Widad – FK UGM
Curriculum Vitae
Nama Dr. Shofwal Widad, SpOG(K)
Tempat & tanggal lahir Kudus, 15 April 1974
Alamat kantor Bagian Obstetri Ginekologi FK UGM/RSUP Dr. Sardjito, Jalan Kesehatan no. 1, Sekip, Yogyakarta
Telepon 08122756049
E-mail [email protected]
Pendidikan Dokter FK UGM, lulus 2000
Dokter Spesialis OBGIN FK UGM, lulus 2005
Konsultan Endokrinologi Reproduksi & Infertilitas
FK UGM, lulus 2009
Kursus Laparoscopy Singapore, (2006), Mumbay, India, (2008), Hanoi, Vietnam (2009),
Strasbourg, France (2012), Bern, Switzerland (2012)
Infertility & IVF MIMR, Monash University, Australia, 2008
Apakah PCOS dapat ditemukan di usia remaja?
Dipresentasikan pada Simposium PCOS, PIT POGI XXI, Denpasar 28 Agustus 2014
Division of Reproductive Endocrinology & InfertilityDepartment of Obstetrics & Gynecology
Faculty of Medicine, Universitas Gadjah MadaDr Sardjito Hospital
Yogyakarta
Dr. Shofwal Widad, SpOG(K)
Disclosure
• I declare no conflict of interest related to this presentation
Widad – Obgyn UGM
Outline
Widad – Obgyn UGM
• Introduction
• Fetal androgen excess
• Hormonal paradigm in pubertal PCOS
• Early diagnosis of PCOS in adolescents
• Diagnosis of PCOS in adolescence
• Evaluation for PCOS in adolescent
• Take home messages
Introduction• Until recent years, the diagnosis of PCOS was reserved for adult women
presenting with subfertility tied to irregular menses/anovulation and hirsutism/hyperandrogenism.
• With increasing awareness of multifactorial diseases in younger populations, PCOS has become a more frequent consideration among pediatric endocrinologists and gynecologists
• However, transferring adult diagnostic criteria for PCOS to the adolescent population has proven to be most challenging, mainly due to overlapping symptoms of normal puberty.
PCOS
Widad – Obgyn UGM
• PCOS has been postulated to originate in fetal androgen excess.
The process was initiated from fetal androgen excess
Ovarian or adrenal fetal
hyperandrogenism
Reduced hypothalamic
sensitivity to steroid negative feed back
on LH
LH hypersecretion
Androgen excessHyperinsulinemia & insulin resistance
Infant: SGA & LGA; puberty: premature
adrenarche PCOS
Diamanti-Kandarakis, Best Pract & Research Clin Obst & Gyn, 2010
Premature Adrenarche
Any sign of androgen action before the age of 8/9 years in prepubertal girls/boys
with other causes excluded
Voutilainen et al. J of Steroid & Mol Biol, 2014
Conclusion: Increased awareness of PCOS in young females is needed. PCOS may occur at a younger age in girls who develop early pubarche and thelarche. Therefore, the diagnosis and workup should be considered in young girls with risk factors suggestive of PCOS
Predisposing factors of PCOSPrenatal exposure to androgens: offspring of mothers with PCOS
Low birth weight/small for gestational age
Premature adrenarche
Onset of type 1 DM (before menarche)
Obesity ± insulin resistance
Family history of PCOS
Etc.
Tharian et al, Pediatrics & Child Health, 2011
Hormonal paradigm in pubertal PCOSPuberty
Awakening of the Hypothalamic-Pituitary Axis
Growth hormone
Increased insulin resistance of liver and muscle
Insulin
Central adipocityTestosteron
LH
Genetically predisposed ovary
Genetically predisposed adolescents may exhibit an exaggerated ovarian response to physiologic and non-physiologic (e.g., obesity) stimuli at puberty, with an ensuing hormonal cascade that is well recognized in the context of PCOS.
Burgert, 2014
Is it important to make early diagnosis of PCOS in adolescents?
Risk factors DiagnosisPCOS
Pat
hoge
nesi
s Subfertility
Metabolic syndrome/DM
Endometrial cancer
genetic
physiologic stimuli
non-physiologic stimuli
Potential medical implicationsUnder-evaluated
Under-treated
Early detection & early intervention may have multiple health benefits
Diagnosis of PCOS in Adolescence
• The overlap in symptoms of physiologic puberty and PCOS had led to a diagnostic hesitation, likely leaving young women under-evaluated and under-treated until reproduction is desired.
