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Volume 2 | Issue 3 | Oct. 2017-Jan. 2018 | Pages 12

...The Newsletter of The PCOS Society of India

■ EditorialPage 03

■ Defining PCOS: What is NormalAnyway?– Ricardo AzzizPage 04

■ Events and Updates –Travelling Seminars on"Understanding PCOS"Page 06

■ Polycystic Ovary Syndrome inAdolescents: Diagnostic Challengesand Emerging Treatments– Kathleen M HoegerPage 08

■ Does L-Carnitine have a Role to Playin PCOS Management?– Dr. Padma Rekha JirgePage 10

■ Announcing 3rd InternationalConferencePage 11

■ New patrons, Life membersPage 12

Professor Robert J Norman■ Professor of Reproductive and Periconceptual

Medicine, Robinson Research Institute, TheUniversity of Adelaide

■ Visiting Medical Specialist in ReproductiveEndocrinology and Infertility Royal AdelaideHospital

■ Co-Director NHMRC Centre for ResearchExcellence in Polycystic Ovary Syndrome

ONLY 100 REGISTRATIONS

Professor Chandrika N Wijeyaratne■ Professor in Reproductive Medicine, Faculty

of Medicine, University of Colombo■ President Sri Lanka Medical Association

2017■ Laureate Awardee for International

Excellence, Endocrine Society of USA 2017

Professor Helena Teede■ President of the Androgen Excess &

PCOS Soceity■ Executive Director Monash Partners Academic

Health Research Translation Centre■ Director Monash Centre for Health Research and

Implementation Monash University■ Chair of the PCOS International Guideline

development group

VENUE: The Lalit, MumbaiDATE: 24th & 25th March 2018

on

Present

& INFERTILITYPCOS

INTERNATIONAL FACULTY

For Registration log on to WWW.PCOSINDIA.ORG

on First ComeFirst Serve Basis

March 24th, 2018■ Introduction Duru Shah, Rob Norman

■ What is PCOS? Is it diagnosed correctly and have we got the name wrong? Helena Teede

■ Phenotype / Genotype in Asians v/s Caucasians CN Wijeyaratne (Sri Lanka)

■ What should we measure in PCOS and how? Androgens, Insulin, AMH and LH and Ultrasound Rob Norman

■ Interaction of Hyperinsulinemia and Hyperandrogenemia – How does it affect Infertility Management? Helena Teede

■ Genes versus environment as aetiology Rob Norman

March 25th, 2018

■ Assessment of Insulin Resistance – Should it be Clinical or Biochemical? CN WijeyaratneBest methods to treat Insulin Resistance

■ Ovulation Induction Agents – The best and the worst Rob Norman

■ Optimising IVF outcomes and reducing complications in PCOS TBC

Morning coffee break

■ Pre-conception – Lifestyle and dietary interventions Helena Teede

Case discussion on■ Pregnancy loss in PCOS TBC■ Treatment of the Metabolic Syndrome in PCOS CN Wijeyaratne

Lunch and ‘Meet the Professor’ – Sessions

■ Case discussion on Infertility Management TBC

■ Analyzing the systemic reviews and meta-analysis in PCOS Helena Teede

■ How to set up a PCOS Clinic and Practice Evidence – based Treatments? Helena Teede, Rob Norman

■ Collaborations in Research Rob Norman, Helena Teede

Valedictory

Editorial

Dr. Duru ShahMD, FRCOG, FCPS, FICS, FICOG, FICMCH, DGO, DFPDirector, Gynaecworld, The Center forWomen’s Fertility & Health, MumbaiPresident, The PCOS Society (India)Chief Editor, Pandora

Editorial Team

Dr. Sabahat RasoolMD, DNB, MNAMS, FMAS, MRCOG (UK)Ian Donald Diplomate in OBGY Ultrasound, CroatiaFertility Consultant, Gynaecworld, MumbaiAssociate Editor, Pandora

Ms. Rochelle LoboAdministrative Assistant

Email: thepcossociety@gmail.comwww.pcosindia.orgDisclaimer – Published by the The PCOS SOCIETY (INDIA).Contributions to the editor are assumed intended for thispublication and are subject to editorial review andacceptance. PANDORA is not responsible for articlessubmitted by any contributor. These contributions arepresented for review and comment and not as a statementon the standard of care. All advertising material is expectedto conform to ethical medical standards, acceptance doesnot imply endorsement by PANDORA.

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Duru ShahFounder President, The PCOS Society, IndiaEditor, Pandora

A Very Happy New Year to all of you!

2017 has been a very exciting year for the PCOS Society of India. Following the Very successful AnnualCongress organized by Dr. Madhuri Patil in Bengaluru in June, 2017, we have had various "TravellingSeminars" on "Understanding PCOS" all over the country. The response has been tremendous and thepictures inside will tell you and speak for themselves! We must thank Ms. Farida Hussain and team of USVwho have contributed to 65 such programs, of which we have completed 30 as of date. Dr. Uday Thanawallahas been in charge of this program, which he has been taking forward very effectively.

Our "Online CertificateProgram" of the "PCOSTutorials" is in its last phase,with 5 Modules available onlineand in print, and the sixth, ie.the last one, is ready to goonline / print. We will soonannounce the final date of the

Certificate Exam. All those who complete the Six Modules and clear the exams, will be offered a Certificateat the Convocation which we will host at the Annual Conference to be held on 22nd to 24th June 2018. inGurugram. The details of this meeting are available on our websitehttp://www.pcosindia.org/ Dr. RaginiAggarwal is the Chair of the local Organizing Committee in Gurgaon and she and her team are workinghard to make this conference a success!

I am delighted to let you know thatIndia was represented by the PCOSSociety of India for the developmentof the PCOS International Guidelines.The Guidelines have been developedby an alliance of various professionalorganizations including AmericanSociety for Reproductive Medicine (ASRM),European Society of Human Reproduction & Embryology (ESHRE),Centre for Research Excellence in Polycystic Ovary Syndrome (CRE-PCOS) and the PCOS Society of India. TheMeeting of the Guidelines was spread over 4 full working days and was intense with the Document beingunder preparation. The entire collaboration is being led by Prof. Helena Teede who is currently the Presidentof the AEPCOS Society and she will be presenting the final approved Guidelines at the forthcoming AnnualESHRE meeting in Barcelona between 1st and 4th July, 2018.

The PCOS Society of India has also beenworking on a Consensus Statementinvolving 7 major Organizations on "Theuse of Oral Contraceptive in IndianPCOS Women". The Document will beready for publication soon and will besent to all of you. We thank Ms.TinaBhatia and the entire team from Ciplafor their support towards this program.

Another exciting program coming up soon is the Master Class on "PCOS and Infertility", organized by thePCOS Society of India in collaboration with the Centre for Research Excellence in Polycystic OvarySyndrome(CRE-PCOS), and the Indian Society of Assisted Reproduction (ISAR) to be held on 24th/ 25th March,2018 at the Hotel Lalit in Mumbai. This will truly be a Master Class with the Masters in PCOS addressing the100 delegate-class room. Please have a look at the Proposed Program in this very Newsletter and registerearly, as registrations will close at 100 delegates! We thank Mr. Rakesh Mehta of Torrent Pharmaceutical fortheir support towards this program.

We have some excellent articles in this issue from 2 Past Presidents of the AE-PCOS Society, both RicardoAzziz and Kathleen M. Hoeger have been faculties for our PCOS Conference and are internationally acclaimedfor their work on PCOS. The article by our own member Dr. Padmarekha Jirge is on a subject not discussedbefore, but definitely needs attention.

I must thank Torrent Pharma for having partly supported this Newsletter which is truly a "Pandora's Box"

Looking forward to seeing you all somewhere, sometime this year, but definitely at the Annual Conferencein Gurugram!

