Best Practice & Research Clinical Endocrinology & Metabolism

Vol. 20, No. 2, pp. 311330, 2006

doi:10.1016/j.beem.2006.02.002
available online at http://www.sciencedirect.com

12

Treatment of PCOS in adolescence

Julia Warren-Ulanch* MD
Adult and Pediatric Endocrinology Fellow, University of Pittsburgh Medical Center
Silva Arslanian MD
Professor of Pediatrics, University of Pittsburgh School of Medicine; Director, Weight Management and
Wellness Center; and Director, General Clinical Research Center
Division of Endocrinology, University of Pittsburgh Medical Center, Childrens Hospital of Pittsburgh, 3705 Fifth Avenue,
Pittsburgh, PA 15213-2583, USA

Polycystic ovary syndrome (PCOS) is increasingly being recognized in adolescent girls seeking
treatment for signs and symptoms of hyperandrogenism. It is difficult to diagnose PCOS in
adolescents, therefore a high index of suspicion is necessary. Timely screening and treatment are
crucial because another important component of the syndrome is insulin resistance/hyper-
insulinemia increasing the risk for type 2 diabetes, dyslipidemia, and cardiovascular sequelae.
Diagnosis of PCOS in adolescents should include a thorough family history, exclusion of other
causes of hyperandrogenism, and appropriate laboratory evaluation. The scarcity of controlled
clinical trials makes treatment controversial. Therapeutic options include lifestyle intervention,
oral contraceptive pills, and insulin sensitizers. Long-term follow-up is needed to determine the
effectiveness of these approaches in changing the natural history of the reproductive and
metabolic outcomes without causing undue harm.

Key words: adolescent; polycystic ovary syndrome; therapeutics; insulin resistance;

hyperandrogenism.

The old adage kids are not little adults applies yet again with regard to polycystic ovary
syndrome (PCOS). The classic signs and symptoms of chronic anovulation and
otherwise unexplained hyperandrogenism is not as easily applied in adolescents. In
addition, while adult women suffering from PCOS are concerned about infertility and
pursue treatment with that in mind, adolescents are more worried about their weight,
heavy and irregular menses, acne, and hirsutism. As PCOS adversely affects quality of
life in adolescence1,2, and the natural history includes increased morbidity, it is
important to recognize, diagnose, and treat adolescents with PCOS as early as possible.

* Corresponding author. Tel.: C1 412 692 7466; fax: C1 412 692 5834.
E-mail address: warrenulanchjg@upmc.edu (J. Warren-Ulanch).

1521-690X/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved.
312 J. Warren-Ulanch and S. Arslanian

Here, we will describe clinical presentation, differential diagnosis, and treatment

modalities in the adolescent setting. We will also address special treatment
considerations for adolescents, such as dosing, duration of therapy, changing or
addition of therapies, and consequences of therapies.

CLINICAL PRESENTATION

At a conference in 1990 held by the National Institute of Child Health and Human
Development, the diagnostic criteria for PCOS3 were established as chronic
anovulation and hyperandrogenism after exclusion of other causes. These criteria
were meant for adult women, without any consideration for the adolescent age
group. Although, it has been said that the clinical manifestations are similar in
adolescents and adults4,5, the anovulation and hyperandrogenism that define PCOS3
do not always adequately characterize the adolescent with PCOS. Even by the third
year after menarche in normal females, 59% of cycles remain anovulatory.6
Moreover, the identification of hyperandrogenemia during the different Tanner
stages of pubertal development is complicated by the lack of well-defined cut-off
points for androgen levels during pubertal maturation. Nonetheless, the common
presentations still include anovulatory symptoms and hyperandrogenism. The 2003
Rotterdam consensus workshop added polycystic ovary morphology as a third
possible criterion for PCOS, and recommended that two out of three suffice to
make the diagnosis.7 Yet again, there were no considerations given to the adolescent
age group. Furthermore, the recommendation of transvaginal ovarian ultrasound
raises major concerns about its practical and ethical applicability in a younger
population, especially in the complete absence of data in this age group. The picture
is further clouded by the fact that multicystic or polycystic ovarian morphology is a
feature of physiologic puberty which subsides with onset of regular menstrual
cycling.8

Anovulatory symptoms

Approximately 66% of adolescents with PCOS will have, and a third will present
with, anovulatory symptoms.4 These may be on a spectrum ranging from primary or
secondary amenorrhea, oligomenorrhea (%6 cycles/year), anovulatory cycles
signified by absence of cramping or scant flow, to dysfunctional uterine bleeding
with heavy, frequent, painful periods. Symptoms may take up to 3 years post-
menarche to present.9 However, early menstrual pattern is predictive of late
menstrual pattern; in a nested case-control study of adolescents, over 50% of
oligomenorrheic 15-year-old girls remained oligomenorrheic at age 18.10 Therefore,
it is appropriate to evaluate oligomenorrhea that persists 2 years beyond menarche
as an early clinical sign of PCOS.11 However, to underscore the variability of this
component of the syndrome, a study of 18 adolescents with hyperinsulinemic
hyperandrogenism, documented to be anovulatory with low (!4 ng/mL) serum
progesterone levels, included four amenorrheic, nine oligomenorrheic, and five
eumenorrheic subjects.12 So, even regular menses may not signify regular ovulation.
Furthermore, the criterion of anovulation is problematic for the diagnosis of the
syndrome in pre-menarchal hyperandrogenic girls.
 Treatment of PCOS in adolescence 313

