AWA: Academic Writing at Auckland

Research Question

Has the increased consumption of phytoestrogens in the western diet led to a rise in the early onset of menarche in modern populations?

Aims

The purpose of the proposed study is to investigate the effects of phytoestrogens in the diet of modern human populations on the onset of menarche. The aim is to discover if an inverse association exists between the ingestion of foods containing high phytoestrogen levels and a decrease in the age of menarche in the young women of these populations. Furthermore, if such an association exists, the present study intends to explore whether the presence of a causal relationship can be inferred. The findings of this study should offer a significant contribution towards understanding the role of phytoestrogens in the onset of menarche.

Critical Review of the Literature

Health foods containing soy or soy by-products have been a recent health craze in the western world. This phenomenon was inspired by research that found that ingesting soy protein as opposed to animal protein had several health benefits (Anderson, Johnstone and Cook-Newell, 1995). The most frequently claimed of said benefits are reductions in total cholesterol concentrations along with decreased LDL cholesterol and triglyseride levels in serum; in addition to considerably elevating HDL cholesterol levels (Anderson, Johnstone and Cook-Newell, 1995; Zhan and Ho, 2005). Moreover, it would be plausible to expect that this increase in consumption would be highest among women since these products supposedly reduce risk factors related to cardiovascular disease and protect against spinal bone loss in postmenopausal women (Potter et al., 1998). These claims in conjunction with suppositions that these compounds can reduce the risk of breast cancer (Cross et al., 2004; Ha et al., 2006) would lead to an intuitive rise in consumption among women.

However, this trend was soon followed by concerns that the phytoestrogens these products contain mimic the effects of estrogen in the human body causing unforeseen and undesirable biological outcomes. The ability of these non-nutrient bioactive compounds to mimic estradiol has led to both claims of reducing breast cancer as well as increasing it. Studies in this area remain inconclusive as clinical and epidemiological evidence tends to be conflicting on the matter. While some studies suggest that these plant-derived compounds possess cancer preventative qualities (Cross et al., 2004) others have discovered no such correlation between breast cancer and phytoestrogens (Peeters, Keinan-Boker, van der Schouw and Grobbee, 2003). The only conclusive aspect appears to be the ability of these compounds to act as structural or functional analogues of mammalian estrogen (Turner, Agatonovic-Kustrin and Glass, 2007). According to Turner et al. (2007), aside from the possession of ring structures, factors that facilitate the binding of phytoestrogens to estrogen receptors are their steric and hydrophobic qualities in addition to hydrogen bonding between phenolic hydroxyl groups and estrogen receptor binding sites.

Nevertheless phytoestrogens are far more common in our diet than many imagine, predominantly found in plants of the family Fabacea, or better known as legumes (Thompson, Boucher, Lui, Cotterchio and Kreiger, 2006), hardly a novelty in the human diet. In spite of this modern western society’s obsession with “good” and “bad” food is in fact a novel artefact of our increasingly medicalized and technological culture. As a consequence, some individuals are likely to consume considerably more of these estradiol-like compounds than would traditionally have been ingested by individuals of these populations.

According to Ashby et al. (2000) modern populations are exposed to considerably high doses of these dietary estrogens, which the author’s claim can effect menstrual cycles in humans and advance sexual maturation in rats. Such claims are supported by Casanova et al. (1999) who claim that dietary genistein considerably accelerates puberty in female Sprague- Dawley rats. However, studies investigating the effects of polybrominated biphenyls (PBB) on sexual maturation were contradictory between rodents and humans. The authors attributed this inconsistency to differences in neuroendocrine development in rodents when compared to primates (Blanck et al., 2000). Nevertheless unlike phytoestrogens, which are naturally occurring plant compounds, PBBs are manufactured chemicals under strict control due to their toxicity (Burgat-Sacaze, Dufaure and Petit, 1983). Thus sustaining concerns about the hormone like functions of these dietary compounds and their resultant consequences.

Cesario and Hughes (2007) assert that at the time of the study, worldwide 1 in 5000 children were afflicted with precocious puberty, a condition that is ten times more common among girls than boys. Precocious puberty in girl as defined by Cesario and Hughes is the development of secondary sex characteristics prior to the age of 8 and menarche occurring prior to the age of 9. Since the authors’ definition is derived from the description of this condition by Marshall and Tanner based on their study in 1969, they further claim that according to statistical evidence American girls are reaching maturity at an earlier age than their counterparts 30 years ago. As a consequence the number of girls being diagnosed with this condition is becoming increasingly more frequent.  While the early onset of puberty entails many significant social issues this condition also gives rise to numerous health concerns. The decline in age at the onset of menarche is of particular concern.

The early onset of menarche is undeniably undesirable, at least in a modern, western society. Aside from numerous social implications this condition may also leads to an earlier onset of menopause (Cramer and Xu, 1996) as a woman will only ever have as many eggs as she is born with. According to Harlow and Signorello (2000) age at onset of menarche, menstrual cycle length, use of oral contraceptives and parity are major determinants of the number of lifetime ovulatory cycles, and consequently the onset of menopause. While work by Cramer and Xu (1996) supports an association between the onset of menarche and the age of menopause, earlier work by Whelan, Sandler, McConnaughey and Weinberg (1990) found no such correlation. This may be due to the complex interactions between the many factors affecting this physiological phenomenon.

