pandora...editorial dr. duru shah md, frcog, fcps, fics, ficog, ficmch, dgo, dfp director,...
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PANDORAwww.pcosindia.org
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Volume 2 | Issue1 | Feb.-May 2017 | Pages 12
■ New patrons, life members& CommitteesPage 02
■ EditorialPage 03
■ Events & UpdatePage 04
■ Announcing2nd InternationalConferencePage 05
■ Scientific Article – Insulin SensitizingProperties of Inositol: ExperimentalStudies– Dr. Fabio Facchinetti &Daniela MenichiniPage 06
■ Scientific Article – Is Letrozole Betterfor Ovulation Induction?– Dr. B. N. Chakravarty, Dr. ShikhaBathwal & Dr. Elavarasan SubramaniPage 07
■ PCOS QuizPage 09
■ PCOS and Obesity– Dr. Jayasshree TodkarPage 11
Executive CommitteeDr. Duru Shah, Founder [email protected]
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Our New Life Members
2
Dr. Anagha Pramod Walavalkar Dr. Indu Kaul Dr. Manjula Anagani
Dr. Nilesh Ramakant Shinde Dr. Rajalaxmi Walavalkar Dr. Sasmita Swair
Dr. Siddhartha Chatterjee Dr. Sripriya Pragasam Dr. Sudhaa Sharma
Congra tula t ionsDr. Duru Shah for taking over as the President of
Indian Society of Assisted Reproduction (ISAR)
on 21st April, 2017.
We wish you a year full of academic excellence!
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: [email protected] – 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.
Dr. Anita SoniMD, DNB, FCPS, DGOConsultant OBGYN, Hiranandani Hospital, PowaiChair, The Newsletter Committee
3
Dear Friends,
When I decided to name the PCOS Newsletter "PANDORA" it originated from "Pandora's Box" which is
a well-known phrase for an action which may be very simple, but as you get deeper and deeper into it, it gets
more and more detrimental – it's a never ending situation with far reaching negative consequences!
In Greek mythology, Pandora was the first woman created by the Gods,
on the instructions of the Greek God Zeus. Pandora was created as
"the beautiful evil" woman after humans stole the gift of fire from
Prometheus. She was created to give humanity a punishing gift to
compensate for the boon (fire) they had stolen. God Zeus commanded
Hephaestus to mould her from earth as, a "beautiful evil" whose
descendants would torment the human race.
According to the myth, Pandora opened a jar (not a box) out of curiosity releasing all the evils of humanity
and she could retain only "Hope" inside the jar once she had closed the lid quickly. So when you open this
Newsletter, all the mysteries of PCOS should disappear and our hope remains, that one day we will be able
to decipher the enigma called PCOS.
Our last issue for the year 2016 was published in late December 2016 which you must have received in early
January 2017. Since then we have had many academic activities, which you will find in this Newsletter and
even on the PCOS Website http://www.pcosindia.org/
We also have many exciting forthcoming events, in which I request you to participate wholeheartedly,
though we may have smaller numbers of delegates, but believe me, the interactions are just brilliant!
Our "Whatapp groups" which are open to only our members, have some amazing discussions and many
queries are sorted out by many of our senior members who contribute their expertise. I thank them for their
time, expertise and love to teach.
We have created beautiful Certificates for our members, which you would love to display on your walls. All
members have been sent their Membership Numbers and will soon receive their Certificates, if their paperwork
is complete. So, please watch out for this precious package which you will soon receive. And if you don't
get it by the middle of May please send us a mail and we will track the package for you.
I welcome you all to the beautiful city of Bengaluru, between 16, 17, 18 June 2017 where we are hosting
our Second Annual International Conference of the PCOS Society of India in collaboration with the
Androgen Excess and PCOS Society. You will find the details of the conference on our Website and in this
Newsletter. Please register at your earliest!
Please also check out our Website for all the archived educational events which are hosted therehttp://
www.pcosindia.org/. These include Power Point Slides, Webinars and Lectures, you will enjoy them.
I must thank all our academic contributors especially Prof. B. N. Chakravarty and team who have written a
brilliant article on "Is Letrozole Better for Ovulation Induction" and Prof. Fabio Facchinetti who has
written an excellent review on "Insulin Sensitizing Properties of Inositol: Experimental Studies"and
abeautiful article by Dr. JayshreeTodkar on "PCOS & Obesity".
I thank my Editorial team for all their help and inputs and Mr. Manoj Purandare from Sun Pharma for offering
us an unrestricted educational grant to make this issue possible.
Dr. Duru Shah
Founder President, PCOS Society
4
Events & Updates
An Update on “Surgical Solutions for PCOS" wasorganized by The PCOS Society, India, incollaboration with Meril Endosurgery Pvt Ltd on 18th-19th March, 2017 at Meril Academy, Daman.Dr. Duru Shah was the chief convenor.
PCOS Symposia – An Update on Surgical Solutions for PCOS
Solutions for PCOS women". The symposia focusedon understanding and optimizing the use of varioussurgical disciplines and imbibing the latest researchtowards a better quality of life for young girls andwomen with PCOS.
The conference was structured as 4 sessions over 2days followed by 3 debates & panel dicussion onBariatric surgery vs. Cosmetic surgery, Laparoscopicvs. Open surgery and OCPs vs. LNG in DUB. The paneldiscussion was moderated by Dr. Duru Shah andDr. Madhuri Patil.
The 1st day sessions included 'Fertility Surgeries inPCOS' & 'Obesity & Laparoscopic Surgery'.
The 2nd day sessions included 'Difficulties atHysteroscopic Surgeries' and 'PCOS and Obesity'.
This exclusive two-day program was meticulouslydesigned to upgrade and discuss various "Surgical
The topics were focused on the very complicatedand vast topic of PCOS and surgical treatment ofPCOS. The impact of PCOS on fertility, and the effectsof fertility enhancing surgeries in PCOS wasextensively discussed.
International Webinar – PCOS Beyond Boundaries – Focusing on Hyperandrogenism in PCOSThe PCOS Society (India) conducted an InternationalWebinar titled PCOS Beyond Boundaries – Focusingon Hyperandrogenism in PCOS, on 4th March, at TajSantacruz – Mumbai with support from Bayer ZydusPharma which connected with 6 webcast centres –Salem, Vizag, Dehradun, Bhubaneshwar, Gurgaon,Patna. Prof. Roy Homburg connected live from Malta
and made an extraordinary presentation on PCOS – TheGlobal Conundrum, & was joined by a multispecialty panel of distinguishedexperts from India – Dr. Duru Shah (Gynaecologist), Dr. Shashank Joshi
(Endocrinologist), Dr. Ashwini Bhalerao (Gynaecologist), Dr. Gulrez Tyebkhan(Dermatologist)
290 doctors participated in the Webinar at the 7 centers, with 254 online viewers,
and the webinar was rated as very educative and informative.
