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Original Study

Do Different Diagnostic Criteria Impact Polycystic Ovary


Syndrome Diagnosis for Adolescents?
€ l MD, PhD *, Yasemin Du
Sinem Akgu € zçeker MD, Nuray Kanbur MD, Orhan Derman MD
Division of Adolescent Medicine, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

a b s t r a c t
Study Objective: Although early diagnosis of polycystic ovary syndrome (PCOS) in adolescents might allow for earlier treatment and
prevention of chronic disorders, incorrect or premature diagnosis carries risks of unnecessary treatment and psychological distress. There
is no consensus concerning which diagnostic criteria to use for adolescents and current criteria vary. The objective of this study was to
determine whether using different diagnostic criteria will affect PCOS diagnosis in adolescents.
Design, Setting, and Participants: Fifty-two patients aged 13-18 years with at least 2 of the following criteria were included in the study: (1)
oligomenorrhea or amenorrhea; (2) Clinical or biochemical hyperandrogenism; and (3) polycystic ovaries on ultrasonography. Patients
were then categorized according to the 6 different criteria for PCOS. National Institutes of Health, Rotterdam criteria, Androgen Excess
Society, Amsterdam criteria, Endocrine Society criteria, and the Pediatric Endocrine Society criteria. The characteristics of adolescents who
were diagnosed with PCOS were also evaluated.
Interventions and Main Outcome Measures: Forty-one patients out of 52 (78.8%) received diagnosis with National Institutes of Health and
Endocrine Society criteria, all with Rotterdam criteria, 45/52 (86.5%) with Androgen Excess Society criteria, 36/52 (69.2%) with Amsterdam
criteria and 34/52 (65.4%) with the Pediatric Endocrine Society criteria.
Results and Conclusion: This study shows that the choice of guideline used does have a great effect on whether an adolescent received the
PCOS diagnosis or not. For physicians using the broader criteria, care should be taken to ensure the patient does not receive diagnosis
because of the physiological changes seen during puberty, which might mimic PCOS. For those using stricter criteria, close monitoring of
patients who do not receive diagnosis is necessary to prevent chronic complications.
Key Words: Adolescents, Diagnostic criteria, Polycystic ovary syndrome

Introduction regular menstrual cycles or those with no hyperandrogenism


might receive diagnosis. So, according to the Rotterdam
Currently, there are different criteria proposed for the phenotypic application models, individuals with all Rotter-
diagnosis of polycystic ovary syndrome (PCOS). Although all dam diagnostic criteria (hyperandrogenism, chronic anov-
require the exclusion of other causes of hyperandrogenism, ulation, and PCOM) are in group 1; with hyperandrogenism
certain differences are found in each guideline and no and chronic anovulation are in group 2; with hyper-
definite consensus has been made concerning the diagnosis androgenism and PCOM are in group 3; and with chronic
in adolescents.1 anovulation and PCOM are in group 4.3
The first criteria were introduced in 1990 by the National However, this application model, especially for the group
Institutes of Health (NIH). The consensus reached by the of patients who do not have hyperandrogenism, led to
NIH concluded that PCOS diagnosis could be made in a significant controversy. Thus, in 2006 the Androgen Excess
patient with clinical and/or biochemical hyperandrogenism Society (AES) criteria were defined, the main difference
associated with a menstrual irregularity.2 stated was that diagnosis required the presence of hyper-
After the NIH criteria, the European Society of Human androgenism, with the associated findings of either men-
Reproduction and Embryology/American Society for Repro- strual irregularity and/or PCOM.4
ductive Medicine criteria were developed, which are often The diagnosis of PCOS during adolescence is difficult
called the Rotterdam criteria, this guideline includes poly- because many of the signs and symptoms of the syndrome
cystic ovary morphology (PCOM) on ultrasonography to the are also normal findings of pubertal development.5 It has
other 2 NIH criteria but allows for combination of any 2 of the been argued that using the diagnostic criteria for adults
3 findings of hyperandrogenism, menstrual irregularity, and might cause overdiagnosis of the syndrome and none of the
PCOM. These guidelines added 2 new phenotypes to those 3 guidelines described previously discussed the diagnosis in
described by the NIH Consensus because women with the adolescent population.6 In 2012 at the European Society
of Human Reproduction and Embryology/American Society
The authors indicate no conflicts of interest. for Reproductive Medicine-sponsored PCOS consensus
* Address correspondence to: Sinem Akgu € l, MD, PhD, Division of Adolescent
workshop held in Amsterdam, it was stated that criteria for
Medicine, Department of Pediatrics, Hacettepe University Faculty of Medicine,
Ankara 06100, Turkey; Phone 0312-3051160 the diagnosis of PCOS in adolescents differ from those used
E-mail address: sinemhusnu@gmail.com (S. Akgu € l). for adult women of reproductive age. These criteria argued
1083-3188/$ - see front matter Ó 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc.
https://doi.org/10.1016/j.jpag.2017.12.002
€ l et al. / J Pediatr Adolesc Gynecol 31 (2018) 258e262
S. Akgu 259

