Molecular and Cellular Endocrinology 373 (2013) 6167

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Molecular and Cellular Endocrinology

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Polycystic ovarian syndrome during puberty and adolescence

Rachel M. Williams a, Ken K. Ong b, David B. Dunger a,
a
University of Cambridge Department of Paediatrics, Cambridge, UK
b
MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK

a r t i c l e i n f o a b s t r a c t

Article history: PCOS has reasonably well dened clinical, biochemical and radiological features in adult women, but in
Available online 4 February 2013 the adolescent population, some of these features may overlap with normal puberty leading to difculties
in making a diagnosis. In addition, the rising prevalence of obesity in the paediatric population may com-
Keywords: pound insulin resistance in girls predisposed to ovarian hyperandrogenism leading to younger age of pre-
Adolescence sentation and more severe phenotype. It is important to distinguish between normal puberty and true
Ovarian hyperandrogenism ovarian hyperandrogenism, as well as excluding other causes of androgen excess such as adrenal tumours
PCOS
or non classical congenital adrenal hyperplasia. The long term co-morbidities associated with ovarian
Insulin resistance
Puberty
hyperandrogenism presenting during adolescence are not well dened but there is likely to be increased
cardiovascular risk. There are little data on intervention in the adolescent population and studies in adult
women often focus on ovulation and fertility which are less of a concern to adolescents. Current options
include insulin sensitisation with metformin, anti androgens, or the oral contraceptive pill, with each girl
being treated on an individual basis. There is a requirement for establishment of normative data in ado-
lescence, in conjunction with physiological phenotyping in order to elucidate potential mechanisms thus
informing potential intervention.
2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Until recently, PCOS was rarely diagnosed during adolescence
but with increasing rates of obesity this is no longer the case.
The diagnosis of PCOS is complicated during puberty and adoles-
cence, as some features that are diagnostic in adult women, may
be part of the normal pubertal process. It has been suggested that
the insulin resistance of puberty may drive the development of
PCOS, while others have proposed that it may originate from devel-
opmental exposures in utero and early patterns of childhood
growth. A detailed understanding of the factors that determine
the timing of puberty and the endocrine changes that occur during
puberty will illuminate the challenges of diagnosing and managing
PCOS in adolescent and young adult women.
2. The endocrinology of puberty
Puberty is a period of between 2 and 5 years when individuals
gain around 16% of their mature height and women double their
body weights and lean body mass. Transition through puberty is
often dened by the development of external secondary sexual
Corresponding author. Address: University of Cambridge Dept. Paediatrics,
Box 116, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK. Fax: +44
01223 336996.
E-mail address: dbd25@cam.ac.uk (D.B. Dunger).
characteristics, which in girls are breast and pubic hair develop-
ment. In girls, growth acceleration and peak height velocity occur
early in puberty whereas menarche, the onset of menstrual bleed-
ing, occurs later at around Tanner stage 3 to 4 (Marshall and Tan-
ner, 1969). Even after menarche, regular ovulatory cycles may not
be established for a further two years and further changes in body
composition and bone mass may continue up to age 25 years.
The onset of puberty is characterised by increases in the fre-
quency and amplitude of luteinising hormone (LH) pulses, which
promote oestrogen secretion (gonadarche) and breast budding.
Pubic hair development is a less convincing marker of gonadotro-
phin induced puberty as it may reect adrenal androgen secretion
(adrenarche), which is discussed later in this article. As the ovary
matures, it may pass through a multi-follicular phase before the
development of a dominant follicle and the onset of menstruation
and ovulatory cycles. Circulating oestrogen levels correlate with
ovarian and uterine development and also promote both total body
fat deposition and its gynaecoid distribution. Low concentrations
of oestrogen also prime growth hormone (GH) release which, in
turn, increases generation of the anabolic hormone insulin-like
growth factor-1 (IGF-1). The high levels of growth hormone during
puberty induce a selective muscle insulin resistance and lead to
compensatory hyperinsulinaemia. In turn, high levels of circulating
insulin play a critical role in pubertal growth but are highly rele-
vant in the development of PCOS features. The 2530% decrease
in insulin sensitivity leads to corresponding increases in circulating

0303-7207/$ - see front matter 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mce.2013.01.005
62 R.M. Williams et al. / Molecular and Cellular Endocrinology 373 (2013) 6167
insulin levels and this has key effects on other tissues which re-
main insulin sensitive (Amiel et al., 1991). High insulin levels inhi-
bit post-absorption proteolysis which leads to protein sparing,
estimated to be roughly 1 g/kg/day of fat free mass (Arslanian
and Suprasongsin, 1997). High insulin levels also suppress SHBG
and IGFBP-1 levels, which in turn leads to greater bioactivities of
sex steroids and IGF-1, respectively. This central role of insulin in
the physiological regulation of pubertal development mediates
the nutritional regulation of the tempo of puberty, which is exem-
plied in the extreme by the dramatic effects of anorexia nervosa,
in arresting pubertal development. Other endocrine signals such as
leptin reect insulin bioactivity and directly impact on GNRH pul-
satility and gonadotrophin secretion (Farooqi, 2002).
