f1 honest hairy truth - cdn.ymaws.com · implications for management adolescents 15–19 years (n =...

3/29/2016

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The Honest Hairy Truth About PCOS: What Your Patient Wants to Know But is Afraid to Ask

Andrea Bonny MDAsma Javed M.B.B.S

Disclosure

• We have no relevant financial disclosures.

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Objectives

• Review the changing phenotype of PCOS across t f lif t i t th di ti h ll stages of life to appreciate the diagnostic challenges

in adolescent PCOS• Questions patients would like to ask: Review

best practice guidelines including new treatment modalities available to address hirsutism, weight gain, acne and acanthosis nigricansg g

• Address current controversies in PCOS evaluation such as ‘mass screening’ for complications such as glucose intolerance and ‘pan androgen testing'

Desired Practice Change

• Establish consistency among disciplines regarding the optimum management of adolescents with PCOS and address common patient centered complaints in light of evidence based medicine

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The Changing Phenotype

PCOS may begin as early as in utero and has varying clinical presentation at each stage of varying clinical presentation at each stage of life multiple changes in presentation • Pre natal• Pre pubertal• Pubertal/adolescent PCOS• Reproductive implications• Reproductive implications• Post menopausal phenotype

The Changing Phenotype: Prenatal

The role of fetal programming The role of fetal programming Programming is ‘setting’ by an early stimulus or insult at a ‘sensitive’ period, resulting in long-term consequences for function.

Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol. 2013

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PCOS in Utero: Fetal Programming

Familial clustering, susceptibility genes

Environmental Influences

Zi-Jiang Chen et al. Genome-wide association study identifies susceptibility loci for PCOS on chromosome 2p16.3, 2p21 and 9q33.3 Nature Genetics 2011

Genome Wide Association Study744 PCOS cases and 895 controls

? FSHR gene

Animal PCOS models- fetal androgen synthesis: The Dumesic Experiments


The Dumesic Experiments▫ Female rhesus monkeys exposed to prenatal androgen excess and

hyperglycemia met all 3 diagnostic criteria plus insulin resistance

Dumesic DA et al Androgen excess fetal programming of female reproduction a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update 2005

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The role of birth weight in PCOS


• A subset of girls born small for gestational age will later develop early pubarche and PCOS

• Newborns with low birth weights had higher AMH levels when measured at 2 to 3 months

Ibanez L et al. Polycystic ovaries after precocious pubarche: relation to prenatal growth. Hum Reprod. 2007Sir-Petermann T et al. Effects of birth weight on anti-mullerian hormone serum concentrations in infant girls. JCEM 2010

The Changing Phenotype: Pre Puberty

Born SGA, Rapid catch up weight gain

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Changing Phenotype: Pre PubertyPP =48 girls Controls= 31Post menarchal

Ibañez L, Potau N, Virdis R, et al. Precocious Pubarche, Hyperinsulinism, and Ovarian Hyperandrogenism in Girls: Relation to Reduced Fetal Growth JCEM 1998

Changing Phenotype: Pre Puberty

? Ideal time for intervention IUGR catch-up growth visceral adiposity and insulin resistance

Ibañez L et al. Postpubertal outcome in girls with premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. JCEM 1993

Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth JCEM 1998 Witchel SF. Puberty and polycystic ovary syndrome Mol Cell Endocrinol. 2006

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Pre-Pubertal Phenotype: Implications for Management

• Peri-pubertal weight gain associated with Peri pubertal weight gain associated with Insulin resistancePremature pubarchePCOS

• Ideal time for Intervention

Diagnostic Challenges in Adolescent PCOS

• Are Young Adult Women with Polycystic Ovary Syndrome Slipping Through the Healthcare Cracks?

Dokras, A Witchel SF. JCEM 05-2014

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Making the Diagnosis in AdolescentsRotterdam: 2 of 3 criteria required

Non Hirsute PCOS

Ovulatory PCOS

*PCOS“Classic”

PCOSInsulin Resistance

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group Revised 2003 consensus. Fertil Steril. 2004

Diagnosis made After exclusion of other hormonal disorders!