that because physiological characteristics of adolescence Oligomenorrhea was defined as the absence of menstru-
might overlap with PCOS signs, to avoid overdiagnosis PCOS ation over 45 days and amenorrhea as no menstrual bleeding
should require all 3 of the Rotterdam consensus and not just for 6 months. Patients were only eligible to enroll 2 years
2 of 3.7 Just 1 year later the Endocrine Society (ES) clinical after menarche. Hyperandrogenism was defined when total
practice guideline for the diagnosis and treatment of PCOS testosterone was greater than 50 ng/mL biochemically, and
was published. This guideline also devoted separate rec- the score was at or greater than 8 according to m-Ferriman-
ommendations for adolescents. Again, the guidelines state Gallwey (mFG) classification clinically.11 A total score of 8-15
that the diagnosis of PCOS in an adolescent girl is different was used to define mild hirsutism, 16-24 moderate hirsut-
from that of an adult and the diagnostic criteria are similar ism, and greater than 24 severe hirsutism.5 Moderate to se-
to that of the NIH criteria in which clinical and/or vere acne was noted for clinical hyperandrogenism.
biochemical evidence of hyperandrogenism after exclusion Exclusion criteria were any other cause for oligomenor-
of other pathologies and oligomenorrhea is required. The rhea or hyperandrogenism such as nonclassic adrenal
difference between the two being that clinical hyper- hyperplasia, androgen secreting neoplasms, Cushing syn-
androgenism is defined with only hirsutism by the ES for drome, thyroid dysfunction, and hyperprolactinemia, any
adolescents whereas it includes acne and alopecia for NIH patients with a history of androgenic/anabolic drug or
criteria. An important point made in this guideline is that contraceptive use, or any patient who refused participation
they state ultrasonography should not be a criterion for in the study.
adolescents because the Rotterdam ultrasound polycystic Systemic physical examination was performed on all
ovary criteria have not been validated for adolescents and patients and the presence of acne, acanthosis nigricans,
the PCOM might be a feature of normal puberty that sub- male pattern hair loss, and virilization were recorded. Pu-
sides with the onset of regular menstrual cycling.8 bertal stages of patients were performed according to the
In 2015, the Pediatric Endocrine Society (PES) invited Marshall-Tanner method.12 Measurements of weight (kilo-
experts to define appropriate diagnostic criteria for the grams) were obtained using electronic scales (Seca 220;
diagnosis of PCOS in adolescence.9 Their consensus sup- Hamburg, Germany), and measurements of height (centi-
ported the criteria of the ES in that persistent hyper- meters) were obtained using the Harpenden stadiometer.
androgenic oligoanovulatory menstrual abnormality on the Measurements were evaluated according to normal values
basis of age- and stage-appropriate standards should be of Turkish children, which were modified according to age
used, with some modification. Biochemical hyper- and gender. Body mass index was calculated by using the
androgenism was defined as persistent testosterone eleva- body weight in kilograms divided by the height in meters