Testosterone levels also increase in girls during puberty and
likely synergise with growth hormone in promoting lean mass
accumulation and linear growth, however there are few data to
support this hypothesis as most of the studies of testosterone have
been carried out in boys. The source of testosterone in girls is lar-
gely ovarian with parallel increases in androstenedione. The pro-
duction of adrenal androgens such as DHEAS also increases
during puberty, and adrenarche starts even before the dominant
LH pulsatility, which signies the beginning of puberty. Adrenar-
che is characterised by a rise in adrenal androgens at an average
age of 89 years in girls, two to three years before the onset of pub-
erty. The regulation and role of adrenarche is still largely unknown
and has been recently reviewed (Ibanez et al., 2000).
3. The timing of puberty
Accurate identication of the timing of onset of puberty re-
quires longitudinal assessment of physical secondary sexual char-
acteristics or biochemical markers such as LH pulsatility or
oestrogen levels. Menarche is a clearly distinct and is usually accu-
rately recalled even many years later. Therefore age at menarche is
used as a marker of pubertal timing in many observational studies,
and there are clear historical trends towards younger age of men-
arche in many settings. However, age at menarche is a late puber-
tal event, and the measurement of the timing of pubertal onset
relies on other markers such a breast development which is far less
straight-forward. For example, a recent study reported surprisingly
early onset of puberty in US children based on observed breast
development. Conditions other than true puberty can cause or mi-
mic breast development, such as obesity and also the thelarche
variant, where early breast development occurs in the presence
of FSH predominance without increases in LH pulsatility. These
conditions may confound the reliance on clinical examination of
breast development alone, without biochemical conrmation, as
a marker of pubertal onset.
There have been considerable advances in our knowledge of the
inuences of early life factors and genetic factors on the timing of
puberty. There are consistent data showing that rapid early infancy
weight gain is associated with a subsequent more rapid tempo of
growth and early puberty. This rapid pattern of early weight gain
is also associated with childhood and later obesity risk and contrib-
utes to the association between obesity and early pubertal devel-
opment. Interestingly, these associations also show trans-
generational effects as obese mothers who had early menarche to
have offspring who show rapid infancy weight gain and a similar
rapid tempo of growth and pubertal development. Timing of men-
arche is highly heritable and family studies estimate that 6080%
of its variance may be genetic. Recent genome wide association
studies have identied 32 loci associated with menarche age. Many
of these loci are also implicated in obesity risk or energy homeosta-
sis and may be relevant to the development of adolescent PCOS.
4. Developmental origins of PCOS
Over the last 20 years, there has been considerable interest in
the possible perinatal determinants of adult disease, initially dri-
ven by epidemiological studies showing associations between
low birth weight and risks for type 2 diabetes and other metabolic
disease. Those associations have become more complex with high
as well as low birth weight being associated with increased T2D
risk. The mechanisms underpinning such associations remain elu-
sive and there is considerable interest in how prenatal exposures
might alter epigenetic marks on genes that regulate appetite and
insulin secretion and which could persist into adult life. Associa-
tions between size at birth and PCOS are equally complex as stud-
ies have linked low birth with later clinical and biochemical
ovarian hyperandrogenism and high birth weight to the polycystic
ovarian morphology on ultrasound. Animal studies have intro-
duced another dimension demonstrating that foetal exposure to
high androgen levels can lead to a PCOS phenotype in female
offspring.