Jessica is 15 years oldJessica is 15 years oldMenarche at 12 yearsMenstrual cycles every 4 monthsIncreased dark hair on chin Darkening of neckBirth history - SGA

di b i f hType 2 diabetes in fatherBMI- 34kg/m2

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Primary care provider obtains lab measuresSerum total testosterone - 65 ng/dl (12-60) Plasma HDL level - 35 mg/dl (>40)Triglycerides - 190 mg/dl (<130)Fasting Glucose – 106 mg/dl (<100)

• Referred to adolescent gynecology


with preliminary diagnosis of PCOS• Told about subfertility risks and

potential for cardiovascular disease and T2DM

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• Melissa is 20 years oldPresents with menstrual irregularity


Presents with menstrual irregularity, recalcitrant acne, excessive facial hair. Diagnosed with ‘premature pubarche’ at 7 years of ageMenarche at age 11Normal weight - BMI 18.5 kg/m2

• Seen in dermatology and started OCPs which she remained on


OCPs which she remained on for 12 years

• Acne and hirsutism improved• Difficulty conceiving• Reproductive endocrinologist

diagnosed PCOSdiagnosed PCOS

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Why did the first adolescent warrant further Why did the first adolescent warrant further testing and referral?

Prevalence of PCOS in adolescents

Implications for Management

Adolescents 15–19 years (n = 137,502)

Provider made dx of PCOS (NIH criteria) (n=774, prevalence of 0.56%)

Additional 789 determined by chart review (not assigned by provider)

Combined prevalence = 1.14%

O i h d b 6 i hi h dd f b i i d Overweight and obese 3-16 times higher odds of being assigned a diagnosis

? Provider Bias

Overall under diagnosis& overestimation of link with obesity

Christensen SB et al. Prevalence of polycystic ovary syndrome in adolescents. Fertil Steril. 2013 Aug

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Adolescent PCOS:Implications for Management

Was ‘precious time’ lost in Melissa’s case?

Insulin resistance: in obese PCOS only?Adolescents

Adults

Prevalence of IR in PCOS= 30-40% (similar rates in obese and lean)

Prevalence of IR in PCOS= 70%Conversion rate from IGT to T2DM is 5 to 10 fold higher in PCOS

Norman RJ et al. Relative risk of conversion from normoglycemia to IGT or non-insulin dependent diabetes mellitus in PCOS. Hum Reprod. 2001Flannery CA et al. Polycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMI. PediatrDiabetes 2013

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A Diagnostic Conundrum in adolescents

59% irregularcycles 2 years post menarche

PCOM in 35% Lack of transvaginal ultrasound screen

Puberty Androgens SHBG

Androgen Assay Limitations

Insulin Resistance at puberty

What your patient wants to ask• Will I get diabetes?g

The likelihood is lower if you change your lifestyle and improve BMI

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Does early intervention improve outcome?

Lass N, et al. Effect of lifestyle intervention on features of PCOS, metabolic , y ,syndrome, and intima media thickness in obese adolescent girls.JCEM November 2011.

59 obese girls with PCOS aged 12–18 years1-yr lifestyle intervention

Main Outcome Measures: Intima media thickness (IMT), metabolic screening

Outcome: 33 girls lost weight (mean –BMI 3.9 kg/m2), 26 girls did notWt. Loss Group: Menstrual regularity, insulin, testosterone, IMT

Metabolic Risk in Adolescent PCOS

• High (metabolic syndrome reported in up to 30%)• More than would be predicted by obesityMore than would be predicted by obesity

PCOS=150OA=98

Javed et al Fasting Glucose Changes in Adolescents with Polycystic Ovary Syndrome Compared with Obese Controls: A Retrospective Cohort StudyJournal of Pediatric and Adolescent Gynecology 2015 Vol 28 (6)Palmert MR, Gordon CM, Kartashov AI, Legro RS, Emans SJ, Dunaif A. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syJ Clin Endocrinol Metab. 2002

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Should Lean PCOS be screened?

Polycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMIglucose tolerance occurs across the spectrum of BMIFlannery CA et al. Pediatr Diabetes. 2013

• 100 adolescents assessed for PCOS, 66 with confirmed PCOS. • Mean age 15.8 ± 0.2 yrs• Abnormal glucose metabolism was present in 12 of 66 (18.2%) • IGT was the most common abnormality, • IGT occurred with equal frequency in obese (OB, mean body mass

index (BMI) 36.9 ± 0.8 kg/m(2) ) and non-obese (NOB, mean BMI de ( ) 36 9 0 8 g/ ( ) ) a d o obese ( O , ea24.5 ± 0.6 kg/m(2) )

Abnormal glucose metabolism is highly prevalent in adolescents with PCOS and can occur across the spectrum of BMI

254 PCOS

• 2 hour OGTT vs. fasting glucose

How should IGT be measured?