tion above adult norms rather than the other serum squared formula. Children within the 85th-95th percentiles
androgens. Clinical hyperandrogenism was defined as were accepted as overweight, whereas at and greater than
moderate-severe hirsutism rather than mild hirsutism or the 95th percentile was accepted as obese.13
moderate-severe inflammatory acne vulgaris. Another dif- The laboratory evaluation included the total blood count,
ference these criteria added was that the criteria for evi- liver and kidney function tests, lipid profile, fasting glucose,
dence of oligoanovulation was defined as abnormal uterine fasting insulin level, Insulin Resistance Homeostasis Model of
bleeding pattern for age or gynecologic age with persistent Assessment (IRHOMA) values, estrogen, total testosterone,
symptoms for 1-2 years. Again, PCOM was not recom- sex hormone binding globulin, dehydroepiandrosterone
mended as a diagnostic criterion by the PES. sulfate, androstenedione, 17-hydroxy-progesterone, follicle-
With all of these different guidelines being used for PCOS stimulating hormone, luteinizing hormone, prolactin levels,
definition, where does this leave the clinician working with free androgen index, and thyroid function tests.
adolescents? PCOS is not only frequently encountered but also Blood samples for laboratory evaluations were drawn
an important cause of morbidity so it is recommended that during early follicular phase (on day 2-3 of the menstrual
the disorder is diagnosed early,10 but will trying to diagnose cycle) in patients with menses. For patients with amenor-
the disorder early on cause over- or premature diagnosis of rhea blood was drawn on the day of clinical examination
the disorder because many findings might be transitory?6 after a 12-hour fasting at 8:00 AM.
The aim of this report was to evaluate whether a PCOS Serum follicle-stimulating hormone, luteinizing hor-
diagnosis would change according to the criteria used and mone, estradiol, prolactin, thyrotropin, free triodothyronine
to evaluate characteristics of adolescents who were diag- and free thyroxine levels were measured using the 2-step
nosed with PCOS. chemiluminescence microparticle immunoassay method.
Sex hormone binding globulin and 17-OH progesterone
Materials and Methods were tested using immunoradiometric assay. Serum dehy-
droepiandrosterone sulfate and total testosterone levels
A retrospective chart evaluation was conducted and fe- were determined using solid phase chemiluminescence
male patients aged 13-18 years who applied to Hacettepe immunoassay. Glucose level was measured using the
University Ihsan Dogramacı Children's Hospital, Division of glucose hexokinase method; total cholesterol was studied
Adolescent Medicine between January and July 2016 with enzymatically using the oxidase method; high-density li-
at least 2 of the following criteria were included in the poprotein cholesterol was studied using the direct non-
study: (1) Oligomenorrhea or amenorrhea; (2) clinical or immunological method; fasting insulin was studied using
biochemical hyperandrogenism; and (3) polycystic ovaries the radioimmunoassay method. Fasting insulin and
on ultrasound scan. IRHOMA values were used in the evaluation of insulin
260 € l et al. / J Pediatr Adolesc Gynecol 31 (2018) 258e262
S. Akgu