Several studies have also highlighted the importance of rapid
infancy weight gain and the developmental of insulin resistance
in the early pathogenesis of adolescent PCOS. This pattern of rapid
early growth has been associated with higher DHEAS levels in nor-
mal children, and Ibanez et al. have highlighted the sequence of
low birth weight, postnatal catch-up weight gain, precocious pub-
arche and the development of later ovarian androgenism. Preco-
cious pubarche in girls is dened as the onset of pubic hair
before age 8 years and these girls typically have advanced bone
ages and raised DHEAS levels, indicative of adrenarche. In some
settings, girls with this phenotype, in particular in conjunction
with low birth weight and postnatal rapid catch-up growth, are
prone to progress to ovarian hyperandrogenism, and this sequence
can be reversed with insulin sensitisation with metformin therapy
(Ibanez et al., 2004a). Studies in other settings have highlighted the
importance of insulin resistance during puberty as a precipitant for
ovarian hyperandrogenism in obese girls. The great diversity in
body weight status between these relatively small observational
studies needs to be resolved by larger longitudinal studies in more
diverse settings. Future genetic studies should utilise variants that
lead to altered childhood BMI, androgen production and insulin
sensitivity in order to conrm the causal nature of these pathways
in the development of PCOS. Meanwhile, a consideration of the
early life origins of PCOS might be of relevance to the evaluation
of adolescents presenting with features of PCOS.
5. Diagnosis of PCOS during adolescence
5.1. Clinical presentation
The presentation of PCOS in adolescents often differs from that
in women, who predominantly present with infertility. In one
study, 30% of adolescents with PCOS at age 9 to 17.5 years pre-
sented with menstrual irregularities and 60% with features of
androgen excess including hirsutism, acne and hair thinning
(Roseneld et al., 2000). A review of 70 referrals to a multidisci-
plinary clinic in Wisconsin, USA for evaluation of adolescent PCOS
at mean [range] age 16.2 [1322] yr reported that: 84% were over-
weight or obese [BMI > 85th centile]; 70% were obese [BMI > 95th
centile]; 43% had oligomenorrhoea, 21% had secondary amenor-
rhoea, 70% had acne in 70%, and 60% had hirsutism. The high fre-
quency of overweight in that study is consistent with other
reports in both adult and adolescent populations. Weight gain
and increased fat mass are common in girls post-menarche
(Ahmed et al., 1999) and it has been suggested that this may accen-
tuate the physiological insulin resistance of puberty leading to
 R.M. Williams et al. / Molecular and Cellular Endocrinology 373 (2013) 6167
hyperandrogenism (Lewy et al., 2001). Indeed PCOS is far more
common in obese rather than lean adolescents and the increasing
rates of adolescent obesity may precipitate PCOS in those with ge-
netic or developmental predispositions (Ibanez et al., 1993).
The physical characteristics of PCOS are diametrically opposed
to those seen as desirable by adolescent girls, and therefore PCOS
often has the associated psychological burden of anxiety, low
self-esteem and depression (Laggari et al., 2009). Importantly,
interventions such as cognitive behavioural therapy may reduce
depression scores and improve quality of life (Rofey et al., 2009)
and in addition to the biological sequelae, the potentially treatable
psychological impact of PCOS should not be underestimated.
5.2. Diagnostic criteria
NIH diagnostic criteria for PCOS in women requires the pres-
ence of clinical or biochemical hyperandrogenism in conjunction
with oligo-or anovulation (Zawadzki and Dunaif, 1995). The
Androgen Excess Society denition of PCOS requires hyperandrog-
enism plus either oligo/anovulation or polycystic ovary appearance
on ultrasound (Azziz et al., 2009). The Rotterdam criteria are per-
haps the most heterogeneous, requiring any 2 out of 3 of hyperan-
drogenism, oligo/anovulation and polycystic ovary appearance on
ultrasound (PCOS, 2004).
With those criteria in mind, the diagnosis of PCOS in adolescent
girls in the rst years post menarche is complicated by the fact that
the phenotypic criteria, hyperandrogenism and oligomenorrhoea
may be normal features at this age, and multiple ovarian cysts
are commonly seen on ultrasound (Fig. 1).
The three main diagnostic components in adults will now be
discussed individually from the adolescent perspective.
5.2.1. Oligo-or anovulation
When considering the appropriateness of oligo-or anovulation
as one of the diagnostic criteria for adolescent PCOS, there must
Fig. 1. Diagnostic components of polycystic ovary syndrome (PCOS) with associ-
ated co-morbidities.