Hyperandrogenism

Clinical hyperandrogenismsuch as acne, hirsutism, or male-pattern baldnessis

present in about 66% of adolescents with PCOS. Similar to anovulatory symptoms,
these will be the presenting complaints in one third. Hirsutismterminal, coarse, dark
hair on the face, back, abdomen, inner thighs, or chestmust be carefully distinguished
from hypertrichosis, which has a non-sexual pattern of distribution (i.e. arms, legs, low
hairline). In adolescents, the leading cause of hirsutism is PCOS.13 Other symptoms of
hyperandrogenism include inflammatory/cystic acne, seborrhea, male-pattern baldness
or hair-thinning, and hyperhydrosis.9 However, these more convincing signs and
symptoms of androgen excess may not have yet developed in the adolescent stages of
PCOS, and absence of these symptoms should not exclude PCOS from consideration.

Obesity

The majority of adolescents with PCOS are overweight or obese, defined as body mass
index (BMI) greater than the 85th percentile for age and gender. Obesity can be the
presenting symptom as frequently as anovulatory symptoms and hyperandrogenism. In
fact, the most common endocrine obesity syndrome in adolescent females is PCOS.9
This is noted world-wide, as a study in Singapore found the prevalence of obesity
(weight O120% of ideal body weight) amongst adolescents with PCOS to be 27%.14
The weight has an android distribution, with waist-to-hip ratios O0.85. Even non-obese
adolescents with PCOS have been found to have twice as much abdominal fat as the
reference population.15 While this type of obesity correlates highly with hyperan-
drogenemia16, it is the overall BMI that correlates with insulin resistance. The insulin
resistance manifests as acanthosis nigricans: velvety, thickened, hyperpigmented skin
around the neck, in the axilla, over the knuckles, and intertriginous areas and skin tags.
This finding may be a presenting sign of PCOS9, but is present in obesity as well.17
Another characteristic of the obesity seen in patients with PCOS is the anecdotal
observation of recalcitrance to efforts at weight loss.

NATURAL HISTORY

Although studies are limited and controversial, there is suggestive evidence that in
some cases PCOS may begin in utero, with initial presentation as low birth weight. In
childhood, these patients appear to have rapid catch-up growth that may lead to obesity
or pre-mature pubarche. When they reach adolescence, the anovulatory symptoms
and hyperandrogenism may become apparent. As early as this, metabolic abnormalities
and increased cardiovascular risk factors are detected. In adulthood, infertility,
cardiovascular dysfunction, and type 2 diabetes are primary concerns. Of particular
interest are studies showing prevention of this natural progression after early, pre-
pubertal treatment with metformin.18 All of these studies are consistent with the idea
that PCOS is a life-long disorder19,20 and may be a result of thrifty genes.21

Small for gestational age (SGA)

PCOS may manifest as early as birth, presenting as low birth weight. In a study of 102
girls with precocious pubarche (PP; presence of pubic hair before the age of 8)
314 J. Warren-Ulanch and S. Arslanian

compared with 83 matched controls, androgen levels were significantly higher and
birth-weight standard deviation scores were lower in PP.22 This study was followed up
with an evaluation of the 3-month ovulation rate of 25 adolescents born SGA compared
with 24 born average for gestational age (AGA). Ovulatory cycles, as determined by
daily fingerstick progesterone levels, were 36% higher in AGA than SGA. Also, 4% of
AGA girls were anovulatory as opposed to 67% of the SGA girls.23 The recently
popularized fetal origins of adult disease is proposed to be driven by insulin resistance
provoked by fetal growth restraint.2427 Even in healthy pre-pubertal children, birth size
was found to be associated with abdominal fat excess in the presence of excessive post-
natal weight gain in Australian children.28 A retrospective chart review of 79 girls and 10
boys with PP found that one quarter were born pre-maturely and 35% were small for
gestational age, both more frequent than in the general population. As SGA and pre-
maturity were associated with PP, they proposed that PP could be a marker of
hyperinsulinism.29 However, not all populations describe this phenomenon. A Finnish
study of over 500 women with PCOS noted no association with low birth weight.30
Moreover, a French study of young women130 with intrauterine growth retardation
versus 150 control women with normal birth weightshowed no differences in
circulating androgen levels.31 In our clinical experience, adolescents with PCOS and a
history of low birth weight are the exception rather than the rule. Thus, the question of
whether or not PP or hyperandrogenism is programmed in utero remains unresolved.