Continued on page 11
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16th June 2017 – PRE-CONGRESS WORKSHOPS
S C I E N T I F I C P R O G R A M M E
09.30 am - 01.30 pm – Workshop 109.30 - 11.00 am – Session I : Ultrasound in PCOS■ Diagnosis of PCOS by USG – What are the new criteria?■ Is ultrasound a good diagnostic method in adolescent
PCOS?■ Should Serum AMH replace ultrasound PCO morphology
as a diagnostic marker?■ Assessment of ovarian blood flow in PCOS, Does 3D power
doppler have any role?■ Discussion
11.30 am - 12.30 pmSession II : Monitoring a Fertility cycle■ Should follicle monitoring be done by the Fertility expert/
Radiologist / USG Nurse?■ How should we monitor the follicles and endometrium
during a COS cycle by ultrasound?
■ How should we assess OHSS by ultrasound, what are thehigh risk markers?
■ Discussion
12.30 pm■ Live Demonstration of Ultrasound in PCOS women
02.30 - 05.30 pm – Workshop 2Practical Management of Ovulation Induction in PCOSCase-based discussion■ Lean / Obese PCOS■ High AMH, Insulin resistance■ Role of Letrozole for OI in PCOS■ Role of Adjuvants in PCOS■ Which Gonadotropin? / Step up or Step down regimen?■ GnRH agonist or antagonist■ Monitoring the Ovulation Induction cycle – USG or USG+
Hormones
■ Avoiding Premature LH surge and lutenization during COH■ Role of laparoscopic drilling, ultrasound only protocols for
monitoring COS cycle
06.30 - 08.00 pm – Inaugural Lectures■ International guidelines in PCOS■ Interaction■ Adipose tissue dysfunction in PCOS■ Interaction■ Abhiyan PCOS – A consortium for Research, Advocacy and
Action■ Interaction
08.00 pm – Inauguration
08.45 pm onwards – Fun filled Tambola
08.45 pm – DINNER
08.30 - 09.30 am – Session I : Free Papers09.30 - 11.00 am – Session II : Basics we need to Know■ Diagnosis of PCOS■ What are the different Phenotypes of PCOS? Its importance
in management■ The role of environmental factors from fetal life to
adulthood in PCOS■ "The thrifty gene" hypothesis--- how has the PCOS
phenotype survived evolution?■ Discussion
11.30 am - 01.00 pm – Session III : Obesity and PCOS■ Metabolic risk of the "lean" PCOS women■ Weight loss drugs – How do we select the right formulation?■ When should we suggest Bariatric surgery in PCOS?■ Is snoring in obese women a health concern?■ Discussion
17th June 2017 – Conference Day 1 – Scientific Session I02.00 - 03.00 pm – Session IV : Keynote Address■ Are we telling patients all they need to know about PCOS?■ Role of GWAS in identifying the PCOS genes
03.00 - 04.00 pmSession V : Hirsutism and hyperandrogenism■ Does Insulin Resistance (IR) cause hyperandrogenemia (HA)
or HA causes IR?■ Medical options for women with Acne and Hirsutism■ Cosmetic options■ Discussion
04.00 - 05.00 pmSession VI: Current update on Inositols■ Pharmacology and Mode of action■ Inositol and Reproductive Function■ Current evidence for its use in Infertility and Pregnancy■ Discussion
05.30 - 06.30 pm – Session VII: The Great ControversiesControversy 1Should Metformin be continued in pregnancy?■ Yes ■ No
Controversy 2Is PCOS is associated with a higher pregnancy loss?■ Yes ■ No
06.30 - 07.30 pmSession VIII : Stump the Experts – Interesting cases■ Menstrual dysfunction in PCOS women■ Insulin resistance and hyperandrogenemia■ Gestational Diabetes Mellitus■ Obstetric complications other than GDM
07.30 pm – General Body Meeting of The PCOS Society (India)
08.30 pm – COCKTAILS & DINNER with Entertainment
18th June 2017 – Conference Day 2 – Scientific Session II08.00 - 09.00 amRound Tables with development of Algorithms1. Vitamin D deficiency and PCOS2. Management of acne, pigmentation3. Increased lipids4. GDM
09.00 - 10.30 am – Session IX : Lifestyle Modification –Does it impact Fertility?■ How do lifestyle changes help in PCOS?■ Do Metformin and Inositols help?■ Exercise in PCOS■ Nutrition in PCOS and role of anti-inflammatory diet■ Discussion
10.30 - 11.30 amSession X : PCOS and Assisted Reproduction■ Does PCOS compromise the oocyte and embryo quality or
the endometrium?■ Should"Freeze all" be a strategy in all PCOS women
undergoing IVF?■ Does pre implantation genetic screening (PGS) followed by
elective single embryo transfer (eSET) have a role in womenwith PCOS?
