Nutrition and Reproduction

Introduction

In males, pulsatile gonadotropin-releasing hormone (GnRH) and gonadotropin secretion are secreted at a mean interval of every 2 hours, a frequency sufficient to maintain testosterone levels, virilization, and spermatogenesis. In females, a more complex series of gonadal tasks must be accomplished, which include maturation of a single follicle, follicular rupture and ovulation, and corpus luteum formation. The mature female hypothalamic-pituitary-ovarian (HPO) axis must respond dynamically with negative, then positive (bimodal) feedback to rising estradiol, which is secreted by the developing follicle. The positive feedback response, in the form of a luteinizing hormone (LH) surge, must be sufficient to initiate the molecular events of follicle rupture and subsequent luteinization. Optimal functioning of the female reproductive system requires more versatility of the HPO axis and is therefore more vulnerable to disruption than the male.

Pulsatile secretion of hypothalamic GnRH and pituitary LH occurs prior to birth and continues throughout the prepubertal period. Pulsatile LH secretion has been detected in children and occurs at a normal, adult frequency in boys and girls ; however, the amplitude of the signal is miniscule and requires highly sensitive measurement methods to detect. Suppression of pulsatile GnRH-LH secretory amplitude in prepuberty has been attributed to a combination of enhanced sensitivity of the childhood reproductive axis to estradiol, as well as a predominance of inhibitory neural and neuroendocrine signals that ultimately dampen the amplitude of the central GnRH pulse generator. This working model hypothesizes that prepubertally, the HP axis is inhibited, and the axis is released from this inhibition during puberty.

Over 50 years ago, Frisch and Revelle noted a direct relationship between body weight and age at the onset of puberty ^, and concluded that a critical amount of body fat was needed for the onset of puberty. These investigators predicted correctly that adipose tissue somehow provided a permissive signal to the reproductive system. The discovery of the endocrine nature of adipose tissue has since led to the identification of a number of adipokines and inflammatory factors that play a role in reproduction. In both animal models and in humans, inadequate leptin is associated with a lack of GnRH secretion, and leptin replacement can restore normal cycles in women who have hypothalamic amenorrhea and hypoleptinemia. However, leptin alone is insufficient to initiate pubertal maturation of the hypothalamic-pituitary-gonadal (HPG) axis.

A critical pathway that activates GnRH-LH secretion during puberty involves kisspeptin and its cognate receptor, G-protein coupled receptor-54 (GPR54). Kisspeptin acts directly on GnRH neurons and amplifies GnRH and consequently LH and follicle-stimulating hormone (FSH) secretion. Both kisspeptin and GPR54 increase coincident with the onset of puberty. In addition to kisspeptin, there are other upstream regulators of GnRH that provide redundancy to prevent reproductive failure.

Puberty is also a time during which the acquisition of functional networks of neurons and glial cells provide necessary communication pathways through which reproductive signaling can occur. For example, glial cells, long believed to be inert but helpful in providing scaffolding, may play a more direct role in GnRH secretion. Microglia, macrophages that differentiate into glial cells, are necessary for optimal GnRH secretion. CSF-1 knockout mice, who lack adequate macrophage function, do not have adequate microglial development and are deficient in hypothalamic GnRH secretion. The interaction of immunomodulatory molecules with reproductive neural networking remains poorly characterized.

Much research to date on abnormalities of pubertal maturation has focused on inadequate nutritional states. However, in the United States as in most developed nations, these conditions are becoming increasingly rare and are being replaced by reproductive dysfunction due to overweight and obesity. Obesity has been linked to altered pubertal progression and adult reproductive dysfunction. Polycystic ovary syndrome (PCOS) has been well studied in its interactions between obesity and anovulation; however, a far greater proportion of the population is affected by simple obesity. Pubertal onset is earlier in obese girls and boys, but the tempo of puberty seems to be slowed in simple obesity. ^, A relative state of hypogonadotropic hypogonadism has been described in obese women without PCOS and is associated with decreased fecundity, increased reproductive wastage, and a less favorable response to fertility treatments. In men, reduced fertility and a marked increase in bioavailable estrogen have been described and termed MOSH Syndrome (male obesity and secondary hypogonadism).

This chapter will discuss the role of overnutrition and undernutrition in relation to reproduction and will provide emerging data from clinical trials designed to ameliorate the adverse effects of obesity on puberty and adult reproductive function. The impact of nutrition on cancer risk and prognosis will also be discussed with respect to reproductive cancers (breast).

Nutrition, Body Weight, and Puberty

• Initiation of puberty likely represents a release from chronic inhibition of the hypothalamic-pituitary-gonadal axis in both boys and girls.

