisors.

It should also be noted that energy intake requirements increase significantly during growth and development in adolescence, with protein requirements doubling from childhood recommendations. This is a factor to consider given that adolescent girls are more likely to adopt a vegetarian or vegan diet in adolescence than boys, which dietary patterns have implications for total energy and protein intake (amongst other nutrients, in particular B12). In this regard, protein intake correlates with total energy intake, such that protein requirements can be met when energy intake is adequate and a variety of higher protein plant foods are included in the diet. Adolescent girls are suggested to get at least 800mg of calcium per day, making their requirements slightly higher than pre-menopausal women (at ~ 700 mg/d). 

It is also important to consider key developmental changes which occur with the onset of puberty, as a physiological characteristic that develops during this lifestage is a higher percent total body fat in girls compared to boys, with sex-dimorphism in the distribution and type of adipose tissue. A primary feature of this differential adipose tissue deposition which develops from puberty is the preferential distribution in central abdominal depots in adolescent males, while adolescent females are characterised by gluteal-femoral deposition. This has important implications for adulthood, as cardiometabolic risk is strongly related with the differential distribution of adipose tissue.

Adulthood

Nutrients of Emphasis

Progressing into adulthood, iron remains the primary nutrient of concern with female-specific considerations. In women aged 19-64 years old, 23% have iron intakes below the lower reference nutrient intake, according to recent NDNS data, and this prevalence increases to 29% in women aged 25-49yrs, while mean iron intake in this age group was 65% of the reference nutrient intake. Thus, consideration should be given to achieving nutritional adequacy through diet, and supplementation if necessary (and with guidance from a nutrition professional). Other specific preconceptual nutritional considerations will be expanded on, below. 

Other nutrients which, depending on other factors, may warrant focus include vitamin B12, vitamin D, iodine, and calcium. Many of these nutrients of focus are generalisable across the population, and not necessarily sex-specific. However, given that women are twice as likely as men to adopt vegetarian or vegan diets, these nutritional considerations are important for these population subgroups. Thus, general advice to supplement with vitamin B12, potentially calcium if dietary intake falls short of requirement, and vitamin D, apply in this context. Iodine has received more focus recently as a nutrient of concern, given the increasing prevalence of plant “milk” substitute consumption, which lack the full nutritional profile of cow’s milk for certain nutrients, in particular iodine. It appears that certain companies are beginning to add iodine through fortification, which is a positive step and iodine adequacy should be considered in the context of vegetarian or vegan diets.

Sex Dimorphism in Adipose Tissue

From puberty, sex dimorphism (difference between sexes in characteristics beyond sex organs) in adipose tissue distribution develops. Men and women exhibit differential levels of total body fat, differences in distribution, and consequently differences in metabolic health influenced by adiposity. The distribution and type of adipose tissue has been identified as the factor influencing metabolic health, independent of adiposity

The adipose tissue beneath the skin is called subcutaneous adipose tissue (SAT), whereas the fat that lines the internal organs is termed visceral adipose tissue (VAT).

  • Subcutaneous adipose tissue [SAT] constitutes >80% of total body fat, and is highly concentrated in the abdominal, gluteal and femoral regions.
  • Intra-abdominal adipose tissue [IAAT] accounts for 10-20% total fat in men and 5-10% in women and is associated with internal organs, in particular metabolic organs and associated visceral adipose tissue [VAT].
  • Both subcutaneous abdominal adipose tissue [SAAT] and VAT are strongly associated with adverse cardiometabolic effects.

Sex steroid hormones have been identified as having a prominent role in the sex dimorphism of adipose tissue distribution. This is supported by the occurrence of the shift in distribution in post-menopausal women to increased intra-abdominal adipose tissue and visceral adipose tissue. In women, oestrogen appears to confer protection against visceral adipose tissue accumulation, and preferentially shift fat deposition toward subcutaneous adipose tissue accumulation in the gluteal-femoral region.

Conversely, androgens are implicated in the accumulation of visceral adipose tissue and abdominal adiposity, supported by the increase in visceral adipose tissue associated with declining testosterone in ageing men, and the increase in central adiposity in women with high-androgen polycystic ovarian syndrome. This significantly lower risk of cardiovascular disease in pre-menopausal women compared to men is associated with the preferential distribution of fat as subcutaneous fat in the gluteal-femoral region. In the Framingham Heart Study, increasing visceral adipose tissue was associated with heart disease risk in women, effects which were not observed for subcutaneous adipose tissue.