Precocious pubarche

A retrospective review of the clinical course of girls with PP revealed that 45%
developed functional ovarian hyperandrogenism at the time of puberty.32 In a limited
study of 33 non-obese pre-pubertal girls (mean age 8 years) with a history of PP and low
birth weight (%2.7 kg), compared with 24 reference girls, the former had higher levels
of testosterone, low-density lipoprotein (LDL) cholesterol, triglycerides, and total body
and abdominal fat mass.32 Additionally, they demonstrated lower levels of high-density
lipoprotein (HDL), sex hormone binding globulin (SHBG), adiponectin, and insulin
sensitivity measured by homeostasis model assessment (HOMA). It was proposed that
these abnormalities were consistent with a pre-PCOS state. However, it remains to be
determined whether differences in body adiposity and fat topography between the two
groups could have been responsible for the observed hormonal and metabolic
differences. When 17 of this original group were followed for another 6 months, their
body composition and biochemical profile continued to worsen.33 It is our clinical
experience that obese girls with PP and advanced bone ages are at higher risk for
progression to PCOS than their thin counterparts. Long-term, well-controlled
longitudinal studies including careful measurements of hormonal and metabolic
parameters, measures of total body and visceral adiposity, assessment of bone age
maturations, and insulin sensitivity are needed to investigate the natural history of PP.
Careful attention should also be given to different ethnic populations, since racial/
genetic background may explain some of the different observations reported in the
literature.

Obesity

A United States study of over 17,000 girls showed a marked increase in BMI Z-score for
69-year-old Caucasian girls pre- and post-pubertally. Moreover, higher BMI Z-scores
 Treatment of PCOS in adolescence 315

were seen in those with pubarche than in those without any evidence of sexual
maturation, demonstrating the important role of obesity in earlier onset of pubarche
and puberty in girls.34 Both in the literature and in our experience, a history of weight
gain frequently precedes the onset of hyperandrogenism and anovulatory symptoms,
suggesting a pathogenic role of obesity in PCOS.35 Actually, the highest dehydroepian-
drosterone sulfate (DHEAS) increases occur concurrently with the largest BMI
increases, suggesting that marked weight gain might be causal in the development of PP
and subsequent manifestations of PCOS in predisposed girls.36 A Finnish study
demonstrated that weight at age 14 and subsequent 17-year weight course was the
strongest predictor of future hormonal and metabolic abnormalities.37 The association
between obesity and PP has also been described in children in the US38 and Australia.29
A study of lean versus obese adolescents with PCOS found more pronounced
abnormalities in the hypothalamicpituitaryadrenal axis in the lean group, but worse
metabolic abnormalities and insulin resistance in the obese group.17 Furthermore, it
appears that the obesity aspect of PCOS explains the lower health-related quality of life
seen in adolescents.2 It is tempting to speculate that the obesity epidemic afflicting children
worldwide may not only expose the rest of the PCOS iceberg but may also worsen the
hormonal, metabolic, cardiovascular and psychological consequences of PCOS.

Metabolic, inflammatory, and cardiovascular abnormalities in adolescents

with PCOS

As the natural history of PCOS includes high risk for type 2 diabetes mellitus, several
investigators have sought out, and found, metabolic abnormalities in adolescents with
PCOS (Figure 1). The spectrum includes hyperinsulinemia/insulin resistance, diabetes,
altered body composition, dysadipocytokinemia, and inflammation. Although these are
in and of themselves alarming, the findings of early cardiovascular disease markers are
perhaps of most concern.

Insulin resistance, hyperinsulinemia, and impaired glucose tolerance

Fasting insulin levels are twice as high in obese, hyperandrogenic adolescents compared
with controls.39,40 Insulin levels in responses to intravenous glucose and mean 24-hour
insulin levels were similarly elevated, even after adjusting for BMI.39 The insulin
resistance of PCOS was isolated from that conferred by obesity when our group40
compared obese adolescents with PCOS to body composition and visceral adiposity-
matched controls using hyperinsulinemiceuglycemic and hyperglycemic clamp
experiments. In vivo peripheral insulin sensitivity was w50% lower in the PCOS
group and was compensated by a 1.5-fold higher first-phase insulin secretion.
A surrogate measure of insulin resistancethe ratio of fasting glucose-to-insulin of
!4.541has been used in adults, but cut-offs in adolescence, a time of physiologic
insulin resistance42, are less specific. Reported levels range from !7 to !1.9.40,43,44
However, in a Greek study of adolescents with biochemical hyperandrogenism and
chronic anovulation45, all participants had glucose/insulin ratios O7. These discrepant
findings stem from the fact that the insulin assay is not standardized across laboratories,
and even the same assay gives different results in different centers as demonstrated by
the American Diabetes Task Force on standardization of the insulin assay.46 Another
factor to consider when using fasting glucose-to-insulin ratios is the unreliability
introduced when abnormalities in glucose tolerance and insulin deficiency develop.
Therefore, we recommend that investigators validate surrogate estimates of insulin
316 J. Warren-Ulanch and S. Arslanian

Figure 1. Abnormalities in adolescent polycystic ovary syndrome (PCOS) and proposed potential solutions.
The abnormalities in PCOS can be broken down into three parts: reproductive, metabolic, and pro-
inflammatory. Therapeutic lifestyle intervention is important to address all of these aspects, but some may be
further treated with metformin, birth-control pills, or anti-androgens. IGT, impaired glucose tolerance;
T2DM, type 2 diabetes mellitus; HS-CRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; TNF-a, tumor
necrosis factor a; PAI-1, plasminogen activator inhibitor-1; OCP, oral contraceptive pill; TZD,
thiazolidinedione. aData are present in adults (5658) but not in adolescents. bAdult data (9294).