63
be appreciation of what is normal at this stage of development
(Diaz et al., 2006; Hickey and Balen, 2003). Particularly in the rst
2 years from menarche, anovulation and irregular menstrual cycles
are common (Apter and Vihko, 1985). Three years post menarche
59% of cycles may remain anovulatory, with regular cycles being
established more quickly (at about 3 years) in those girls with ear-
lier menarche (Vihko and Apter, 1984). Features of the menstrual
cycle in the rst 2 years after menarche in US (Diaz et al., 2006)
and UK (Hickey and Balen, 2003) girls are similar and are summa-
rised in Table 1. By the third year post menarche, cycle length is be-
tween 21 and 34 days in the majority of girls (Hickey and Balen,
2003). Thus, in the evaluation of the menstrual cycle of girls up
to 2 years from menarche an irregular cycle with a long intermen-
strual interval is not necessarily abnormal. However, in a longitu-
dinal study of Dutch adolescents recruited from the general
population, 50% of those girls with oligomenorrhoea at age
15 years still had oligomenorrhoea at 18 years in association with
higher BMI, biochemical features of PCOS (raised androgens and
LH) along with polycystic ovary appearance on ultrasound (van
Hooff et al., 2004). This suggests that a signicant proportion of
adolescents with early menstrual irregularity do have, or will de-
velop PCOS by adult criteria. The challenge is to distinguish be-
tween the two groups.
Recent work published from the Raine cohort (a predominantly
Caucasian population in Australia) reports the prevalence of fea-
tures of PCOS in 244 healthy post-menarchal girls aged between
14 and 16 years. The denition of menstrual irregularity was <21
or >35 days in duration, or a cycle length that varied by more than
4 days on prospective recording (Treloar, 1981). Interestingly, in
these unselected girls, 51.7% met the criteria for menstrual irregu-
larity at recruitment, with 8% reporting absent menses for >60 days
and one girl for >90 days. Furthermore menstrual irregularity was
not particularly related to other features of PCOS such as hyperan-
drogenaemia or polycystic ovarian morphology on ultrasound
(Hickey et al., 2011). In summary, over 50% of healthy adolescents
may full the requirement for menstrual irregularity and thus be
half-way to the diagnosis of PCOS by the NIH or Rotterdam criteria.
5.2.2. Ovarian appearances on ultrasound
The best resolution for ultrasound imaging of the ovaries is
achieved either trans-vaginally or trans-rectally, which are highly
inappropriate in the adolescent girl. Trans-abdominal ultrasound
imaging may be further compromised in obese girls even when
performed by skilled and experienced personnel. During adoles-
cence 26% of ovaries having a multicystic appearance, and this is
therefore a physiological feature consistent with normal pubertal
maturation (Bridges et al., 1993; Venturoli et al., 1995). In addition
to a multicystic appearance, increased ovarian volume is further
support for a diagnosis of PCOS in adult women (Jonard et al.,
2005). However, there are only limited normative data on ovarian
volume in adolescence. In 40 normal premenarchal girls up to the
age of 14, mean ovarian volume was approximately 2 cm3 (Stan-
hope et al., 1985). 35% of girls in the population-based Raine cohort
Table 1
Characteristics of the menstrual cycle in healthy girls from the United States and
Europe in the rst 2 years following menarche.
Diaz et al. Hickey and Balen
(2006) (2003)
Age at Menarche (yrs) 12.4 1213
Menstrual cycle interval (days) 2145 2145
95th centile for cycle interval (days) 90 90
Menstrual ow length (days) <7 27
Number of changes of sanitary 36 per day 36 per day
protection
64 R.M. Williams et al. / Molecular and Cellular Endocrinology 373 (2013) 6167
(Hickey et al., 2011). met the criteria for polycystic ovary appear-
ance on trans-abdominal ultrasound (P1 ovary with vol-
ume >10 cm3) or 12 or more follicles with diameter 2 to 9 mm)
(Balen et al., 2003). Median (IQR) ovarian volume was 6.7 (4.9
8.4) cm3 indicating that ovarian volume might be increased in ado-
lescents. Other reported ultrasound data are taken from adoles-
cents with features of PCOS, so do not represent normal
references. Increased ovarian volume (dened as > 10 cm3) is seen
in 43% of girls (aged 1018 years) with a diagnosis of PCOS (Shah
et al., 2009). Increased ovarian volume has also been reported in
the daughters of women with PCOS in comparison to healthy con-
trols (Sir-Petermann et al., 2009). Interestingly, it is not until these
girls reach Tanner stage 5, that their ovarian volume is abnormal
by adult standards (mean volume 13.9 [SD 4.4] cm3 vs. 6.9 [3.9]
in control girls (Sir-Petermann et al., 2009). Prospective study of
ovarian morphology and volume in healthy girls throughout pub-
erty and into early adulthood would be helpful in order to provide
normative data for each stage of puberty, although it would still
not address the technical difculties.