■ Discussion
12.00 noon - 01.00 pmSession XI : Surgical options in PCOS■ Ovarian Drilling – Current Status
■ Endometrial Polyps■ Other ovarian pathologies associated with PCOS■ Discussion
01.00 - 02.00 pm – Session XII: Long-term effect of PCOS■ COS and Cancer Risk■ Dysfunctional Uterine Bleeding■ Liver and PCOS: what we really know?■ Discussion
02.00 pm – Valedictory
02.15 pm – LUNCH
International FacultyAbha MajumdarAmeet PatkiAnita SoniArti PrasadArulmozhi RamarajanBina VasanChander LullaChitra GaneshDevika Gunasheela
National FacultyDuru ShahGanapathi B.Gita ArjunGulrez TyebkhanJyotika DesaiKamini RaoKanthi BansalKedar GanlaKorula George
M. G. BhatMadhuri PatilMirudhubashiniGovindarajanNalini MahajanPadmarekha JirgePaul PGPiya BallaniPratap Kumar
Priti VenkateshRagini AgrawalRama VaidyaReeta BilliangadyRekha ShethS. SureshSachin KulkarniSadhana DesaiSadhana Patwardhan
Sangeeta AgrawalShashank JoshiSheela ManeShilpa JoshiShobha GudiShobhana PattedSmita MahaleSonia MalikSujata Kar
Sujata MisraSuma KumarSusheela RaniUday ThanawalaUsha Sriram
...many more
Anuja Dokras,USA
Enrico Carmina, Italy
Helena Teede, Australia
Joop Laven, Netherlands
Richard Legro,USA
Dr. Fabio FacchinettiChairman, Unit of Obstetrics andGynecology, Department of Medicaland Surgical Sciences for Childrenand Adults, University of Modenaand Reggio Emilia, Italy
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Introduction'Inositol' refers to a group of molecules called'stereoisomers' of inositol. They exist in nine possibleforms, all composed of the same basic structure,named myo-, scyllo-, epi-, D-chiro-, L-chiro, neo-,allo-, cis-, and muco-isomers1. Inositol sugarscomprise of a cyclic six-carbon structure with onehydroxyl group at each carbon. Among the isomers,Myo-Inositol (MI) is the most abundant, naturallypresent in animal and plant cells, either in its freeform or as a bound-component of phospholipids orinositol phosphate derivatives. It is a precursor forphosphorylated compounds known asphosphoinositides, which are involved in signaltransduction, including diacylglycerol and inositoltriphosphate (IP3), a second messenger, responsiblefor the regulation of many hormones such as insulin,thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH)2. For this reason, MI isessential for the smooth running of a wide range ofcell functions, including cell growth and survival3,development and function of peripheral nerves 4,osteogenesis 5 and reproduction6. It is absorbed bythe tissues via a sodium-dependent inositol co-transporter that also mediates glucose uptake(competitively inhibits inositol uptake)7. In addition,the minor isomer, D-chiro-inositol (DCI) is involvedin insulin signaling and has been speculated to beassociated with glucose homeostasis sinceabnormalities in their metabolism are associated toinsulin-resistance and long-term diabeticmicrovascular complications in diabetic subjects 8.Indeed, in primary sites for the development ofdiabetic microvascular complications such as kidneys,sciatic nerve, retina and lens, a concomitant depletionof intracellular MI and accumulation of intracellularsorbitol is commonly observed in diabetic animalmodels and human subjects9.
1. Experimental studies: animal modelsSeveral experimental studies have shown that MIdepletion in experimental models of rhesusmonkeys10 and GotoKakizaki (GK) rat11 resulted inan excessive excretion of MI and decreased amountsof DCI in urine (a phenomenon called inosituria).The same inositol abnormal pattern is observed ininsulin sensitive tissues (liver, muscle, fat and kidney)of human12 and animal11 diabetic subjects.
Excessive urinary MI excretion reduces its plasma leveland consequently emphasizes MI intracellulardepletion, which results in a decreased productionof DCI from MI, reducing the availability ofintracellular DCI for its incorporation into IPGs,second messengers of insulin. Therefore, thedecreased DCI content in insulin target tissuesreduces insulin signal transduction involving IPGs andfurther enhances or contributes to insulin resistancein those tissues. Depleted plasma levels of DCI are,
resistance. Yet, whereas DCI contributes in mediatinginsulin activity mainly on non-ovarian tissues, MIdisplays specific effects on ovary, chiefly bymodulating glucose metabolism and FSH-signaling.Moreover, MI may also improve ovarian functionsby modulating steroid metabolism through non-insulin-dependent pathways. As DCI and MI activitylikely involves different biological mechanisms, bothinositol isoforms can be synergistically integratedaccording to a multitargeted design, by combiningMI and DCI in a ratio corresponding to theirphysiological plasma relative amount (40:1). Newexperimental and clinical evidence with MI plus DCIevidenced the suitability of such integrated approach,and provided promising results. Further studies needto investigate thoroughly the molecular mechanismand confirm such preliminary data15.
MI administration increases clinical pregnancy ratesand reduces the total FSH dose and the duration ofovulation induction. This had been demonstrated bya study conducted in Turkey which investigated theeffect of MI on pregnancy rates of patients diagnosedwith PCOS who underwent controlled ovulation
Insulin Sensitizing Propertiesof Inositol: Experimental Studies
Daniela MenichiniResearcher, Department of MaternalFetal Medicine, University of TexasHealth Science Centre at Houston,USA.
in fact, observed in Polycystic Ovary Syndrome (PCOS)patients, emphasizing the correlation betweenimpaired plasma DCI and insulin resistance8.
A recent study evaluated the therapeutic efficacy ofMI in models of hyperlipidemic and insulin-resistantrats. Hyperlipidemia was induced by singleintraperitoneal injection of Triton WR-1339 (200 mg/kg) suspended in phosphate-buffered-saline in ratsfed with high-fat diet (HFD) for 5 weeks, while insulinresistance was created by feeding the rats with high-fat diet (HFD) and with streptozotocin. They foundthat in hyperlipidemic rats, MI exhibited significantreductions in total cholesterol and triglycerides whileinsulin-resistant diabetic rats receiving MI showedsignificant reductions in fasting blood glucose &plasma insulin level when compared with controls.The inositol treatment significantly normalized thehyperglycemia-induced biochemical abnormalities ininsulin-resistant diabetic rats suggesting that MIcould play an effective role in glucose disposal intoadipose tissue by insulin-dependent signalingcascade mechanism; hence it could be used in thetreatment of obesity-associated T2DM13.
2. Experimental studies conducted in pregnancyA mixture of MI and DCI has recently been tested inpregnant obese mouse model and in pregnantmetabolic-like syndrome mouse model obtainedfrom the offspring born to hypertensive dams lackingendothelial nitric oxide synthase, fed with HFD. Thetreatment with combined inositol during pregnancyimproved blood pressure, glucose levels at theglucose tolerance test, and leptin levels in pregnantdams with metabolic-like syndrome phenotype butnot in obese pregnant dams. In addition, inositoltreatment resulted in lower gestational weight gainin the obese but not in the metabolic-like syndromepregnant dams2.
MI has also been clinically experimented on pregnantoverweight women with the aim of reducinggestational diabetes mellitus (GDM) rate. An open-label randomized trial evaluated the effectivenessof the supplementation of MI or placebo from thefirst trimester to delivery in pregnant overweight non-obese women. The incidence of GDM wassignificantly reduced in the MI group compared tothe placebo group, driving to the conclusion thatMI supplementation, since early pregnancy, reducesGDM incidence in overweight non-obese women14.