These associations may relate to the differential metabolic and endocrine activity of regional adipose tissue depots. The deposition of fat influences a myriad of factors, including:

  • Inflammation
  • Insulin sensitivity
  • Levels of adipokines (cell-signaling proteins secreted by adipose tissue) 
  • Release of non-esterified fatty acids (NEFA)
  • Lipolysis (the process by which triglycerides are broken down)
  • Lipogenesis (the process of fatty acid and triglyceride synthesis from glucose or other substrates)

In women, greater storage in the gluteal-femoral region is associated with an increased number and size of adipocytes. This results in a greater capacity for fat storage in lower body subcutaneous adipose tissue, preventing NEFA from accumulating in visceral depots, and preserving insulin sensitivity. Conversely, men have significantly greater levels of intra-abdominal adipose tissue than women, a fat depot which is particularly implicated in impaired glucose tolerance, insulin resistance and a stronger correlate to cardiometabolic risk than anthropometric measures.

Thus, the gluteal-femoral region may protect against adverse cardiometabolic effects of high circulating NEFA by serving as a “metabolic sink” for circulating fatty acids. Women with lower-body adiposity may be protected to a greater degree from cardiometabolic complications of elevated NEFA, due to their increased direct uptake of NEFA into femoral subcutaneous adipose tissue, compared with increased NEFA accumulation in visceral adipose tissue in men. A cardioprotective effect of lower-body adiposity has been observed in women, who displayed less aortic calcification compared to women with central adiposity. Conversely, women with central adiposity exhibit similar metabolic complications as men. 

Thus, we have contrasting fat distribution between men and women:

  • The central adiposity of men - defined by higher intra-abdominal adipose tissue and visceral adipose tissue
  • The gluteal-femoral adiposity of women - defined by greater subcutaneous adipose tissue

Crucially, the primary difference in adipose tissue distribution is more than a benign difference in regional deposition. Differences in NEFA storage, insulin sensitivity, inflammatory and endocrine signalling all favour a protective effect against cardiometabolic risk factors of gluteal-femoral subcutaneous adipose tissue in women. And these effects are more evident in the premenopausal lifestage due to the mediating effects of oestrogen. However, certain androgen-dominant conditions, in particular PCOS, may alter this sex-dimorphism, resulting in visceral adiposity and increased visceral adipose tissue which is associated with cardiometabolic risk factors, including dyslipidemia, insulin resistance and inflammation. These factors are important considerations in the assessment and cardiovascular and diabetes risk, warranting sex-specific evaluations of risk. PCOS will be examined in more detail later in this statement.

Pregnancy & Lactation

Preconception nutrition is a critical factor influencing successful pregnancies and a healthy child, yet current evidence suggests that in high-income countries many women will not have nutritional adequacy for pregnancy. An important caveat to the entirety of this literature is unplanned pregnancies, where the scope to consider prophylactic nutritional intake is limited at the individual level. This places a greater emphasis on general good nutrition across the lifespan at the whole-population level in supporting maternal nutritional status, many barriers to which are socio-economic and environmentally driven.

The most common nutrient insufficiencies (i.e., below the lower reference nutrient intake) in women of reproductive age between 18-42 include:

  • Iodine
  • Iron
  • Potassium
  • Selenium

In women aged between 18 and 25 years old, 77% had iodine intakes below the LRNI, while 96% of women across reproductive ages (defined as 18-42 in this study) had intakes of folate and iron below levels recommended specifically for pregnancy. This may reflect typical dietary patterns in high-income countries, characterised by high intakes of refined grains and sugars, red meat, and processed foods. Conversely, prospective cohort studies have indicated that dietary patterns high in fruit, vegetables, legumes, nuts, and fish, for up to 3 years prior to pregnancy are associated with reduced risk of gestational diabetes, hypertensive disorders, and preterm births. However, given that the preconception period is defined as the 3 months prior to conception, it is difficult to account for 3 years prior when conception may not even be considered. At the outset, it should be stated that general advice is to consume a prenatal multivitamin supplement, maintained during pregnancy, which are generally formulated for additional folic acid and iron.