With warm regards

Ricardo AzzizDept. of Obstetrics & Gynecology,Albany Medical College, Albany The State University of New York(SUNY) System Administration,Albany, New York

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The Polycystic Ovary Syndrome (PCOS) is the singlemost common endocrine disorder of reproductive-

aged women and perhaps all humans. It affects,depending on diagnostic criteria used, between 5and 15% of reproductive-aged women (some

investigators even claim that it may affect up to 20%of women using the broadest of the definition used– Rotterdam 2003). However, and much more

importantly than what criteria is used, is the factthat PCOS is defined by a combination of featuresthat include hyperandrogenism (HA), either

biochemical or clinical, and ovarian dysfunction,including oligo-anovulation (OA) and polycysticovarian morphology (PCOM). Combinations of these

four features results in four recognized phenotypesof PCOS namely, Phenotype A, also known as"classic" or "complete" PCOS (HA+OA+PCOM);

Phenotype B, also a form of "classic" PCOS, withoutPCOM (HA+OA); Phenotype C, also known as"ovulatory PCOS" (HA+PCOM), and the more

heterogeneous and less certain Phenotype D, alsoknown as "non-hyperandrogenic PCOS"(OA+PCOM)1.

Identifying the phenotypes of PCOS, and diagnosingPCOS depends greatly on how well one is able todefine the four features that make up the syndrome,

biochemical HA, clinical HA, OA and PCOM. Forexample, biochemical HA is usually defined by asingle measurement of circulating androgen levels

(i.e. hyperandrogenemia), but could be defined by24-hour urinary excretion of androgen metabolites,or multiple repeat blood measurements, etc. If we

focus solely on the single blood measure, for practicalpurposes, then questions will arise concerning whichandrogens (or androgen metabolites) to measure.

And importantly, how best to assay for theandrogens.The same goes for how we define clinicalHA (usually by the presence of hirsutism measured

by the visual modified Ferriman [mFG] scoringmethod), AO (usually by the degree of menstrualdysfunction reported), or PCOM (usually based on

the number of cysts 2-9 mm in diameter or theovarian volume, detected ultrasonographically in atleast one ovary).

What we rarely consider is how do we define whatis abnormal? Or more specifically, what is normal?

For androgen levels, we often take whatever themanufacturer or the laboratory provides as the'normal range'. For hirsutism, we often use the mFGscore value of 8 or greater, as initially reported by

Hatch and colleagues2 based on the original 1961

Defining PCOS: What is Normal Anyway?data of Ferriman and Gallwey3. For PCOM we use

the definition as stated in the original Rotterdam2003 statements4. But are these accurate? Do thesereally define what "normal" is and, consequently,

what "abnormal" is? Probably not.

Let us use two examples, to illustrate this issue. First

and as we mentioned, clinical hirsutism is usuallyassessed by the presence of hirsutism, which in turnis assessed by the mFG scoring method. The mFG

visually assesses for presence of terminal hairs (i.e.those hairs that would grow longer than 5 mm ifleft unmolested, are medullated under the

microscope, and often have varied shapes and color),in nine areas of the body where terminal hair growthis present primarily in men (upper lip, chin and upper

neck, mid-chest, upper abdomen, lower abdomen,upper back, lower back, upper arms, and front andback of thighs/buttocks). Scores are given from 0 to

4, where '0' means no terminal hairs are seen (it isusually left blank in the scoring sheet - Figure 1), '1'means barely visible terminal hairs are seen in the

skin area, '2' is more than just visible, but less thanthat of a man, '3' is equivalent to a less hairy man,and '4' is when the terminal hair growth in the bodyarea is the same as that of a hairy man. The scores

of all the body parts are then summed to obtain the'mFG score'. A color atlas has been published to assistin standardizing the scoring5.

The question that we should ask then is what thecut-off is to distinguish patients that are 'hirsute (i.e.

suffer from having too much terminal hair growthon their bodies in a male pattern) from those thatare not. Ferriman and Gallwey noted in their original

1961 study, that of 161 English white women ages18-38 years assessed, a total "hormonal" score (i.e.the sum of the nine body areas, as mentioned above)

above 5 was observed in 9.9%, a score above 7 in4.3%, and a score above 10 in 1.2% of subjects.

percentile cut-off as 5% of either the bottom (lower

limit) or the top (upper limit) values. However, thechoice of "5%" (or 10%, etc.) is often basederroneously on two unrelated concepts. First, if we

assume that the distribution of values follows aGaussian (normal distribution) curve, whereby 2.5%

F e r r i m a nsubsequently used an mFG

score of 5 or more as defining 'hirsutism'6,7.

However, in a subsequent review (which included anice graphical representation of the mFG score -making the article much more citable), Hatch and

colleagues defined 'hirsutism' as a score of 8 or morebecause "Only 5% of premenopausal women havea score of 8 or more" based on the original Ferriman-

Gallwey data2.

However, defining "abnormal" by percentile isproblematic. More often, we choose the specific

of upper and lower values are considered 'extreme'.

However, values in endocrinology (and in humansin general) often do not follow a Gaussiandistribution, as for example the mFG score3,8.

Secondly, we hark back to the 'p value' that we useto define 'significance' in biological experiments, i.e.0.05 or 5%. However, both of these approaches havelittle to do with defining a 'disease state'.

In fact, we would not define the presence of type 2diabetes mellitus (T2DM) by the 5% of a population's

fasting blood sugar (FBS) levels (which would becloser to 160 mg/dL) or define obesity by the 5th

percentile of the body mass index (BMI) distribution

in a population, or define hypertension by the 5th

percentile of diastolic (or systolic) blood pressures ina population? Or that of many other disorders9

because percentile often has nothing to do with'disease'. The definitions of T2DM, obesity,hypertension and much more are based on whether

the specific measures and cut-off values define apopulation that is 'sicker' or more 'disease-prone'.For example, a FBS of 126 mg/dL (by ADA standards)

identifies individuals who will have a much higherrisk of microvascular and other complications in laterlife. And a BMI of 30 kg/m2 or more identifies

individuals who have a much greater risk of T2DM,and other metabolic and cardiovascular dysfunction.And so on.

So what is then the 'true cut-off' value for an mFGscore that defines 'abnormal' or 'disease state'? Toanswer this question we studied the mFG distribution

in 283 unselected White and 350 unselected Blackwomen8. Using variations of cluster analysis (astatistical test that helps identify 'groupings' or

'clusters' of subjects that are more similar) we wereable to identify two groups: women who had mFGscores of 2 or less and women with scores of 3 or

more. Overall, an mFG score of at least 3 wasobserved in 22.1% of all subjects (i.e. the upper

5

quartile); of these subjects, 70% complained of beinghirsute, compared with 16% of women with an mFG

score below this value, and similar to the proportionof women with an mFG score of at least 8 whoconsidered themselves to be hirsute (i.e. 70.0%). In

addition, almost 60% of women with a mFGscoreof 3 or more used some form of cosmetic treatmentfor unwanted hair, compared to 42% of women. In

a separate study, over 50% of 228 consecutivepatients presenting with minimal unwanted hairgrowth (mFG scores of 1 to 5) had an androgen

excess disorder, notably PCOS10. Overall, these datasuggest that an mFG score of 3 or more indicates'abnormal' or 'disease state'. These data are

consistent with that of other studies in Caucasianwomen (see discussion in reference 8).

Of note, in our study there were no significant

differences between Black and White women8.Furthermore, in a cross-sectional, population-basedstudy of a representative sample of 2,988 women

aged 20-45 years from the general population ofSouthern China, cluster analysis identified a mFGscore of 5 or more as the cut-off value that

defined'abnormal' terminal facial and body hairgrowth in a male pattern (i.e., hirsutism), with aprevalence of hirsutism in that population of

10.5%11. Consequently, it appears that in womenof Black, White and East Asian descent, a mFG scoreof 3 to 5 or more denotes 'abnormal' or 'disease

state', with little racial difference, although theprevalence of hirsutism may vary by race.Consequently, the use of an mFG of 8 or more simply

will miss many affected women.

A similar finding applies to the measurement ofandrogens in the circulation. 'Abnormal' cut-off

levels denoting an 'abnormal' orhyperandrogenemia' population can be establishedin two manners. The first is to assess the androgen

levels of 'super controls', i.e. women who have beenverified carefully to be healthy "normal" (confirmedregular predictable ovulation, absence of polycystic

ovaries, mFG scores of 0 to 2, etc.). In this populationthe 'upper normal limit' is the maximum androgen

levels exhibited by the population of 'supercontrols', although in order to account for spuriouslaboratory values we often take the 95th to the

98th percentile of all values (assuming at least100 'super controls' have been studied). Weused this approach in our early epidemiologic

studies12.