5.2.3. Biochemical hyperandrogenism
Puberty is associated with rapid changes in pituitary, gonadal
and adrenal hormone levels and there is a paucity of robust norma-
tive data. Longitudinal data from a cohort of British girls is given in
Table 2 (Lynn Ahmed, PhD thesis, 2009) and demonstrate the stea-
dy rise in androgen concentrations coupled with a fall in SHBG dur-
ing puberty.
Puberty is also associated with a physiological increase in insu-
lin resistance with compensatory hyperinsulinaemia (Caprio et al.,
1989). The interpretation of indices of insulin resistance such as
fasting insulin may be difcult as an apparent elevation in fasting
insulin concentration may reect a physiological rather that path-
ological insulin resistance (Caprio et al., 1989).
It is also important to consider the validity of laboratory andro-
gen assays. Most clinicians would dene biochemical hyperan-
drogenism as a testosterone concentration >2 SD above the mean
for a normal population. In adult women, a testosterone concentra-
tion above 1.9 nmol/l (56 mg/dl) is often used. For Tanner stage 5
girls, however, the upper limit of the interquartile range is
1.6 nmol/l, indicating that the adult cut-offs may not be applicable
to the adolescent population (Table 2). In adolescent girls, we are
in need of population-based normative data at each stage of pub-
erty before elevated androgen concentrations can be conrmed
with any certainty. Furthermore, raised total androgen concentra-
tions do not necessarily reect levels of bio available free andro-
gens. The physiological rise in insulin resistance and circulating
insulin concentrations during adolescence leads to reductions in
concentrations of sex hormone binding globulin (SHBG) Table 2,
and this results in relatively greater increases in the proportion
of unbound, or biologically active androgens.
Contemporaneous reference data from the Raine cohort show
that median total testosterone was 1.2 nmol/l, similar to that
shown at Tanner stage 5 in Table 2 (Hickey et al., 2011).
Table 2
Longitudinal concentrations of androgens and SHBG in healthy British girls (n = 27) by Puberty [Tanner] Stage. Data expressed as median (IQR). Reproduced with permission from
Ahmed (2008).
Tanner stage
1 2
Age (yr) 10.2 (9.610.7) 11.4 (10.511.9)
Testosterone (nmol/l) 0.3 (0.30.5) 0.3 (0.30.8)
SHBG (nmol/l) 66 (5694) 57 (4869)
DHEAS (mcmol/l) 3.5 (2.45.2) 5.1 (2.47.5)
A4 (nmol/l) 3.3 (2.74.0) 4.2 (3.44.8)
In addition to biochemical hyperandrogenaemia, the determi-
nation of serum anti mullerian hormone (AMH), which is released
by the ovarian granulosa cells, has recently been proposed as a as a
marker for follicular count and PCOS in adult women (La Marca
et al., 2006). Higher concentrations of AMH in comparison to con-
trols have been demonstrated in girls born to mothers with PCOS
both in infancy and pre-pubertally (47 years), which may suggest
that follicular development is altered in this population (Sir-Peter-
mann et al., 2006) as early as infancy. Prior to recommending this
as part of the biochemical work up for PCOS in adolescents, ade-
quate longitudinal reference data throughout childhood and pub-
erty in is required.
5.3. Summary
In summary, the currently accepted criteria for the diagnosis of
PCOS are based around adult women, who tend to present with dif-
ferent concerns and expectations. Furthermore, the PCOS criteria in
adult women may include normal features in adolescent girls lead-
ing to over diagnosis in this age group. In the Raine cohort, 21% of
girls would have met Rotterdam criteria for the diagnosis of PCOS
(using HA dened as the highest 10% of free testosterone concen-
trations). Whilst many of these girls may be normal, a number of
them may indeed have PCOS with the accompanying disease asso-
ciations that are so well described in adult women. Some authors
argue that a diagnosis of PCOS should not be made before the
age of 18 in order to minimise inappropriate labelling of normal
adolescent physiology with a condition that raises concerns of
infertility along with cardiovascular and metabolic co-morbidities
(Shayya and chang, 2010). The most recent consensus statement
advocates that a formal diagnosis of PCOS should not be made until
2 years after menarche (PCOS, 2004; Fauser et al., 2012). Other
authors advocate that in the adolescent population, all three of
the Rotterdam criteria should be present (Carmina et al., 2010)
however without good normative data for the biochemical compo-
nents of the triad, it is difcult to address biochemical
hyperandrogenism.