Certain nutritional factors in this lifestage are more well-established, in particular the 70% reduction in risk for neural tube defects from folic acid supplementation in the 2-3 months prior to, and after, conception. Folic acid fortification in the food supply is now mandated in 87 countries globally, and this policy has been associated with reduced prevalence of neural tube defects in certain countries, but is currently not mandatory in Europe. The recommended folate concentration for pregnancy (>906nmol/L) is difficult to achieve through diet alone, and thus folic acid supplementation is recommended in addition to a folate-rich diet. However, the short-term time-course of effect for folic acid supplementation in planned pregnancy means that daily supplementation 3 months prior to conception appears sufficient to reduce risk, not only of neural tube defects, but low birthweight, miscarriage, and neonatal mortality.

The role of iodine in preconception nutrition is less well established, however, there are valid concerns over the high prevalence of iodine insufficiency during reproductive years, and the fact the World Health Organisation has stated iodine deficiency to be “the single most important preventable cause of brain damage” globally. Similar to folate, iodine is required in the preconceptual period due to the significant upregulation of thyroid hormone production in early pregnancy. This increased requirement resulted in the WHO increasing the recommended daily intake of iodine from 150 mcg/d for general reproductive years to 250 mcg/d during pregnancy and lactation. Iodine deficiency during pregnancy is associated with lower intelligence quotient (IQ) in offspring children, as well as other neurological and cognitive disorders. However, to date, evidence from intervention studies on iodine supplementation during pregnancy and cognitive outcomes in children is mixed, potentially reflecting differential thyroid health of the women, and iodine status of both intervention and control groups. The mechanisms through which iron deficiency may increase risk for impaired growth, development, and cognition, may have a relationship with iodine, and similar to both folate and iodine, iron sufficiency early in the preconception period is important to ensure nutritional adequacy. Iron deficiency during late gestation to 2 years of age is associated with impaired cognition, specifically the domains of processing, affect, and learning and memory. These factors, coupled with the widespread levels of iron insufficiency in the population (detailed above), indicate the critical importance of iron repletion prior to conception, as later repletion may not rectify cognitive damage associated from maternofetal iron deficiency. 

The long-chain polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are preferentially incorporated into nervous system cell membranes, and critical nutrients during the infant “brain growth spurt”, defined as the last trimester through the first 2 years of infancy. However, although AA is essential in this lifestage, AA levels are maintained at a relative constant through endogenous triglyceride lipolysis, while maternal DHA levels are dependent on dietary intake. Overall, maternal DHA status appears to be the strongest predictor of cognitive development. It is possible that gestation has a greater influence on cognitive development than breastfeeding: greater umbilical cord DHA stores, not breastmilk DHA, have been associated with increased cognition at 11 months in full-term infants. Increased maternal DHA through supplementation at 600 mg/d has been shown to result in longer gestation duration and birth weight. This is supported by the observation that higher maternal DHA levels at birth correspond to increased maturation of attention and distractibility faculties in infants at 12 and 18 months. Supplementation with DHA in breastfeeding mothers over 4 months of feeding has been shown to result in increased psychomotor function, primarily sustained attention, at 5 years. The fact that other parameters, such as visual acuity, were not significantly different between the supplemented and control group may reflect the fact that breastmilk itself contains preformed long-chain PUFAs: the magnitude of effect may thus be more pronounced in breastfeeding mothers with low dietary DHA intake.

With regard to obtaining adequate DHA during pregnancy and lactation, advice may include consumption of a maximum of 2 servings (12oz total) of low-mercury oily fish, with additional supplementation of 200-300 mg/d of DHA. However, dietary restrictions or decisions to exclude fish for the currency of pregnancy due to concerns over pollutants, are common. Supplementation with a direct source of long-chain PUFA’s DHA and AA, either through maternal supplementation or fortified infant formula. Without dietary DHA, an advised dose would be 600mg DHA/d from 20 weeks gestation, with infant formula supplemented with at least 0.2% DHA and 0.35% AA  (or 2:1 ratio AA to DHA). It should be noted that although the optimal amounts and ratios of AA to DHA for infant formula remains unknown, the evidence suggests that DHA levels should not exceed AA levels.