The alternative approach is similar to thatobtained for the mFG score, i.e. a large

population of unselected women is assessed andthen cluster analysis is performed to identify

'natural' groupings. Investigators in China and Iran,

among others, have used this approach in Chinesewomen13-15. Of concern, in one study of 127laboratories in 47 states in the U.S., only 9% of

laboratories, where in-house total testosteronetesting was performed, created a reference rangeunique to their region16. Most, if not all, used mean

plus two standard deviations to define the 'uppernormal limit'.

One final caveat. Regardless

of approach at determining'cut-offs', their accuracy indifferentiating 'normal' from

'abnormal' depends a lot onhow much overlap there is inthe parameter of interest between 'healthy' and

'diseased' populations. For the mFG score thisappears to be somewhat modest. Alternatively, forandrogen measures (total or free testosterone,

androstenedione, DHEAS, etc.) this can besignificant, owing to wide spread of androgen levelsin the normal population. Consequently, even when

a cut-off is defined carefully thisvalue may not sufficeto identify 'diseased state'.

In summary, when defining any complex disorder,

be it T2DM, obesity, hypertension, cardiovasculardisease, metabolic syndrome, or PCOS, it is criticalthat we understand very well the

limitations of defining theseaccording to the parameters wemeasure including assay

selected, assay quality, and, veryimportantly, normative ranges. Asimple percentile (or for that

matter, mean plus SD),particularly when applied to ageneral or unselected

population, is a poor method fordistinguishing 'normal' from'abnormal'. Those of us who

practice endocrinology and wantto ensure the highest degree ofaccuracy to our investigations

and the best care for our patientsshould not hesitate indemanding well defined 'normal

ranges' for the tools we use.

References1. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L,

Azziz R. Criteria, prevalence, and phenotypes of polycystic ovarysyndrome. Fertil Steril. 2016;106:6-15.

2. Hatch R, Rosenfield RL, Kim MH, Tredway D. Hirsutism:implications, etiology, and management. Am J Obstet Gynecol.1981;140:815-30.

3. Ferriman D, Gallwey JD. Clinical assessment of body hair growthin women. J ClinEndocrinolMetab. 1961;21:1440-47.

4. The Rotterdam ESHRE/ASRM-Sponsored PCOS consensusworkshop group. Revised 2003 consensus on diagnostic criteriaand long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81:19-25.

5. Yildiz BO, Bolour S, Woods K, Moore A, Azziz R. Visually scoringhirsutism. Hum Reprod Update. 2010;16:51-64.

6. Ferriman D, Purdie AW. Association of oligomenorrhoea,hirsuties, and infertility. BMJ 1965; 2:69-72.

7. Ferriman D, Purdie AW. The aetiology of oligomenorrhoea and/or hirsuties: A study of 467 patients. Postgrad Med J. 1983;59:17-20.

8. DeUgarte CM, Woods KS, Bartolucci AA, Azziz R.Degree offacial and body terminal hair growth in unselected black andwhite women: toward a populational definition of hirsutism. JClinEndocrinolMetab. 2006;91:1345-50.

9. Schwartz LM, Woloshin S. Changing disease definitions:implications for disease prevalence. Analysis of the ThirdNational Health and Nutrition Examination Survey, 1988-1994.EffClinPract. 1999;2:76-85.

10. Souter I, Sanchez LA, Perez M, Bartolucci AA, Azziz R. Theprevalence of androgen excess among patients with minimalunwanted hair growth.Am J Obstet Gynecol. 2004;191:1914-20.

11. Zhao X, Ni R, Li L, Mo Y, Huang J, Huang M, Azziz R, Yang D.Defining hirsutism in Chinese women: a cross-sectional study.Fertil Steril. 2011;96:792-6

12. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, BootsLR, Azziz R. Prevalence of the polycystic ovary syndrome inunselected black and white women of the southeastern UnitedStates: a prospective study. J ClinEndocrinolMetab.1998;83:3078-82.

13. Zhao X, He Z, Mo Y, Chen X, Chen Y, Yang D. Determining thenormal cut-off levels for hyperandrogenemia in Chinese womenof reproductive age. Eur J ObstetGynecolReprod Biol.2011;154:187-91.

14. Zhou Z, Ni R, Hong Y, Li Y, Wang Y, Zhao X, Yang D. Defininghyperandrogenaemia according to the free androgen index inChinese women: a cross-sectional study. ClinEndocrinol (Oxf).2012;77:446-52.

15. Hashemi S, RamezaniTehrani F, Noroozzadeh M, Azizi F. Normalcut-off values for hyperandrogenaemia in Iranian women ofreproductive age. Eur J ObstetGynecolReprod Biol. 2014;172:51-55.

16. Le M, Flores D, May D, Gourley E, Nangia AK. Current practicesof measuring and reference range reporting of free and totaltestosterone in the United States.J Urol. 2016;195:1556-61.

FIGURE LEGENDFig. 1.The modified Ferriman-Gallwey (mFG) scoring system for hirsutism.Seetext for description of how the scoring is performed (copyright 2005 by RicardoAzziz, reproduced with permission).

Events and Updates

The PCOS Society's Travelling Seminars on "Understanding

PCOS" are aimed at educating the treating gynaecologists about

the basics of the multifaceted disorder called PCOS. This "Travelling

Seminar" was conceptualized to bring to your door steps the latest

and best evidence-based medicine for preventing and treating the

various symptoms and health consequences arising from PCOS

through exhaustive interactive sessions and case discussions. Experts

from the PCOS Society, India, have been delivering lectures in various

parts countrywide. The Travelling Seminars are being conducted

with an unconditional educational grant from USV and till December,

2017, twenty one travelling seminars have been conducted

throughout the various states of the country.

BARODA GUNTUR

HAZARIBAGH

COIMBATORE HOOGLY

DHANABAD IMPHAL

November 19th 2017Dr. Uma ShankarDr. Ch AnithaDr. N SujataDr. Sushmita

November 12th 2017Dr. Ranjana SharanDr. Samir HazraDr. Soumya Srivastava

November 18th 2017Dr. Ananda ChatterjeeDr. Partha Mukherjee

September 23rd 2017Dr. James ElanybumDr. Arun BaruahDr. L Ranjit SinghDr. Digel Singh

September 23rd 2017Dr. Andaleeb AgarwalDr. Sunita ChandraDr. Sumati saxenaDr. Manju Verma

Dr. Duru ShahConvenor

Dr. Uday ThanawalaConvenor

ALLAHABAD

BEHRAMPUR

September 17th 2017Dr. Minaxi PatelDr. Manoj PandyaDr. Vipul KapadiaDr. Binal ShahDr. Poorvi Patel

October 11th 2017Dr. Bharti MisraDr. Sujata KarDr. Sanghamitro MohapatraDr. Nina Misra

October 6th 2017Dr. MirudhubashiniGovindarajanDr. Pramya NDr. GeethaDr. Ramya Jeyaram

October 14th 2017Dr. SK DasDr. Pratibha RoyDr. NM Das

6

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JORHAT SALEM

MIDNAGPUR SAMBALPUR

NASIK SATARA

PURNEA THANJAVUR

RANCHI THANE

RATLAM TRICHY

October 21st 2017Dr. RK TalukdarDr. Arum BaruahDr. Amal PhulkanDr. Ranjan K Mahanta

October 25th 2017Dr. KK DharaDr. AK MaliickDr. Dipankar Mondal

August 12th 2017Dr. Ranjit JoshiDr. Vikranti More

October 7th 2017Dr. Bibha JhaDr. Poonam RamanDr. Gopi Bhagat

October 15th 2017Dr. Renuka SinhaDr. Usha RaniDr. Usha MadhulikaDr. Samrina Alam

October 1st 2017Dr. Dolly MehraDr. Nivedita Dashore

September 24th 2017Dr. Vidhya PrabhakaranDr. Vani PujariDr. Premkumar

November 5th 2017Dr. Ojoswini PatelDr. Pyarilal TripathiDr. Sarmila PradhanDr. Narahari Agasti