sensitivity at their own centers/institutions, and not rely on measures obtained by

others, until such time when the insulin assay becomes standardized across different
centers.
Compensatory first- and second-phase hyperinsulinemia40 in adolescents with
PCOS contrasted with adult studies demonstrating impaired b-cell function.47,48
However, a follow-up study by us comparing obese PCOS adolescents with and without
impaired glucose tolerance (IGT) demonstrated lower first-phase insulin secretion and
glucose disposition index in those with IGT.49 This study demonstrated that the
metabolic precursors of type 2 diabetesincluding severe insulin resistance, deficiency
in first-phase insulin secretion and increased hepatic glucose productionare present
early in the course of PCOS in adolescents.
Adult women and adolescents with PCOS are at increased risk for IGT and type 2
diabetes.50,51 A diagnosis of PCOS confers a 510-fold increased risk of developing type
2 diabetes.44 In a small study of 27 adolescents with PCOS, both lean and obese, the
rate of IGTwas 30% and undiagnosed diabetes 3.7%.44 Therefore, periodic screening of
adolescents with PCOS using OGTT is recommended to detect these abnormalities in
glucose metabolism without unnecessary delay.43,44 In fact, the progression from
normal glucose tolerance to type 2 diabetes in high-risk adolescents with PCOS could
be as fast as 5 years 52. Even though severe insulin resistance is present early in the
course of adolescent PCOS, transition from normal to abnormal glucose tolerance was
found to be associated with significant weight gain and remarkable decompensation in
insulin secretion relative to insulin resistance. In such situations of transitioning from
 Treatment of PCOS in adolescence 317

NGT to IGT to diabetes, surrogate estimates of insulin sensitivity using fasting glucose
and insulin concentrations were not reliable in reflecting the changes in in vivo insulin
sensitivity.52

Dyslipidemia and altered body composition

Levels of LDL cholesterol are higher and HDL lower in PP than in the reference
population. Hypertriglyceridemia and an elevated LDL/HDL ratio were also present.
When left untreated for 12 months, these abnormalities continued to worsen.18
Although these differences have been attributed in some cases to the excess abdominal
fat observed in lean, hyperandrogenic, hyperinsulinemic adolescents53,54, a study of US
obese adolescents with versus without PCOS found no difference in fat mass or fat
distribution between the two groups.40

Dysadipocytokinemia and inflammation

Levels of pro-inflammatory interleukin-6 (IL-6) were reported to be higher than
reference norms in 32 lean adolescents with hyperandrogenism. Adiponectin, an anti-
inflammatory adipocytokine, was lower in this PCOS variant.33 Open-label trials of
metformin in girls with PP at risk for PCOS were shown to improve IL-6 and
adiponectin levels.18,33 We demonstrated that hypoadiponectinemia in otherwise
healthy young people is a strong and independent correlate of insulin resistance, b-cell
dysfunction, and visceral adiposity.55 The anti-diabetogenic and anti-atherogenic
properties of adiponectin are evident early in life, and are compromised by simple
obesity in youth. It remains to be determined whether PCOS over and above obesity
confers additional risk for further reductions in adiponectin and alterations in IL-6.
Other inflammatory markers such as C-reactive protein56, tumor necrosis factor a
(TNF-a)57 and plasminogen activator inhibitor-1 (PAI-1)58 have previously been found
to be elevated in populations of obese women with PCOS, but this has not been
evaluated in adolescents.

Vascular dysfunction
Although, the rate of cardiovascular events in PCOS is controversial59,60, three types of
cardiovascular dysfunction have been described in PCOS: loss of diurnal variation of
blood pressure, elevated serum markers of vascular dysfunction, and increased carotid
intima-media thickness on ultrasound. Absence of physiologic nocturnal dipping in
blood pressure was noted in 11 obese adolescents with PCOS and IGT.49 Endothelin-1,
a serum marker of vasculopathy, was found to be four times higher in lean and obese
women with PCOS than in age-matched controls.61 Carotid intima-media thickness
is reported to be 2376% higher in women with PCOS compared with healthy
women.6265 Additional research is needed in this area to determine: (1) the role of
androgen levels; (2) whether or not these early markers of vascular dysfunction can be
reversed with lifestyle or pharmacological interventions; (3) whether or not these early
abnormalities translate into increased cardiovascular events in women with PCOS; and
(4) if not, why not.

Functional adrenal hyperandrogenism

Functional adrenal hyperandrogenism (FAH) is characterized by hyperresponsiveness
of DHEA, 17-hydroxypregnenolone, androstenedione, and 17-hydroxyprogesterone to
318 J. Warren-Ulanch and S. Arslanian

adrenocorticotropic hormone (ACTH) stimulation.66 FAH is observed in 4070% of

females with PCOS. The proposed mechanism of action is relative dysregulation of the
17,20-lyase activity by hyperinsulinemia.67,68 In a study of obese adolescents with
PCOS, the androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenolone
responses to ACTH stimulation were w50% higher than in the normative reference
group.68 Moreover, the 17-hydroxypregnenelone response to ACTH stimulation
correlated positively with fasting insulin levels, and the adrenal hyperresponsiveness
improved significantly following insulin-sensitizing therapy with metformin.68 These
observations are consistent with the concept of hyperinsulinemia-driven FAH. It
remains to be seen whether PP in some girls is mediated through a common mechanism
of insulin-driven adrenal hyperandrogenism.