• Low amplitude hormone fluctuations may occur during the prepubertal period.

• Birth weight and the degree of “catch-up” growth that occurs can modulate the timing and tempo of puberty.

• Body weight or body fat appears to function as a permissive maturational signal to the hypothalamic-pituitary-gonadal axis in girls, but the relationship is less clear in boys.

• Race, socioeconomic status, and environmental exposures may have independent or additive effects on the timing of puberty in relation to BMI.

The known and conjectured mechanisms initiating puberty are reviewed elsewhere in this volume. We will focus on the relevant epidemiology of normal puberty in boys and girls.

Puberty appears to be imminent when hypothalamic-pituitary sensitivity to negative feedback inhibition by estradiol is reduced, and attendant inhibitory neural networks diminish in activity. These processes lead to increased GnRH secretion as well as increased gonadotropin pulsatility, initially at night, which then extends throughout 24 hours. The result is folliculogenesis in girls, spermatogenesis and testosterone production in boys, and the attainment of fertility milestones. In females, the ultimate maturation of the HPO axis is the manifestation of positive hypothalamic-pituitary feedback to increasing estradiol, which initiates an LH surge and ovulation of the preovulatory dominant follicle.

Sexual maturation is a progressive process, but it is not linear. Girls who have their first menstrual period do not always continue to ovulate monthly thereafter. Older epidemiological studies have observed that the attainment of regular menstruation takes from as little as 2 ²⁸ to as much as 7 years after menarche. This broad range of gynecologic age may stem from variations in the sensitivity of different methods to identify ovulatory cycles One study of 112 Caucasian girls, followed every 6 months over the perimenarcheal period, observed elevated urinary progesterone levels consistent with regular ovulation within 1 year of menarche in the majority. However, sampling was only done every 6 months, a frequency inadequate for the detection of monthly ovulatory events. Zhang and colleagues completed a study of perimenarcheal girls using daily urinary sampling, and the findings reinforce the notion that regular ovulation occurs relatively rapidly, within months instead of years after menarche. Metcalf and colleagues 29 and Borsos and colleagues, who did weekly hormonal assessments in perimenarcheal girls, concluded that a mature pattern of ovulatory cycles was established in a majority of girls after the 20th menstrual period. However, even weekly urine sampling may be inadequate for the detection of brief excursions of progesterone, or its urinary metabolite, pregnanediol glucuronide (Pdg), as even adolescents with regular menses can have luteal phases far shorter than the average 14 days of their adult counterparts. Thus the timing of the achievement of ovulatory cycles in relation to menarche is not definitive. Data from our group indicates that the capacity to produce an ovulatory LH surge in response to estrogen is present even before the onset of the first menses. ^, These findings indicate that, at least in some girls, a biphasic feedback response to estradiol is not the rate-limiting step in attaining regular, ovulatory menses. Irregular menstruation has been associated with low gynecological age, low BMI, chronic nonspecific lung disease or allergic disease, weight loss, and stress. Rosenfield has hypothesized that low-amplitude hormonal cycles occur in early puberty, with nighttime levels greater than daytime. Indeed, it may be that all the hormonal components of the HPO axis are functioning at an adult frequency, but the hormonal signals are dampened and slowly increase to detectable levels. If this is the case, and the timing of pubertal development is not dependent on the maturation of the HPO axis itself, other factors such as nutritional status and increase in body weight may contribute to the timing of reproductive development.

Investigation into the association between children born small for gestational age (SGA) and onset of puberty may provide some insight into the relationship between nutritional status, body weight, and pubertal maturation. Low birth weight (LBW), SGA status, and prematurity are all associated with precocious pubarche (appearance of pubic hair earlier than 8 years of age) and early and exaggerated adrenarche in girls. Prenatal stress associated with prematurity may have an independent or additive effect on the programming resulting from growth restriction. LBW children have higher dehydroepiandrosterone (DHEA) levels compared to children of normal weight, indicating amplified adrenarche, ^, and LBW has also been associated with an increased likelihood of developing PCOS. Although a majority of studies indicate that SGA is associated with premature pubarche (PP) and earlier onset of menarche, van Weissenbruch and colleagues observed no differences in the timing and progression of puberty, including age at menarche, between SGA and appropriate for gestational age (AGA) girls ; another study found SGA to be associated with pubertal delay. ^, More recently, Shim et al observed lower adult height in girls born with SGA, yet birth weight was not associated with age at menarche. Studies associating birth weight with age at menarche have been similarly variable in outcomes, with findings ranging from no association to lower birth weight being linked to earlier pubertal onset. The findings relating to the relationship between birth weight and puberty initiation are variable and imply that there is not a simple, direct relationship. The variability may in part be explained by the different methods used for documenting pubertal initiation and progression; the use of Tanner staging, initiation of breast development, adrenarche, growth velocity, initiation of a growth spurt or menarche, and variability in the measures of assessing fat mass or body composition.

