5th Congress of the Asia Pacific Initiative on Reproduction, Brisbane, Australia, 4-6 April 2014
An overview
How to diagnose
PCOS in adolescence
Delfin A. Tan, MD
Section of Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
St. Luke’s Medical Center
Quezon City, Philippines
How to diagnose PCOS in adolescence
Why is it important to diagnose
PCOS in the adolescent?
Part 1
2
How to diagnose PCOS in adolescence
Key point 1
The prevalence of PCOS in the
adolescent is increasing secondary to,
and aggravated by, the recent trend of
increasing obesity among teenagers.
Hassan A, Gordon CM. Curr Opin Pediatr. 2007 Aug;19(4):389-97. Huang J, et al. Reprod Biol
Endocrinol. 2010 Nov 17;8:142.
3
How to diagnose PCOS in adolescence
4
PCOS and obesity in adolescence
Prevalence of polycystic
ovary syndrome, range %
Prevalence of obesity in
PCOS patients, range %
70
70
60
60
50
50
40
40
26
30
20
10
0
20
10
5
30
11
Reproductive-aged Adolescent girls
women
Franks S. N Engl J Med. 1995 Sep 28;333(13):853-61.
Driscoll DA. Ann N Y Acad Sci. 2003 Nov;997:49-55.
58
53.8
42
27
10
0
Reproductive-aged Adolescent girls
women
Azziz R, et al. J Clin Endocrinol Metab. 2004
Jun;89(6):2745-9. Li L, et al. J Pediatr Adolesc Gynecol.
2012 Dec;25(6):390-5. Rahmanpour H, et al. J Pediatr
Adolesc Gynecol. 2012 Jun;25(3):208-12.
How to diagnose PCOS in adolescence
5
Adolescent PCOS: metabolic abnormalities
are prevalent, worsened by obesity
Study: 128 Chinese adolescents with PCOS vs. age- and BMI-matched controls
Prevalence, %, in adolescents with PCOS
50
46.9
40
30
29.7
20
10
22.7
11.7
4.7
0
Pre-diabetes
Insulin resistance Hyperinsulinemia
Dyslipidemia
Metabolic
syndrome
Continued →
How to diagnose PCOS in adolescence
6
Adolescent PCOS: metabolic abnormalities are prevalent,
worsened by obesity continued →
Prevalence, %, in PCOS adolescents with BMI ≥85th (21.4 kg/m2)
80
74.4
60
67.4
40
20
0
39.5
16.3
14
Pre-diabetes
Hyperinsulinemia Dyslipidemia
Metabolic
2)
Prevalence,Insulin
%, in resistance
PCOS adolescents
with BMI <85th (21.4 kg/m
syndrome
80
60
40
20
0
9.4
Pre-diabetes
32.9
10.6
Insulin resistance Hyperinsulinemia
Huang J, et al. Reprod Biol Endocrinol. 2010 Nov 17;8:142.
14.1
0
Dyslipidemia
Metabolic
syndrome
How to diagnose PCOS in adolescence
7
Key point 2
Adolescents with PCOS are as insulin
resistant as their adult counterparts.
Palmert MR, et al. J Clin Endocrinol Metab. 2002 Mar;87(3):1017-23. Arslanian SA, et al. J Clin
Endocrinol Metab. 2001 Jan;86(1):66-71.
How to diagnose PCOS in adolescence
8
Obese adolescents with PCOS: low
adiponectin, high insulin levels
Study: 44 Adolescent girls grouped based on body mass index and presence of
PCOS
Adiponectin levels, µg/mL
20
20
16.9
15
10
Insulin levels
18
10.5
5
p<0.05
15
10
12.3
7.4
5
4.5
0
0
Obese
Lean adolescent Lean adolescent
adolescent with with PCOS
without PCOS
PCOS
Obese
Lean adolescent Lean adolescent
adolescent with with PCOS
without PCOS
PCOS
Leptin elevated in obese adolescents with PCOS vs normal weight adolescents ± PCOS.
Pinhas-Hamiel O, et al. Clin Endocrinol (Oxf). 2009 Apr 7. [Epub ahead of print].
How to diagnose PCOS in adolescence
9
Early impairment of endothelial structure and
function in young normal-weight PCOS women
Study: 30 normal-weight PCOS women, mean age 22.2 years vs 30 age-matched
controls
Flow-mediated
dilation, %
P < 0.05
20
0.7
18.1
15
Intima media
thickness, mm
14.3
1.5
P < 0.05
0.6
0.5
10
P < 0.05
1
0.53
0.4
0.39
5
Serum endothelin-1,
pmol/L
1.1
0.5
0.5
0.3
0
0.2
PCOS
Controls
0
PCOS
Controls
Orio F Jr, et al. J Clin Endocrinol Metab. 2004 Sep;89(9):4588-93.
