Forum
Central Obesity,
Faster Maturation,
and ‘PCOS’ in Girls$
Francis de Zegher,1,*
Abel López-Bermejo,2 and
Lourdes Ibáñez3,4,*
Polycystic ovary syndrome (PCOS)
development commonly starts
with a mismatch between pre-
and postnatal weight gain, leading
to hepatovisceral fat excess. To
escape from such central obesity,
girls may accelerate their growth
and/or maturation. This homeo-
static mechanism is lost upon
reaching adult height, and PCOS
may ensue. Prevention and/or
treatment of PCOS should aim at
reducing central fat excess.
The Early Origins of PCOS
In 1998, based on longitudinal observa-
tions in girls (from birth until late adoles-
cence), we posited that Polycystic Ovary
Syndrome (PCOS) is the outcome of ‘a
simple sequence of prenatal onset’ [1].
Evidence gathered during the first decen-
nium of the concept pointed to the limited
capacity to store fat safely in subcutane-
ous depots, and to a key role of ectopic
fat storage [2]. Here, we summarize how
the hypothesis has evolved over the past
decennium, how it recently led to the
recognition of the adaptive nature of
PCOS, and how it is now leading toward
preventive and therapeutic strategies,
$ term delivery), possibly with neurocogni-
On the occasion of the 5th anniversary of the
National Institute of Child Health and Human Devel-
opment’s recommendation to expeditiously assign
another name to Polycystic Ovary Syndrome,
because this name is thought to cause confusion,
to be an impediment to progress, and a barrier to
effective education and communication.
and perhaps even toward a renewal of childhood (4–9 years of age) and pres-
the PCOS acronym. ent with a relatively tall stature, early
pubarche (appearance of pubic hair,
driven by an exaggerated adrenarche,
The Pediatric Highway to Earlier with high concentrations of circulating
Pubarche, Earlier Puberty, Earlier DHEAS), and advanced bone age [7]. A
Menarche, and/or PCOS
second acceleration of growth and mat-
Figure 1 summarizes an increasingly
uration may result from an early and/or
prevalent trajectory toward adolescent
PCOS, the main diagnostic criteria of
rapidly advancing puberty [i.e., breast
development, driven by luteinizing hor-
which are hirsutism and oligo-amenor-
mone (LH) hypersecretion, and ovarian
rhea (>2 years beyond menarche) [3].
estrogen secretion], potentially resulting
This trajectory starts (Figure 1, infancy
in an early menarche [8]. Many associ-
and early childhood) with a multifactorial
ations between an earlier menarche and
mismatch between (less) prenatal and
augmented morbidity in adulthood may
(more) postnatal weight gain, so that
in fact be based on (even closer) asso-
more fat has to be stored than is safely
ciations between more central adiposity
feasible in subcutaneous adipose tissue
in childhood and more morbidity in
[2,4]. One way to assess this mismatch
later life.
(Figure 2) is to calculate the Z-score incre-
ment between weight at birth and body As shown in Figure 1 (adolescence and
mass index (BMI) at PCOS diagnosis; adulthood), the feedback effect of body
more risk for PCOS may be conferred growth on central adiposity is essentially
per Z-score lower birthweight (i.e., less lost upon reaching adult height (approxi-
subcutaneous adipogenesis, thus less mately 2 years post menarche) [9], but the
capacity for safe fat storage) than per LH hypersecretion and other accelera-
Z-score higher BMI (i.e., more net lipo- tion-mediating mechanisms (including
genesis, thus more demand for fat stor- high insulinemia and low circulating
age) [4]. SHBG concentrations) persist, thus lead-
ing to end-stage PCOS with hepatovisc-
From early childhood onward, such a mis- eral adiposity, androgen excess, and
match results in an excess of hepatovisc- oligo-anovulation [10,11]. Genetic poly-
eral fat [5,6], which, in turn, accelerates morphisms (Figure 1, gene names in
body growth and maturation within an green), epigenetic modulations, and daily
adaptive feedback mode that attempts lifestyle are increasingly recognized as
to reduce central adiposity [7]. Potential modulators of many interactions within
mediators of this acceleration include the updated concept.
higher concentrations of circulating insu-
When the subfertility of end-stage PCOS
lin, insulin-like growth factor I (IGF-I), and
dehydroepiandrosterone is overcome [by assisted reproduction
sulfate
(DHEAS), and lower levels of high-molec- techniques (ART)], then the ensuing preg-
ular-weight (HMW) adiponectin and sex nancies carry a multifold risk for compli-
hormone-binding globulin (SHBG); the cations (in particular for gestational
diabetes mellitus, hypertension, and pre-
roles of other adipokines (such as leptin),
hepatokines (such as follistatin), and non-
coding RNAs remain to be defined. tive sequelae into the next generation
[12]. Thus, the subfertility of PCOS can
As shown in Figure 1 (late childhood and be viewed as an adaptive mode, revers-
puberty), a first acceleration of growth ibly preventing a cascade of complica-
and maturation may occur during tions in mother and offspring.
Trends in Endocrinology & Metabolism, December 2018, Vol. 29, No. 12 815
 Mismatch between pcos PCOS
less prenatal weight gain and
more postnatal weight gain pediatric Postpubertal
central Central
obesity Obesity
Fat excess in sequence Syndrome
subcutaneous
adipose Ɵssue AdapƟve mechanism to AdapƟve mechanism to
reduce central obesity prevent high-risk pregnancy