2.1 Experimental studies: Polycystic ovarysyndrome (PCOS)PCOS is an endocrine disorder affecting up to 10-15% of women in reproductive age, mainly causinginfertility. Insulin resistance (IR) plays a key role insuch syndrome. Recently, MI and DCI have shownto be an efficient and safe alternative in PCOSmanagement, as both inositol isoforms cancounteract downstream consequences of insulin
induction and intrauterine insemination (IUI). Infertilepatients diagnosed with PCOS were given 4g MI and400mg folic acid before and during ovulationinduction. The patients underwent controlled ovarianhyper stimulation (COH) with recombinant FSH andIUI. The patients in the control group were givenrecombinant FSH directly and 400mg folic acid. Theprimary outcome measure of this study was theclinical pregnancy rate. The treatment group womenneeded significantly lower doses of FSH and lowercycle duration, and had higher clinical pregnancyrates than the control group16.
ConclusionDietary supplement of inositol isomers was foundto be efficient in lowering post-prandial plasmaglucose in several animal models of diabetes orinsulin resistance8. The insulin-mimetic properties ofdietary inositol supplements are believed to berelated to the production of inositol glycan secondarymessengers containing either MI or DCI.
Randomized control trials on inositol dietarysupplements gave positive results in the improvementof insulin resistance and reduced cardiovascular riskin women with PCOS, gestational diabetes mellitusor metabolic syndrome and obesity (also inpregnancy).
Inositol has a role in restoring maternal cardiovascularand metabolic compliance in pregnancies affectedby obesity and metabolic syndrome.
Continued on page 11
Dr. Shikha BathwalInstitute of Reproductive Medicine,Kolkata
Dr. B. N. ChakravartyInstitute of Reproductive Medicine,Kolkata
IntroductionOver the past five decades, clomiphene citrate (CC)continues to be the first line treatment primarily forovulation induction and also for ovulationaugmentation in unexplained infertility and inintrauterine insemination (IUI) cycles1. However, it isreported that 20-25% of women fail to ovulate dueto CC-resistance2. In view of this, administration ofgonadotropins is considered to be the conventionaloption in such cases. Though use of gonadotropinsis highly effective, it is associated with inevitable riskof multiple pregnancies and ovarian hyperstimulationin a significant proportion of women3. As analternative management to gonadotropins, use oflaparoscopic ovarian drilling (LOD) in CC-resistantwomen has also been advocated4. Addition of CCwith Gonadotropins (FSH/hMG) helps in decreasingthe dose of total amount of gonadotropins requiredfor optimum stimulation and makes it more cost-effective in women who fail to respond to only CCtreatment5. Acceptable pregnancy rates with CC andsequential hMG ovulation induction protocol in IUIfollowing previous CC and IUI treatment failure havealso been reported6. However, supra-physiologicallevel of estradiol (E2) is an undesirable consequenceof both CC and gonadotropin stimulation. Apartfrom risk of hyperstimulation and multiplepregnancies, adverse effects of supra-physiologicallevel of E2 have been observed at several levels. Theseare – Dyssynchrony between endometrium andembryo maturation during 'implantation window'period, abnormal expression of endometrialpinopodes, defective endometrial estrogen –progesterone receptors, abnormal endometrial bloodflow and abnormal integrin expression. These aresome of the reasons for low pregnancy rate in spiteof having good ovulatory response following CCinduction in anovulatory infertility.
These limitations motivated researchers to find outan alternative drug which would be less expensivethan gonadotropins and at the same time safe,simple and equally if not more effective thanclomiphene. Letrozole was considered to be analternative acceptable molecule.
How and Why Letrozole?In women with intact hypothalamic-pituitary-ovarianaxis, the commonest cause of anovulation isPolycystic Ovarian Syndrome (PCOS). One of thesignificant causes of anovulation in PCOS women is'static' (not pulsatile) elevated or normal level ofoestrogen. Static level of estrogen through 'negativefeed-back' mechanism on 'hypothalamic-pituitary(HP) axis' inhibits adequate release of pituitary FSH.Low (not absent) level of FSH results in inadequategrowth and development of follicles, – not allowingthem to reach maturity and ovulation. At the sametime, tonic elevated level of oestrogen through'positive feed-back' effect on HP axis results in releaseof static elevated 'tonic' level of LH. There is no LH
Dr. Elavarasan SubramaniInstitute of Reproductive Medicine,Kolkata
surge and therefore anovulation. Aromataseinhibitors (letrozole) by inhibiting oestrogen synthesistemporarily release hypothalamic-pituitary block bytonic elevated oestrogen thereby normalizingfluctuating (and not tonic) release of pituitary FSHwhich helps in restoration of normal ovulatory cycle.Therefore, letrozole was considered to be an effectivedrug for induction of ovulation.
rate of congenital malformations among childrenborn to mothers who conceived naturally or afterletrozole or CC treatment was observed to becomparable12. Our group has conducted one of thelargest-ever randomized clinical trials to explore theefficacy of letrozole in ovulation induction on 1387infertile PCOS women who failed to conceive withCC treatment14. This study showed that letrozoleappears to be a suitable ovulation inducing agent inpolycystic ovary syndrome (PCOS) women with CCfailure and is found to be most effective whenbaseline E2 level >60 pg/ml. It is well known thatinfertility itself is a risk factor and is associated withincreased malformation risk as compared to thegeneral population. Several published studies, bothcontrolled and non controlled, comparing letrozolewith CC alone or in combination with gonadotropinsconfirm the effectiveness of letrozole as an ovulationinducing agent15-18. Based on these various reports,Government of India, Ministry of Health and FamilyWelfare removed the ban on use of letrozole asovulation induction agent.
Literature review:Several research groups have studied the new groupof drugs (aromatase inhibitors) for ovulationinduction in the past few years7-9. Letrozole, a potentand highly specific nonsteroidal aromatase inhibitor,has been observed to be effective in inducingovulation in anovulatory and ovulatory infertilewomen with inadequate response to CC. Initially,letrozole was primarily used as a potent reversibleoral aromatase inhibitor which acts achemotherapeutic agent in postmenopausal womenwith metastatic breast cancer10. Being achemotherapeutic agent, when the drug was usedfor ovulation induction, concerns were raised aboutteratogenic effect on oocyte and embryo. Moreover,the resulting hypo-estrogenic may have adverseimpact on bone mineral metabolism leading toosteoporosis. The other controversy relating to theuse of letrozole as a first-line agent, before CC hasbeen used, is based on the fact that in normo-gonadotropic women, aromatase inhibition is likelyto be effective only when baseline estradiol iselevated. The cut-off level of the elevated baselineestrogen is not yet demarcated. Hence use ofletrozole as a primary ovulation-inducing drugreplacing clomiphene warrants further investigation.An abstract presented at American Society forReproductive Medicine (ASRM) meeting 2005regarding increased teratogenic risk of cardiacmalformations with letrozole11 and other safetyconcerns eventually led to the ban on this drug inIndia in 2011. Nevertheless, there is an increasedconcern on the factuality of the observation due tothe shortcomings and biases of this study.