Nonetheless, given our present consumer driven society and women becoming increasingly more career orientated the early onset of menopause could lead to an increase in demand for in vitro fertilization; further exacerbating debates surrounding this issue. Nevertheless, the early onset of menarche can lead to decidedly more fatal outcomes than lost reproductive opportunities. The premature decline in estrogen levels associated with menopause can result in increased risk of osteoporosis, coronary heart disease (Harlow and Signorello, 2000) and perhaps even advance the onset of Alzheimer’s disease (Kawas et al., 1997). Although the advent of hormone replacement therapy has made it possible to try offset these undesirable outcomes, the treatment itself has be found to increase the risk of breast and endometrial cancer (Harlow and Signorello, 2000; Henderson, 1989) in addition to being financially costly.

Furthermore, Stoll (1998) states that a reduced age at menarche along with adult tallness are indicators of increased risk of developing breast cancer. The author further states that in a western context, earlier menarche is often associated with the earlier onset of hyperinsulinaemia, a condition which also signals elevated breast cancer risk. This correlation is of concern since breast cancer is one of the leading causes of cancer death among women, second only to lung cancer (Imagins, 2010). Therefore, as decreased age at menarche is associated with elevated estradiol levels, increased concentrations of dietary compounds that mimic this hormone is a significant health concern.

Food containing these dietary estrogens may be incorporated into the human diet as early as infancy. Due to the estrogenic nature of these bioactive compounds and their presence in soy-based infant formulas numerous concerns have been raised about the effect of phytoestrogens on the growth and development of infants (Irvine, Fitzpatrick and Alexander, 1998). In an effort to investigate the effects of these diverse compounds on infants several studies have been performed.

Irvine et al. (1998) focused on the prevalence of a specific phytoestrogen, isoflavone, in the typical western infant diet. The authors examined the total genistein and daidzein contents of soy-based infant formulae as well as infant cereals, dinners and rusks. They discovered that, when fed in accordance with the manufacturer’s instructions, soy-based formulae provided infants with a daily dosage of about 3mg/kg body weight of total isofalvones and was sustained at a relatively constant level from 0 to 4 months of age. Furthermore, the authors discovered that the addition of a single serving of cereal to the diet of a 4 month old infant caused an increase in isolflavone intake. Depending on the brand of cereal chosen, the increase in intake was greater than 25%. According to the authors this rate of intake of isoflavones by infants is significantly greater than that witnessed in adults to alter reproductive hormones. As stated by the authors this evidence is of significance due to the fact that neonates are typically more sensitive to disturbances in sex steroid conditions as well as their ability to digest and absorb these dietary compounds in active forms.

Research conducted by Chen and Donovan (2004) uncovered that genistein, a tyrosine kinase inhibiting phytoestrogen, produced biphasic effects in intestinal cell division through estrogen receptors. The authors claim that low levels of the estrogenic compound stimulated cell proliferation in the intestine while higher doses resulted in inhibition, potentially compromising the infant’s growth and development. This fact is particularly concerning since 15% of infants in the United States are fed soy formulas containing high levels of this phytoestrogen (Chen and Donovan, 2004). Furthermore, although several other infant studies have concluded that soy-based infant formulas provide adequate nutrition and are safe for consumption and not harmful to infants they all maintain that further study is required (Merritt and Jenks, 2004; Miniello et al., 2003; Strom et al., 2001).

Storm et al. (2001) conducted a retrospective study of individuals involved in a controlled feeding study from 1965 to 1978 in which infants were fed soy and cow milk. Although there were no records of the levels of isoflavone ingested by the infants, there have been very few changes to the manufacturing procedure allowing the authors to estimate ingestion levels. Furthermore, since each individual’s diet and resultant exposure to soy products is obtained from clinical records rather than recall the data is significantly more reliable. The authors found little difference between the two groups of infants. The most statistically significant difference being the slightly prolonged duration of menstrual bleeding of girls exposed to soy milk as infants, which is of importance due to its clinical implications.

While Strom et al. (2001) primarily concluded that soy-based infant formula was safe for consumption by infants; they still concede that they had a few results to the contrary and that these concerns should be further examined. Furthermore, Chen and Rogan’s (2004) review of isoflavones in soy-based infant formula and possible associated endocrine effects also concludes that the current clinical and epidemiological evidence is inconclusive and that further investigation on the matter is necessary. Moreover, there doesn’t appear to be as much research focusing on the possible influence of phytoestrogens on the onset of menarche.