Hepato-visceral fat excess

(central obesity)
PNPLA3, TM6SF2, GCKR, MBOAT7
CYP19A1
Growth and maturaƟon LHCG-R
Bone age
Early adrenarche - pubarche FSH-B
Gonadotropin secreƟon DENND1A
AR
Early puberty - menarche
Insulin, IGF-I, DHEAS FSH-B Ov. Androgens (HirsuƟsm)
SHBG, HMW adipo OvulaƟon rate (Oligo-Am)
PNPLA3 hepatokines ? miRNA ? PCOS

Infancy Early childhood Late childhood Puberty Adolescence Adulthood

Figure 1. Consecutive Steps in the pediatric central obesity sequence (pcos) toward the Postpubertal Central Obesity Syndrome (PCOS). During
infancy and early childhood, a mismatch between pre- and postnatal weight gain results in central obesity. During late childhood and puberty, girls can accelerate their
growth and maturation in a homeostatic attempt to reduce their central obesity. Upon reaching adult height (adolescence and adulthood), the negative feedback on
central obesity is lost, but the underlying drivers persist, and full-blown polycystic ovary syndrome (PCOS) emerges. Thus, both pcos and PCOS are driven by central
obesity and are adaptive mechanisms resulting in earlier and safer reproduction, respectively. Names in green are those of selected genes conferring genetic or
epigenetic modulations. Green arrows refer to stimulatory effects; red arrows refer to inhibitory feedback effects on central obesity. Blue-filled text boxes are positioned
along the age range wherein they start to be active; however, their action may last up into adulthood. Abbreviations: DHEAS, dehydroepiandrosterone sulfate; HMW
adipo, high-molecular-weight adiponectin; IGF-I, insulin-like growth factor I; oligo-am, oligo-amenorrhea; ov, ovarian; SHBG, sex hormone-binding globulin.

Central Obesity: from Pediatric times, this homeostatic sequence must be called the ‘Postpubertal Central Obe-
Sequence to Postpubertal have conferred an evolutionary advantage sity Syndrome’ (PCOS) instead of PCOS.
Syndrome by allowing for earlier reproduction, and, In ancient times, this homeostatic ensem-
The adaptive mode of accelerated growth thus, for a shorter timespan between con- ble must have conferred an evolutionary
and maturation, which attempts to atten- secutive generations. advantage by allowing for less morbidity
uate central obesity during childhood and and/or mortality in mother and/or off-
puberty, could be called the pediatric Upon linear growth arrest after menarche, spring, and, thus, for safer reproduction.
central obesity sequence (pcos); the the adaptive mode of reversible subfertil-
image to keep in mind is that of girls ity, which reduces the complications of It is possible that pcos is not followed by
advancing ‘in the fa(s)t lane’. In ancient central obesity in mother/offspring, could PCOS; for example, when a reduction of