resistance. IRHOMA was calculated by using the formula of Table 2


Symptoms of Patients Diagnosed With PCOS
IRHOMA: (fasting insulin in milli-International Units per
milliliter)  (fasting blood glucose in millimoles per liter) Symptom n/52 (%)

divided by 22.5, and patients with IRHOMA value of greater MI 28 (53.4)


Hirsutism 5 (9.6)
than 2.5 was accepted as insulin resistant.
MI and hirsutism 1 (1.9)
Ultrasonographic findings of PCOS were considered as Acne 4 (7.6)
having 12 or more follicles measuring between 2 and 9 mm MI and acne 1 (1.9)
and/or an ovarian volume greater than 10 cm3. Weight gain 7 (13.4)
Abnormal uterine bleeding 3 (5.7)
Patients were then categorized according to the 6 Amenorrhea 2 (3.8)
different criteria for PCOS (Table 1), then additionally Psychosocial problems 4 (7.7)
Other problem irrelevant to PCOS 5 (9.6)
categorized according to the Rotterdam Phenotypical
model. MI, menstrual irregularity; PCOS, polycystic ovary syndrome.

Approval for this study was obtained from Hacettepe


University Research Ethics Board (number GO:16/503).
The mean body mass index of patients was 25.5 (5.6).
One patient was underweight (1.9%), 22/52 patients (42.3%)
Statistical Analyses had normal weight, 15/52 patients (28.8%) were over-
weight, and 14/52 patients (26.9%) were obese.
SPSS (version 23; IBM Corp) was used for statistical The mean mFG score was 7.5 (7.8; range, 0-34) and the
analysis. In the statistical analysis of data, descriptive sta- score was 8 or more in 23/52 cases (44.2%).
tistics such as mean (SD) or median (range) was used for Ten patients (43.5%) had mild, 8/52 (34.8%) had moderate,
continuous variables, whereas number of cases and per- and 5/52 (21.7%) had severe hirsutism according to the mFG
centages were used for nominal variables. score. Moderate to severe acne was present in 32/52 patients
(61.5%) and acanthosis nigricans was present in 6/52 patients
(11.5%). Biochemical hyperandrogenism was detected in 40/
Results
52 (76.9%) patients. Although 18/52 patients (34.6%) had
clinical as well as biochemical hyperandrogenism, 22/52
Fifty-two patients met the inclusion criteria. The mean
(42.3%) had only biochemical, 5/52 (9.6%) had only clinical,
age of patients was 15.6 (1.29) years and the mean age of
and 7/52 patients (13.4%) had neither clinical nor biochem-
menarche was 12.2 (1.3; range,10-15.4) years. The symp-
ical hyperandrogenism.
toms of patients are given in Table 2, some patients had
Ultrasonographically, 38/52 patients (73%) had bilateral
more than 1 symptom. The most frequent symptom was
PCOM, 5/52 patients (10.4%) had unilateral PCOM, 3/52
menstrual irregularity.
patients (5.7%) had ovary volumes greater than 10 cm3 and
When findings were categorized according to which
6/52 patients (11.5%) had normal ovary morphology.
diagnostic criteria were used, 34/52 (65.4%) received a
Nineteen patients (36.5%) had insulin resistance
diagnosis according to the PES criteria, 36/52 (69.2%) with
(IRHOMA O2.5) and 20/52 patients (38.5%) had dyslipide-
Amsterdam criteria, 41/52 (78.8%) with NIH and ES criteria,
mia; hepatosteatosis was not detected in any patient.
45/52 (86.5%) with AES criteria, and all with Rotterdam
criteria.
The patients were also categorized according to the Discussion
Rotterdam phenotypic application model. Thirty-six pa-
tients (69.2%) were grouped in group 1, 5/52 (9.6%) in group In our study, we aimed to evaluate whether PCOS diag-
2, 4/52 (7.7%) in group 3, and 7/52 (13.5%) in group 4. nosis will change according to which criteria was used and
we found that there was an important difference depending
on selected criteria. As expected, all adolescents received a
Table 1 diagnosis according to the Rotterdam criteria whereas this
Diagnostic Criteria for PCOS According to Different Published Definitions decreased by more than 30% when evaluated according to
Criteria Hyperandrogenism Chronic Polycystic the Amsterdam and PES criteria. This result, in turn leads
Anovulation Ovaries the clinician to ask 2 important questions. Will using the
National Institutes of Health þ þ  Rotterdam criteria lead to an overdiagnosis or using the
1990 Amsterdam or PES criteria lead to an underdiagnosis, and
Rotterdam 2003* þ/ þ/ þ/
Androgen Excess Society 2006y þ þ/ þ/ what will the consequences be?
Amsterdam 2012 þ þ þ Although PCOS often presents during adolescence, the
Endocrine Society 2013 þ þ  diagnosis in this age group is complicated by the com-
Pediatric Endocrine Societyz þ þx 
monality between the PCOS signs and symptoms and
þ indicates definite criterion, þ/ indicates might or might not be a criterion.
* Two of the 3 criteria must be met.
physiologic findings observed during the normal progres-
y
Hyperandrogenism and at least 1 of the other 2 criteria must be met. sion of puberty, which are described as follows.14,15
z
Biochemical hyperandrogenism: persistent testosterone elevation above adult
norms. Clinical hyperandrogenism: moderate-severe hirsutism or moderate-severe
(1) Oligomenorrhea is common and physiological after
inflammatory acne vulgaris.
x
Abnormal uterine bleeding pattern for age or gynecologic age, persistent menarche during normal puberty and is therefore not
symptoms for 1-2 years. specific to adolescents with PCOS. Anovulatory cycles
€ l et al. / J Pediatr Adolesc Gynecol 31 (2018) 258e262
S. Akgu 261