However, in many adolescents, PCOS features are persistent and
treatment may both alleviate acute symptoms and modify later
disease risks. Clinical trials in Barcelona have demonstrated that
early intervention with insulin sensitisers and androgen blockade
in low birth weight girls presenting with premature pubarche pre-
vent progression to a PCOS phenotype post menarche (Ibanez et al.,
2004a, 2004b). The challenge then is to distinguish girls with nor-
mal physiological changes from those with signicant pathology
and the burden of associated disease risks. Clear diagnostic criteria
for PCOS specic for the adolescent population are required along
with references that describe the ranges of normal variation. A fo-
cus on biochemical HA may be the most discriminating, but further
studies are required in order to ascertain the abilities of such crite-
ria to predict risks of persistence and progression to adult PCOS
and to responses to treatment. If those adolescents with a true
PCOS phenotype could be distinguished from those with normal
pubertal physiology, in theory they could receive targeted inter-
3 4 5
12.2 (11.612.8) 13.2 (12.613.8) 14.9 (14.215.2)
0.8 (0.51.1) 1.1 (0.81.5) 1.4 (1.11.6)
57 (4071) 45 (3466) 43 (3361)
6.8 (4.59.6) 7.0 (4.610.0) 12.1 (9.017.7)
5.8 (5.17.9) 6.1 (5.77.5) 8.7 (7.411.3)
 R.M. Williams et al. / Molecular and Cellular Endocrinology 373 (2013) 6167
vention in order to minimise risks of long-term co-morbidities
such as the metabolic syndrome and infertility. Therefore in addi-
tion to research that informs regarding identication of at risk
girls, there must be longitudinal follow up to determine risk of
co-morbidities. Finally, there is a requirement for adequately pow-
ered randomised controlled trials in well-characterised cohorts to
evaluate safety and efcacy of any intervention in the short, med-
ium and long term.
6. Treatment
As is seen in adults with PCOS, many adolescents presenting
with features of PCOS are obese. Obesity exacerbates insulin resis-
tance, and further reduces SHBG, compounding hyperandrogena-
emia. In the obese adolescent, where adherence is achieved,
lifestyle and dietary modications are the rst line of treatment
and can be effective in weight loss and the restoration of menses,
at least in the short term (Ornstein et al., 2011). Lifestyle and exer-
cise alone leads to reductions in biochemical hyperandrogenism in
adolescents with PCOS (Hoeger et al., 2008). However, rapid
weight gain often occurs once the intervention period is over (Tang
et al., 2009) and poor adherence to lifestyle programmes in the
long term means that results are often disappointing in all but
the most motivated girls (Reinehr et al., 2009).
6.1. The oral contraceptive pill
The primary aim of treatment with the oral contraceptive pill
(OCP) in PCOS is to restore cyclical menses. In addition, combina-
tion of Ethinyl Estradiol (EE) with the anti-androgen drospirenone
(EE/D) may improve symptoms of HA. However, there are concerns
around reports suggesting that OCP use may increase insulin resis-
tance, which is particularly undesirable in PCOS. Effects of OCPs on
insulin resistance vary, probably reecting differences between
preparations, assay variability and the many available derived indi-
ces of insulin sensitivity. In non-hyperandrogenic women, even
OCPs containing low dose oestrogens (2035 lg) and less andro-
genic progestins may adversely affect insulin resistance and glu-
cose tolerance (Teede et al., 2008). Drospirenone containing OCPs
have been shown to reduce hyperandrogenism but worsen indices
of insulin resistance and central adiposity in lean adolescents with
PCOS (Ibanez and de Zegher, 2004). A recently published clinical
trial from US compared 6 months treatment with EE/D and the
thiazolidinedione rosiglitazone (Tfayli et al., 2011). In the EE/D
arm, concentrations of total cholesterol and the cardiovascular risk
marker hsCRP increased despite favourable effects on biochemical
HA (Tfayli et al., 2011). In a randomised trial of metformin versus
the OCP in obese (mean BMI 39 kg/m2) hyperinsulinaemic girls,
the OCP alone resulted in weight loss, reductions in concentrations
of androgens and increased insulin sensitivity which was commen-
surate with the degree of weight loss this making it difcult to dis-
tinguish between a direct effect of the OCP or a secondary effect of
the associated weight loss (Allen et al., 2005).
