Received: 9 August 2019 Revised: 21 September 2019 Accepted: 1 October 2019

DOI: 10.1111/ijpo.12586

SHORT COMMUNICATION

Polycystic ovary syndrome in adolescent girls

Lourdes Ibáñez MD, PhD1,2 | Francis de Zegher MD, PhD3

1
Endocrinology, Pediatric Research Institute
Sant Joan de Déu, Barcelona, Spain Summary
2
Network Biomedical Research Center of PCOS is already a prevalent endocrinopathy in adolescent girls, and its prevalence is
Diabetes and Associated Metabolic Disorders
rising further since, in essence, it is the result of a mismatch between an energy‐
(CIBERDEM), Health Institute Carlos III,
Madrid, Spain sparing (epi)genetic background and a (relatively) obesogenic environment. This mis-
3
Department of Development & Regeneration, match results in an excess of fat storage in ectopic depots, notably in the liver and vis-
University of Leuven, Leuven, Belgium
cera (= hepato‐visceral, or central fat). There is still no FDA‐approved treatment for
Correspondence adolescent PCOS. The prime aim should be a preferential loss of central fat, through
Lourdes Ibáñez, MD, PhD, Hospital Sant Joan
de Déu, University of Barcelona, Passeig de
lifestyle measures. Failure to sustain these measures is frequent, and the standard
Sant Joan de Déu, 2; 08950 Esplugues. approach is to add an estroprogestagen contraceptive, even for girls who do not need
Barcelona, Spain. ext. 4424;.
Email: libanez@sjdhospitalbarcelona.org
contraception. Treatment with SPIOMET, a low‐dose combination of spironolactone
(to antagonize androgen and mineralocorticoid effects, and to activate BAT thereby
raising energy expenditure), pioglitazone (to raise circulating HMW adiponectin con-
centrations) and metformin, is an alternative approach that holds the potential to
revert the PCOS phenotype.

K E Y W OR D S

androgen excess, central fat, hepatic fat, hirsutism, metformin, ovulation, pioglitazone, polycystic
ovary syndrome, spironolactone, visceral fat

1 | I N T RO D U CT I O N
Recent progress in the understanding, diagnosis and treatment of
adolescent PCOS has been remarkable. Table 1 summarizes how the
paradigm is changing.
Adolescent PCOS is now defined by the co‐presence of irregular
menses and androgen excess (clinical evidence + biochemical confir-
mation) >2 years after menarche, and by the exclusion of disorders
such as an androgen‐secreting tumor, 21‐hydroxylase deficiency, and
prolactin excess; ovarian morphology is not a diagnostic criterion 1.
Worldwide, PCOS is one of the most prevalent endocrinopathies
of adolescent girls (≈10%), and its prevalence is rising since, in
essence, adolescent PCOS is the outcome of a mismatch between an
energy‐sparing (epi)genetic background and a (relatively) obesogenic
2
environment . In any variant of such a mismatch, there is a chronic
need to store more fat than is safely feasible in subcutaneous adipose
Abbreviations: BAT, Brown adipose tissue; BMI, Body mass index; FAI, Free androgen index;
HMW, High molecular weight; LH, Luteinizing hormone; PCOS, Polycystic ovary syndrome;
SHBG, Sex hormone binding globulin
tissue, and the excess of fat ends up being stored in ectopic depots,
notably in the liver and viscera (= hepato‐visceral or central fat) 2.
Adolescent PCOS is typically driven by an ensemble including central
obesity, insulin resistance, LH hypersecretion, and low concentrations
of circulating HMW adiponectin, which is a key adipokine with insulin‐
2,3
sensitizing properties .
Adolescent PCOS is commonly heralded by an upward Z‐score
change from weight‐at‐birth to BMI‐in‐childhood 2. The magnitude
of this Z‐score increment is partly driven by genetic variants that con-
trol appetite and/or BMI [Suppl File 1, a]. A higher Z‐score increment
associates with more insulin resistance and with more central adipos-
ity in childhood, and also with a faster maturation toward an early
menarche; weight‐at‐birth tends to be below average in PCOS girls
without obesity, but not in PCOS girls with obesity [Suppl File 1, b,c,d].
Oligo‐anovulation may result from an adaptive neuroendocrine
response to a deficit of central fat (as in athletic amenorrhea) or to
an excess of central fat (as in PCOS), and there is genetic variation
in the hypothalamo‐pituitary responsiveness to central adiposity. Girls

