On the rising incidence of early breast development: puberty as an adaptive escape from ectopic adiposity in mismatch girls

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  • 1 University of Leuven, University of Leuven, Leuven, Belgium
  • 2 University of Barcelona, Barcelona, Spain

Correspondence should be addressed to F de Zegher Email Francis.deZegher@uzleuven.be

Over the past decades, there has been a worldwide trend towards younger ages of pubertal onset in girls (1). Overall, this trend has been estimated at 3 months per decade (1) but some regions are experiencing faster transitions, in parallel with rapid gains in body weight. In Korea, for example, the prevalence of precocious puberty in girls has increased >10-fold within a single generation (2). Such alarming rises are not readily attributable to exposures to endocrine disruptors (3) and are still under active investigation.

One of the proposed hypotheses is that an earlier/faster maturation in girls is the phenotypic expression of an adaptive mechanism whereby girls attempt to escape from ectopic adiposity which, in turn, ensues from a mismatch between reduced prenatal weight gain (with reduced s.c. adipogenesis, thus a reduced capacity for safe lipid storage) and augmented postnatal weight gain (with augmented lipogenesis, and thus an augmented need for lipid storage) (4). This hypothesis builds upon the more general mismatch concept that offers an explanation for a variety of recent trends and emerging phenotypes (5). For example, the mismatch between reduced prenatal weight gain and augmented postnatal weight gain contributes to explain the trends towards higher blood pressures in early childhood (6), towards exaggerated adrenarche (higher concentrations of circulating DHEAS sometimes eliciting a precocious pubarche) (7), towards younger ages at menarche (8), and towards higher incidences of polycystic ovary syndrome (9). In the context of precocious puberty, the presence or absence of such a mismatch can readily be estimated by calculating the upward change in Z-score (or centile) between birthweight-for-gestational-age and BMI-at-onset-of-puberty (4, 10). Hitherto, however, this mismatch hypothesis has remained untested as a potential explanation for the increasing incidence of precocious puberty.

In a recent issue of the European Journal of Endocrinology, Harbulot et al. (11) reported how they performed the first test of the mismatch hypothesis, by analysing their single-centre cohort of girls with isolated variants of central precocious puberty (n = 319) in an unprecedented way: they distinguished three subgroups and calculated the Z-scores of birthweight-for-gestational-age and BMI-at-diagnosis-of-central-precocious-puberty in each subgroup. Their findings (Fig. 1) endorse the mismatch concept since the three subgroups ('familial', 'sporadic', and 'adopted') tended to differ in birthweight (average centiles 50, 34, and 10, respectively) and also in BMI-at-diagnosis (centiles 96, 90, and 76), so that the upward changes between birth and puberty amounted on average to 46, 56, and 66 centiles. These marked increments are likely to be underestimated since the early (= pre-diagnosis) phase of central precocious puberty is characterised by an acceleration of height gain that often has a lowering effect on BMI; it is by growing faster that girls can escape from ectopic adiposity.

Figure 1
Figure 1

Mismatch between prenatal weight gain and postnatal weight gain in girls with isolated variants of central precocious puberty (CPP; n = 319). Weight at birth is expressed in centiles for sex and gestational age. BMI at diagnosis of CPP is expressed in centiles for sex and chronological age. The authors of the original paper (11) distinguished three subgroups of girls with isolated CPP. In the 'familial' subgroup (red), the average centile rose from 50 (weight at birth) to 96 (BMI at diagnosis of CPP), for an upward mismatch of 46 centiles. In the 'sporadic' subgroup (orange), the average centile rose from 34 to 90, for an upward mismatch of 56 centiles. In the 'adopted' subgroup (green), the average centile rose from 10 to 76, for an upward mismatch of 66 centiles. Marked mismatches are known to be associated with insulin resistance and ectopic fat in girls aged 8 years (10).

Citation: European Journal of Endocrinology 185, 1; 10.1530/EJE-21-0287

In conclusion, a vast majority of girls with isolated variants of central precocious puberty were found to have experienced an upward mismatch between prenatal and postnatal weight gain. The clinical data of Harbulot et al. (11) allowed us to infer this simple message which, however, implies that treatment in most girls with precocious puberty should aim not only at silencing the gonadotropic axis but also at reducing weight gain and/or ectopic fat. Central precocious puberty in girls should henceforth be viewed as possibly reflecting the activation of the gonadotropic axis in a homeostatic and evolutionarily conserved attempt to escape from ectopic adiposity.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this article.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