October 4th 2017Dr. Sanjay JadhavDr. Mahananda ShiteDr. Manisha ThoratDr. Kiran SonvalkarDr. Sadhna DharmadhikariDr. Shirish Phadke

October 8th 2017Dr. TamilmaniDr. PadmapriyaDr. ShreelakshmiDr. ArchanaDr. Lakshmi Prabha

September 9 th 2017Dr. Alka GodboleDr. Mini NampootriDr. Roopa ShettyDr. Bharati Moorey

October 29th 2017Dr. Sripriya PragasamDr. VanithlDr. Punitha RajeshDr. PriyankaDr. Gladys Kamaraj

Kathleen M HoegerMD, MPHProfessor of Obstetrics and GynecologyUniversity of Rochester Medical Center

Polycystic Ovary Syndrome in Adolescents:Diagnostic Challenges and Emerging Treatments

Diagnosis of PCOSClinical criteriaThe diagnosis of PCOS in adult women is based uponclinical criteria including 2 of the following:hyperandrogenism, menstrual dysfunction and/orfindings of PCO morphology on ovarian ultrasound2.These criteria are difficult to assess in adolescentwomen due to overlap with normal physiology ofmenstrual cycles immediately post menarche, and lackof definitive diagnostic profile. Nonetheless it isimportant to identify girls who may demonstratedefinitive pathology to allow for best management atthis crucial developmental stage. If diagnosis is notable to be definitively established however, it is bestto identify these adolescents as "at risk for PCOS"and reexamine at regular intervals for definitivediagnosis, even if treatment is indicated for otherconcerns.

In adolescent women immediately post menarche,menstrual dysfunction is physiologic, with the majorityof menstrual cycles falling out of the 28 day ovulatoryframework in the first 1-2 years. It is however unusualfor irregular cycles to persist more than 2 years in anormal adolescent. Therefore irregular bleedingpresenting more than 2 years after menarche, or lackof menses more than 2 years after thelarche shouldbe investigated in the adolescent. In a populationbased study, 51% of girls who were oligo-amenorrheicat 15 years remained so at age 18 years3. While cyclesare often irregular in adolescence, it is also importantto note that many are ovulatory and ovulation isdifficult to predict, so unintended pregnancy is stillpossible despite menstrual irregularity.

Evaluation of androgen excess is challenged in theadolescent. The visual scoring system most commonlyused in the evaluation of hirsutism, the modifiedFerriman-Gallaway (FG) score4, has not been wellstudied in adolescence nor in multiethnic groups so itis not clear what a valid cutoff would be to definehyperandrogenism. Currently a cut off of >7 on theFG score is hirsute but this may underestimate theprevalence. Hirsutism must be differentiated fromhypertrichosis which is defined as excessive vellus hairdistributed in a non-sexual pattern. This is notandrogen related. Acne is a common problem inadolescence but is usually transient and not anindication of hyperandrogenism. Severe, cystic acnemay be related to hyperandrogenaemia however.Alopecia is uncommon and not felt to be a part of thediagnostic criteria for PCOS in adolescents. From abiochemical assessment perspective, there are no goodreference ranges for testosterone in adolescent womenand normative values are not clear with the literaturesupporting both <42 and <55 ng/dL as normal inadolescents depending on the assay. In fact adolescenttransient hyperandrogenaemia is a feature of thedeveloping hypothalamic-pituitary-ovarian axis duringpuberty, making androgen assays difficult to interpretin adolescents. Androgen abnormalities are seen earlyin the development of PCOS in adolescents however5.

The presence of enlarged ovaries with increasednumber of follicles is known as PCO morphology orPCOM. An ultrasound diagnosis in adolescent women

is difficult since many normal young women will haverobust follicular presence and ovarian volumes, whichmay overlap with the diagnostic criteria for PCOM.Using the older criteria, ultrasound diagnosis ofpolycystic ovary includes more than 12 follicles and/oran increased volume of 10ccs in at least one ovary6.This was updated in the Androgen Excess PCOS(AEPCOS)7 Society task force recommendation to morethan 24 follicles. Criteria were primarily establishedfor transvaginal ultrasound approaches and in manyyounger adolescents a transabdominal approach isused, with some loss in resolution, making distinctionbetween normal and abnormal difficult. It is notcurrently recommended that ultrasound criteria beused to define PCOS in adolescence as a primarycriterion.

Hormonal evaluationThe work up when PCOS is suspected should includean assessment of other endocrine disorders includingan evaluation of thyroid function and prolactin levelsin the presence of menstrual dysfunction. Late onsetcongenital adrenal hyperplasia due to 21-hydroxylasedeficiency can mimic the symptoms of PCOS. Amorning serum 17-hydroxyprogesteroneconcentration can be used as a screening test and ifelevated, can be followed up with an ACTH stimulationtest for diagnosis of congenital adrenal hyperplasia. Ifclinical hyperandrogenism is not clearly seen,biochemical assessment using serum testosteroneconcentration should be measured. However, thereare notably significant concerns with the reliability ofthe assay in the low ranges8. Free testosterone valuesare very unreliable as measured by radioimmunoassaywithout extraction. Methodological problems withall testosterone assays exist and mostrecommendations advocate using a high quality liquidchromatography/tandem mass spectrometry (LC-MD/MS) but other high quality assays with extraction canbe acceptable. At this time no clear cutoff is availablein the literature but available guidelines range from>42-55 ng/dL as consistent with hyperandrogenaemia.An assessment of sex hormone binding globulin(SHBG) may allow for an estimation of the freehormone concentration9. FSH level should bemeasured if there is a concern related to the possibilityof premature ovarian insufficiency. While it is notedthat in adolescents with PCOS there is often asignificant adrenal androgen component at the timeof adrenarche, measurement of other serum androgenconcentrations is not necessary in the diagnosis ofPCOS.

Pathophysiology of PCOSThe pathophysiology of PCOS is complex with impacton multiple systems. Overall there are several keyfeatures although the underlying disorder is associatedwith excessive androgen production, primarily fromthe ovary, although adrenal androgens may beelevated as well10. The key pathophysiologic featuresinclude 1. primary ovarian pathophysiology,2.hyperinsulinemia/insulin resistance, 3.neuroendocrine alterations, 4. genetics/epigenetics, 5.altered sympathetic tone. Individuals may manifestdifferent aspects of these abnormalities.

Ovarian pathophysiologyThe human ovary contains 2-3 million primordialfollicles at birth and there is control of the number offollicles that enter the ovarian cycle following pubertyto maintain an ovarian follicular reserve11. In PCOS thebalance between androgen production by the follicles,Antimullerian hormone (AMH) and FSH is disorderedleading to follicular arrest and chronic anovulation.Therefore there is a growth of small follicles but asubsequent arrest of growth leading to the typical PCOmorphology on exam. Theca cells in PCOS appear todemonstrate increased steroidogenic production,particularly increased CYP171A or P450c17 activityleading to ovarian androgen overproduction12.

Hyperinsulinemia/insulin resistance (IR)IR is a common finding in PCOS and independent ofobesity or adiposity. This reflects the interaction ofgenetics, intra and extra-uterine environmental factorsand inherent difference in energy expenditure13.Puberty is a naturally insulin resistant state anddysfunction. Obesity at the time of puberty mayexacerbate this IR and lead to increase in peripubertalhyperandrogenism. This has significant implications formetabolic dysfunction in PCOS, particularly increasedglucose metabolism alterations.

Neuroendocrine alterationsOne of the hallmarks of PCOS is a deregulation ofFSH and LH in which LH secretion is favored leadingto increased LH:FSH ratio and increased LH pulsefrequency. LH is not however consistently elevated inall patients particularly in the presence of obesity. Itappears androgens may disrupt regulation of GnRH/LH with diminished negative feedback, particularly inprogesterone feedback leading to increased GnRHpulse frequency. More recently, it has been reportedthat there is altered kisspeptin signaling leading todisruption in the GnRH pulse generator14. Severalanimal models indicate a role for androgen in thisdisruption in PCOS models. The role in PCOS howeverhas yet to be fully elucidated. Other neuroendocrinesignals such as GABA, AMH, as well as adiponectinmay alter GnRH signaling in PCOS.