Given the lack of conclusive evidence on the effects of phytoestrogens on human health, particularly in regards to the onset of menarche, the proposed study would contribute considerably to our current understanding of this diverse group of hormone mimicking compounds. Furthermore, in view of the fact that precocious puberty is becoming increasingly more frequent and more commonly so among girls by a considerable margin further emphasises the relevance of the study. In addition, the serious health implications associated with the early onset of menarche such as the risk of breast cancer which claims the lives of about 465,000 women worldwide annually, (Imagins, 2010) brings into focus the importance of such a study.

Participants and Methods

In order to ensure that the subjects involved in this study consume the compound of interest participants of high socioeconomic status would be recruited from around the central Auckland area. The reason for choosing individuals that may be classified as “well-off” is due to the fact that these individuals are more likely to be choosy about their diet be it a consequence of health or social motivations. Furthermore, unlike subjects of low socioeconomic status, these individuals are unlikely to be constrained by financial parameters when incorporating phytoestrogens into their diets.

High socioeconomic status will be defined by meeting several of the following criteria. Individuals will own their own home; the house has 3 or more bedrooms, two or more cars per household and the house is located in the school-zone of a high Decile school or other such desirable location. Children will attend a high Decile school, 9 or higher. This is an important indicator since a school’s Decile value indicates the proportion of its students from low socioeconomic backgrounds. Decile 1 schools encompass the 10% of schools with the greatest percentage of students from low socioeconomic communities, while Decile 10 schools comprise of the 10% of schools with the smallest proportion of such students (Ministry of Education, 2010). Parents will have at least tertiary level education and occupations classified as “professionals” (doctors, lawyers, accountants, etc.). The total annual household income before tax exceeds $80,000 (NZ); this value is based on the threshold value of parental income for Student Allowance as defined by StudyLink (2010).

As for phytoestrogen intake, a proportion of the sample population would be recruited based on the consumption of high levels of these compounds while it would not be an explicit component in the diets of the rest of the sample population. Consumption levels will be based on phytoestrogen levels in particular foods as defined by Thompson et al. (2006) in conjunction with manufacturers’ information on nutrient content.

Other variables that would have to be taken into consideration when interpreting the data are prenatal exposure to phytoestrogens, other exogenous source of estrogen and known chemical compounds that influence typical development. Exposure to other exogenous sources of estrogen and chemical compounds affecting development are also of significance postnatally and must be adjusted for when explaining findings. Furthermore, participants should be generally defined as healthy, having balanced diets and exercising regularly. This is of relevance since the archetypal modern western diet of high fat and low fibre when combined with insufficient exercise can result in the early onset of puberty, which in girls leads to an earlier onset of menarche (Stoll, 1998).

The study will involve a total of 60 families, each family consisting of three generations of women. These families will be separated into two groups where 30 families have phytoestrogen rich diets and the rest lack an explicitly phytoestrogen rich diet. Each dietary group will be further sub-categorized based on three loosely defined “ethnicities” derived from self-reported ancestry. These will be classified as “European”, including all individuals of European ancestry; “South Asian”, encompassing India and the surrounding regions; and “East Asia”, broadly consisting of countries such as China, Korea and Japan. Each of the sub-categories will comprise of 10 families.

By incorporating a wide range of ancestry, the study attempts to encompass an extensive amount of genetic diversity in addition to the associated differences in developmental timing. Furthermore, this range should account for a variety of dietary patterns; which is of importance since, unlike the modern western diet, phytoestrogen rich foods have been a traditional component of the oriental diet and may have influenced the response of these people to phytoestrogens. In addition, maintaining a similar developmental setting controls for variations in developmental environments.

Data will be gathered on age of menarche, dietary phytoestrogen intake, general dietary patterns, level of exercise and exogenous estrogen exposure. Since information will be self-reported and dependent on recall it may be subject to bias and inaccuracies. Dietary information such as phytoestrogen intake can be supplemented based on popular consumption patterns for a given generation. Nevertheless, retrospective measures on the onset of menarche have been found to be highly accurate, even up to 19 years later   (Bergsten-Brucefors, 1976; Casey et al., 1991).

While the proposed study is a retrospective cross sectional study, aspects of the statistical treatment of data will resemble that of a longitudinal study. Since the data for women from a given family isn’t independent, the measures of age of menarche will therefore be treated similar to measurements in a longitudinal study. Each woman will act as single measurement in time illustrating the response of each gene pool to changing levels phytoestrogen exposure. Furthermore, due to this genetic association non-independence would arise between women of the same generation (Blanck et al., 2000). In order to prevent this only one woman from each generation for a given family would be utilized in the statistical analysis.

An F-test will be performed to examine the variation within each dietary treatment compared to the variation between them. If the variation between the two dietary groups is greater than the variation with each group this would offer evidence against the null hypothesis and support the hypothesis that dietary phytoestrogens influence the onset of menarche. A Chi-Square test will test to check whether the observed data resemble the expected. If the observed data is in concordance with the expected the null hypothesis would be true and there would be no evidence for an association between phytoestrogen intake and age of menarche. A linear regression of the data will illustrate the overall pattern of the data and the extent of correlation between the variables phytoestrogen content and age of menarche. The results are assumed to be normally distributed in order to compare to the population of interest.

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