Preconception energy intake and dietary protein appear to be important factors, particularly as these factors may relate to underweight, which is significantly associated with:

  • Preterm birth
  • Babies with weight below the 10th percentile for gestational age
  • Increased risk for spontaneous miscarriage

The importance of adequate energy and protein nutrition was demonstrated in a Taiwanese intervention, in which mothers began supplementing with 800kcal and 40g protein per day 3-weeks after the birth of a first baby, which continued through birth and lactation of a second baby. The birthweight of the second baby was increased relative to the first baby, compared to a control group supplemented with only 80kcal extra per day. Although energy requirements are difficult to generalise, standard recommendations during pregnancy are for an additional ~300kcal per day, however, this is a mean estimation for a full term, and in fact energy requirements are similar for the first trimester, increasing to 340kcal  in the second and 452kcal in the third trimester. Average daily protein requirements increase from the general 0.8g per kilogram bodyweight per day, to 1.1g/kg/d, generally amounting to an addition of 10-15g/d.

Both caffeine and alcohol warrant comment. In relation to caffeine, consistent findings in prospective studies demonstrate that, comparing high to low caffeine intakes, higher caffeine intake during pregnancy is associated with low birth weight, with effects on gestational weight evident across all three trimesters. A recent meta-analysis also demonstrated a 21% relative risk increase (HR 1.21, 95% CI 1.08-1.37) for pregnancy loss from higher caffeine intake; that the effect size was 10% (HR 1.10, 95% CI 1.01-1.19) for coffee itself indicates that the adverse effects are stronger for caffeine itself. These effects are generally observed with high - i.e., >4 cups coffee per day. There may not be a perinatal risk at levels of <200mg/d caffeine.

However, the discussion over any potential safe dose threshold for alcohol intake during pregnancy is more controversial. However, heavy maternal alcohol intake may result in fetal alcohol spectrum disorders with consequent adverse physical, behavioural, and learning effects. Given that the current evidence is not sufficient to exclude risk from low-moderate levels of intake, advice to limit alcohol intake during pregnancy is prudent.

Gestational diabetes (GDM)  is defined as carbohydrate intolerance induced hyperglycaemia during pregnancy, experienced by up to a quarter of pregnant women, and may be associated with complications, in particular pre-eclampsia. Declining insulin sensitivity is a normal feature of pregnancy, developing from the second trimester, a physiological alteration to facilitate enhanced placental glucose transport to the fetus. In GDM, increased insulin resistance underpins maternal hyperglycaemia, which may result in:

  1. Increased placental glucose transport
  2. Fetal hyperinsulinaemia
  3. Accelerated fetal growth

From a dietary perspective, high glycaemic index (GI), low fibre diets have been associated with increased GDM risk. A recent systematic review and meta-analysis demonstrated that while low GI diets are superior to control diets for decreases in fasting and postprandial glucose, DASH (Dietary Approaches to Stop Hypertension) dietary pattern interventions exhibited the the most favourable effects on overall glycaemic control parameters (fasting and postprandial glucose, HbA1c, and insulin resistance), in addition to improved outcomes for infant birth weight and macrosomia (newborn is much larger than average).

Polycystic Ovarian Syndrome (PCOS)

Polycystic Ovarian Syndrome (PCOS) is the most common reproductive hormone disorder of women in reproductive years, with a 5-10% prevalence rate in this population group. As the name suggests, a number of small cysts are present around the edge of the ovaries.  PCOS is categorised as a multifactorial female reproductive disorder, encompassing neuroendocrine, ovarian and metabolic dysfunctions. In particular, clinical presentations of PCOS may include:

  • Menstrual irregularities
  • Hyperandrogenism (excessive levels of androgen hormones, including testosterone)
  • Central adiposity
  • Insulin resistance
  • Elevated serum luteinizing hormone (LH), driven by disturbances of the hypothalamic-pituitary-ovarian axis dysfunction
  • Hyperinsulinaemia

A characteristic feature of PCOS pathophysiology is gonadotropic dysfunction; where there is increased gonadotropin-releasing hormone (GnRH) causing the hypersecretion of luteinizing hormone. This in turn stimulates androgen production from the ovaries. Inadequate follicle-stimulating hormone (FSH) may be a proximate cause of  the absence of ovulation that occurs in PCOS.