Genetics/epigeneticsThere is significant evidence of heritability of PCOSand with the advent of large Genome WideAssociation Studies (GWAS), there has beenelucidation of several candidate genes15. DENND1Aand FSHB genes have been implicated as abnormal inGWAS studies of PCOS. There is also evidence, viagenome wide methylation studies in PCOS, that thereare alterations seen in DNA methylation of genesassociated with abnormal steroidogenesis as well asmetabolic pathways and immune response pathways.Regulation of gene expression by microRNAs may alsoconstitute another source of epigenetic alterationleading to dysregulation.

Altered sympathetic toneAn altered sympathetic nervous system activity hasbeen proposed to contribute to the development of

Table 1. Metabolic Consequences ofPCOS in Adolescent Women

GlucoseIntolerance/Type 2 diabetes

Recommendedassessment

MetabolicFeature

Assessment of family history ofdiabetes. Administer 2 hour oralglucose challenge test at diagnosisin overweight / obese girls andperiodically there after.

Dyslipidemia Measurement of serum lipids atdiagnosis. If Triglycerides areelevated, monitor periodicallyespecially if treatment with oralcontraceptives is used.

Hypertension Blood pressure measurement atdiagnosis and regularly thereafter,particularly if managing on oralcontraceptives.

8

PCOS. There is evidence of high sympathetic activityin PCOS that is independent of BMI. Additionally thereis evidence of heart rate variability and recovery afterexercise in young women with PCOS16. Animal modelssupport increased sympathetic innervations in theappearance of ovarian cysts.

Metabolic consequences of PCOSInsulin resistance and diabetesAs noted above, the presence of insulin resistance (IR)is clearly evident in adolescents with PCOS17. Obesityis a confounding presence in PCOS, and obeseadolescents with PCOS will have marked insulinresistance and are at least a 3-fold increased risk fordevelopment of impaired glucose tolerance and type2 diabetes, even at an early age of diagnosis18. Thelifetime risk of developing diabetes is significantlyhigher in women with PCOS and it is recommendedthat evaluation for glucose abnormalities via OGTT bedone at the time of diagnosis and periodicallythereafter. However the diagnosis of IR is not necessaryin adolescents who are being evaluated for PCOS asthe clinical tools for assessing IR are confounded andtreatment does not vary whether or not this is present.

Metabolic syndrome and cardiovascular riskfactorsMetabolic syndrome, a constellation of increasedcardiovascular risk factors whose components includeserum triglycerides, HDL cholesterol, waistcircumference, fasting glucose and blood pressure, hasbeen shown to be more common in adult women withPCOS19. Dyslipidemia including increased triglyceridesand decreased HDL is common in PCOS, particularlyassociated with insulin resistance. There is someevidence that Metabolic Syndrome may be increasedin adolescent women with PCOS and related toandrogen excess20 but other studies suggest primarilya link with increased BMI17. In obese adolescents,measurements of serum lipids, blood pressure andscreening for risk factors for cardiovascular diseaseshould be performed at diagnosis and then at periodicintervals throughout adulthood.

Psychological manifestations and quality of lifeimpactThe onset of PCOS in adolescence, with its associatedfactors of excess hair growth, acne and increased riskof obesity, will impact the quality of life and self-imageof adolescent women with this disorder. There isevidence that adolescent women with PCOS havereduced quality of life21. Impact of concerns regardingweight are often most prominent in survey of qualityof life in adolescent women with PCOS22. Studies todate have shown an increased prevalence ofdepression and anxiety in women with PCOS23.Screening for depression and anxiety in the office inadolescents with PCOS can pick up these concernsearly.

Impact of obesityExcess weight and obesity are now prevalentconditions in adolescents all over the world24. It isunclear if the increasing rate of obesity influences thediagnosis of PCOS or whether the incidence isincreasing due to obesity. Nonetheless obesity is acommon finding in PCOS with a prevalence rate inseveral studies of more than 60%. The adolescent withPCOS and obesity is more likely to demonstrateincreased androgenic symptoms such as acne andhirsutism, more significant menstrual dysfunction andmetabolic disturbance such as impaired glucosetolerance and type 2 diabetes17.

Treatment of PCOS in adolescenceNot all adolescents presenting with menstrual concernsshould be labelled as PCOS and over diagnosis shouldbe avoided. The issues unique to treatment of PCOSin the adolescent patient include education about thediagnosis of PCOS, as well as the long-termimplications and strategies to prevent diseaseconsequences, and attention to the self-imageconcerns and possible mental health concerns that

emerge in adolescenceand shape the individualinto adulthood.Treatment options needto be tailored to thepresenting needs of theadolescent. The aims oftreatment should be toregulate menses, improveandrogenic concerns,assess and improvemetabolic status, withtreatment of lifestyleissues.

Obese or overweightindividuals should beginwith lifestylemodifications, as this canbe both primary therapyand reduce the chancesof long-termcomplications such astype 2 diabetes25. Thereare few studies thatexamine the success ofweight loss programs toaddress theconsequences of PCOS in adolescent women. Supportgroups and peer mentoring may be of advantage inmaintaining lifestyle choices. With weight reductionimprovement in serum androgens is noted and weightloss improves insulin resistance26. Maintenance ofimproved lifestyle changes is challenging but shouldbe emphasized and reinforced for long-term benefit.

The primary aim in treating menstrual dysfunctionshould be to control menorrhagia and protect theendometrium from risk of hyperplasia with regularprogestin exposure. Combination oral contraceptivesare a valuable tool in management of PCOS in theadolescent. Studies demonstrate satisfactory controlof menstrual cycles with combination oralcontraceptives as well as reducing serum testosteroneconcentrations with improvements in visual hirsutismscores27.

Symptoms of androgen excess can be quite distressingin the adolescent and use of regimens for androgensuppression should be considered due to the impactof androgen excess symptoms, such as acne orhirsutism on self-image. Antiandrogen treatment suchas spironolactone can be effective for acne andhirsutism, especially in combination with an oralcontraceptive28. While there are some data on use offlutamide and finasteride use as antiandrogens inadolescent women, these are associated with potentialfor liver toxicity and should not be routinely used forthis indication. Cyproterone acetate, a progestationalagent, is also reported, in combination OCs, to beantiandrogenic. These formulations are available onlyoutside the US.

Insulin sensitizing therapy such as use of metforminhas been studied in very limited fashion in adolescentswith PCOS. Studies using doses of 500mg to 2000mghave been reported26,29,30. Metformin can besuccessfully used in those with impaired glucosetolerance who have been unsuccessful with lifestylechanges and there may be some added benefit inmodest androgen reduction in obese adolescents whoare undertaking lifestyle changes. Metformin isassociated with a greater improvement in BMI overOCP alone31. Pioglitazone has been used in small seriesto improve insulin resistance but is associated withliver dysfunction and bladder cancer.

Dyslipidemia, particularly reduced HDL cholesterol andincreased triglycerides, may be increased in PCOS32.There is evidence that diet and lifestyle changes mayprovide improvement, however, there is no evidencethat metformin alone improves these parameters33.Oral contraceptives have been shown, in some studies,

to worsen hypertriglyceridemia, and triglyceridemeasurement should be followed in those withevidence of elevated triglycerides if oral contraceptivesare used27,34.

SummaryPCOS is a common disorder presenting in adolescenceand should be in the differential diagnosis for thosewith irregular menses persisting more than 2 yearspost menarche. Diagnosis is challenging but shouldbe based on signs and symptoms of hyperandrogenismin this setting. Since symptoms are worsened byobesity, attention to prevent and control obesity inadolescence is an important component in the longterm management of the disease. The practitionershould be aware of the increased risk of metabolicdysfunction, particularly impaired glucose toleranceand diabetes, and screen for these conditions withappropriate management, if found.