Pediatric Obesity. 2020;15:e12586. wileyonlinelibrary.com/journal/ijpo © 2019 World Obesity Federation 1 of 4

https://doi.org/10.1111/ijpo.12586
2 of 4 IBÁÑEZ AND DE ZEGHER

TABLE 1 Adolescent PCOS: A changing paradigm

Standard Update

The essence of PCOS
PCOS acronym stands for
Sequence
Highly heritable disorder of the Mismatch disorder in obesogenic world:
hypothalamic–pituitary‐‐ovarian axis absolute or relative excess of subcutaneous fat → hepato‐
visceral (central) fat excess d,e
e
Polycystic ovary syndrome Postpubertal central obesity syndrome
PCOS → BMI BMI → PCOS f

Potential forerunners
Evolutionary rationale
(Epi)genetics
Clinical presentation
b l
Diagnostic criteria
•androgen excess c
Prenatal or prepubertal androgen excess? Upward mismatch between BW Z‐score and subsequent
BMI Z‐score
→ early adrenarche/pubarche,
→ early puberty/menarche b,c,d
Unexplained paradox? (Epi‐)genetically high sensitivity of the gonadotropic axis to
central adiposity allowed to adapt reproduction to the
environment, in particular to nutrition e
Monogenic disorder? • at least 19 susceptibility loci linked to genes associated
with metabolic traits of PCOS j
• epigenetic modulations (differential methylation, miRNAs) k
§,1,3,4
Hirsutism, severe acne/seborrhea, irregular menses
d
Presence of at least 2 of these 3 criteria Presence of both upper criteria

•oligo‐amenorrhea
•polycystic ovaries (US)
•polycystic ovaries (US)
Treatment There is still no FDA‐approved treatment for adolescent PCOS
•lifestyle intervention Healthy diet & exercise n

•medications Silencing the hypothalamic–pituitary‐ovarian axis with an Fat repartitioning from ectopic toward eutopic depots p

Reproductive perspective
•fertility
(oral) estro‐progestagen as to reduce the androgen Brown adipose tissue activation r,q
excess and to obtain regular pseudo‐menses;
contraceptive effect may be welcome l,m,o Contraceptive measures may be needed
Oligo‐anovulation Aim for normo‐ovulation p,x

•conception ART Aim for spontaneous conception

•pregnancy GDM, preeclampsia, preterm delivery i,j
Aim for uncomplicated pregnancy
•next generation More risk for neurological sequelae k,l
Aim for healthy offspring
Long‐term outcome Increased risk for type 2 diabetes, vascular disorders, Aim at reverting the endocrine‐metabolic abnormalities
cancer, anxiety/depression w,y,z,aa underpinning those risks

Abbreviations: subc, subcutaneous; BMI, body mass index; BW, birth weight; US, ultrasound; GDM, gestational diabetes mellitus; ART, assisted reproduc-
tive technologies
a
Hirsutism is assessed with the modified Ferriman and Gallwey score; a level > 6 is considered abnormal, depending on ethnicity. Irregular menses are
defined as persistent oligo‐amenorrhea (menstrual cycles >45 days) at least 2 years beyond menarche; excepcionally, primary amenorrhea in girls with com-
pleted puberty.
b
After exclusion of specific disorders.
c
Clinical and/or biochemical (by liquid chromatography tandem spectrometry).
d
Ibáñez L, et al. Horm Res Paediatr 2017; 88:371–395.
e
de Zegher F, et al. Trends Endocrinol Metab 2018; 29:815–818.
f
Brower MA, et al. Hum Reprod 2019; 34:127–136.
g
de Zegher F, et al. Obesity (Silver Spring) 2017; 25:1486–1489.
h
de Zegher F, et al. Pediatr Ob 2019; e12533.
i
Koivuaho E, et al. Int J Obes (Lond) 2019; 43:1370–1379.
j
Day F, et al. PLoS Genet 2018; 14:e1007813.
k
Nilsson E, et al. J Clin Endocrinol Metab 2018; 103:4465–4477.
l
McCartney CR, et al. N Engl J Med 2016; 375:54–64.
IBÁÑEZ AND DE ZEGHER 3 of 4

