Impact of yesterday’s genes and today’s diet and chemicals on tomorrow’s women

A previous editorial in this journal (Puberty - Whither goest?) discussed whether pubertal maturation was occurring earlier in U.S. girls, and the potential causes of those changes.¹ Several original manuscripts, review papers, and convened consensus groups have discussed these topics, and most of the published works have accepted that 1) there is a decrease in the age of onset of puberty, as defined by breast development, and 2) there is a more modest decrease in the age of menarche (reviewed by Kaplowitz).² Black women experience menarche approximately six months earlier than white women, whereas their breast development appears to be up to one year earlier than white women. When examining the potential causes of the continued decrease in age of onset of puberty in girls, many have noted that there has been a coincident epidemic in rates and degrees of obesity. They concluded that increased body mass index (BMI) accounts for much of the change in age of onset of puberty in girls; the changes in pubertal onset, and association with increased BMI, are not as clear in boys.

The relationship between onset of breast development and age of menarche appears to have changed over the past 50 years, however. For example, the correlation between onset of breast development and menarche was 0.86, as reported by Reynolds and Wines in women born in the 1930s, ³ contrasted to 0.37 in women born in the late 1970s. ⁴ This changing relationship suggests that other factors could be contributing differentially to earlier onset of breast development, when contrasted to decrease in age of menarche; these factors could include, in addition to increased BMI, exposure to endocrine disrupting chemicals (EDCs), or hyperinsulinism and/or insulin resistance.⁵ There has been a growing body of scientific literature regarding the impact of purported EDCs. These include the effect of certain environmental exposures on body composition (phthalates and increased central obesity⁶; phytoestrogens and reduced adiposity⁷); onset of earlier puberty (phthalates and early thelarche⁸; polybrominated biphenyls [PBBs]) and early thelarche⁹; DDE and precocious puberty¹⁰; and DDE and earlier menarche).^11–12 Other exposures have been observed to delay pubertal maturation (lead and menarche).^13–15 However, some studies have not shown a relationship between these same chemicals with changes in pubertal milestones (for example, Denham 2002).¹³ The impact of endocrine disruptors on breast development and on pubertal maturation has been reviewed recently.^14–18 The relationship of EDCs and puberty may be very complex, with interactions between timing of exposure, exposure levels, body composition, and genetics. For example, in a cross sectional study, phytoestrogen biomarker concentrations were lower among girls with breast development, but the effect was seen in those with lower BMI.¹⁹ These studies are limited by small numbers or cross-sectional design, but find stronger support in the animal literature.

Studies have suggested that there has been a selective advantage in lower age of maturation, yielding more progeny over a period of several decades. Genetic variation has been estimated to account for 57–100% variation of pubertal timing,²⁰ with the remainder of the variability accounted by environmental influences. The trait of earlier maturation is conserved,^21–23 and the timing of reproductive functioning sensitive to environmental cues to maximize reproductive success.²⁴ However, the advantage conferred to the human species in the past may provide a disadvantage in the contemporary setting. Cultural changes proceed faster than genetic accommodations, which Eaton has described as the mismatch of “Stone Age” genes with “Space Age” circumstances.²⁵ For example, the contemporary milieu has eliminated programmed biochemical cycles from feast-famine and physical activity-rest cycles, which would be experienced by hunter-gatherer societies, and provides food abundance with physical inactivity, which has led to biochemical changes and obesity, with subsequent insulin resistance.²⁶ Thus, the “thrifty phenotype” conferred a survival advantage to the hunter-gatherer, but it has become a risky phenotype for obesity and diabetes, as observed in contemporary Native American populations who adapted sedentary occupations over recent generations.²⁷ Regular physical activity has decreased dramatically when contrasted to earlier times (see Table).²⁸ In contemporary adolescent girls, higher BMI has been shown to be associated with greater declines in physical activity.²⁹ Additionally, in a young adult population followed since adolescence, the faction of selected adverse health outcomes attributed to watching television for more than two hours a day included 17% of that group’s overweight status, 15% of the elevation noted in cholesterol levels, 17% of tobacco smoking, as well as 15% of poor fitness in that group.³⁰ In brief, earlier pubertal maturation with an earlier ability to reproduce would have provided a selective advantage, especially 5,000 or more years ago. If the biologic price was an increase in hormone-dependent and/or reproductive tract factors in the fifth decade, that trait would be selected and preserved.

Table. It’s Greek to me, but the Goddesses of Yesteryear lived well, though not long, and Today live longer but….

	Greece of 2000 BC	United States of 2000 AD
Age of menarche	17	12
Interval menarche to first birth (years)	3 years	12 years
Number of children	6	1.8
Duration of breast feeding	3 years	0–6 months
Daily energy expenditure	20 kcal/kg/day	< 5 kcal/kg/day
Age at death	40 years	75 years
Risk of breast cancer	Unknown (minimal)	1 in 8

The costs to earlier maturation in 21^st century girls are many. Girls who mature earlier have lower self-esteem during adolescence and lower levels of body satisfaction,³¹ greater likelihood of depression³² and eating disorders³³, greater perceived stress,^34–35 greater vulnerability to peer pressures,³⁴ younger ages of sexual initiation,^36–37 and smoking and drug use.^38–39 As adults, early maturing girls exhibit poorer adjustment⁴⁰ and lower life-long academic achievement⁴¹. They also have greater weight and BMI,⁴² as well as insulin resistance and cardiovascular disease⁴³; additionally, women with breast cancer are noted to have young age of menarche.^44–48 Of note, when age at peak growth is included in the analysis, the age of menarche is not associated with risk of breast cancer; menarche, as well as age of peak growth, may reflect age at onset of puberty.⁴⁹ With earlier age of menarche, and later age at first birth, there is a longer interval from menarche to first birth; this lengthened period potentially leads to a longer period of susceptibility of breast tissue to carcinogens.⁵⁰ Additionally, contemporary women have a greater number of ovulatory cycles, contrasted to women from several centuries ago,⁵¹ again increasing the risk for hormone-dependent tumors (Table).²⁸

In short, the fertility goddess of the Bronze Age 2000 BC would have had children at a younger age, and more children. The goddess of the year AD 2009 would have insulin resistance and be more likely to develop breast cancer. It is food for thought that much of this difference could be preventable.