Attention towards management of the mostdistressing features of PCOS is most important inadolescence when lifetime habits and self-image areemerging. Additional research in diagnosis andtreatment approaches is needed for this complexcondition.

References1. Ibanez L, Oberfield SE, Witchel SF, et al. An International

Consortium Update: Pathophysiology, Diagnosis, and Treatmentof Polycystic Ovarian Syndrome in Adolescence. Horm ResPaediatr 2017; Vol.:307-331.

2. Revised 2003 consensus on diagnostic criteria and long-termhealth risks related to polycystic ovary syndrome (PCOS). HumReprod 2004; 19:41-7.

3. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA,Koppenaal C, Schoemaker J. Predictive value of menstrual cyclepattern, body mass index, hormone levels and polycystic ovariesat age 15 years for oligo-amenorrhoea at age 18 years. HumReprod 2004; 19:383-92.

4. Ferriman D, Gallwey JD. Clinical assessment of body hair growthin women. J Clin Endocrinol Metab 1961; 21:1440-7.

5. Burt Solorzano CM, McCartney CR, Blank SK, Knudsen KL,Marshall JC. Hyperandrogenaemia in adolescent girls: originsof abnormal gonadotropin-releasing hormone secretion. Bjog2010; 117:143-9.

6. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessmentof the polycystic ovary: international consensus definitions. HumReprod Update 2003; 9:505-14.

7. Dewailly D, Lujan ME, Carmina E, et al. Definition andsignificance of polycystic ovarian morphology: a task force reportfrom the Androgen Excess and Polycystic Ovary SyndromeSociety. Hum Reprod Update 2014; 20:334-52.

8. Rosner W, Vesper H. Toward excellence in testosterone testing:a consensus statement. J Clin Endocrinol Metab 2010; 95:4542-8.

9. Legro RS, Schlaff WD, Diamond MP, et al. Total testosteroneassays in women with polycystic ovary syndrome: precision andcorrelation with hirsutism. J Clin Endocrinol Metab 2010;

Continued on page 10

Presentation ■ Irregular menses more than 2 years post menarche■ And evidence of clinical androgen excess

Diagnosis ■ Measure serum testosterone with reliable assay(possibly SHBG) if unclear hyperandrogenic symptoms

■ Measure TSH, PRL, AM 17 hydroxyprogesterone, FSH■ If unclear define patient at at risk for PCOS but not

definitive and reassess

Confirmation ofabnormal profile

■ Assess other metabolic risk factors■ Determine if lifestyle intervention is feasible

Figure1: Flow diagram of diagnosis andmanagement of PCOS in adolescents

Irregularmenses

■ Consider combination oral contraceptive■ Intermittant progestin therapy

Hirsutism orsevere acne

■ Addition of antiandrogen suchas spironolactone

Obesity, Glucoseintolerance or diabetes

■ Focus on diet and exercise changes■ Metformin therapy

9

Dr. Padma Rekha JirgeMRCOG, FICOG, MBAIVF Specialist

Does L-Carnitine have a Role toPlay in PCOS Management?

10

IntroductionPolycystic ovarian syndrome (PCOS) is identified in 7-10% of women in their reproductive yearsand isassociated with hyperinsulinaemia1. Even though itsetiology in its entirety still remains an enigma,successful management of PCOS needs a multi-prongapproach, as no single management option includinglife style modification or oral hypoglycemic agents canreverse its diverse endocrine and metabolic changes.Role of amino acids are being studied for their effectin improving the metabolic status in PCOS.Carnitine is a trimethylamine synthesized in liver andkidney. Additionally, intestinal absorption from dietarysources such as red meat plays an important role inmaintaining its plasma concentration2. Recent interestin the possible role of L-Carnitine in the managementof PCOS stems from its physiological role in variousmetabolic pathways. It facilitates the transport of long-chain free fatty acids into mitochondria, so that theyare available for the most important metabolicpathway for energy production, ß-oxidation. Inaddition, carnitine plays a key role in glucosemetabolism and reduces the lipid induced insulinresistance. It is a potent antioxidant as well3.Clinical Evidence of Role of L-Carnitine inManagement of PCOSOne of the confounding factors influencing many ofthe manifestations of PCOS is indeed obesity. An earlystudy looking at the role of L-carnitine in PCOS showedthat non-obese women with PCOS have a lowerplasma concentration of L-Carnitine compared tohealthy controls. In addition, its level is negativelycorrelated with fasting insulin, HOMA-IR index andfree androgen index; and positively correlated to SHBG,suggesting that PCOS independently has a negative

effect on L-Carnitine levels 4. A more recent studycomparing obese and non-obese women with PCOSfound that women belonging to both these groupshad a significantly lower plasma L-Carnitine levels incomparison to healthy controls, but the negativecorrelation was limited to BMI and HOMA-IR index,suggesting that it is the obesity or insulin resistancerather than PCOS itself, which affects the L-carnitinelevels 5. However, in the current clinical scenario,physiological role of L-Carnitine in mitochondrialfunction and glucose metabolism, coupled with someevidence that women with PCOS have a low plasmalevels of L-Carnitine have raised the possibility that L-Carnitine supplementation may have a beneficial rolein the clinical management of PCOS. The clinicalevidence of benefits from L-Carnitine is limited to veryfew studies involving small numbers of women withPCOS at present. Evidence suggests that high dailydoses of L-Carnitine (2-4 gm per day) administeredover a period of a few weeks lead to reduction ininsulin resistance6,7. Women with PCOS, treated with250mg /day of L-Carnitine over twelve weeks haveshown a reduction in weight, BMI, waistcircumference, fasting plasma glucose and insulinlevels without any effect on androgens or lipid profile8.There is a single study published evaluating the roleof L-Carnitine in PCOS-related infertility. This involved85 women with Clomiphene Citrate (CC)-resistantPCOS who received 250 mg daily of CC from day 3 ofthe cycle through to day 7 along with 3 gm /day of L-Carnitine throughout the cycle. They were comparedwith another 85 women with CC resistance whoreceived the same dose of CC but with a placebo. Theresults showed that the rate of ovulation andpregnancy were significantly higher in the study groupcompared to the control group receiving placebo. Inaddition, over a period of twelve weeks there was asignificant improvement in the lipid profile and asignificant decrease in the BMI seen in the study group.ConclusionL-Carnitine plays an important role in the oxidativeprocess within the mitochondria and has a beneficialrole in glucose metabolism. Women with PCOS havelower plasma concentrations of L-Carnitine levels

compared to healthy non-PCOS women. WhetherPCOS in itself or the associated obesity is the causativefactor is unclear at present. However, administrationof L-Carnitine in women with PCOS is shown to reduceinsulin resistance and to improve the androgen andlipid profile, with weight loss and improvements inanthropometric measurements. A single study hasshown an improvement in ovulation and pregnancyrate in CC resistant women receiving L-Carnitine. It isimportant to evaluate whether its beneficial effectssurpass that of lifestyle modification and metforminin PCOS and effective dose and duration of therapy.This requires large randomized controlled trials withadequate sample size replicating the initial evidence.

References1. Diamanti-Kandarakis E, Dunaif A. 2012. Insulin resistance and

the polycys- tic ovary syndrome revisited: an update onmechanisms and implica- tions. Endocrine Research 33:981-1030.

2. Bremer J. Carnitine-metabolism and functions, Physiol Rev,1983;63:1420-1480

3. Power RA, Hulver MW, Zhang JY, Dubois J, Marchand RM,Ilkayeva O, Muoio DM, Mynatt RL. Carnitine revisited: potentialuse as adjunctive treatment in diabetes. Diabetologia2007;50:824-832

4. Fenkci SM, Fenkci V, Oztekin O, Rota S, Karagenc N. Serumtotal L-carnitine levels in non-obese women with polycystic ovarysyndrome.Hum Reprod. 2008;23:1602-6.