DIFFERENTIAL DIAGNOSES

Diagnosis of PCOS in adolescents is less straightforward than in adults. Therefore, a

detailed history inquiring about the presence of risk factors that pre-dispose to PCOS is
needed. A key risk factor is family history. A thorough family history should be obtained
with respect to menstrual irregularities, infertility, hirsutism, acne, male-pattern
baldness, ovarian cysts and/or surgery, or outright PCOS in female relatives. Also, any
history of type 2 diabetes, dyslipidemia, and increased cardiovascular disease morbidity
or mortality increases the risk.19,6971 Low birth weight, PP, and obesity, as described
above, should raise the suspicion of PCOS in symptomatic girls.
PCOS is, by definition, a diagnosis of exclusion. Therefore, it is important to rule out
the other diagnoses of hyperandrogenism, including late-onset congenital adrenal
hyperplasia (CAH), Cushings syndrome, hyperprolactinemia, hypothyroidism, and
ovarian or adrenal tumors. The history, physical findings, and laboratory are usually
quite distinct in the setting of a tumor72 with rapid onset and progression of symptoms,
virilization, and total testosterone levels in excess of 200 ng/dL (ovarian) or DHEA
levels O7000 ng/dL (adrenal).73 Similarly, cortisol, prolactin, or TSH excess is rather
simple to assess biochemically. However, the most difficult condition to distinguish is
congenital adrenal hyperplasia, as PCOS seems to be affiliated with a functional block of
3b-hydroxysteroid dehydrogenase.74 Because 21-hydroxylase deficiency is the most
common form of CAH, a study in adult women yielded a recommendation to perform
an ACTH-stimulation test whether a follicular-phase (if possible, and random if not) 17-
hydroxyprogesterone level is O2 ng/mL. However, this finding has not been validated in
adolescents. In our clinical practice we routinely perform ACTH-stimulation tests to
rule out late-onset CAH. The latter condition typically manifests peripubertally with
signs of virilization in girls.75 Gonadotrophin levels may be helpful to rule out ovarian
failure as a cause of menstrual irregularity, but an LH:FSH ratio O2 is only about 60%
sensitive for diagnosing PCOS in adult women72, and the obese adolescent does not
demonstrate this laboratory abnormality.19 The typical hormonal and metabolic profile
of adolescents with PCOS is depicted in Table 1.

TREATMENT (FIGURE 1)

While the dogma has been to treat PCOS symptomatically9, newer studies are
emerging demonstrating the presence of metabolic syndrome and other cardiovascular
 Treatment of PCOS in adolescence 319

Table 1. Hormonal and metabolic features in adolescents with hyperandrogenism.

Free testosterone [
Androstenedione [4
Dehydroepiandrosterone sulfate (DHEAS) [4
Luteinizing hormone (LH) [4
Follicle-stimulating hormone (FSH) 4
LH/FSH [4
Insulin [
Insulin-like growth factor binding protein-1 (IGF-BP1) Y
Sex hormone binding globulin (SHBG) Y

disease risk factors in adolescents that may not be alleviated with simple regulation of
menses or lowering of hyperandrogenemia. Here, we discuss several treatment
options, ranging from lifestyle changes through ovarian suppression to insulin
sensitization. Of note, only very few studies have evaluated combination treatment
in adolescents, and even fewer have compared different treatment modalities head-to-
head.

Lifestyle intervention and weight loss

Few studies have investigated the role of lifestyle modification in adolescents with
PCOS. If, however, one agrees that PCOS is similar to metabolic syndrome in its natural
history of diabetes and cardiovascular disease, two convincing studiesthe Finnish
Diabetes Prevention Study (DPS)76 and the Diabetes Prevention Program77have
demonstrated the ability of lifestyle modification to prevent diabetes in 55% compared
with the control group. Effective exercise and nutritional counseling are important for
adolescents to develop and maintain these habits that will accompany them into
adulthood.50 In obese adult women with PCOS, a 510% weight reduction yielded
lower biochemical78,79 and clinical80 hyperandrogenism, as well as lower fasting
insulinemia and improved ovulation. Although no studies have isolated the effect of
therapeutic lifestyle on PCOS in adolescents, common sense and studies done in similar
populations dictate that it would be beneficial in many areas, including correction of
dyslipidemia.19 The enthusiasm for therapeutic lifestyle change5,11,81 likely stems from
its safety profile, lack of side-effects, and freedom from medication commitment, rather
than documented effectiveness. Currently, there are no effective non-surgical
treatments that result in permanent weight loss. An estimated 9095% of those who
do achieve weight loss will regain it.82 Even though behavioral family-based lifestyle
intervention for simple childhood obesity has been shown to be fairly effective in the
research setting83, clinical experience has not been that promising.84 Moreover, there
are very few pediatric centers with the expertise to deliver cognitive behavioral
intervention to children and families. Additionally, there are no centers particularly
devoted to the obese PCOS adolescent where syndrome-specific issues, physiological
or psychological, could be operative. It is our clinical experience that lifestyle
intervention produces positive results only in the highly motivated adolescent with
PCOS who has the support and commitment of her family. However, overall, this mode
of therapy alone produces limited results, in both extent and duration. Therefore, for
the moment, the importance of this mode of therapy is stressed to the patient and the
family, but it is combined with pharmacologic therapy. Investigations in adolescents,
320 J. Warren-Ulanch and S. Arslanian

similar to those done in adult women85, are needed to assess the efficacy of lifestyle
intervention alone and in combination with drugs to achieve short- and long-term
improvements.