The most commonly accepted, albeit not without debate, classification criteria for PCOS is the 'Rotterdam Criteria', adopted by both the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM).  These criteria attempt to synthesise the multiple clinical presentations of PCOS, which may include a number of different phenotypes:

  1. Hyperandrogenism with clinical anovulation (absence of ovulation)
  2. Hyperandrogenism with polycystic ovaries present on ultrasound but with ovulatory cycles
  3. Clinical anovulation with polycystic ovaries on ultrasound but without hyperandrogenism
  4. Hyperandrogenism, clinical anovulation and polycystic ovaries on ultrasound

There are notable differences in the pathophysiology of PCOS between different phenotypes.  Phenotypes characterised by  hyperandrogenism are typically associated with higher bodyweight, insulin resistance and central adiposity.  In contrast, phenotypes without hyperandrogenism display normal insulin sensitivity and a metabolic profile similar to women without PCOS of the same BMI.  Impaired carbohydrate metabolism is a consistent feature of PCOS, and the condition is considered an independent risk factor for the development of glucose intolerant states. There may also be abnormalities in adipocyte (fat cell) structure and function. The abdominal adipose tissue is commonly characterised by enlarged fat cells and impaired lipolysis.

PCOS in lean women is characterised by:

  1. Greater LH/FSH ratio
  2. Elevated leptin levels
  3. Lower insulinaemia and insulin resistance

It is possible that PCOS in lean women is driven by leptin/oestrogen to a greater degree than the insulin-stimulated androgen production that occurs in the hyperandrogenic phenotypes.  This could mean that weight loss could act as a driver for menstrual irregularities and LH dominance in lean women with PCOS, by affecting leptin levels and further aggravating hypothalamic-pituitary-ovarian axis dysfunction.

In relation to nutrition interventions, there is some evidence for dietary modifications, specific macronutrient compositions, and particular supplements which may benefit PCOS. There is utility for lower carbohydrate diets in PCOS, specifically in the high androgen phenotypes, as hyperinsulinaemia drives androgen pathways. In dietary intervention conducted in energy balance comparing 55% carbohydrate to a  41% carbohydrate diet (protein was matched), the lower carb diet resulted in preferential loss of abdominal fat mass and improvements in insulin response and sensitivity, which corresponded to decreases in circulating testosterone levels. It is interesting to note that the higher carb diet resulted in preferential fat mass increases, which may be a result of hypertrophic adipocyte dysfunction observed in PCOS.

High (30%) protein, low GI diets have been shown to reduce androgen levels and insulin resistance, however under hypocaloric conditions it is possible energy restriction per se underpinned the demonstrated effects. A recent review found a number of influences of diet on PCOS, with  improved menstrual regularity from low GI diets; increased androgens from high carb diets; greater reductions in insulin resistance from low carb or low GI diets.

Flaxseed has also been shown to reduce androgen levels in PCOS: lignans in flax increased circulating levels of sex-hormone binding globulin, which resulted in reduced circulating androgen levels.

Certain individual nutrients have shown efficacy, or emerging promise, as supplements PCOS, in particular inositol. Myo-inositol, which acts as a second messenger for hormonal regulation, produces second messengers for FSH and glucose uptake, and d-chiro-inositol, provides second messengers for glucose uptake and glycogen synthesis. Myo-inositol alone has been shown to have beneficial effects on reproductive function. Myo-inositol has also demonstrated metabolic improvements, while d-chiro-inositol appears superior for reductions in hyperandrogenism. The current evidence supports combined therapy of myo-inositol and d-chiro-inositol administered in the physiological ration of 40:1, which is associated with improved clinical outcomes compared to either inositol variant alone, including decreased insulin resistance, decreased androgen levels, reduced cardiovascular risk factors, and regularisation of menstrual cycles with spontaneous ovulation.

N-acetyl-cysteine (NAC) has been used as an adjuvant therapy to clomiphene for ovulation induction in women with PCOS who are clomiphene resistant, which is observed in between 15-40% of women with PCOS. However, the evidence for NAC is mixed with regard to ovulation induction. In clomiphene resistant women with PCOS, the addition of metformin to clomiphene has been shown to be more efficacious than the addition of NAC to clomiphene in inducing ovulation and achieving pregnancy.

Vitamin D and calcium may have important implications for PCOS beyond insulin resistance; combined treatment of vitamin D and calcium in a small study of 13 women with PCOS resulted in:

  • Normalised menstrual cycles within 2 months for seven women
  • Two experienced resolution of their dysfunctional bleeding
  • Two became pregnant
  • The other four patients maintained normal menstrual cycles

Regulation of menstrual irregularities with calcium and vitamin D have been demonstrated more recently, administered concomitantly with metformin.