Work by several investigators provides further insight into the progression of puberty in girls with precocious pubarche. ^, Ibanez et al. documented differences in the timing of the onset of puberty and menarche dependent on the degree of prenatal growth restraint in 187 Northern Spanish girls followed from birth through adult stature. Girls with precocious puberty and LBW had menarche 8 to 10 months earlier and obtained an adult stature that was as much as 6.5 cm lower than non-LBW girls. While the LBW-PP girls demonstrated an accelerated onset of puberty and progression to adult stature, most of the height loss was observed prior to the onset of puberty and even before the development of PP. Low circulating levels of sex hormone-binding globulin (SHBG) (a marker for hyperinsulinemic insulin resistance in nondiabetic girls) and hyperleptinemia may contribute to the accelerated onset and progression of puberty in these LBW-PP girls. Severe pre- and postnatal growth restriction associated with insulin resistance and precocious puberty phenotype may be related to insulin-like growth factor-II (IGF-II) methylation abnormalities; however, further studies are needed to elucidate the exact mechanism for this relationship. The DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) Study evaluated 215 children for the effects of early life exposures on the initiation of puberty. The authors found that children weighing between 2500 and 3000 g at birth initiated their growth spurt (defined as the age at minimal height velocity at the onset of the pubertal growth spurt) approximately 7 months earlier than children weighing more than 3000 g at birth. Children with LBW and rapid weight gain in the first 2 years of life displayed initiation of the growth spurt 4 months earlier than those with normal weight gain, indicating earlier pubertal onset. These children also had an earlier age at peak height velocity and earlier menarche in girls, indicating more advanced pubertal maturation. The associations were independent of prepubertal BMI, suggesting that other early life factors may influence the timing of puberty independent of the influences of body fat mass. Indeed, the timing of postnatal weight gain is an important predictive factor for the age at menarche, with earlier age at menarche more strongly associated with early postnatal weight gain in infants born with LBW or IUGR. ^,

Several studies on underweight prepubertal populations support the notion that body weight or body fat is a permissive maturational signal to the hypothalamic-pituitary axis. Matejek and colleagues studied the relationship between leptin levels, fat stores, and reproductive hormone levels in 13 female juvenile elite gymnasts and 9 adolescent girls with anorexia nervosa. Leptin levels were subnormal and were related to body fat mass in girls with anorexia nervosa, and even lower in the elite gymnasts. In both groups, estradiol levels were low and menarche was delayed. Similarly, Pugliese and colleagues evaluated nine boys and five girls, ages 9 to 17 years, with growth failure and delay in puberty (7 of the 14) due to malnutrition resulting from self-imposed caloric restriction. In these children, who restricted caloric intake for fear of becoming obese, increased linear growth and pubertal progression resumed with the resumption of age-appropriate caloric intake. Clinical data also demonstrate that catch-up height and weight in immigrant and adopted children, who move from developing to developed countries, is associated with precocious menarche.

Epidemiological studies in the United States are likewise largely supportive of the positive correlation between increased average BMI and earlier onset of puberty. However, older epidemiological studies documenting the age of attainment of regular menstruation were conducted in populations of girls who differ from our modern-day U.S. population with regard to race, socioeconomic distribution, and average BMI. It is also possible that prior populations studied have been enriched in girls who were nutritionally marginal, certainly so by today’s standards. However, weight or BMI data are not available from these earlier studies. ^{, ,} While the virtual elimination of undernutrition in the postindustrialized United States might be expected to reduce the overall age at menarche in population studies, this is not uniformly the case, perhaps in part due to the limits on representation of diversity in the older studies. In one 50-year cohort and family study of a population sample in Ohio, higher BMI was not shown to be independently related to an earlier age at menarche. The mean age at menarche in this study was 12.7 prior to 1954 and 12.6 after 1954, a minimal decrease. It is possible that overall body composition or BMI in this sample was optimal prior to 1954 (i.e., few girls who were critically underweight were present in this sample). Given the high rates of obesity among adolescents in the current U.S. population and the increase in body fat in adolescent women in the United States over the past century, it is likely that any restraint that low body weight might place upon the HPO axis is minimally operative in our current society. Furthermore, this study population reflects minimal minority representation, and African-American girls are known to attain menarche and to undergo pubertal maturation earlier than Caucasian girls. This has been related in part to increased body mass index (BMI) but may also be due to other factors. Data from the NHANES 1999–2004 examining age at first menarche in 6788 females over 20 years in the United States demonstrated a decline in the mean age at menarche from 13.3 years prior to 1920 to 12.4 years in those youth born between 1980 and 1984. While the downward trend was most notable for non-Hispanic black girls, significant declines in age at menarche were also documented among non-Hispanic white and Mexican American youth. The association between BMI and age at first menarche was not examined in this study. More recently, data from the Centers for Disease Control and Prevention using the National Survey of Family Growth showed a decline in median age at menarche of 12.1 years in 1995 to 11.9 years from 2013 to 2017 in a nationally representative sample.