• To date there is no unified approach to the diagnosis of PCOS in adolescence.
Widad – Obgyn UGM
Burgert, 2014
Tackling the Definition• In general terms, PCOS is defined by a
constellation of signs and symptoms, after other organic causes have been excluded:– adrenal disorders (i.e., late-onset congenital
adrenal hyperplasia), – thyroid disorders, – primary or secondary ovarian insufficiency,– hyperprolactinemia, – androgen-producing tumors, and pregnancy.
Widad – Obgyn UGM
Legro, 2012
Burgert, 2014
NIH Consensus
• The first unifying approach to adult PCOS was proposed during a 1990 consensus meeting at the National Institutes of Health (NIH).
• The so-called NIH Criteria require the presence of – chronic anovulation and– clinical and/or biochemical
hyperandrogenism.
Widad – Obgyn UGM
PCOSHyperandrogenism
Legro, 2012
Rotterdam Consensus• In 2003, another PCOS consensus workshop in Rotterdam, broadened
the definition to allow ultrasound evidence of polycystic ovaries (PCO) to substitute for either anovulation or hyperandrogenism.
• Revised 2003 Rotterdam consensus on diagnostic criteria of PCOS
• Hence, 3 following potential phenotypes of PCOS were created:1. Anovulation + hyperandrogenism2. Anovulation + PCO on ultrasound
(non-hyperandrogenemic phenotype)
3. PCO + hyperandrogenism.
Widad – Obgyn UGM
PCOSHyperandrogenism
Burgert, 20142003 Rotterdam PCOS Consensus, Fertil Steril 2004
Diagnostic dilemma in adolescents
AES Consensus• Appreciating a need for clarification, the Androgen Excess Society (AES)
convened in 2009 to define PCOS by the presence of hyperandrogenism plus one of two signs: either ovarian dysfunction/oligo-anovulation (disturbed menstrual cycles) or ultrasound PCO morphology.
Burgert, 2014
• PCOS without hyperandrogenism is not PCOS
• PCO with hyerandrogenism is really PCOS
Hyperandrogenism
Oligo/anovulation
PCO
PCOS
Legro, 2012
Diagnostic paradigms for PCOS
Society consensus criteriaNIH 1990 Rotterdam 2003 AES 2006
Signs/symptoms Oligomenorrhea + androgen excess
Any 2 of 3 Androgen excess + either anovulation or PCO
Oligomenorrhea or anovulation
+ +/- +/-
Hyperandrogenism (Biochemical and/or clinical)
+ +/- +
PCO on ultrasound - +/- +/-
Widad – Obgyn UGM
Legro, 2012
Diagnostic dilemma of PCOS in adolescents
• For adolescents, an important finding has emerged since AES definition.
• Beyond the clinical presentation, the presence of biochemical hyperandrogenemia (despite the absence of clinical hyperandrogenism) is the singular finding that crystallizes out PCOS from other pubertal “noise” of adolescence.
• Problem:– Still actual comparable testosterone cut-offs across laboratories remain
elusive, since laboratory assays very widely between laboratories– normative data for testosterone levels in the adolescents is lacking.
Widad – Obgyn UGM
Burgert, 2014
• Given these diagnostic dilemmas, Carmina et al. have suggested that for adolescents the diagnosis of PCOS can be securely made only when hyperandrogenemia and chronic anovulation and ovarian morphologic changes (enlarged ovaries or classic PCO morphology) are evident.
• In contrast, PCOS diagnosis is only probable when hyperandrogenemia and anovulation alone (AES criteria) manifest during adolescence.
Widad – Obgyn UGM
Burgert, 2014
Carmina et al, Am J Obstet Gynecol, 2010
• Adolescents with incomplete criteria for a firm diagnosis of PCOS should be followed up carefully and may be diagnosed at a later time.
Teasing Apart Diagnostic Parameters
Irregular menstruation/Anovulation• While menarche is the first sign of an intact of hypotahalamic-pituitary-
ovarian (HPO) fedback loop, the HPO system may take up to 5 years to mature fully.
• Therefore, “physiological anovulation” has become the main assumption in examining adolescents with menstrual irregularity.
• A large Finnish Cohort of adolescent girls with irregular menses had higher testosterone levels than their eumenorrhoic counterparts, indicating that irregular menses at age 15-16 years may denote a non-physiologic state a regular menstrual pattern at age15-16 years excludes the risk of hyperandrogenemia with a specificity of 72%.