PCOS
Controls
How to diagnose PCOS in adolescence
Key point 3
Early and accurate diagnosis is important
given the long-term implications of
polycystic ovary syndrome.
Hardy TS, Norman RJ. Steroids. 2013 Apr 24. [Epub ahead of print]
10
How to diagnose PCOS in adolescence
How is PCOS diagnosed in the
adolescent?
Part 2
11
How to diagnose PCOS in adolescence
12
Polycystic ovary syndrome definitions 1990-2009
PCOS definition
Clinical
hyperandrogenism
(Ferriman-Gallwey score ≥8)
or
Biochemical
hyperandrogenism
Oligomenorrhea
(<6-9 menses per year)
or
Oligo-ovulation
Polycystic ovaries on
ultrasound
(≥12 antral follicles in one
ovary or ovarian volume
≥10 cm3)
(elevated total/free
testosterone)
NICHD 19901
Yes
Yes
No
Rotterdam 20032
Yes
Yes
Yes
Yes
Yes
2 of 3 criteria
AE-PCOS Society
20093
Yes
1 of 2 criteria
NICHD National Institute of Child Health and Human Development. AE-PCOS Androgen Excess and Polycystic Ovary Syndrome Society.
1Zawadski JK,
Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP,
Merriam GR, eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific Publications; 1992:377-384. 2Rotterdam ESHRE/ASRM-Sponsored PCOS
Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil
Steril. 2004;81:19-25. 3Azziz R, Carmina E, Dewailly D, et al; Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen
Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil
Steril. 2009;91:456-488.
How to diagnose PCOS in adolescence
13
Polycystic ovary syndrome definitions 1990-2009
PCOS definition
Clinical
hyperandrogenism
(Ferriman-Gallwey score ≥8)
or
Biochemical
hyperandrogenism
NICHD 19901
Rotterdam 20032
AE-PCOS Society
20093
Oligomenorrhea
(<6-9 menses per year)
or
Oligo-ovulation
None has proposed
(elevated total/free
testosterone)
different criteria for
Yes
diagnosis Yes
of PCOS in
Yes
Yes
2 of 3 criteriathe adolescent
Yes
Yes
population.
Polycystic ovaries on
ultrasound
(≥12 antral follicles in one
ovary or ovarian volume
≥10 cm3)
No
Yes
Yes
1 of 2 criteria
NICHD National Institute of Child Health and Human Development. AE-PCOS Androgen Excess and Polycystic Ovary Syndrome Society.
1Zawadski JK,
Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP,
Merriam GR, eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific Publications; 1992:377-384. 2Rotterdam ESHRE/ASRM-Sponsored PCOS
Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil
Steril. 2004;81:19-25. 3Azziz R, Carmina E, Dewailly D, et al; Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen
Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil
Steril. 2009;91:456-488.
How to diagnose PCOS in adolescence
14
Adolescent polycystic ovary syndrome
Diagnostic 1 High rate of menstrual disturbance
confusion
and anovulatory cycles
2 Uncertainty regarding significance
of polycystic ovarian morphology
3 Difficulty in interpreting clinical
and biochemical evidence of
hyperandrogenism
4 Lack of high quality evidence
Hardy TS, Norman RJ. Steroids. 2013 Aug;78(8):751-4. Epub 2013 Apr 24.
How to diagnose PCOS in adolescence
15
Diagnostic uncertainty for PCOS in the
adolescent population
Effects
1 Difficulty in estimating prevalence
•
Variability in clinical approach to diagnosis
even among specialists
Bonny AE, et al. NASPAG Research Committee. J Pediatr Adolesc Gynecol
2012;25:259–61.
2 Underdiagnosis/delay in diagnosis or
overdiagnosis
•
•
Symptoms of PCOS disregarded as part of
normal puberty or
Normal variants of pubertal development
mistaken for PCOS
Hardy TS, Norman RJ. Steroids. 2013 Aug;78(8):751-4.
How to diagnose PCOS in adolescence
Key point 4
The diagnosis of PCOS in adolescents may
require a unique set of criteria; ….. there are
no generally accepted recommendations for
the diagnostic work-up.