m
Teede H, et al. Hum Reprod 2018; 33:1602–1618.
n
Lass N, et al. J Clin Endocrinol Metab 2011; 96:3533–3540.
o
Rosenfield RL. Pediatrics 2015; 136:1154–1165.
p
Ibañez L, et al. J Adolesc Health 2017; 61:446–453.
q
Shorakae S, et al. Clin Endocrinol (Oxf) 2019; 90:425–432.
r
Thuzar M, et al. Diabetes Obes Metab 2019; 21:509–516.
s
de Wilde MA, et al. Fertil Steril 2017; 108: 333–340.
t
Palomba S, et al. Hum Reprod Update 2015; 21:575–592.
u
Bell GA, et al. Hum Reprod 2018; 33:1307–1315.
v
Drenth Olivares M, et al. Early Hum Dev 2019;129:38–44.
w
Kuchenbecker WK, et al. Hum Reprod 2011; 26:2505–2512.
x
Lo JC, et al. J Diabetes Res 2017; 2017:5250162.
y
Calderon‐Margalit R, et al. Arterioscler Thromb Vasc Biol 2014; 34:2688–2694.
z
Yin W, et al. JAMA Oncol 2019; 5:106–107.
aa
Hart R, et al. J Clin Endocrinol Metab 2015; 100:911–919.
ab
References from a to q are included in Supplemental File 1

genetically attuned to the harshest environments are nowadays the
most vulnerable to develop PCOS under circumstances of physical
inactivity and/or nutritional abundance. From an evolutionary per-
spective, it must have been a reproductive advantage to dispose of
an ovulatory function that is highly sensitive to central adiposity, since
such sensitivity allows for swift adjustments of fertility to environmen-
tal changes, notably to food availability.
Genetic susceptibility to PCOS is controlled by at least 19 loci
mainly linked to genes associated with metabolic traits; epigenetic
modulations also influence the PCOS phenotype, including via
differential DNA methylation, and via alterations in the profile of
non‐coding RNAs that regulate gene expression at the post‐
transcriptional level [Suppl File 1, e,f].
Adolescent PCOS presents typically with moderate‐to‐severe,
slowly progressive hirsutism, acne and/or seborrhea (rarely with alo-
pecia), and with oligo‐amenorrhea (menstrual cycles >45 days). Hirsut-
ism is the prime clinical marker of androgen excess, is defined by an
increase of terminal hair in androgen‐dependent areas, and is assessed
by the modified Ferriman & Gallwey score. In general, a score > 6 is
considered abnormal, but a score > 5 may already point to androgen
excess in young girls and in Asian adolescents. Rapidly progressive hir-
sutism and/or virilization (clitoromegaly, deeper voice) requires
prompt exclusion of an androgen‐secreting tumor and adrenal hyper-
plasia. Most girls develop regular ovulatory/menstrual cycles (21–
35 days) within 2 years after menarche; current consensus is therefore
that oligo‐amenorrhea in the first years post‐menarche can still be
viewed as a variant of maturation, but that a more prolonged oligo‐
amenorrhea may warrant a screen for androgen excess; rarely does
PCOS present with primary amenorrhea in girls with completed
1,3,4
growth and puberty . So‐called SPIOMET is an alternative addition under investigation in
Biochemical confirmation of androgen excess requires an assess-
ment of the circulating concentrations of testosterone (preferably by
liquid chromatography tandem spectrometry) and/or an estimate of
free testosterone: FAI = testosterone (nmol/L) x 100/SHBG (nmol/
L). The upper limits of the normal range (2 SD above the mean) may
vary across populations and, therefore, no sharp cut‐offs for androgen
excess have been defined. However, a testosterone level > 40 ng/dL
or > 1.4 nmol/L (and certainly >50 ng/dL or > 1.7 nmol/L) and/or a
FAI >5 are generally viewed as a confirmation of androgen excess. A
baseline 17‐OH‐progesterone level < 200 ng/dL excludes a clinically
relevant 21‐hydroxylase deficiency 1.
There is still no FDA‐approved treatment for adolescent PCOS.
Given the presumably crucial role of central fat excess, the prime
aim should be a preferential loss of central fat. Such a loss can revert
the entire PCOS phenotype, and can be achieved with sustained life-
style measures that involve multiple factors including diet, exercise,
sleep and biorhythm, all within an environment that may remain stub-
bornly obesogenic 5.
Failure to sustain these lifestyle measures is frequent, and the
standard approach is then to add an estroprogestagen contraceptive
3,4
. This adjunct silences the gonadotropic axis, reduces the andro-
gen excess (in part via a pharmacological increment of circulating
SHBG), and leads to regular and anovulatory pseudo‐menses, but it
does not solve the core problem, and thus channels the adolescent
girl toward a post‐treatment rebound of androgen excess and
oligo‐anovulatory subfertility, in other words, toward adult PCOS 6.
Subsequent pregnancies carry a double‐to‐triple risk of complica-
tions (such as gestational diabetes, preeclampsia, and preterm deliv-
ery) and are followed by less favorable neurological outcomes in the
next generation, independently of how conception occurred [Suppl
File 1, j,k,l,m,].
Alternative additions could aim at enhancing the effects of lifestyle
measures, by switching fat from ectopic to eutopic depots, and/or by
stimulating BAT activity, thereby increasing energy expenditure.
adolescents with PCOS without obesity and with no need for contra-
ception 6. SPIOMET is a low‐dose combination of three generics:
spironolactone (to antagonize androgen and mineralocorticoid effects,
and to activate BAT 7), pioglitazone (mainly to reduce central fat, and
to raise HMW adiponectinemia), and metformin. Evidence is still limited
4 of 4 IBÁÑEZ AND DE ZEGHER