OCPs in combination with the anti androgen, cyproterone ace-
tate, are commonly used in UK girls with HA but there has been lit-
tle formal evaluation of their efcacy. 3 studies, all from the same
group have reported effects of cyproterone acetate treatment in
adolescents with PCOS. The rst compared 12 months treatment
with either desogesterol or cyproterone acetate both combined
with ethinyl estradiol in 24 young women (aged 1419 years) with
PCOS. Menses were restored and hirsutism decreased in both
groups, with benecial decreases in both total and LDL cholesterol
and increase in HDL-C, but also a rise in triglyceride levels, in the
cyproterone arm (Creatsas et al., 2000). The second study was sim-
ilar both in design and results, reporting an increase in triglyceride
65
concentrations in the cyproterone acetate group (Mastorakos et al.,
2002). The third reported increased insulin resistance in the cypro-
terone acetate group (Mastorakos et al., 2006). Thus cyproterone
acetate containing OCPs may provide symptomatic relief in PCOS
but may have undesirable effects on lipid metabolism and insulin
sensitivity (Creatsas et al., 2000; Mastorakos et al., 2002, 2006).
Very rarely, liver toxicity has been described with cyproterone
acetate and liver function tests should be monitored 6 monthly
when it is used (Thole et al., 2004). In general, OCP preparations
should be avoided in women at high risk of thromboembolism
and some have argued that there is an increased risk of thrombo-
embolism in women taking cyproterone acetate preparations com-
pared to those taking OCPs containing levonorgestrol or
norethisterone (Martinez and Avecilla, 2007; Seaman et al.,
2003). Reports from larger data sets however are more reassuring
(Franks et al., 2008; Seaman et al., 2004).
In some countries, combined OCP preparations containing
cyproterone acetate are licensed for the treatment of androgen ex-
cess, but not for contraception (although they do function as reli-
able contraceptive agents) and thus use should be limited to
those in whom HA is the predominant presenting feature. As with
all prescription drugs, prescribing should follow guidance of the
relevant local authority.
6.2. Metformin
There is much evidence that PCOS is primarily a disorder of
insulin resistance (Goodarzi et al., 2011). As such, insulin sensiti-
sation with metformin seems a logical intervention. The effect of
metformin in adolescent girls with PCOS has been assessed in both
obese and non-obese populations. In obese PCOS girls with im-
paired glucose tolerance, metformin (850 mg/twice daily for three
months), improved glucose tolerance, insulin sensitivity and re-
duced androgen concentrations (Arslanian et al., 2002). In combi-
nation with lifestyle intervention, metformin resulted in modest
weight loss with restoration of menses, increased insulin sensitiv-
ity and improvements in lipid proles (Glueck et al., 2006).
A randomised, double-blind placebo controlled trial conducted
in 22 adolescent girls (aged 1318 years) with PCOS, compared
12 weeks treatment with metformin (750 mg twice daily) versus
placebo combined with lifestyle counselling; metformin effectively
reduced HA and restored cyclical menses. HDL cholesterol also in-
creased in the metformin arm but there were no discernable effects
on parameters of insulin sensitivity derived from an oral glucose
tolerance test (Bridger et al., 2006).
Ibanez and de Zegher have conducted a series of trials demon-
strating that treatment with metformin corrects insulin resistance,
dyslipidaemia and hirsutism, and establishes regular menses in
Catalan girls presenting with precocious pubarche (Ibanez et al.,
2000).