Further, within developing countries, pubertal timing variations exist between girls in well-off versus underprivileged conditions, with earlier ages at menarche in well-off girls. Utilizing data from the 1959–1962 National Health Examination Survey (NHES) and the NHANES from 1971 through 1994, and 1999 through 2008, Krieger et al. evaluated the 50-year U.S. trend in age at menarche among non-Hispanic Black and White women and its association with socioeconomic status (SES) and race/ethnicity. While the average age of menarche declined in both groups over the 50-year time interval, white women in the lowest income percentiles had a higher average age at menarche than those in the highest income percentiles prior to 1962 with a reversal in this trend by 2005–2008 with a lower average age at menarche in women in the lowest income percentile. In contrast, no socioeconomic trends were observed among Black women over this time period. Over time, an increasing proportion of women with menarche at age less than 11 years occurred in both White and Black women with lower SES. Although this study did not examine the association between BMI and age at first menarches, the overall declining age at menarche among both Black and White women is likely due to improved nutrition associated with pre-1970 declines in childhood poverty followed by increasing adiposity among all socioeconomic strata and racial/ethnic groups. ^, Lundeen et al recently examined the association between early growth and the timing and tempo of puberty in predominantly Black South African adolescents from low SES families in Soweto. Analyzing the anthropometric and pubertal data annually from age 9 through 16 years of age in 3273 children born in early 1990, the authors found both height and BMI in early childhood were positively associated with the tempo of puberty. The authors hypothesize that efforts to improve child health and growth in this area following the collapse of Apartheid may have contributed to a secular trend of lowered age of puberty over the study period. These studies taken together suggest that improved nutrition among girls of lower SES in industrialized societies may have contributed to a trend in earlier puberty by increasing the average BMI in this population.

However, while the data supporting this assertion in girls are generally supportive, the data regarding the correlation between BMI and pubertal onset in boys are variable. Busch et al. found in 2020 that pubertal onset, defined as testicular enlargement greater than 4 mL, was significantly earlier in a cohort of 218 obese boys compared to controls. However, these data came from Denmark, with a study population far more racially and ethnically homogenous than that of the United States. Conversely, a German study by Reinehr and colleagues evaluating the effect of weight loss on timing of puberty found that BMI-SDS (standard deviation score) reduction in overweight children was associated with the earlier gonadotropin-dependent onset of puberty in boys and later onset of puberty in girls. Furthermore, in a racially diverse, community-based sample of almost 4000 boys in the United States, Lee et al found evidence of earlier puberty for overweight compared with normal weight or obese boys, and later puberty for obese boys compared with normal weight or overweight boys. These contradicting studies demonstrate the need for further study into the effect of body weight on male reproductive maturation.

It should be noted, too, that environmental exposures are also hypothesized to contribute to the trend of earlier puberty in Western societies. Endocrine disruptors contained in plastics, such as bisphenol A, are ubiquitous in industrialized societies and most individuals demonstrate appreciable levels of exposure. ^, In general, these compounds bind weakly to sex steroid receptors and their signaling is likely to be overridden by endogenous sex steroids in gonadally intact, reproductive-aged males and females. However, at the extremes of reproductive life in women and prepubertally in men, these mixed-sex steroid agonists may play a role in providing nonphysiologic input to the reproductive axis.

Additional research evaluating the interaction between, BMI, SES, and race and ethnicity is needed to explain these trends and to provide a more in-depth understanding of the societal and biological determinants of age at menarche. Whether these differences relate to nutritional status, physical activity or energy expenditure, or perceived environmental stressors related to income is not known.

How Does Fat Signal the HPO Axis?

• Leptin is a permissive signal to the hypothalamic-pituitary-gonadal axis and appears to signal when nutritional stores are adequate for reproduction.

• Other adipokines may exert effects on the hypothalamic-pituitary-gonadal axis, but their effects may be indirect and/or mediated by inflammation.

• There are compelling linkages between orexigenic peptide and sex steroid secretion in human and animal models.

How Does Body Weight Modify Puberty and Adult Reproduction?

• Birth weight and the degree of “catch-up” growth that occurs can modulate the timing and tempo of puberty.