5. Celik F, Kose M, Yilmazer M, Köken GN, Arioz DT, Kanat PektasM. Plasma L-carnitine levels of obese and non-obese polycysticovary syndrome patients. J Obstet Gynaecol. 2017;37:476-479

6. Molfino, A., Cascino, A., Conte, C. et al.Caloric restric- tion andL-carnitine administration improves insulin sensitivity in patientswith impaired glucose metabolism. JPEN. Journal of Parenteraland Enteral Nutrition. 2010;34:295-299.

7. Ruggenenti, P., Cattaneo, D., Loriga, G. et al. Ameliorat- inghypertension and insulin resistance in subjects at increasedcardiovascular risk: effects of acetyl-L-carnitine therapy.Hypertension 2009;54:567-574.

8. Samimi M, Jamilian M, Ebrahimi FA, Rahimi M, Tajbakhsh B,Asemi Z. Oral carnitine supplementation reduces body weightand insulin resistance in women with polycystic ovary syndrome:a randomized, double-blind, placebo-controlled trial. ClinEndocrinol (Oxf). 2016;84(6):851-857

9. Jamilian H, Jamilian M, Samimi M, Afshar Ebrahimi F, Rahimi M,Bahmani F, Aghababayan S, Kouhi M, Shahabbaspour S, AsemiZ. Oral carnitine supplementation influences mental healthparameters and biomarkers of oxidative stress in women withpolycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Gynecol Endocrinol. 2017;33:442-447.

Continued from page 09Polycystic Ovary Syndrome inAdolescents: Diagnostic Challenges andEmerging Treatments

95:5305-13.10. Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome.

Nat Rev Dis Primers 2016; 2:16057.11. Hsueh AJ, Kawamura K, Cheng Y, Fauser BC. Intraovarian

control of early folliculogenesis. Endocr Rev 2015; 36:1-24.12. Marti N, Galvan JA, Pandey AV, et al. Genes and proteins of the

alternative steroid backdoor pathway for dihydrotestosteronesynthesis are expressed in the human ovary and seem enhancedin the polycystic ovary syndrome. Mol Cell Endocrinol 2017;441:116-123.

13. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and thepolycystic ovary syndrome revisited: an update on mechanismsand implications. Endocr Rev 2012; 33:981-1030.

14. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M.Kisspeptins and reproduction: physiological roles and regulatorymechanisms. Physiol Rev 2012; 92:1235-316.

15. Day FR, Hinds DA, Tung JY, et al. Causal mechanisms andbalancing selection inferred from genetic associations withpolycystic ovary syndrome. Nat Commun 2015; 6:8464.

16. Tekin G, Tekin A, Kilicarslan EB, et al. Altered autonomic neuralcontrol of the cardiovascular system in patients with polycysticovary syndrome. Int J Cardiol 2008; 130:49-55.

17. Rossi B, Sukalich S, Droz J, et al. Prevalence of metabolicsyndrome and related characteristics in obese adolescents withand without polycystic ovary syndrome. J Clin Endocrinol Metab2008; 93:4780-6.

18. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalenceand predictors of risk for type 2 diabetes mellitus and impairedglucose tolerance in polycystic ovary syndrome: a prospective,controlled study in 254 affected women. J Clin Endocrinol Metab1999; 84:165-9.

19. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, GhazziMN. Prevalence and Predictors of the Metabolic Syndrome inWomen with Polycystic Ovary Syndrome (PCOS). J ClinEndocrinol Metab 2005.

20. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycysticovary syndrome have an increased risk of the metabolicsyndrome associated with increasing androgen levelsindependent of obesity and insulin resistance. J Clin EndocrinolMetab 2006; 91:492-7.

21. Trent M, Austin SB, Rich M, Gordon CM. Overweight status ofadolescent girls with polycystic ovary syndrome: body mass indexas mediator of quality of life. Ambul Pediatr 2005; 5:107-11.

22. Harris-Glocker M, Davidson K, Kochman L, Guzick D, HoegerK. Improvement in quality-of-life questionnaire measures inobese adolescent females with polycystic ovary syndrometreated with lifestyle changes and oral contraceptives, with orwithout metformin. Fertil Steril 2010; 93:1016-9.

23. Dokras A, Clifton S, Futterweit W, Wild R. Increased risk forabnormal depression scores in women with polycystic ovarysyndrome: a systematic review and meta-analysis. ObstetGynecol 2011; 117:145-52.

24. Flegal KM, Ogden CL, Yanovski JA, et al. High adiposity andhigh body mass index-for-age in US children and adolescentsoverall and by race-ethnic group. Am J Clin Nutr 2010; 91:1020-6.

25. Hoeger KM. Role of lifestyle modification in the managementof polycystic ovary syndrome. Best Pract Res Clin EndocrinolMetab 2006; 20:293-310.

26. Hoeger K, Davidson K, Kochman L, Cherry T, Kopin L, GuzickDS. The impact of metformin, oral contraceptives, and lifestylemodification on polycystic ovary syndrome in obese adolescentwomen in two randomized, placebo-controlled clinical trials. JClin Endocrinol Metab 2008; 93:4299-306.

27. Creatsas G, Koliopoulos C, Mastorakos G. Combined oralcontraceptive treatment of adolescent girls with polycystic ovarysyndrome. Lipid profile. Ann N Y Acad Sci 2000; 900:245-52.

28. Koulouri O, Conway GS. A systematic review of commonly usedmedical treatments for hirsutism in women. Clin Endocrinol(Oxf) 2008; 68:800-5.

29. Allen HF, Mazzoni C, Heptulla RA, et al. Randomized controlledtrial evaluating response to metformin versus standard therapyin the treatment of adolescents with polycystic ovary syndrome.J Pediatr Endocrinol Metab 2005; 18:761-8.

30. Bridger T, MacDonald S, Baltzer F, Rodd C. Randomized placebo-controlled trial of metformin for adolescents with polycysticovary syndrome. Arch Pediatr Adolesc Med 2006; 160:241-6.

31. Al Khalifah RA, Florez ID, Dennis B, Thabane L, Bassilious E.Metformin or Oral Contraceptives for Adolescents WithPolycystic Ovarian Syndrome: A Meta-analysis. Pediatrics 2016;137.

32. Ehrmann DA. Insulin resistance and polycystic ovary syndrome.Curr Diab Rep 2002; 2:71-6.

33. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metaboliceffects of metformin added to ethinyl estradiol-cyproteroneacetate in non-obese women with polycystic ovarian syndrome:a randomized controlled study. Hum Reprod 2002; 17:1729-37.

34. Mastorakos G, Koliopoulos C, Creatsas G. Androgen and lipidprofiles in adolescents with polycystic ovary syndrome who weretreated with two forms of combined oral contraceptives. FertilSteril 2002; 77:919-27.

For more Information log on to WWW.PCOSINDIA.ORG

11

Jointly Organized byThe PCOS Society (India) &

The Androgen Excess &PCOS Society (International)

Dates: June 22 - 24, 2018Venue: Leela Ambience Hotel, Gurugram, near Delhi Airport, India

S C I E N T I F I C P R O G R A M M E

8.00-9.00 am – Session 7 – Invited free papers

9.00-10.30 am – Session 8: Diagnosis of PCOS■ Ultrasonography for PCOS – What are the new criteria for

Polycystic Ovarian Morphology (PCOM)?■ Is Anti Mullerian Hormone a new marker for PCOS?■ Do we need to measure androgens and insulin in all cases

of PCOS?■ Discussion

11.00 am-12.00 noon – Session 9: Keynote Address■ International Guidelines on PCOS■ Adipose tissue and Skeletal muscle in women with PCOS

12.00 noon-1.30 pm – Session 10: DermatologicalManifestations – Current Trends in Management■ Acanthosis Nigricans ■ Alopecia■ Hirsutism ■ Discussion

2.30-4.00 pm – Session 11: Metabolic Syndrome and PCOS■ Does Metabolic Syndrome present differently in Indian Women?■ Is there a difference in Metabolic risks of Lean and Obese PCOS?■ How should we reduce the risk of Cardiovascular Disease

in PCOS?■ Discussion4.00-5.30 pm – Session 12: Impact of Stress on Quality ofLife and how to reduce it?