In the later years, various studies indicated thatletrozole is not associated with increased teratogenicrisk12,13. Our earlier study showed that the overall
Evolution of aromatase inhibitors for clinical useAromatase inhibitors suppress estrogen productionby inhibiting the conversion of androgens toestrogens. Letrozole, the drug commonly used inclinical practice, has been developed followingextensive trial through three generations ofaromatase inhibitors. Third generation aromataseinhibitors like letrozole and anastrozole have been agreat leap forward in the treatment of breast cancer.Their clinical efficacy, excellent tolerability and safetyprofile compare favourably with that of tamoxifen,which has been the cornerstone of endocrine therapyfor years.
Concept leading to the use of letrozole forinduction of ovulationThe goal of ovulation induction is to inducemonofollicular development and subsequentovulation in anovulatory infertile women. Asdiscussed in previous paragraphs, anovulation inPCOS or any normogonadotropic anovulatory cycleis due to the block of hypothalamic receptors by staticelevated supraphysiological level of oestradiol, whichis preventing the release of pulsatile luteinizinghormone-releasing hormone (LHRH). Decline in staticelevated oestrogen level can help in restoration of
Is Letrozole Better for Ovulation Induction?
7
8
synchronized and pulsatile LHRH release.Antiestrogenic effect of letrozole was the conceptbehind using it for ovulation induction. This was firstreported in literature by Mitwally et al.19, inanovulatory women resistant to ovulation inductionby CC.
Need of an alternative drug for ovulationinduction other than clomiphene citrateSeveral drawbacks with CC had been the reason forlookout for an alternative ovulation inducing agentin certain cases. CC remains bound with oestrogenreceptors for 60 days because of its long half life. Incase CC fails to induce ovulation or establishpregnancy, other ovulation inducing drugs cannotbe initiated before 60 days. It is thought that doseof 150 mg or more will confer no benefit. CC inducesovulation in 70-85% of patients while only 20-40%will conceive. The pregnancy rate per cycle is around10-20%. About 20-25% anovulatory women areclomiphene resistant.
CC has unfavourable effects on endometrialthickness and cervical mucus due to its antiestrogeniceffect. The incidence of miscarriage after CC therapyhas been reported to be about 23.6%. It has beenshown that with prolonged CC use, along with lowendometrial thickness, there is also decreased uterineblood flow during early luteal and peri-implantationphase. There have been evidences suggesting thatsupra-physiological serum luteinizing hormone (LH)level from day 9 until the LH surge, together withpremature luteinisation and higher serum oestrogenlevels throughout the cycle can lead to higherchances of either non-conception or miscarriage.
Difference in mechanism of action of CC andletrozoleIn CC, hypothalamic receptors are bound tooestrogenic component of CC and therefore thesereceptors become unaware of presence of supra-physiological levels of circulating estrogens, allowinghypothalamus to release effective synchronizedpulsatile LHRH, thereby leading to LH surge andovulation.
Letrozole causes direct inhibition of oestrogensynthesis thereby allowing follicle-stimulatinghormone (FSH) to induce active folliculogenesis. Thishypo-estrogenic state is quickly reversible due to theshort half-life of letrozole (45 hours). There is noantioestrogenic effect on endometrium. Also thereis temporary elevation of testosterone to an optimumlevel which is beneficial as it increases the follicularsensitivity to gonadotropin. Excess levels of androgencause detrimental effects whereas a very low levelof testosterone impairs follicular development.
Common features in mechanism of action of CCand letrozoleThough the drugs act in different ways, there aresome common features in their mechanism ofactions. These are: (a) Release of hypothalamus fromnegative tonic feedback effect of static normal orelevated level of oestrogen (b) Allowing release ofpulsatile gonadotropin-releasing hormone (GnRH) (c)FSH & LH ratio is synchronized (d) LH surge effectivefor ovulation. These have been illustrated in Fig-1&Fig-2.
Ovulation induction in anovulatory womenwith PCOS Letrozole versus CC in PCOS women has been testedin several randomized trials14, 20-23. However, theefficacy of letrozole in ovulation induction remainsunclear. One of the largest randomized controlledtrials conducted in our institute comparing efficacyof letrozole with continuous gonadotropins and CC-gonadotropin combination for ovulation inductionin 1387 PCOS women after clomiphene citrate failureconcluded that the ovulation and pregnancy ratewith letrozole was significantly higher with letrozolecompared to CC-rFSH combination (79.30% vs56.95%, p value <0.0001 and 23.39% vs 14.35%,p value <0.0001 respectively) (14). Also there was asignificantly lower cycle cancellation rate withletrozole compared to CC-rFSH (20.70% vs 43.05%,p value <0.0001). Another group had reportedcomparable pregnancy rate with letrozole and CC-hMG therapy in a pilot study24. An analysis of fourearly randomized studies observed a significantlyhigher pregnancy and delivery rate in women treatedwith aromatase inhibitor compared with CC25.Nonetheless, the trials involved were heterogeneouswith a limited number of patients.
A recent well-designed double blind multicentrerandomized control trial comparing letrozole versusclomiphene for infertile PCOS women has concluded
that letrozole was associated with higher live birthand ovulation rates. Therefore, letrozole is consideredto be superior than CC as a treatment for anovulatoryinfertility in women with PCOS26. Similar findingswere observed by other studies27, 28. A meta-analysispublished in 2015 analysed 4999 ovulation cycles(2455 with letrozole, 2544 with CC) indicated thatlive birth and pregnancy rates were higher in patientswith PCOS following treatment with letrozole ascompared to CC. However, there was no differencein ovulation rate/cycle, miscarriage rate or multiplepregnancy rate between the two drugs29. A studyby Liu et al. on 141 CC-resistant PCOS womenshowed comparison between letrozole and LOD.They found letrozole had superior reproductiveoutcomes compared with LOD in women with CCresistant PCOS and that letrozole could be used as1st line treatment for women with CC-resistant PCOS.The number of cycles with synchronised follicularand endometrial growth was also significantly higherin letrozole group30. A study comparing efficacy ofletrozole with tamoxifen observed that tamoxifenwas inferior to letrozole in terms of ovulation andpregnancy rate31.