References

  • 1

    Eckert-Lind C, Busch AS, Petersen JH, Biro FM, Butler G, Bräuner EV & Juul A Worldwide secular trends in age at pubertal onset assessed by breast development among girls: a systematic review and meta-analysis. JAMA Pediatrics 2020 174 e195881. (https://doi.org/10.1001/jamapediatrics.2019.5881)

    • Search Google Scholar
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  • 2

    Kim YJ, Kwon A, Jung MK, Kim KE, Suh J, Chae HW, Kim DH, Ha S, Seo GH & Kim HS Incidence and prevalence of central precocious puberty in Korea: an epidemiologic study based on a national database. Journal of Pediatrics 2019 208 221228. (https://doi.org/10.1016/j.jpeds.2018.12.022)

    • Search Google Scholar
    • Export Citation
  • 3

    Jung MK, Choi HS, Suh J, Kwon A, Chae HW, Lee WJ, Yoo EG & Kim HS The analysis of endocrine disruptors in patients with central precocious puberty. BMC Pediatrics 2019 19 323. (https://doi.org/10.1186/s12887-019-1703-4)

    • Search Google Scholar
    • Export Citation
  • 4

    de Zegher F, López-Bermejo A & Ibáñez L Central obesity, faster maturation, and 'PCOS' in girls. Trends in Endocrinology and Metabolism 2018 29 815818. (https://doi.org/10.1016/j.tem.2018.09.005)

    • Search Google Scholar
    • Export Citation
  • 5

    Gluckman PD & Hanson MA Living with the past: evolution, development, and patterns of disease. Science 2004 305 1733173 6. (https://doi.org/10.1126/science.1095292)

    • Search Google Scholar
    • Export Citation
  • 6

    Ong YY, Sadananthan SA, Aris IM, Tint MT, Yuan WL, Huang JY, Chan YH, Ng S, Loy SL & Velan SS et al. Mismatch between poor fetal growth and rapid postnatal weight gain in the first 2 years of life is associated with higher blood pressure and insulin resistance without increased adiposity in childhood: the GUSTO cohort study. International Journal of Epidemiology 2020 49 15911603. (https://doi.org/10.1093/ije/dyaa143)

    • Search Google Scholar
    • Export Citation
  • 7

    Ong KK, Potau N, Petry CJ, Jones R, Ness AR, Honour JW, de Zegher F, Ibáñez L, Dunger DBAvon Longitudinal Study of Parents and Children Study Team. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. Journal of Clinical Endocrinology and Metabolism 2004 89 264726 51. (https://doi.org/10.1210/jc.2003-031848)

    • Search Google Scholar
    • Export Citation
  • 8

    Sloboda DM, Hart R, Doherty DA, Pennell CE & Hickey M Age at menarche: influences of prenatal and postnatal growth. Journal of Clinical Endocrinology and Metabolism 2007 92 4650. (https://doi.org/10.1210/jc.2006-1378)

    • Search Google Scholar
    • Export Citation
  • 9

    de Zegher F, Reinehr T, Malpique R, Darendeliler F, López-Bermejo A & Ibáñez L Reduced prenatal weight gain and/or augmented postnatal weight gain precedes polycystic ovary syndrome in adolescent girls. Obesity 2017 25 14861489. (https://doi.org/10.1002/oby.21935)

    • Search Google Scholar
    • Export Citation
  • 10

    de Zegher F, Malpique R, Garcia-Beltran C & Ibáñez L Towards a simple marker of hepato-visceral adiposity and insulin resistance: the Z-score change from weight-at-birth to BMI-in-childhood. Pediatric Obesity 2019 14 e12533. (https://doi.org/10.1111/ijpo.12533)

    • Search Google Scholar
    • Export Citation
  • 11

    Harbulot C, Lessim S, Simon D, Martinerie L, Storey C, Ecosse E, De Roux N, Carel JC & Léger J Prevalence and clinical characteristics of isolated forms of central precocious puberty: a cohort study at a single academic center. European Journal of Endocrinology 2021 184 243251. (https://doi.org/10.1530/EJE-20-0862)

    • Search Google Scholar
    • Export Citation

 

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    Mismatch between prenatal weight gain and postnatal weight gain in girls with isolated variants of central precocious puberty (CPP; n = 319). Weight at birth is expressed in centiles for sex and gestational age. BMI at diagnosis of CPP is expressed in centiles for sex and chronological age. The authors of the original paper (11) distinguished three subgroups of girls with isolated CPP. In the 'familial' subgroup (red), the average centile rose from 50 (weight at birth) to 96 (BMI at diagnosis of CPP), for an upward mismatch of 46 centiles. In the 'sporadic' subgroup (orange), the average centile rose from 34 to 90, for an upward mismatch of 56 centiles. In the 'adopted' subgroup (green), the average centile rose from 10 to 76, for an upward mismatch of 66 centiles. Marked mismatches are known to be associated with insulin resistance and ectopic fat in girls aged 8 years (10).

