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 sh_widad@yahoo.com

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!)

sh_widad@yahoo.com

• 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