22nd June 2018 – PRE-CONGRESS WORKSHOPS9.30 am-1.30 pm – Workshop 1Nutrition, Exercise and Lifestyle in PCOS9.30-11.00 am – Session 1: Impact of Lifestyle in PCOS■ PCOS – Is it a body image disorder?■ How does obesity affect PCOS?■ How do nutrition and exercises play a role in PCOS?■ Discussion

11.00 am-12.30 pm – Session 2: Life Style Interventions■ What is the role of an anti inflammatory diet?■ Mediterranean / South Beach/Paleolithic / Atkins diets –

What do all these diets mean?■ Which exercises benefit obese PCOS women the most?■ Which exercises benefit lean PCOS women the most?■ Discussion

12.30-1.00 pm – Session 3■ If Lifestyle Fails - Role of Bariatric surgery■ Discussion

1.00-1.30 pm – Session 4Demonstration of different types of exercises that benefit PCOSwomen- Cardio, Weight training, Pilates, Yoga, Resistance Exercise,Functional Training etc.

2.30-6.00 pm – Workshop 2Watch out … What you see is not always what you get!!!PCOS: A Diagnosis of Exclusion – Case based Discussions2.30- 4.30 pm – Session 5■ Understanding the Endocrinology of the Reproductive System■ Hypothyroidism■ Hyperprolactinemia

23rd June 2018 – CONFERENCE DAY 1 – SCIENTIFIC SESSION I■ The Scientific basis of Stress in PCOS■ A revealing discussion with Psychiatrists, Gynecologists,

Dermatologists and Lifestyle Gurus on dealing with Stress

6.00-7.30 pm – Session 13: Pregnancy and PCOS■ Recurrent Pregnancy loss – Is PCOS a Causative factor?■ What should we expect when a patient with PCOS

conceives?■ The Obese PCOS Pregnancy■ Discussion7.30 pm – Session 14: Poster Session with Cocktails8.30 pm – Cultural program9.00 pm – Banquet

24th June 2018 – CONFERENCE DAY 2 – SCIENTIFIC SESSION II8.00-9.30 am – Session 15: Round Tables with Experts1. Luteal Support for Infertility Management in PCOS women.2. Letrozole v/s Clomiphene Citrate in Ovulation Induction in

PCOS3. Gonadotropins for Ovulation Induction in PCOS4. Therapeutics for Obesity5. Oral Contraceptive Pills in Adolescent PCOS6. Metformin & Weight Reduction in PCOS7. Inositols in the management of PCOS8. Vitamin D in PCOS

9. Agonists and Antagonists in PCOS10. Gestational Diabetes Mellitus

9.30-11.00 am – Session 16: Evidence-based Treatment forEnhancing Fertility■ How should we maintain Efficacy and Safety during Ovulation

Induction in PCOS women?■ When is IVF indicated?■ Freeze-All: Should it be a policy in all PCOS women?■ Discussion

11.30 am-12.30 pm – Session 17: Key Note Address

■ Ovarian Function and Inflammation■ How does Ovarian Drilling fit in modern management of

Infertility?

12.30- 2.00 pm – Session 18: Great Debates■ Weight Reduction is a must in a 35 year old Obese PCOS

before commencing ART.■ GnRh Agonist Protocol is the best for Ovulation Induction

in ART■ The Ovary is the Villain in PCOS

2.00 pm – Valedictory

■ Cushing's Syndrome and Acromegaly■ Adrenal disorders - CAH and Adrenal Tumors■ Case Discussion

4.30-6.30 pm – Session 6■ Androgen-secreting Ovarian Tumors■ Premature Ovarian Failure■ Uterine Abnormalities■ Case Discussion

7.00-8.00 pm – Panel Discussion: "How do we reduce theprevalence of PCOS in our country?"A discussion with experts from various professions: Medical,Legal, Political, Public health, Media and Activists.

8.00-9.00 pm – Inauguration

Dear Friends & Colleagues,

Welcome to the third Annual Congress of the PCOS Society of India, being held in collaborationwith the Androgen Excess and PCOS Society on 22nd, 23rd and 24th June 2018 in GurugramNCR, Delhi at the beautiful Leela Ambience Hotel.

PCOS affects women at all stages of life, hence this conference is dedicated to and entitled"PCOS... through the cycle of life". The Conference will focus on the different stages oflife, including the prenatal, childhood, adolescent, reproductive and post-menopausal periods.As gynaecologists, we are the primary – care physicians of women and manage many PCOSpatients with different presentations at different ages. We are the physicians who can trulyassist PCOS women by guiding them through the knowledge we have gained through suchbrilliant meetings.

The Registration to this Conference includes Registration for 2 Pre-congress Workshops whichwill be extremely interactive and will give in-depth knowledge on both the subjects. Learningfrom experts from various disciplines of medicine can add to our understanding of this complexendocrine problem.

We welcome you to this amazing Conference which we have put together and is being hostedby Dr. Ragini Agrawal and her team in the North of India. We are confident that it will exciteyou with the latest knowledge and cutting edge research on PCOS.

For any queries, you may contact us at pcosconference2018@gmail.com orthepcossociety@gmail.com

Looking forward to meeting with you.

With warm regards,Thanking You,

Duru ShahFounder PresidentThe PCOS Society, India

Ragini AgrawalOrganising ChairpersonThe PCOS Society, India

Helena TeedePresidentThe AE-PCOS Society

Enrico CarminaExecutive DirectorThe AE-PCOS Society

Madhuri PatilScientific Chair – ConferenceThe PCOS Society, India

Piya ThakkarScientific Chair –Precongress WorkshopsThe PCOS Society, India

Welcoming....Our New Patrons

Our New Life Members

Dr. Anju Soni Dr. Anjumazara Mulla Dr. Rohit Raina Dr. Sandhya Rani Panigrahy Dr. Savita Rani Singhal

Dr. Anita Aggarwal

Dr. Anitha K

Dr. Bharti Kalra

Dr. Dhara Niraj Mehta

Dr. Dipti Nabh

Dr. Farah Pervez Durrani

Dr. Hanslata Gehlot

Dr. Hemlata Jharbade

Dr. Jaya Choudhary

Dr. Jayshree Dhirenkumar Patel

Dr. Jyoti Arora

Dr. Kaveri Gupta

Dr. Kusum Sahni

Dr. Lakhimi Pathak Medhi

Dr. Madhura Prasad Tengshe

Dr. Mahadevi S. Dama

Dr. Mangala Athavale

Dr. Manoj Bhavsar

Dr. Manorhita Gaikwad

Dr. Mayuri Ahuja

Dr. Meenakshi Bharath

Dr. Meenakshi Sood

Dr. Minal Naguekar

Dr. Monica Chauhan

Dr. Narinder Batta

Dr. Neeta Varma

Dr. Nishi Singh

Dr. Nivedita Khandelwal

Dr. Pallavi Dhawan

Dr. Payal G Arora

Dr. Pratibha Kailash Bothare

Dr. Pratibha S. Baldawa

Dr. Preeti Niranjan

Dr. Pushpa Jaiswal

Dr. Rajapriya Ayyappan

Dr. Rama Shankarnarayana

Dr. Rekha Jakhar

Dr. Renu Malik

Dr. Ritu Goyal

Dr. Roza Olyai

Dr. Sanjay Makwana

Dr. Saswati Sanyal Choudhury

Dr. Shikha Bhatnagar

Dr. Shikha Gupta

Dr. Shikha Jain

Dr. Shuchi Bhargava

Dr. Suchitra Dalvie

Dr. Sudha Agarwal

Dr. Sujata Umbarje

Dr. Sulbha Mukund Zambre

Dr. Suman Mian

Dr. Sumita Paul

Dr. Surheeta Kareem

Dr. Susheela Gupta

Dr. Sushma Arya

Dr. T.P. Kanagu

Dr. Tanuja Sanjay Joshi

Dr. Teena Gupta

Dr. Uma Bissa

Dr. Vaijayanti Kolekar

Dr. Vandana Batra

Dr. Vandana Punjabi

Dr. Vasim Piprani

Dr. Vimal Chensukhlal Munot

Dr. Vinita Ojha