Perimenopause

The perimenopausal period represents an important lifestage with regard to chronic disease risk and associated nutritional factors. With increased life expectancy in the developed world, women may spend up to 30 years or more in the post-menopausal phase, indicating the importance of this lifestage transition to consider from a health and dietary perspective.

Cardiovascular Disease Risk

In particular, the decline in oestrogen is associated with notable shifts in cardiovascular disease (CVD) risk post-menopause. However, this sex difference in CVD risk has also been suggested to reflect declining rates of CVD mortality in men, thereby creating an appearance of an effect of menopause which may in fact just reflect the increase in CVD with chronological age. Nonetheless, this decline in sex-specific mortality does not entirely explain the difference in mortality if chronological age is examined: in Europe before the age of 65, there are 490,000 deaths from CVD each year in men compared to 193,000 in women. Whether mediated by changes in oestrogen or by other other mechanisms, the evidence supports an alteration in blood lipid profiles between pre- and post-menopause that would be congruent with increased CVD risk.

In the Study of Women Across the Nation (SWAN) cohort, LDL-cholesterol and apolipoprotein B (a marker for all circulating atherogenic lipoproteins) increased substantially within one year of menopause, independent of chronological ageing. Changes in other CVD risk factors were associated with chronological ageing.

Cardiovascular disease remains the leading cause of mortality in post-menopausal women, and increases in atherogenic lipoproteins in this lifestage provide strong biological plausibility for this association, given the causal role of LDL-C in atherosclerosis. In this regard, it is important to note that the magnitude of risk reduction for major coronary and cardiovascular events per unit reduction in LDL-C from statin therapy is similar in women as with men. Lipid-lowering  drugs are not recommended during pregnancy or lactation, with the exception of familial hypercholesterolaemia, in which bile acid sequestrants may be utilised (inhibiting cholesterol absorption in the gut, the drug itself is not absorbed).

Dietary advice remains similar, with recommendations to:

  • Increase dietary fibre
  • Reduce saturated fat to <10% of calories and concomitantly increase unsaturated fat (in particular polyunsaturated fats and omega-3 fatty acids)
  • From a 'functional food' perspective, consume:

All of which are associated with significant reductions in LDL-C and other CVD risk factors. There do not appear to be any sex-specific differences in diabetes risk.

Breast Cancer Risk

Substantial scientific inquiry has been devoted to the role of diet, specifically dietary fat, in breast cancer. Case-control studies initially suggested an association between higher total fat diets and breast cancer, however, this association has not been as strongly demonstrated in prospective cohort studies, or in intervention studies which examined reductions in dietary fat and breast cancer. The associations are largely null for specific fat subtypes, although this may reflect the choice of substitution analysis, with replacing saturated fat with carbohydrate not demonstrating any risk reduction in a pooled analysis of cohort studies. The associations may also reflect the breast cancer subtype, with potential differences of the effects of diet on the expression of receptors for estrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2).

In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, comparing high to low dietary saturated fat intake was associated with a 28% relative risk increase (HR 1.28, 95% CI 1.09-1.52) for breast cancer in both ER-positive and PR-positive subtypes, but not either ER-negative or PR-negative types. Indicating the relevance of subtype relative to earlier cohort studies, high total fat intake was also associated with an increase in risk in both ER-positive and PR-positive subtypes only , which was not statistically significant but trended to positive association (HR 1.20, 95% CI 1.00-1.45). There was no association for any type of fat or total fat in relation to R-negative or PR-negative breast cancer.

Marine omega-3 fatty acids may also be an important nutrient in relation to breast cancer risk, with 1,860mg of eicosapentaenoic acid (EPA) and 1,500mg of docosahexaenoic acid (DHA) per day associated with a significant decreases in breast cancer biomarkersin a small pilot intervention study.