80 ControlsAge 14-44

Legro RS et al. Prevalence and predictors of risk for type 2 DM and IGT in PCOS: a prospective, controlled study in 254 affected women. JCEM 1999

Out of 79 PCOS with IGT, only 10 were diagnosed by fasting glucose

Not enough to obtain fasting glucose and fasting insulin!

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What your patient wants to ask

• Will I stop needing to shave/remove hair so often?

Yes, after the underlying androgen excess is targeted, the time between hair removal sessions should increase

Quantifying Hirsutism

3 site Ferriman Gallwey Vs.

Serial measurements by same provider may Vs.

9 site Ferriman Gallweyby same provider may be important to trackprogress

Reanalyzing the modified Ferriman-Gallwey score: is there a simpler method for assessing the extent of hirsutism? Heather Cook et al Fertility Sterility 2011

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Metformin versus OCP for hirsutism

• 52 subjects randomized to receive either metformin (500 mg, three times daily) or Dianette (ethinyl estradiol 35 micro g; three times daily) or Dianette (ethinyl estradiol, 35 micro g; cyproterone acetate, 2 mg) treatment for 12 months, with assessments before treatment, at 6 months, and at 12 months.

• Both Metformin and OCP showed similar efficacy in reducing hirsutism symptoms with metformin superior in some areas

• Hirsutism is likely secondary to both insulin resistance and excess androgens

Harborne L et al. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome J Clin Endocrinol Metab. 2003 Sep

Other treatment modalities for hirsutism

• Spironolactone at a starting dose of 25 mg once day• Check creatinine at baseline and serum potassium at

2 weeks after therapy• Can escalate to 50 -100 mg BID• Particularly useful if contraindication to estrogen

useMechanism of action: Blocks androgen actionMechanism of action: Blocks androgen actionCyproterone acetate used in Europe but not approved in U.S

Somani N et al. Hirsutism: an evidence-based treatment update. Am J Clin Dermatol 2014 Jul

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Other treatment modalities for hirsutism

• Eflornithine (Vaniqa)For facial hirsutism aloneBest results when used in conjunction with laser therapy

Lapidoth M et al. Best practice options for hair removal in patients with unwanted facial hair using combination therapy with laser: guidelines drawn up by an expert working group. Dermatology 2010.

Temporary Hair Removal TechniquesOther treatment modalities for hirsutism

WaxingShavingPluckingBleachingHair removal chemicals

Permanent Hair RemovalElectrolysis and laser treatmentElectrolysis and laser treatment

Both permanent forms are painful and may not be permanent

Best to delay these permanent forms of hair removal until after 6 months on hormone therapy

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• How long will it take for the hair growth to improve?

• Set realistic expectations• Hormone treatment prevents new terminal hairs from

developing and may slow the growth rate of existing hairs.

• About six months of hormone therapy is required before • About six months of hormone therapy is required before the rate of hair growth decreases significantly.

• Once a hormone treatment has proven to be effective, it may be continued indefinitely.

• Electrolysis or laser can remove any hair remaining after hormone therapy.

Remember: Not all Hirsutism is PCOS!

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• Will the darkening on my skin go away?

Yes, if you lose weight

Other treatment Options for acanthosis -Metformin-Oral contraceptive pill-Topical treatments e.g. tretinoin 0.05%, ammonium l t t % C l i t i l d h lli d l lactate 12% cream, Calcipotriol, podophyllin, adapalene, and salicylic acid (variable results)-Dietary fish oils-Dermabrasion and laser therapy in severe cases

Adigun CG, Pandya AG. Improvement of idiopathic acanthosis nigricans with a triple combination depigmenting cream. J Eur Acad Dermatol Venereol. 20Schwartz RA. Efficacy of topical 0.1% adapalene gel for use in the treatment of childhood acanthosis nigricans: a pilot study. Dermatol Ther. 2015 Jul

What your patient wants to ask• What about the large, painful bumps (hidradenitis

suppurativa) I have?pp

• Strong association between PCOS and insulin resistance and HS (38% of HS cases had PCOS)

• Apocrine gland-bearing areas have painful, deep-seated lesions and draining sinus tracts

Kraft JN, Searles GE Hidradenitis suppurativa in 64 female patients: retrospective study comparing oral antibiotics and antiandrogen therapy. J Cutan Med Surg 2007 Jul-Aug

draining sinus tracts

• Anti androgen therapy reduces recurrences

• May need antibiotics +/- surgical treatment

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• Will I be able to have children one day?• Will I be able to have children one day?