comprise 85% of menstrual cycles in the first year after The NIH and Rotterdam classifications consider hirsutism,
menarche, 59% in the third year, and 25% by the sixth acne, and alopecia as signs of hyperandrogenism in adults. In
year.16 contrast, the AES and ES classification only accepts the pres-
(2) Acne, a clinical sign of hyperandrogenism is a transitory ence of hirsutism as a genuine marker of hyperandrogenism
common finding of adolescence17 and therefore many in adolescents. The ES and PES criteria are very similar except
authors suggest that it should not be used in isolation to that the PES criteria require moderate to severe hirsutism to
define hyperandrogenism in adolescents.6 be clinically significant for hyperandrogenism. For patients
(3) Diagnosing hirsutism, the main clinical sign of hyper- without biochemical hyperandrogenism when we only
androgenism, using the Ferriman-Gallwey scoring sys- accepted patients with an mFG score greater than 16, diag-
tem might also be difficult in adolescents. It has been nosis of PCOS decreased from 78.8% to 65.4%. Clinical hyper-
suggested that because of less cumulative time of androgenism is usually reported as high in the adolescent
exposure to androgens, the cutoff might require modi- population24; in our study we found 44.2% of patients to have
fication for use in adolescents.18 An additional problem hirsutism. Although 61.2% of patients had moderate to severe
for adolescents might be difficulty in scoring because of acne, we did not accept this on its own as a sign of hyper-
hair removal for cosmetic reasons. We have found that androgenism because it is a common finding in this age
when we ask adolescents to refrain from hair removal to group. A study by Hickey at al,25 in which diagnostic markers
evaluate hirsutism they find complying to this very for diagnosis in adolescence were evaluated, they reported no
difficult. relationship between acne score and free testosterone level or
(4) Another problem concerns the definition of biochemical PCOM and they concluded that acne should not be used as a
hyperandrogenism in this age group because during specific marker of hyperandrogenism in PCOS. The PES
normal pubertal development there is a lack of well- criteria state that girls with persistent acne should be evalu-
defined cutoff points for androgen levels.19 ated for the presence of hyperandrogenemia but again do not
(5) Finally, the PCOM finding on ultrasonography also poses use it as a criterion on its own.9
difficulty for the adolescent. In the guidelines published Although hirsutism is an important clinical marker
by the ES, ultrasonography was removed from the of hyperandrogenism, some authors have argued that
criteria because of a few factors. Primarily, they stated biochemical hyperandrogenism is a more reliable and
that PCOM should be evaluated transvaginally rather consistent marker of hyperandrogenism in the diagnosis of
that transabdominally, which would lead to practical PCOS in adolescents.26 In our study, biochemical hyper-
and ethical concerns in adolescents. Secondarily, that androgenism (76.9%) was close to double that of clinical
transabdominal ultrasound is limited in evaluating the hyperandrogenism but we did have cases that did not
ovaries especially in obese patients, which is common in overlap thus, both should be evaluated in the workup.
this patient population. Finally, even if multifollicular Oligomenorrhea is a problematic criterion when it comes
ovaries were observed, this could be a feature of normal to PCOS diagnosis in adolescents. For this reason, when
puberty.8 Several studies of healthy adolescents with using this criterion certain recommendations have been
regular cycles have reported the incidence of PCOM to made when defining menstrual irregularity in adolescents.
be 33%-35%. A study by Mortensen et al20 reported that The first of this is that at least 2 years have passed after
54% of healthy eumenorrheic girls between 1.3 and menarche.1 Merino et al27 suggested that the absence of
3.8 years postmenarche had PCOM. menstrual periods exceeding 90 days, or if cycles were
longer than 45 days should suggest the presence of ovula-
tory dysfunction in an adolescent. In our study 92.3% of
Because of the physiological reasons stated previously patients had menstrual irregularity.
using a broader definition such as the Rotterdam criteria PCOS is associated with metabolic abnormalities including
(especially group 3 or 4) might be problematic. Incorrectly obesity, insulin resistance, type 2 diabetes, nonalcoholic fatty
assigning a diagnostic label of PCOS to an adolescent might liver disease, and dyslipidemia.28 Although obesity is com-
result in unnecessary treatment and also impose psycho- mon in adults as well as in adolescents with PCOS and many
logical distress.6 However, using more strict criteria such as studies show that prevalence in adolescents is greater than
the PES or Amsterdam criteria might lead to underdiagnosis 60%,29 it is important not forget that patients might be of
and there has been growing attention to early recognition normal weight and in our study close to half of the patient
and treatment of the disorder to prevent chronic conditions population was of normal weight. Of all patients, 36.5% had
such as metabolic syndrome, type 2 diabetes, cardiovascu- insulin resistance (IRHOMA O 2.5) and 38.5% had dyslipi-
lar problems, and endometrial cancer.21 Additionally, demia; these findings are similar to other adolescent PCOS
studies have shown that the physical signs of PCOS such as studies.30
hirsutism and obesity might lead to depression in teens so Other diagnostic criteria have also been proposed for
early intervention is important from this aspect, too.22 adolescents. It has even been suggested that diagnosis
Hyperandrogenism is a hallmark of PCOS23; the NIH, AES, should be avoided until the age of 18 years.6 Sultan and
Amsterdam, PES, and ES criteria all require clinical and/or Paris,31 for example, have proposed a different and more
biochemical hyperandrogenism for the diagnosis of PCOS, strict approach in which they suggest that at least 4 of the 5
whereas the Rotterdam criteria recognize a phenotype of following criteria be met: clinical hyperandrogenism, bio-
PCOS without androgen excess. In our study group, 13.5% of logical hyperandrogenemia, insulin resistance and hyper-
the patients were in the group with no hyperandrogenism. insulinism, oligoamenorrhea persisting for 2 years
262 € l et al. / J Pediatr Adolesc Gynecol 31 (2018) 258e262
S. Akgu

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