Specific fat foods may also be protective, as evident in a secondary analysis of the PREDIMED intervention in which the risk of breast cancer in the extra-virgin olive oil arm of the intervention was associated with a 69% reduction in risk (HR 0.31, 95% CI 0.13-0.77) for breast cancer incidence. However, such effects were not observed in the ‘mixed nuts’ arm of the study. The absolute incidence rates per 1,000 person years were 1.1 for the olive oil and 1.8 for the mixed nuts arm, respectively. It should be noted that these interventions were in the context of a wider Mediterranean dietary pattern, and specific components of this dietary pattern - in particular fish, vegetables, fruits, and legumes - have been independently associated with reduced breast cancer risk in a case-control study of Greek-Cypriot women. In a meta-analysis of prospective cohort studies, a Mediterranean diet was associated with a significant reduction in breast cancer risk in post-menopausal women with ER-negative receptors.

However, it is necessary to distinguish the effects of dairy on breast cancer risk, which may be mediated by calcium intake. The hypothesis that dairy increases breast cancer risk by increasing levels of insulin-like growth-factor-1 (IGF-1) in a hormone-dependent cancer, are not born out by the wider literature. In the US Cancer Prevention Study II Nutrition Cohort,  2-3 servings of dairy per day compared to <0.5 servings was associated with a 19% reduction (RR 0.81, 95% CI 0.69-0.95) in breast cancer risk. This effect was shown to be driven by low-fat dairy consumption when low-fat and high-fat sources were analysed separately. These associations for low-fat dairy were stronger in women with ER-positive tumours, with a 24% risk reduction (RR 0.76, 95% CI 0.61-0.94) in participants with this receptor expression.

There may also be a mediating effect of timing of menopause. In the US Nurses Health Study, high intake of low-fat dairy was associated with a 32% relative risk reduction (RR 0.68, 95% CI 0.55-0.86) in pre-menopausal, but not post-menopausal, women. The effect of calcium was also demonstrated in the Women's Health Study, in which high dietary calcium intakes were associated with a 39% relative risk reduction (HR 0.61, 95% CI 0.40-0.92) in pre-menopausal women. Thus, the overall direction of effect indicates that low-fat dairy may be protective, potentially mediated by calcium intake, and stronger in the perimenopausal stage.

Overall, the evidence suggests that dietary patterns inclusive of high amounts polyphenols, isothiocyanates, carotenoids, fibre, and low-fat dairy, are broadly associated with reductions in breast cancer risk, while specific reductions in total and saturated fat may be considered in cases of ER-positive and PR-positive receptor types.

Osteoporosis Risk

Osteoporosis risk is associated with increasing age and/or menopause. And increased bone resorption rates and declining bone mineral density (BMD) may also reflect the change in the oestrogens, which inhibit bone resorption and remodelling. Debate over the effect of calcium supplementation with regard to osteoporosis may reflect differences in outcomes, i.e., BMD itself versus the 'hard' endpoint of fractures. Indeed, it appears that calcium supplementation in vitamin D-replete participants may be effective in preventing fractures even in circumstances where the change in BMD is a modest 1-4%. In a review of intervention studies, calcium supplementation in postmenopausal women was shown to result in a rate of bone loss of 0.014% per year, compared to 1.0% in controls.

Another factor to bear in mind in relation to cases where there are 'null' findings is that the placebo group in controlled intervention studies may already have calcium intakes in a range of sufficiency and therefore at which bone protective effects may be observed (>700mg/d). This was evident in the Women's Health Initiative RCT, rendering it difficult to detect an effect of supplementation over one year. Interventions with up to 4 years follow-up have demonstrated calcium supplementation is effective in reducing parathyroid hormone levels and preserving BMD.

Vitamin D has also shown efficacy, with or without concomitant calcium. Adding 200 IU/d of vitamin D in post-menopausal women supplementing calcium reduced bone loss in the whole body and spine over 3 years. Supplementation of vitamin D3 alone over 2 years in post-menopausal women was also shown to reduce parathyroid hormone secretion and increase femoral neck BMD. Combination calcium and vitamin D supplement was also shown in a 3 year RCT to result in modest reductions in bone loss, but significant reductions in fracture risk.