Widad – Obgyn UGMBurgert, 2014
Pinola et al, Hum Reprod, 2012
Ultrasound Evaluation• The Rotterdam Criteria, which first introduced the application
of ultrasound evidence in the diagnosis of PCOS, defined PCO as having 12 or more small follicles (2-9 mm) and/or enlarged ovarian volume greater than 10 cm3.
• Unilateral manifestation is sufficient for PCO diagnosis.• Timing:
– in the early follicular phase (days 3-5) of a spontaneous menstrual cycle or – 3-5 days after a progestin withdrawal bleed.
• Reference data regarding normal ovarian size in adolescent have not been unified.
Widad – Obgyn UGMBurgert, 2014
Clinical Hyperandrogenism• Difficult to interpret in adolescents.• In puberty, central axis immaturity and physiologic insulin resistance are
often coupled with ovarian anovulation and mild acne/hirsutism mimicking a PCOS phenotype.
• Acne is a very common, transitory phenomenon during adolescents not diagnostic in PCOS.
• Hirsutism and androgenic alopecia are usually less marked in adolescents because it takes time for hyperandroagenemia to affect the hair follicles.
• Persistent and progressive facial hair during adolescents should prompt an evaluation for hyperandrogenemia in any female.
Widad – Obgyn UGM
• For adult women with concern for hirsutism, the modified Ferriman-Gallwey scoring system is used and includes examination of body areas such as the chin, chest, upper arm, upper and lower back, thigh, groin, and lower and upper abdominal area.
Burgert, 2014A score 6–8 generally defines hirsutism Yildiz et al, Hum Reprod Update, 2010
Visually Scoring Hirsutism
Uncommon in the Asian population
Widad – Obgyn UGMYildiz et al, Hum Reprod Update, 2010
However, since adolescents may only manifest upper-lip hair, a high hirsutism score
should not be sought as the prime manifestation of hyperandrogenism in
adolescents Burgert, 2014
Widad – Obgyn UGMYildiz et al, Hum Reprod Update, 2010
Evaluation for PCOS in adolescents population
Assessment Considerations Implications
Supporting PCOS
Clinical Menstrual disturbance of oligomenorrhea, primary or secondary amenorrhea.
Physical examination of acanthosis nigricans, central weight distribution, facial hair/hirsutism.
Family history of PCOS, infertility, gestational DM, type 2 DM.
Laboratory Elevation of morning total testosterone, free testosterone (low SHBG)
>200 ng/dL suggestive of ovarian androgen-secreting tumor
Imaging Transabdominal ultrasound with finding of spherical enlarged ovary(ies) where mostly the central stroma is increased-peripheral arrangement of small follicles (string of pearls)
Widad – Obgyn UGM
• Biochemical hyperandrogenism is helpful in the diagnosis of androgen excess adolescents.
• For adolescents, determining total testosterone and SHBG is recommended for diagnosis.
Burgert, 2014
Evaluation for PCOS in adolescents populationAssessment Considerations Implications
Ruling out other conditionsLaboratory 17-OH progesterone (morning) >200 ng/dL suggestive of Late-onset CAH
DHEAS Adrenal hyperandrogenism/>800 microgram/dL suggestive of adrenal tumor
TSH Thyroid disorder
LH, FSH, E2 Elevated FSL/H and low E2 suggest primary ovarian insuffeciency. Normal to low FSH, LH and low E2 suggest hypothalamo-pituitary disfunction
hCG Rule out pregnancy
Prolactin Prolactinoma or drug-induced cause for elevated prolactin
Urinary cortisol assessment/dexamethasone suppression test
Rare condition such as Cushing’s syndrome are not routinely ruled out but should be considered if clinical suspicion arises (e.g. adolescent with elevated blood pressure)
Widad – Obgyn UGMBurgert, 2014
Take home messages• PCOS can be occured in adolescent.• Diagnosis of PCOS poses unique challenges given overlapping
symptoms of puberty.• A timely diagnosis of PCOS in the adolescent is important for early
intervention and prevention for long-term medical implications.• Hyperandrogenemia is the key to PCOS diagnosis in adolescence.• To date there is no unified approach to the diagnosis of PCOS in
adolescence, however Carmina et al. have suggested that for adolescents the diagnosis of PCOS can be securely made only when hyperandrogenemia and chronic anovulation and ovarian morphologic changes (enlarged ovaries or classic PCO morphology) are evident.