Oral contraceptives

Use of oral contraceptives with a non-androgenic progestin to suppress ovarian

function restores regular menstrual cycles and normalizes androgen levels. In fact,
ethinyl estradiol/norgestimate (ortho-tri-cyclen) has been FDA-approved for use to
treat acne vulgaris in females. In obese women, 50 mg of ethinyl estradiol may be
necessary to affect irregular periods.9 Greek investigators found 150 mg desogestrel
combined with 30 mg ethinyl estradiol to be effective in lowering androgen levels,
regulating menses, and decreasing hirsutism in adolescents. It was well tolerated, and
did not worsen the lipid profile, weight, or waist-to-hip ratio.45
In addition to the hormonal benefits, OCPs are useful in preventing pregnancy in this
population who are found to be at risk for seeking pregnancy in an effort to prove their
femininity.1 Clearly, patients with unexplained thrombophlebitis are not candidates for
this mode of therapy, and in those with migraine and diabetes mellitus it should be used
only at low doses after careful consideration. Weight control, already a problem for
some adolescents with PCOS, may be more difficult on OCPs.9
The fourth-generation OCP ethinyl estradiol/drospirenone has a particularly anti-
androgenic progesterone component. It is similar in structure to spironolactone, and
has some anti-mineralocorticoid properties.86 When compared sequentially with a
gestodene-containing OCP, ethinyl estradiol/drospirenone lowered total and abdomi-
nal adiposity and increased lean mass87 in non-obese adult women on flutamide and
metformin. This study emphasizes the importance of the progestin component of the
OCP even while an anti-androgen is being taken. In a study of 32 lean adolescent girls
with hyperinsulinemic hyperandrogenism, ethinyl estradiol/drospirenone improved the
hyperandrogenic profile, lowered the hirsutism score, increased SHBG fourfold,
decreased testosterone, and increased HDL. However, there was worsening of the
metabolic and cardiovascular disease profile and body composition. Triglycerides, fat
mass, and abdominal fat increased, adiponectin decreased, and IL-6 increased. No
changes were seen in BMI or LDL cholesterol.15

Insulin sensitizers

Presently, there is consensus that hyperinsulinemia leads to hyperandrogenemia. This is

based on initial observations in adult women that correction or suppression of
hyperinsulinemia, through either weight loss or medications, led to lowering of
androgen levels and improvement in ovulatory function and induction of fertility.88 The
promising results in adult women led to studies investigating the use of metformin in
adolescents. Even though there are no large-scale, double-blind, placebo-controlled
studies in the adolescent age group, the available data in the literature show promise. In
10 non-obese adolescent girls with hyperandrogenism and a history of PP, metformin at
1275 mg daily for 6 months decreased hirsutism, hyperinsulinism, and hyperandrogen-
emia. This was accompanied by decrements in total cholesterol, triglycerides, and LDL
cholesterol. HDL cholesterol increased. Menses normalized in 100% of the subjects by
4 months.89 Another group found that a combination of metformin at 500850 mg
three times per day and a high-protein, low-carbohydrate diet restored regular menses
 Treatment of PCOS in adolescence 321

in 11 lean and obese adolescents with PCOS after 10.5 months of therapy.90 As it is well
established that regular menses do not necessarily signify ovulation, another study
assessed ovulation with weekly serum progesterone before and after the same
metformin regimen. After 4 months, 78% of non-obese adolescents with anovulatory
hyperandrogenism had ovulated.12 In obese, severely insulin-resistant adolescents with
PCOS and impaired glucose tolerance, 3 months of metformin therapy at 850 mg twice
a day led to normalization of glucose tolerance in 53%, lowering of total and free
testosterone levels by 3540%, decrements in BMI and subcutaneous abdominal
adipose tissue, and improvement in insulin sensitivity.68 In addition, we observed
significant improvement in functional adrenal hyperandrogenism detected by
attenuation of the adrenal hyperresponsivness to ACTH.68 Lean, eumenorrheic
adolescents born small for gestational age with insulin resistance and hyperandrogen-
emia responded to 850 mg/day of metformin for 3 months, with 69% showing ovulation
within 11 weeks of initiating therapy.91 Of concern, however, is that normalization of
ovulation will increase fertility, a possible unwanted effect in this vulnerable and risk-
taking adolescent population.20 Therefore, careful counseling must be provided to
adolescents regarding the risk of pregnancy when treatment with metformin is initiated.
It may be necessary to add an oral contraceptive to prevent pregnancy, rather than for
PCOS treatment, in the sexually active adolescent.1
Thiazolidinediones have also been found to decrease the functional adrenal
hyperandrogenism in adult women9294, but these medications have not yet been
studied in adolescents. A recent study in obese women with PCOS compared the
effects of 2550 mg metformin divided into three doses daily to those of pioglitazone
30 mg daily.95 While weight increased by 6% in the pioglitazone group, and decreased by
3.8% in the metformin group, both groups had similar (w30%) decreases in hirsutism
score and serum free testosterone level. Hyperinsulinemia, as measured by area under
the curve and fasting insulin level, improved in both groups, but significantly more so in
the pioglitazone group (26 versus 16.3%). This study proved that the insulin-sensitizing
effect of the thiazolidinedione was beneficial in excess of the detriment of weight gain,
likely due to the change in distribution of the body fat.
The positive effects of metformin should be tempered by the fact that all of the
studies are small and short in duration. In addition, concern exists about the ability of an
adolescent PCOS patient to endure the common gastrointestinal side-effects of
metformin. It is our clinical experience that most adolescents tolerate metformin
well68, and it is rare that the drug has to be discontinued due to intolerable
gastrointestinal side-effects. Even though the common treatmentsOCPs and anti-
androgensdo not positively affect the insulin resistance, some feel11,20 that the
approach to most adolescent patients with PCOS should be symptom-driven, with
reservation of metformin for those with hyperinsulinemia and failed weight-loss
therapy.
This controversy is further demonstrated in a survey of pediatric endocrinologists in
the USA, which showed that 30% would prescribe metformin for all PCOS patients and
68% would use it for obese PCOS patients.96