Ságodi L, Barkai L. Orv Hetil. 2013 Jan 27;154(4):136-42.
16
How to diagnose PCOS in adolescence
17
Suggested criteria for diagnosis of PCOS in
adolescents
1
Sultan C, Paris
F. 2006
Four of 5 criteria
• oligo- or amenorrhea >2 years after
menarche
• clinical hyperandrogenism
• biochemical hyperandrogenism
• insulin resistance or hyperinsulinemia
• polycystic ovaries on ultrasound
2
Carmina E, et
al. 2010
Apply Rotterdam criteria
• limit to adolescent who met all 3 criteria
• adolescents with only 2 of 3 criteria should
be followed and reevaluated
Continued →
How to diagnose PCOS in adolescence
Suggested criteria for diagnosis of PCOS in adolescents
continued →
3
4
Roe AH, Dokras Use AE-PCOS Society criteria
A. 2011
• hyperandrogenemia is the most reliable
finding
• metabolic workup should be performed
Merino PM, et Diagnosis should be based on
al. 2011
• presence of hirsutism and biochemical
hyperandrogenism
• menstrual cycles persistently longer than
45 days
Sultan C, Paris F. Fertil Steril. 2006 Jul;86 Suppl 1:S6. Carmina E, et al. Am J Obstet Gynecol. 2010
Sep;203(3):201.e1-5. Epub 2010 May 1. Roe AH, Dokras A. Rev Obstet Gynecol. 2011 Summer;4(2):45-51.
18
How to diagnose PCOS in adolescence
Suggested criteria for diagnosis of PCOS in adolescents
continued →
3
Roe AH, Dokras Use AE-PCOS Society criteria
A. 2011
• hyperandrogenemia is the most reliable
finding
• metabolic workup should be performed
4 Merino PM, et Diagnosis should be based on
al. 2011
• presence of hirsutism and biochemical
hyperandrogenism
• menstrual cycles persistently longer than
‘These proposed adolescent
criteria are stricter than
45 days
their adult counterparts, may limit inappropriate
early diagnosis, but are currently not endorsed by
expert panels or societies in the field.’
Sultan C, Paris F. Fertil Steril. 2006 Jul;86 Suppl 1:S6. Carmina E, et al. Am J Obstet Gynecol. 2010
Sep;203(3):201.e1-5. Epub 2010 May 1. Roe AH, Dokras A. Rev Obstet Gynecol. 2011 Summer;4(2):45-51.
Roe AH, Dokras A. Rev Obstet Gynecol. 2011 Summer;4(2):45-51.
19
How to diagnose PCOS in adolescence
20
Menstrual irregularity
How is PCOS diagnosed in the adolescent?
How to diagnose PCOS in adolescence
21
Diagnosing PCOS in adolescents
Need to define and detect ovulatory dysfunction
Difficulties
1 Peri-menarcheal
period
Hardy TS, Norman RJ. Steroids.
2013 Apr 24. [Epub ahead of print]
2 Age at menarche
Teede HJ, et al. Med J Aust. 2011
Sep 19;195(6):S65-112.
3 Body weight
Norman RJ, et al. Lancet. 2007 Aug
25;370(9588):685-97.
• Adjustment period in establishing
regular ovulatory cycles
• No high quality evidence to delineate
maturity of hypothalamic-pituitaryovarian axis
• Faster progression to regular
ovulatory cycles with early (<12
years) vs. late (>13 years) menarche
• Overweight children are more
susceptible to premature pubarche
and thelarche
How to diagnose PCOS in adolescence
PCOS Australian Alliance
Med J Aust. 2011 Sep 19;195(6):S65-112.
22
How to diagnose PCOS in adolescence
PCOS Australian Alliance
Med J Aust. 2011 Sep 19;195(6):S65-112.
The PCOS Australian Alliance recommends
‘consideration of PCOS based on cycle
irregularity in the third year post-menarche.’
23
How to diagnose PCOS in adolescence
24
Polycystic ovarian
morphology
How is PCOS diagnosed in the adolescent?
How to diagnose PCOS in adolescence
25
Diagnosing PCOS in adolescents
Ovarian morphology must be interpreted with caution, may
have limited value
Difficulties
1
2
Transvaginal
scanning
Inappropriate in virginal patients
Ovarian
morphology
Changes throughout life cycle
Khan U. J Pediatr Adolesc Gynecol. 2007;20:101–4.
Mortensen M, et al. J Clin Endocrinol Metab 2006;91:3786–90.