• Yes, BMI is a strong predictor of successfulpregnancy and childbirth but referral to fertility specialist may be needed

Pregnancy in PCOS: A challenge at each step

Poor Oocyte Quality

Abnormal endometrium

Hyperinsulinemia effects

?EPL, CI, GDM, HTN effects

Heijnen EM et al. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006Legro RS. Pregnancy considerations in women with polycystic ovary syndrome. Clin Obstet Gynecol. 2007

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PCOS: Reproductive Implications

• BMI reduction and maintenance

• Ovulation induction options in PCOS include lifestyle modification, clomiphene, metformin, gonadotropins

• Newer options such as letrozole available

? M tf i li it d l d b t ti • ? Metformin- limited role, debate continues

Legro RS et al. The pregnancy in polycystic ovary syndrome study: baseline characteristics of the randomized cohort including racialeffects. Fertil Steril 2006

Tang T et al Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol)for PCOS, oligo amenorrhoea and subfertility Cochrane Database Syst Rev 2012

Richard S. Legro et al. Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome N Engl J Med 2014


• Will my periods become regular one day without medication?

It is possible, particularly with lifestyle changes

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Adolescent PCOS:Implications for Management

Does early intervention improve outcome?

Lass N, et al. Effect of lifestyle intervention on features of PCOS, metabolic syndrome, and intima media thickness in obese adolescent girls.JCEM November 2011.

59 obese girls with PCOS aged 12–18 years1-yr lifestyle intervention

Main Outcome Measures: Intima media thickness (IMT), metabolic screening

Outcome: 33 girls lost weight (mean –BMI 3.9 kg/m2), 26 girls did notWt. Loss Group: Menstrual regularity, insulin, testosterone, IMT

What your patient wants to know

• You mentioned, hormone imbalance. Am I a girl?

Yes, both boys and girls have boy and girl hormone. The ratio of boy hormone may be slightly higher in PCOS but you still have more girl hormone than boy and are a girl.

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What your adolescent patient would like to know• What else am I at risk of?

Obstructive Sleep ApneaFatty Liver Disease

Both of these should be screened for, particularly p yin the obese.Reduction in weight and adoption of healthy lifestyle improves the above

What your patient wants to know• What else am I at risk of?

-Depression (33%) Higher risk of anxiety (13-16%), somatization, eating disorders (7%)

-Discussion of maintenance of healthy lifestyle should be ‘sensitive’ d/t propensity to develop disordered eating

Annagür BB et al. Psychiatric comorbidity in women with polycystic ovary syndrome. J Obstet Gynaecol Res.2015

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Recommended testingBiochemical testing of hyperandrogenism

h d R l C i l -17 hydroxyprogesterone- Rule out Congenital adrenal hyperplasia (non classic form)-DHEA-S – Rule out adrenal tumor-Total and free/bioavailable testosterone- confirm diagnosis of PCOSI f hi ti th t t l f In presence of hirsutism, the total or free testosterone concentrations at upper end of normal can be indicative of PCOS

Recommended testing

• Documentation of Polycystic Ovarian Morphology

-Not always necessary-Obtain if biochemical testing is borderline

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Recommended testing

Screening for associated co-morbidities-OGTT 2 hour-Lipid panel-Liver function tests-Sleep studyp y-PHQ-9 and screening questions for mood concerns-Confidential interview is essential

Adolescent PCOS: Summary

• Adolescence is a high risk group

i i i diffi l i d l d/ l i h b• Diagnosis is difficult in adolescence d/t overlap with puberty changes

• Once diagnosis is confirmed, screening for metabolic risk (BP, 2 hour OGTT, lipid screen etc.) is essential in BOTH lean and obese

Ad l h di h di i d • Adolescents have many concerns regarding the diagnosis and significant psychiatric pathology may co-exist

• Early intervention may improve outcomes

f1 honest hairy truth - cdn.ymaws.com · implications for management adolescents 15–19 years (n =...

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