Anti-androgens

Flutamide is a non-steroidal anti-androgen that blocks at the level of the nuclear

receptor.97 After its use in adult women with PCOS proved successful in treating
hirsutism, its use at a dose of 250 mg daily for 18 months in 18 non-obese adolescents
322 J. Warren-Ulanch and S. Arslanian

with functional ovarian hyperandrogenism resulted in improvements in both clinical and

biochemical hyperandrogenism. However, menses, b-cell function, and insulin
resistance did not improve.89 The drug was reported to be well-tolerated, with no
effect on liver function tests. However, a majority of clinicians and investigators remain
hesitant in using this drug in the adolescent age group for fear of its liver toxicity. When
compared head-to-head in adult non-obese women with PCOS, 250 mg daily of
flutamide versus 850 mg of metformin three times daily both lowered androgen levels,
but flutamide did not improve insulin resistance whereas metformin did. This study was
only 4 weeks in duration.
Cyproterone acetate (CPA) is the most commonly used anti-androgen when
combined with ethinyl estradiol. This drug is not currently available in the United States.
Studies in women with PCOS demonstrate the ability of this medication to treat
hirsutism (O50% reduction of hirsutism score)98 and acne.99 The dose is 2 mg in
combination with ethinyl estradiol, but when increased by 10100 mg/day in the first
10 days of the active pill cycle, the more resistant acne cases responded.100 This drug
did not worsen insulin resistance or HDL cholesterol101, but did worsen triglyceride
levels45; also, it is associated with venous thrombosis.102
Prospective clinical trials of 6103 and 12 months of spironolactone104 have been
done in adolescent and young adult PCOS patients. The doses used were 25 mg
twice a day and 100 mg/day, and in both settings there was improvement in clinical
hyperandrogenism. Compared to metformin at 500 mg twice a day, spironolactone
performed slightly better than metformin with regard to hirsutism, menstrual cycle
frequency, and hormonal derangements, but did not significantly improve the
metabolic abnormalities.103 When combined with lifestyle changes in the obese
subgroup, decreases in insulin resistance and hyperinsulinemia were also seen.
Among the anti-androgenic drugs, spironolactone is the one most commonly used in
adolescents in the US.

Combination therapy

No particular drug seems to be the magic bullet, especially when consideration is given
to treating the hyperandrogenemia and the insulin resistance-associated metabolic
derangements. Therefore, investigators have looked at effects of combined therapy.
Multiple combinations have been tried, including flutamide/metformin54, ethinyl
estradiol/drospirenone with flutamide/metformin15, and metformin and ethinyl
estradiol/drospirenone with or without flutamide.87,105 Overall, these combination
therapies improve the hyperandrogenemia, but show variable outcomes in insulin
resistance, adipokines, and inflammatory markers. Until such time as results of large-
scale, long-term, prospective, double-blind, placebo-controlled studies using uniform
doses of drugs in well-defined PCOS adolescents become available, the authors
recommend a cautious approach in using drug cocktails in adolescents.

SPECIAL TREATMENT CONSIDERATIONS

Dosing

No dose-response studies have been performed in adolescents. Consequently,

literature reports involving adolescents vary widely in the dose of medication, from
 Treatment of PCOS in adolescence 323

50 to 100% of that prescribed for adult women with PCOS. In our study of obese
adolescents we used the adult metformin dose of 850 mg twice a day68, but those
studying lean subjects have used a wide spectrum of doses.12,15,18,33,91 A study of adult
obese (BMI 3037 kg/m2) women with PCOS demonstrated significantly more weight
loss at 2550 mg/day of metformin than at 1500 mg/day, but changes in hormone levels
and lipid panel were not dose-related.106
Oral contraceptives, when used cyclically, may allow ovarian testosterone
production during the hormone-free days.107 Long-cycle treatment lowers androgen
levels more effectively, prevents conception more effectively, prevents endometrial
cancer, and leads to a higher quality of life108, but this method of dosing may increase
cardiovascular risks even when dosed cyclically109, much less as long-cycle treatment.
Studies comparing cyclic versus long-cycle dosing of OCPs in adolescents have not yet
been done.