6.3. Thiazolidinediones (TZDs)
The TZDs are insulin sensitising drugs, which bind the orphan
PPAR gamma receptor. In adult women, treatment with TZDs leads
to the establishment of regular menses along with clinical and bio-
chemical reductions in hyperandrogenism (Azziz et al., 2003; Rau-
tio et al., 2006; Garmes et al., 2005; Dunaif et al., 1996). However,
TZDs are contraindicated in pregnancy and therefore should not be
used where pregnancy is a possibility, which is a concern because
treatment can improve fertility. Ibanez and de Zegher have pub-
lished the results of up to 24 months treatment with Pioglitazone
in non-obese young women (aged 19 years) with hyperandroge-
nism exploring the effects of combination therapy with a TZD, u-
tamide, metformin and a transdermal combined contraceptive
preparation, They report improvements in insulin sensitivity and
66 R.M. Williams et al. / Molecular and Cellular Endocrinology 373 (2013) 6167
cardiovascular risk factors such as visceral fat and intima-media
thickness (Ibanez et al., 2007, 2009, 2008). A recent RCT in obese
adolescents with PCOS reported that rosiglitazone had more
favourable effects on insulin sensitivity and biomarkers for cardio-
vascular risk than treatment with EE/D. However, EE/D was more
effective in restoring cyclical menses and reduction in HA (Tfayli
et al., 2011). Recently however, there have been concerns raised
about the safety proles of several of the thiazoladinediones, most
recently cardiovascular disease risk in patients using rosiglitazone.
As such, their use in adolescents with PCOS is not recommended.
6.4. Anti androgens
In addition to cyproterone acetate, other anti-androgens have
been studied in PCOS adolescent girls. Spironolactone inhibits 5
a reductase other enzymes involved in androgen biosynthesis
and has been used in the treatment of hirsutism associated with
PCOS. In adolescents and young women (mean age 22 years) with
PCOS, 6 months treatment with Spironolactone (50 mg/day) was as
effective as metformin at improving glucose tolerance in addition
to reducing hyperandrogenaemia (Ganie et al., 2004). There ap-
peared to be fewer side effects from spironolactone, but it was
an open label design. Flutamide is a non-steroidal androgen recep-
tor blocker mainly used to treat prostate cancer (Sciarra et al.,
2004). In adolescents with PCOS 4 weeks treatment with Flutamide
250 mg/day led to reductions in hirsutism score, free androgen in-
dex, testosterone and androstenedione concentrations with in-
creases in concentrations of SHBG. Effects on the menstrual cycle
and metabolic parameters were less impressive (Ibanez et al.,
2000). Concerns about Flutamide have been raised regarding hep-
atotoxicity but this appears to be dose dependent, having been pre-
dominantly described in men being treated at much higher doses
(total daily dose of 750 mg per day) for prostate cancer (Thole
et al., 2004). Liver enzyme monitoring with doses of 62.5 mg to
250 mg per day of Flutamide for a mean duration of 19 months
has recently been reported, with no evidence of elevation of liver
enzymes in an adolescent population (n = 190) Ibanez et al., 2005.
6.5. Summary
In summary, a number of options for treatment of PCOS features
in the adolescent are available., In addition, beyond the effective
alleviation of current symptoms, a number of high quality trials
have recently described persisting metabolic and body composi-
tion benets of some treatments, which contrasts with the some-
what disappointing long-term results of lifestyle intervention.
However, the evidence base is still small. In particular, these stud-
ies have yet been carried out only in selected populations and the
potential benets of targeted intervention in well-dened patient
groups need to be conrmed in more heterogenous settings. Mean-
while, a pragmatic approach should be taken, considering each girl
individually and addressing the specic PCOS features that cause
them distress. Lifestyle intervention should be the rst option
especially in those girls who are overweight. Thereafter, use of
the OCP to achieve regular menses or anti-androgens to address
HA may be benecial. Interventions with insulin sensitising agents
such as metformin may be of help particularly in those girls with
clinical and biochemical evidence of insulin resistance.
7. The way forward
Adolescent girls are increasingly presenting with specic PCOS
features and various treatments are being used. Many of these
PCOS features are normal or are exaggerated components of puber-
tal development. Adult diagnostic criteria for PCOS are therefore
not appropriate and may risk inappropriately labelling of healthy
girls. There is a need for representative population-based reference
data on the clinical, biochemical and radiological measures at.each
developmental stage in order to distinguish pathological condi-
tions from physiological changes.
So do we need separate consensus diagnostic criteria for adoles-
cent PCOS? This debate should not simply be driven by the recog-
nition of adolescent-specic normal references, but rather should
be based on the utility of such criteria to identify those girls who
are at longer-term risks for adult PCOS and related metabolic co-
morbidities. Possible factors could include not only clinical and
biochemical assessment of hyperandrogenism and and insulin
resistance, but should also consider the potential contributions of
history of low birth weight and the ages at adrenarche, gonadarche
and menarche. Criteria that identify those girls who will respond to
insulin sensitisation therapy would also be benecial to guide fu-
ture appropriate targeted of treatment.
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