but suggests that SPIOMET does indeed hold the potential to revert the 2. de Zegher F, López‐Bermejo A, Ibáñez L. Central obesity, faster matura-
PCOS phenotype 2,6. tion, and 'PCOS' in girls. Trends Endocrinol Metab. 2018;29(12):815‐818.

In conclusion, adolescent PCOS itself is transiting from a disruptive 3. McCartney CR, Marshall JC. Polycystic ovary syndrome. N Engl J Med.
2016;375(1):54‐64.
endocrine‐gynecological disorder toward an adaptive endocrine‐
4. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the
metabolic mode, wherein central fat is taking center stage. New insights
international evidence‐based guideline for the assessment and manage-
into PCOS development are leading to diagnostic and therapeutic ment of polycystic ovary syndrome. Hum Reprod.
advances that will undoubtedly improve the care for adolescent girls 2018;33(9):1602‐1618.
with PCOS. Stay tuned! 5. Lass N, Kleber M, Winkel K, Wunsch R, Reinehr T. Effect of lifestyle
intervention on features of polycystic ovarian syndrome, metabolic syn-
CONF LICT OF INT E RE ST S drome, and intima‐media thickness in obese adolescent girls. J Clin
Endocrinol Metab. 2011;96(11):3533‐3540.
The authors have no conflicts of interest to disclose. 6. Ibáñez L, del Río L, Díaz M, et al. Normalizing ovulation rate by prefer-
ential reduction of hepato‐visceral fat in adolescent girls with
ACKNOWLEDGEMEN TS polycystic ovary syndrome. J Adolesc Health. 2017;61(4):446‐453.
7. Thuzar M, Law WP, Dimeski G, Stowasser M, Ho KKY. Mineralocorti-
coid antagonism enhances brown adipose tissue function in humans: a
AUTHOR CONTRIBUTIONS randomized placebo‐controlled cross‐over study. Diabetes Obes Metab.
LI contributed to study design and data interpretation, wrote manu- 2019;21(3):509‐516.
script and reviewed/edited manuscript. FdZ contributed to study
design and data interpretation, wrote manuscript and SUPPORTING INFORMATION
reviewed/edited the manuscript. Additional supporting information may be found online in the
Supporting Information section at the end of the article.
ORCID
Lourdes Ibáñez https://orcid.org/0000-0002-5058-1603
Francis de Zegher https://orcid.org/0000-0002-2491-5884 How to cite this article: Ibáñez L, de Zegher F. Polycystic
ovary syndrome in adolescent girls. Pediatric Obesity.
RE FE R ENC E S 2020;15:e12586. https://doi.org/10.1111/ijpo.12586
1. Ibáñez L, Oberfield SE, Witchel SF, et al. An international consortium
update: pathophysiology, diagnosis, and treatment of polycystic ovarian
syndrome in adolescence. Horm Res Paediatr. 2017;88(6):371‐395.