Widad – Obgyn UGM
“When a thing ceases to be a subject of controversy, it ceases to be a subject of interest.”
William Hazlitt (1778–1830), English essayist
Widad – Obgyn UGM
This presentation will have to be modified because of new developments next year (or possibly even next week!)
• Hyperandrogenism and chronic anovulation are the primary disturbances in younger women with PCOS; whereas, obesity, insulin resistance, and metabolic disturbances are predominant in older women with PCOS.
Diagnostic components of PCOS with associated co-morbidities
Williams, Mol & Cell Endocrinol, 2013
Dysregulation of HPO axis in PCOS
A. Normal follicular ovarian development and ovulation
Widad – Obgyn UGM
B. In PCOS, increased GnRH pulsatility leads to exaggerated LH release and loss of the mid-cycle LH surge resulting in anovulatory cycles
Tharian et al, Pediatrics & Child Health, 2011
Relative population prevalence of PCOS (%) based on individual diagnostic criteria
Diagnostic criteriaNIH (1990) Rotterdam (2003) AES (2009)
March et al (2010) 8.7 17.8 12
Yildiz et (2012) 6.1 19.9 15.3
Mehrabian et al (2011) 7.0 15.2 7.9
Widad – Obgyn UGM
• Very few studies have been conducted looking at the long-term benefits of early interventions for adolescent PCOS
• However, data are available for a group of non-obese adolescents who developed PCOS after being diagnosed with premature adrenarche, a common conditions recognized as heralding PCOS.
• For this group of adolescents, Ibanez and de Zegher have extensively studied the metabolic effects of various interventions and have collected long-term and early intervention data.
• It appears that early diagnosis and treatment improves menstrual symptoms, body composition, and most importantly, cardio-metabolic profile in patients with PCOS.
• Unfortunately, once therapy is discontinued, many of the metabolic benefits cannot be sustained.
Widad – Obgyn UGM
Diagnostic criteria and their associated phenotypes
A B C D E F G H I J K L M N O P
Hyperandrogenemia + + + + - - + - + - + - - - + -
Hirsutism + + - - + + + + - - + - - + - -
Oligo-anovulation + + + + + + - - - + - - + - - -
Polycystic ovaries + - + - + - + + + + - + - - - -
NIH 1990
Rotterdam 2003
AE-PCOS 2006
Widad – Obgyn UGM
Widad – Obgyn UGM
Legro, 2012
Tending to What Ultimately Matters: Metabolic Complications of PCOS
• Even though obesity and insulin resistance are not part of the PCOS definition, they are closely linked morbidities that tie into perpetuating the clinical phenotype and ultimately are responsible for the development of T2DM, the most serious metabolic and cardiovascular risk in PCOS.
• Other metabolic risk factors such as dyslipidemia, hypertension, impaired glucose metabolism, and obstructive sleep apnea either pave the road to T2DM, or are found at the time of diagnosis as concomitant comorbidities.
Widad – Obgyn UGM
• The Metabolic Syndrome• The metabolic syndrome is a constellation of metabolic disturbances that
is associated with cardiovascular disease.• While the diagnosis of the metabolic syndrome in adults and adolescents
remains disjointed across the scientific world, the most common definitions require at least three of the following criteria: (central) obesity, dyslipidemia (related to either triglycerides or HDL), hypertension, or impaired glucose metabolism.
• Adolescents with PCOS are 4.5 times more likely to have metabolic syndrome than age-matched adolescents from the Third National Health and Nutrition Examination Survey (NHANES III) after adjusting for BMI.
Widad – Obgyn UGM
Metabolic considerations after diagnosis of PCOS in an adolescents population
Considerations ImplicationsLaboratory Fasting glucose, insulin, and 2-
h oral glucose tolerance test with 75 g of glucose
Examine for prediabetes, DM, insulin resistance
Fasting lipid profile Examine for dyslipidemia as knowledge may impact on treatment choice, e.g., caution is advised when using oral contraceptive regimen in the setting of moderate to severe trigliceridemia.
Sleep study Examine for obstructive sleep apnea
Widad – Obgyn UGM
Efficacy of commonly utilized therapeutic options for managing PCOS-related problems
Treatments Menstrual dysfunction Hyperandrogenism Metabolic benefitInsulin sensitizer
Metformin± ± +
OCP + + -
Cyclic progesterone + - -
OCP + metformin + + +
Anti-androgen ± + ±
Widad – Obgyn UGM