Criteria regarding ovarian size or morphology differ
between ethnic groups
Chen Y, et al. J Pediatr Adolesc Gynecol 2008;21:347–5.
3
PCOM
May be physiologic
Codner E, et al. Fertil Steril 2011;95:702–6. Hickey M, et al. Hum Reprod
2011;26(6):1469–77.
Unrelated to menstrual or metabolic abnormalities
Venturoli S, et al. Pediatr Res 1995;38:974–80.
How to diagnose PCOS in adolescence
26
Serum anti-Mullerian hormone is not a reliable
predictor of PCOM or PCOS in adolescents
Study
244 Adolescent girls, median age 15.1 years (range 14.5 – 17.6 years)
Diagnosis missed at
AMH threshold of 30
pmol/L, %
Serum AMH, pmol/L
PCOM or PCOS diagnosis
Control
40
P<0.001
30
20
32
P<0.002
31
22
50
P<0.048
40
30
24
23
45
48
30
20
10
10
0
0
PCOM vs.
control
PCOS-R vs.
control
PCOS-N vs.
control
Hart R, et al. Fertil Steril. 2010 Aug;94(3):1118-21.
PCOM
PCOS
How to diagnose PCOS in adolescence
27
Clinical and biochemical
evidence of
hyperandrogenism
How is PCOS diagnosed in the adolescent?
How to diagnose PCOS in adolescence
28
Diagnosing PCOS in adolescents
Need to refine approach to hyperandrogenism
Difficulties
1 Clinical
hyperandrogenism
Clinical signs vary according to time since
puberty, ethnicity, and treatment
Biro FM, Emans SJ. J Adolesc Health. 2008 Aug;43(2):103-5.
Dismissed as normal element of pubarche
Rosenfield RL. J Clin Endocrinol Metab. 2007 Mar;92(3):787-96.
2 Biochemical
hyperandrogenism
Routine androgen assays may not be
accurate in adolescents
Carmina E, et al. Am J Obstet Gynecol. 2010 Sep;203(3):201.
Physiological increase in androgens due
to increased growth hormone and
decreased sex hormone binding globulin
Hannon TS, et al. Pediatr Res 2006;60:759–63.
How to diagnose PCOS in adolescence
Key point 5
Androgen excess [biochemical
hyperandrogenism] may be the most
useful diagnostic feature in
adolescents.
Carmina E, et al. Am J Obstet Gynecol 2010;203:201.e1-5. Roe AH, Dokras A. Rev Obstet Gynecol.
2011 Summer;4(2):45-51.
29
How to diagnose PCOS in adolescence
30
Adolescents diagnosed with PCOS based on the
AE-PCOS criteria: increased risk of metabolic
abnormality
Study
205 Adolescents (>2 years postmenarche) evaluated for PCOS and
metabolic risk using Androgen Excess-PCOS Society criteria
Presence of ≥1 metabolic risk
factor, %
P=0.002
80
60
Prevalence of metabolic
syndrome (≥3 risk factors), %
80
60
63.6
40
40
33.3
20
0
20
0
PCOS
No PCOS
P<0.04
10.8
1.7
PCOS
No PCOS
Roe AH, et al. J Pediatr. 2013 May;162(5):937-41. Epub 2012 Dec 20.
How to diagnose PCOS in adolescence
Diagnosing PCOS in the
adolescent: summary
Part 3
31
How to diagnose PCOS in adolescence
32
Diagnosing PCOS in the adolescent
Summary 1 Important to make the diagnosis
• Increasing prevalence worsened by
increasing rates of obesity
• Affected adolescents are equally
insulin-resistant as adults
• Allows treatment to minimize
symptoms, reduce risk of later
metabolic sequelae
Continued →
How to diagnose PCOS in adolescence
33
Diagnosing PCOS in the adolescent continued →
Summary 2 Adult criteria for diagnosis do not
apply
• High background rate of menstrual
disturbance and anovulatory cycles
• Uncertain significance of PCOM
• Difficulty in interpreting clinical and
biochemical evidence of
hyperandrogenism
Continued →
How to diagnose PCOS in adolescence
34
Diagnosing PCOS in the adolescent continued →
Summary 3 Only firm criteria should be used
for diagnosis
• Investigate menstrual disorders 2
years postmenarche
• Less reliance on polycystic ovarian
morphology
• Greater reliance on accurate
assessment of hyperandrogenic and
metabolic features
• When diagnosis is not clear, repeat
evaluation in 6 to 12 months
Tan D. 2014