816 Trends in Endocrinology & Metabolism, December 2018, Vol. 29, No. 12
 Balance versus mismatch between pre- and postnatal weight gain

+2

Balance between
prenatal weight gain & Z-score
postnatal weight gain

-2
Birth weight Child/adolescent BMI

GeneƟc polymorphisms
EpigeneƟcs (early history) +2
Lifestyle (nutriƟon and exercise)
Mismatch between Z-score
less prenatal weight gain &
more postnatal weight gain

-2
Birth weight Child/adolescent BMI

Figure 2. Balance versus Mismatch between Pre- and Postnatal Weight Gain. When there is a balance between pre- and postnatal weight gain, then the
endocrine-metabolic system tends to remain in balance. When there is a mismatch between pre- and postnatal weight gain (related to genetic, epigenetic, and/or
lifestyle factors), then there is an augmented risk to become centrally obese. Prenatal weight gain is judged here by birthweight Z-score (for sex and gestational age);
postnatal weight gain is judged here by body mass index (BMI; for sex and age) during childhood or adolescence. Available evidence suggests that more risk for central
obesity and pediatric central obesity sequence (pcos)/postpubertal central obesity syndrome (PCOS)/Polycystic Ovary Syndrome (PCOS) is conferred per negative Z-
score for birthweight than per positive Z-score for later BMI [4]. Many girls with pcos/PCOS/PCOS are neither born small-for-gestational-age, nor frankly obese, but
experience a Z-score increment from, for example, 1.0 or 0.5 (birthweight) to +1.0 or +1.5 (BMI).

central obesity is achieved with lifestyle
measures in obese girls [13], or when
calorie restriction is mimicked with met-
formin treatment in nonobese low-birth-
weight girls with accelerated maturation
[7]. Conversely, it is possible that PCOS is
not preceded by pcos; for example, in
normal-birthweight women who were
not obese as girls, but became obese
after menarche.
A Natural Model for Human
PCOS
In a cascade of >40 manuscripts over
>40 years, Amitabh Krishna et al.
described the reproductive cycle of the
Asiatic yellow bat (Scotophilus heathii) at
Banaras Hindu University in Varanasi,
India; a noteworthy feature of this annual
cycle is the sequence of food and/or
insect abundance (between August and
October) followed by food and/or insect
scarcity (between December and Febru-
ary), leading to a sequence of seasonal
adiposity (on average, 50% gain of body
weight, as fat mass, by November), fol-
lowed by a gradual return to pre-abun-
dance body composition; the endocrine
course toward such seasonal adiposity is
characterized by an approximate tripling
of circulating insulin, by an approximate
quintupling of circulating androgens, and,
finally, by a seasonal state of gonadotro-
pin-resistant anovulation; during the
ensuing winter, the gradual loss of adi-
posity is accompanied by a reversal of
hyperinsulinemia and hyperandrogene-
mia toward normal and, ultimately, by
spontaneous resumption of ovulation;
seasonally adipose and anovulatory bats
respond to exogenous adiponectin by
reducing their central and peripheral fat
excess, and by reversing their androgen
excess and anovulation [14]. The latter
findings corroborate a paradigm wherein
a reversal of PCOS features in girls is
partly targeted via an upregulation of
endogenous adiponectinemia [15].
Toward Early Interventions
Guided by Pathogenesis
In younger girls with pcos, only the effects
of metformin monotherapy have so far
been explored in a randomized controlled
trial, and only in those girls with pcos who
experienced a sequence wherein a lower
birthweight was followed by a higher BMI,
and then by precocious pubarche and/or
early puberty; in such girls, metformin
intake for 4 years (age 8–12 years) was
accompanied by a preferential reduction
in hepatovisceral adiposity [7], by the
almost disappearance of the pcos

Trends in Endocrinology & Metabolism, December 2018, Vol. 29, No. 12 817
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