Finally, vitamin K is a nutrient of particular interest with regard to bone health. In post-menopausal women in Japan, high intake of natto (>200mcg per day of the vitamin K2 isoform, MK-7) was associated with preserved BMD, effects not observed in pre-menopausal women. It should be noted, however, that as a fermented soy product natto also contains soy isoflavones, which may have benefits for bone health. Nonetheless, an intervention study in post-menopausal women provided 180mcg/d MK-7 over 3 years and demonstrated protection against age-related declines in BMD at the spine and femoral neck. Another vitamin K2 isoform, MK-4, is used pharmacologically in Japan for the treatment of osteoporosis. A meta-analysis of MK-4 interventions in post-menopausal women indicated that supplementation of 45mg/d MK-4 resulted in increased BMD and reduced incidence of fractures. However, the included studies were small and not all studies were controlled. The effect of vitamin K2 in interventions has not consistently been demonstrated, and null findings may also reflect participants also receiving calcium and vitamin D supplements. Currently, the data on vitamin K2 for osteoporosis treatment in post-menopausal women remains promising, but equivocal, and confined largely to Japanese populations with other dietary factors associated with bone health.

Menopausal Symptoms

Specific supplements are often proposed to alleviate menopausal symptoms, although the evidence is often not as robust as common indications may suggest. With regard to dehydroepiandrosterone (DHEA), a small number of intervention studies have suggested a benefit to supplementation:

  1. Reductions in hot flashes
  2. Increased oestrogenic hormones
  3. Decreased overall symptoms

A phytoestrogen supplement, Pueraria Mirifica, has been shown in preliminary studies to reduce menopausal symptoms at doses of 25-50mg/d. However, these effects need to be confirmed in larger, controlled trials. Black cohosh has received substantial attention as a supplement for menopausal symptoms, with a meta-analysis of 9 studies indicating a benefit in 6/9, and overall significant reduction in symptoms. However, as of yet these effects have not been consistent in larger controlled trials.

Summary of Key Points

  1. Risk of iron deficiency increases after onset of menstrual cycle and 23% of adult women have iron intakes below the lower reference nutrient intake.

  2. In women, oestrogen appears to confer protection against visceral adipose tissue accumulation, and preferentially shift fat deposition toward subcutaneous adipose tissue accumulation.

  3. Due to this preferential distribution of fat as subcutaneous fat, pre-menopausal women carry a lower risk of cardiovascular disease compared to men.

  4. After menopause there is a shift in fat distribution to greater intra-abdominal adipose tissue and visceral adipose tissue, relative to subcutaneous fat tissue.

  5. Energy requirements during pregnancy are similar to normal in the first trimester, increasing by 340 kcal/d  in the second trimester and by 452 kcal/d in the third trimester.

  6. Folic acid supplementation should occur in the 2-3 months prior to, and after, conception.

  7. Maternal DHA status is strongest predictor of cognitive development.

  8. High caffeine intake (equivalent of > 4 cups coffee/day) during pregnancy is associated with detrimental effects, including lower birth weight.

  9. Alcohol consumption during pregnancy should be avoided.

  10. In women of reproductive age, 5-10% suffer from polycystic ovarian syndrome (PCOS).

  11. A number of nutritional interventions may have benefit in PCOS cases, including: lower carbohydrate intakes, high-protein diets, low GI diets, inositol supplementation, vitamin D supplementation, calcium supplementation and flaxseed consumption.

  12. Menopause has implications for risk profile for cardiovascular disease, breast cancer and osteoporosis, leading to important dietary considerations at this time.
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Statement Author: Alan Flanagan, PhD (c)
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Alan is the Research Communication Officer here at Sigma Nutrition. Alan is currently pursuing his PhD in nutrition at the University of Surrey, UK, with a research focus in chrononutrition. Alan previuosly completed a Masters in Nutritional Medicine at the same institution.

Originally a lawyer by background in Dublin, Ireland, Alan combines an investigative and logical approach to nutrition together with advocacy skills to communicate the often complicated world of nutrition science, and is dedicated to guiding healthcare professionals and the lay public in science-based nutrition.

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Comments

  1. Reply

    This article was absolutely brilliant!
    I would say I understood about 85% of it (I’m a PT currently studying PN L1 so wouldnt be familiar with all terminology)
    I really appreciated that recommended intakes of various foods were laid out clearly throughout the article as I don’t always see this mix of theory & practicality in other articles.

    I’m wondering if you have any nutritional advice/research on women suffering from Endometriosis? In the past 2 years, I’ve had 7 clients present with this and in most cases it has taken them many years of testing to be diagnosed meaning they are long time sufferers and are likely to make the discovery at a time where they’d also like to start a family.

    Thanks Alan, Danny & team for more amazing work!

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