Responses to cessation of therapy

A few small studies have shown either regression to baseline or worsening33,54,89 of

initial androgen levels after discontinuation of therapy. This phenomenon was common
to flutamide89, metformin33, and their combination54, and happened by the third month
after stopping the medications. Interestingly, treatment with cyproterone acetate
continued to show an improved hirsutism score, even 24 months after treatment was
stopped, in 44% of subjects.110 Duration of treatment benefit after stopping correlated
with the duration of therapy prior to stopping. It remains questionable whether
adolescents with PCOS will need lifelong treatment. It is possible that some cases may
be transient, and manifest only during the physiological ovarian and adrenal
hyperactivity present during puberty.

Long-term effects

As the above studies suggest, the benefits of therapy disappear upon discontinuation of
therapy. Therefore, PCOS should be considered a chronic disease that requires both
early and extended treatment. However, in adolescents we must consider the
consequences of treatment on other innocent bystander organ systems. For example,
potent hormonal therapies, such as high-dose OCPs, have unknown sequelae on the
developing neuroendocrine system of adolescents.9 The skeleton may also be affected.
In adult women with PCOS bone density is preserved, if not elevated. This has been
attributed to elevated levels of insulin111 or androgen.112 OCPs113, metformin alone114,
and combined flutamide/metformin54 have been shown to decrease the rate of bone
mineral accrual54,113 and bone formation114 in adolescents. More studies are needed to
further evaluate this phenomenon.

SUMMARY

No special considerations have been given to the definition and diagnosis of PCOS
in adolescents despite the existing ones in adults. PCOS is more difficult to
diagnose in adolescents than in adult women, given the physiologic irregular
ovulation, insulin resistance, and polycystic ovarian morphology characteristic of
324 J. Warren-Ulanch and S. Arslanian

normal adolescents. Signs and symptoms of hyperandrogenism in the backdrop of a

positive family history of PCOS should prompt clinicians to look for PCOS.
Ancillary information of low birth weight with rapid catch-up growth and early
pubarche may further suggest the diagnosis. Perhaps the best tool to define the
diagnosis is biochemical hyperandrogenemia as measured by free dialyzable
testosterone with exclusion of other causes. However, as difficult as the diagnosis
may be to establish, it is important to seek it as it has important implications for
health, both in the adolescent, and, if left untreated, in the adult. Several treatment
modalities have been proven effective in lowering androgen levels in adolescents,
but only weight loss and insulin sensitizers seem to address the insulin
resistance/hyperinsulinemia and its metabolic consequences. Only few trials have
compared these treatments against each other, and even fewer have studied
combined treatments. When treatment is discontinued, the disease appears to
worsen, supporting the need for chronic treatment. Careful, long-term observation
of these treated adolescents is needed to evaluate therapeutic outcomes.

FUTURE DIRECTIONS

Despite increasing awareness of the existence of PCOS in adolescents, there

continues to be important knowledge gaps not only in making the diagnosis in this
young age group but also in its treatment. Future research is needed with respect to
the natural history of hyperandrogenism, PP and PCOS in the pediatric age group.
Well-designed, multicenter, prospective longitudinal studies must be conducted to:
(1) track the path of childhood PCOS and the early risk factors (low birth weight,
obesity, visceral adiposity, racial pre-dispositions, genetic and environmental factors);
(2) design safe and effective therapeutic interventions and prevention studies for
children; and (3) assess long-term outcomes of such interventions with respect to
hormonal, metabolic, cardiovascular and inflammatory consequences. Only then, can
we start practicing evidence-based medicine.

Practice points

the diagnosis of PCOS in adolescents is difficult because some of the symptoms

overlap with the physiological changes of puberty and because there are no
well-defined hormonal cut-points
a high index of suspicion is necessary to screen for the presence of PCOS in
adolescents
appropriate screening for PCOS in adolescents should include obtaining a
through family history of PCOS, performing a careful physical examination for
signs of hyperandrogenism and insulin resistance, exclusion of other causes of
hyperandrogenism, and appropriate diagnostic tools which should include a
free testosterone level
in treating adolescents with PCOS, besides managing hyperandrogenism,
attention must be given to treating insulin resistance and associated
derangements
 Treatment of PCOS in adolescence 325

Research agenda

establish the best screening and diagnostic tools for PCOS in adolescents
characterize the natural history of hyperandrogenism, PP and PCOS in the
pediatric age group
evaluate other co-morbidities of PCOS in adolescents, such as depression and
obstructive sleep apnea
establish the effectiveness of lifestyle intervention in adolescents with PCOS
establish the role of early treatment to prevent PCOS
establish the ability of long-term treatment to alter the natural history of the
development of type 2 diabetes, infertility, endometrial cancer, and vascular
dysfunction
assess the outcome of pharmacological interventions, using double-blind,
placebo-controlled studies, in hyperandrogenism, insulin resistance, and
associated abnormalities

ACKNOWLEDGEMENTS

This manuscript was supported by the United States Public Health Service grant RO1
HD27503, K24 HD01357, M01-RR00084 General Clinical Research Center, the
Renzihausen Trust Fund, National Research Service Award 5 T32 DK063686 and the
Endocrine Fellows Foundation.

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