  • 1

    Eckert-Lind C, Busch AS, Petersen JH, Biro FM, Butler G, Bräuner EV & Juul A Worldwide secular trends in age at pubertal onset assessed by breast development among girls: a systematic review and meta-analysis. JAMA Pediatrics 2020 174 e195881. (https://doi.org/10.1001/jamapediatrics.2019.5881)

    • Search Google Scholar
    • Export Citation
  • 2

    Kim YJ, Kwon A, Jung MK, Kim KE, Suh J, Chae HW, Kim DH, Ha S, Seo GH & Kim HS Incidence and prevalence of central precocious puberty in Korea: an epidemiologic study based on a national database. Journal of Pediatrics 2019 208 221228. (https://doi.org/10.1016/j.jpeds.2018.12.022)

    • Search Google Scholar
    • Export Citation
  • 3

    Jung MK, Choi HS, Suh J, Kwon A, Chae HW, Lee WJ, Yoo EG & Kim HS The analysis of endocrine disruptors in patients with central precocious puberty. BMC Pediatrics 2019 19 323. (https://doi.org/10.1186/s12887-019-1703-4)

    • Search Google Scholar
    • Export Citation
  • 4

    de Zegher F, López-Bermejo A & Ibáñez L Central obesity, faster maturation, and 'PCOS' in girls. Trends in Endocrinology and Metabolism 2018 29 815818. (https://doi.org/10.1016/j.tem.2018.09.005)

    • Search Google Scholar
    • Export Citation
  • 5

    Gluckman PD & Hanson MA Living with the past: evolution, development, and patterns of disease. Science 2004 305 1733173 6. (https://doi.org/10.1126/science.1095292)

    • Search Google Scholar
    • Export Citation
  • 6

    Ong YY, Sadananthan SA, Aris IM, Tint MT, Yuan WL, Huang JY, Chan YH, Ng S, Loy SL & Velan SS et al. Mismatch between poor fetal growth and rapid postnatal weight gain in the first 2 years of life is associated with higher blood pressure and insulin resistance without increased adiposity in childhood: the GUSTO cohort study. International Journal of Epidemiology 2020 49 15911603. (https://doi.org/10.1093/ije/dyaa143)

    • Search Google Scholar
    • Export Citation
  • 7

    Ong KK, Potau N, Petry CJ, Jones R, Ness AR, Honour JW, de Zegher F, Ibáñez L, Dunger DBAvon Longitudinal Study of Parents and Children Study Team. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. Journal of Clinical Endocrinology and Metabolism 2004 89 264726 51. (https://doi.org/10.1210/jc.2003-031848)

    • Search Google Scholar
    • Export Citation
  • 8

    Sloboda DM, Hart R, Doherty DA, Pennell CE & Hickey M Age at menarche: influences of prenatal and postnatal growth. Journal of Clinical Endocrinology and Metabolism 2007 92 4650. (https://doi.org/10.1210/jc.2006-1378)

    • Search Google Scholar
    • Export Citation
  • 9

    de Zegher F, Reinehr T, Malpique R, Darendeliler F, López-Bermejo A & Ibáñez L Reduced prenatal weight gain and/or augmented postnatal weight gain precedes polycystic ovary syndrome in adolescent girls. Obesity 2017 25 14861489. (https://doi.org/10.1002/oby.21935)

    • Search Google Scholar
    • Export Citation
  • 10

    de Zegher F, Malpique R, Garcia-Beltran C & Ibáñez L Towards a simple marker of hepato-visceral adiposity and insulin resistance: the Z-score change from weight-at-birth to BMI-in-childhood. Pediatric Obesity 2019 14 e12533. (https://doi.org/10.1111/ijpo.12533)

    • Search Google Scholar
    • Export Citation
  • 11

    Harbulot C, Lessim S, Simon D, Martinerie L, Storey C, Ecosse E, De Roux N, Carel JC & Léger J Prevalence and clinical characteristics of isolated forms of central precocious puberty: a cohort study at a single academic center. European Journal of Endocrinology 2021 184 243251. (https://doi.org/10.1530/EJE-20-0862)

    • Search Google Scholar
    • Export Citation