Ovulation induction/stimulation in unexplainedinfertilityAromatase inhibitors are recommended as analternative drug to CC in women with unexplainedinfertility, either alone or with gonadotrophins.Nonetheless, it is likely to be less efficaciouscompared with treatment in PCOS women. Letrozoleresults in lesser number of mature follicles (mono-ovulation) in comparison to CC because it has lessanti-estrogenic effects in the later part of follicularphase. Thus, it may not be the first choice in patientswith unexplained infertility. A meta-analysis of sevenrandomized control trials showed comparable clinicalpregnancy rates between aromatase inhibitor andCC in women with unexplained infertility32. Thesefindings are in good agreement with another largetrial where no statistically significant difference wasobserved between 100 mg of CC versus 5 mg ofletrozole in terms of clinical pregnancy rate inunexplained infertility33. A recent large multicentretrial on 900 women with unexplained infertilityconcluded that letrozole resulted in lower frequencyof multiple pregnancies but also lower live birth ratesas compared to gonadotropins. However, whenletrozole was compared to clomiphene alone,pregnancy rates were similar34.
Safety concerns with letrozoleConcerns had beenraised regarding the useof letrozole for ovulationinduction, as it mightinterrupt the normalaromatase function intissues during early fetaldevelopment and can bepotentially teratogenic35.This issue was discussedin the Annual Meetingof the American Societyfor ReproductiveMedicine in 2005. Anabstract presentation bythe authors discussingthe use of letrozole for
Fig-1: mechanism of action (ovulationinduction) with CC
Fig-2: mechanism of action (ovulationinduction) with letrozole
9
PCOS Quiz1. Metformin is the drug of choice fora. Glucose intoleranceb. CC resistant PCOSc. High risk of hyperstimulationd. All the above
2. To avoid the risk of OHSS in PCOSpatients, the best protocol for ovulationinduction is
a. low dose step up protocolb. step down protocolc. Long protocold. All three
3. What percentage of PCOS patients havehyperandrogenaemia?
a. 50% b. 60-80%c. 20-30% d. <10%
4. Which of these statements is not trueabout Asian PCOS women?a. Have lower BMIb. Higher prevalence of Metabolic Syndromec. More severe hyperandrogenismd. All of the above
5. Which is the the most commondeterminant of ovulation outcome inPCOS women?
a. Obesityb. Insulin Resistancec. Antral follicle count & AMHd. Both a & b
6. PCOS patients needing Bariatric surgerieshave a BMI of
a. 30 & above b. 26 & abovec. 35 & above d. 45 & above
7. The ability of an oocyteto resume meiosis, getfertilized and become a blastocyst isknown as
a. oocyte qualityb. oocyte competencec. both a & bd. none of the above
8. What contributes to adverse pregnancyand Perinatal outcomes in PCOS patients?
a. Oocyte competenceb. Oocyte qualityc. Phenotypic severityd. Both a & ce. Both a, b & c
9. Which of the following are true aboutovulation induction in PCOS?
a. Women with PCOS are about 50% more likelyto have a live birth with letrozole compared toclomiphene citrate (CC)
b. With letrozole ovulation induction, estradiollevels are lowered and luteal progesteronelevels are increased
c. Letrozole has lower multiple pregnancy ratescompared to CC
d. a+b+ce. b+c
10. The following statements aboutMetformin use in PCOS are correct:a. Prolonged treatment is required before it
becomes efficaciousb. Immediate release is better than extended
release for ovulationc. Is more useful when used alone rather than
with CCd. none of the above
infertility treatment may be associated with a higherrisk of congenital cardiac and bone malformationsin the newborns11. Following this, NovartisPharmaceuticals, the company that developedletrozole for breast cancer treatment, issued awarning to infertility clinics asserting that it does notadvocate letrozole use for infertility treatment. InOctober 2011 the Ministry of Health and FamilyWelfare, India issued a directive to suspend the useof letrozole in infertile women with immediate effectciting concerns regarding its safety. A study analysing911 newborns born after infertility treatment witheither CC or letrozole found no difference in overallrates of major and minor congenital malformationsbetween the two groups36. In a recent retrospectivetrial from Asian sub-continent analysing 646 women,congenital malformations were found to becomparable following natural conception, letrozoleand CC12. Most recent trial by Tatsumi et al. (2017)reported that no increase in the risk of majorcongenital anomalies or adverse pregnancy orneonatal outcomes was observed in letrozole treatedwomen compared with natural cycles in womenundergoing ART37. Considering these reports, IndianHealth Ministry has recently removed the ban onletrozole for use in infertility. Therefore, letrozole may
be considered as a safe option for ovulationinduction.
References1. Dankert T, Kremer JAM, Cohlen BJ, Hamilton CJCM, Pasker-de Jong PCM,
Straatman H, van Dop PA. A randomized clinical trial of clomiphene citrateversus low dose recombinant FSH for ovarian hyperstimulation inintrauterine insemination cycles for unexplained and male subfertility.Hum Reprod. 2007;22:792-797.
2. Elnashar A, Fouad H, Eldosoky M, Saeid N. Letrozole induction of ovulationin women with clomiphene citrate-resistant polycystic ovary syndromemay not depend on the period of infertility, the body mass index, or theluteinizing hormone/follicle-stimulating hormone ratio. Fertil Steril.2006;85:511-513.
3. Eijkemans MJ, Polinder S, Mulders AG, Laven JS. Habbema JDF, FauserBC: Individualized cost-effective conventional ovulation inductiontreatment in normogonadotrophic anovulatoryinfertility (WHO group 2).Hum Reprod. 2005;20:2830-2837.
4. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.Consensus on infertility treatment related to polycystic ovary syndrome.Fertil Steril. 2008;89:505-522.
5. Mitwally MFM, Casper RF. Aromatase inhibition reduces gonadotrophindose required for controlled ovarian stimulation in women withunexplained infertility. Hum Reprod. 2003;8:1588-1597.
6. Brzechffa P, Daneshmand S, Buyalos R. Sequential clomiphene citrateand human menopausal gonadotrophin with intrauterine insemination:the effect of patient age on clinical outcome. Hum Reprod. 1998;13:2110-2114.
7. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, ChaudhuryK, Chakravarty BN, Kabir SN. A randomized singleblind controlled trialof letrozole as a low-cost IVF protocol in women with poor ovarianresponse: a preliminary report. Hum Reprod. 2004;19:2031-2035.
8. Casper RF, Mitwally MFM. Review: Aromatase Inhibitors for OvulationInduction. J Clin Endocrinol Metab. 2006;91:760-771.
9. Barroso G, Menocal G, Felix H, Rojas-Ruiz JC, Arslan M, Oehninger S.Comparison of the efficacy of the aromatase inhibitor letrozole andclomiphene citrate as adjuvants to recombinant follicle-stimulatinghormone in controlled ovarian hyperstimulation: a prospective,randomized, blinded clinical trial. Fertil Steril. 2006;86:1428-1431.
10. Harriet M. Lamb, Julie C. Adkins. Letrozole-A Review of its Use inPostmenopausal Women with Advanced Breast Cancer. Drugs,1998;56:1125-1140.
11. Al-Fadhli R, Sylvestre C, Buckett W, Tan SL, Tulandi T. A randomized trialof superovulation with two different doses of letrozole. Fertil Steril.2006;85:161-164. (Presented at the American Society for ReproductiveMedicine 61st Annual Meeting; October 14-19, 2005; Montreal, Quebec.Abstract O-91).
12. Sharma S, Ghosh S, Singh S, Chakravarty A, Ganesh A, Rajani S,Chakravarty BN. Congenital malformations among babies born followingletrozole or clomiphene for infertility treatment. PLoS One.2014;9:e108219.
13. Tatsumi T, Jwa SC, Kuwahara A, Irahara M, Kubota T, Saito H. Noincreased risk of major congenital anomalies or adverse pregnancy orneonatal outcomes following letrozole use in assisted reproductivetechnology. Hum Reprod. 2017;32:125-132.
14. Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, ChakravartyB. Comparison of letrozole with continuous gonadotropins andclomiphene-gonadotropin combination for ovulation induction in 1387PCOS women after clomiphene citrate failure: a randomized prospectiveclinical trial. J Assist Reprod Genet. 2009;26:19-24.
15. Mattenberg C, Fondop JJ, Romoscanu I, Luyet C, Bianchi-Demicheli F, deZiegler D. Use of aromatase inhibitors in infertile women. Gynecol ObstetFertil. 2005;33:348-355.
16. Bedaiwy MA, Forman R, Mousa NA, Al Inany HG, Casper RF. Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarianstimulation. Hum Reprod. 2006;21:2838-2844.
17. Jee BC, Ku SY, Suh CS, Kim KC, Lee WD, Kim SH. Use of letrozole versusclomiphene citrate combined with gonadotropins in intrauterineinsemination cycles: a pilot study. Fertil Steril. 2006;85:1774-1777.
18. Homburg R. Oral agents for ovulation-induction-clomiphene citrate versusaromatase inhibitors. Hum Fertil (Camb). 2008;11:17-22.
19. Mitwally MFM, Casper RF. Use of an aromatase inhibitor for induction ofovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001;75:305- 309
20. Casper RF. Letrozole versus clomiphene citrate: which is better forovulation induction? Fertil Steril. 2009;92:858-859.
21. Quintero RB, Urban R, Lathi RB, Westphal LM, Dahan MH. A comparisonof letrozole to gonadotropins for ovulation induction, in subjects whofailed to conceive with clomiphene citrate. Fertil Steril. 2007;88:879-885.
22. Barroso G, Menocal G, Felix H, Rojas-Ruiz JC, Arslan M, OehningerS.Comparison of the efficacy of the aromatase inhibitor letrozole andclomiphene citrate as adjuvants to recombinant follicle-stimulatinghormone in controlled ovarian hyperstimulation: a prospective,randomized, blinded clinical trial. Fertil Steril. 2006;86:1428-1431
23. Bayar U, Tanriverdi HA, Barut A, Ayo?lu F, Ozcan O, Kaya E. Letrozole vs.clomiphene citrate in patients with ovulatory infertility. Fertil Steril.2006;85:1045-1048.
24. Jee BC, Ku SY, Suh CS, Kim KC, Lee WD, Kim SH. Use of letrozole versusclomiphene citrate combined with gonadotropins in intrauterineinsemination cycles: a pilot study. Fertil Steril. 2006;85:1774-1777.
25. Polyzos NP, Tsappi M, Mauri D, Atay V, Cortinovis I, Casazza G. Aromataseinhibitors for infertility in polycystic ovary syndrome. The beginning orthe end of a new era? Fertil Steril. 2008;89:278-280.
26. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P,Christman GM, Huang H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT,Bates GW, Usadi R, Lucidi S, Baker V, Trussell JC, Krawetz SA, Snyder P,Ohl D, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive MedicineNetwork. Letrozole versus clomiphene for infertility in the polycystic ovarysyndrome. N Engl J Med. 2014;371:119-129.
27. Banerjee Ray P, Ray A, Chakraborti PS. Comparison of efficacy of letrozoleand clomiphene citrate in ovulation induction in Indian women withpolycystic ovarian syndrome. Arch Gynecol Obstet. 2012;285:873-877.
28. Roy KK, Baruah J, Singla S, Sharma JB, Singh N, Jain SK, Goyal M. Aprospective randomized trial comparing the efficacy of Letrozole andClomiphene citrate in induction of ovulation in polycystic ovariansyndrome. J Hum Reprod Sci. 2012;5:20-25.
29. Roque M, Tostes AC, Valle M, Sampaio M, Geber S. Letrozole versusclomiphene citrate in polycystic ovary syndrome: systematic review andmeta-analysis. Gynecol Endocrinol. 2015;31:917-921.
30. Liu W, Dong S, Li Y, Shi L, Zhou W, Liu Y, Liu J, Ji Y. Randomized controlledtrial comparing letrozole with laparoscopic ovarian drilling in womenwith clomiphene citrate-resistant polycystic ovary syndrome. Exp TherMed. 2015;10:1297-1302.
31. El-Gharib MN, Mahfouz AE, Farahat MA. Comparison of letrozole versustamoxifen effects in clomiphen citrate resistant women with polycysticovarian syndrome. J Reprod Infertil. 2015;16:30-35.
32. Polyzos NP, Tzioras S, Mauri D, Tsappi M, Cortinovis I, Tsali L, Casazza G.Treatment of unexplained infertility with aromatase inhibitors orclomiphene citrate: a systematic review and meta-analysis. Obstet GynecolSurv. 2008;63:472-479.
33. Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromataseinhibitors for superovulation in women with unexplained infertilityundergoing intrauterine insemination: a prospective randomized trial.Fertil Steril. 2009;92(4):1355-1359.
34. Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P,Christman GM, Ager J, Huang H, Hansen KR, Baker V, Usadi R,Seungdamrong A, Bates GW, Rosen RM, Haisenleder D, Krawetz SA,Barnhart K, Trussell JC, Ohl D, Jin Y, Santoro N, Eisenberg E, Zhang H;NICHD Reproductive Medicine Network. Letrozole, Gonadotropin, orClomiphene for Unexplained Infertility. N Engl J Med. 2015;373:1230-1240.
35. Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies followingthe treatment with letrozole or letrozole and gonadotropins. Fertil Steril.200;)84: O-231.
36. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, Librach C,Greenblatt E, Casper RF. Congenital malformations among 911 newbornsconceived after infertility treatment with letrozole or clomiphene citrate.Fertil Steril. 2006;85:1761-1765.
37. Tatsumi T, Jwa SC, Kuwahara A, Irahara M, Kubota T, Saito H. No increasedrisk of major congenital anomalies or adverse pregnancy or neonataloutcomes following letrozole use in assisted reproductive technology.Hum Reprod. 2017;32:125-132.Answers for PCOS QUIZ 1. D | 2. A | 3.B | 4. C | 5. D | 6. C | 7. B | 8.D | 9. D | 10. D
10
Dr. Jayasshree TodkarLaparoscopic and Bariatric Surgeon,Fellow – Gastro Obeso Centre, Brazil,Cleveland Clinic, Ohio, USA
PCOS and Obesity
IntroductionSince its original description in 1935, obesity hasbeen recognized as a common feature of thePolycystic Ovary Syndrome (PCOS). Moreover, obesityexacerbates many of the reproductive and metabolicabnormalities associated with PCOS. This reviewexplores the available data on the mechanisms ofthis association.
Obesity is a medical condition in which excess bodyfat has accumulated to the extent that it may have anegative effect on health. People are generallyconsidered obese when their body mass index (BMI),a measurement obtained by dividing a person'sweight in kgs by the square of the person's heightin metres, is over 30 kg/m2, with the range 25-30kg/m2 defined as overweight.
PathophysiologyPCOS has metabolic characteristics that includeprominent defects in insulin and b-cell function thatconfer a substantially increased risk for glucoseintolerance and type 2 diabetes. Furthermore, themetabolic abnormalities associated with PCOS, suchas b-cell dysfunction and type 2 diabetes, haveheritable components in families of women withPCOS. To date, the genes responsible for PCOS havenot been clearly identified. Considering the closeassociation between PCOS and obesity, it is likelythat similar or interrelated genes may also predisposeto obesity in affected women. No doubtenvironmental factors (high-caloric diets and reducedexercise) also play a major role in the high prevalenceof obesity in women with PCOS1,2. Insulin resistanceis a predominant finding in PCOS. Insulin-mediatedglucose disposal, reflecting mainly insulin action onskeletal muscle, is decreased by 35-40% in womenwith PCOS compared to weight comparablereproductively normal women. This defect issignificantly correlated to obesity. Hepatic insulinresistance, characterized by both increased postabsorptive glucose production and reduced sensitivityto insulin, is present in obese women with PCOS3.
Fasting insulin levels are increased in PCOS & aremore pronounced in women with PCOS who have afirst-degree relative with type 2 diabetes. Undernormal circumstances, the relation between insulinsecretion and sensitivity is constant so that changesin insulin sensitivity are accompanied by reciprocalchanges in insulin secretion that maintain normalglucose tolerance; this relationship is known as the"disposition index." Women with PCOS have a lowerdisposition index compared to weight-matchednormal women4. PCOS is associated with high ratesof glucose intolerance resulting from defects ininsulin action and b-cell function. Detection ofglucose abnormalities in women with PCOS is bestperformed by means of glucose tolerance testing,since fasting glucose levels may be normal despitepresence of glucose intolerance5,6.
Treatment for PCOSPCOS treatment starts with a proper diagnosis.Treatments are then chosen based on a woman's
symptoms, age and future pregnancy plans.Treatment for PCOS is not effective unless thebaseline metabolic disorders-Obesity and InsulinResistance are dealt with scientifically.
As per the scientific and clinical evidence, these arethe treatments options for Obesity/Adiposity and theInsulin Resistance:
1. Supervised Diet and Exercise Modificationsare a must in this treatment. But may not beeffective enough alone7.
2. Pharmacotherapy – Apart from Metformin,inositols and Orlistat, no pharmacotherapy in reallyavailable to treat adiposity/obesity/ metabolicsyndrome.
3. Bariatric Surgery in PCOS – 10% of womenworld wide are suffering from PCOS, and will seekhelp for gynaecological disorders or body image.Many such women are at a risk of MetabolicSyndrome, predisposed to glucose abnormalitiesie. DM, Dyslipidemia, Cardiovascular diseases.Metabolic Syndrome (MS) and obesity co-exist.Bariatric surgery can be an effective and safemeans of treatment for obese women with PCOS.Bariatric surgery can prevent or reverse MetabolicSyndrome associated with PCOS, leading toreproductive benefits4.
■ Improvement is noted in glucose abnormalities,dyslipidemia and hypertension.
■ Insulin abnormalities may improve very early post-operatively in pre-menopausal women with MS.
■ Bariatric procedures showed improved insulinvalues proportional to changes in BMI.
■ The effects on hypertension have been shown tobe independent of the magnitude of weight loss.
Reproductive age women fitting the profile of PCOSare included in many of the studies. Most womenregained normal menstrual function and most haddocumented spontaneous ovulation. Patients hadsignificant improvement in hirsutism & androgenprofiles post Bariatric Surgery. Follow up for morethan 2 years showed that all women resumed normalmenstrual cycles, half had resolution of hirsutism andHbA1C decreased from 8.2% to 5.1%. Dyslipidemia,hypertension and diabetes mellitus almostcompletely resolved. Interestingly, women becamepregnant spontaneously after surgery. 78% ofwomen saw improvement in MS and 48% showedimprovement in PCOS specifically with regards tomenstrual cycles, fertility and/or hirsutism. PCOSpresents a unique challenge since many obese PCOSwomen are adolescents. Although patients andphysicians may at first be wary of a young patientconsidering surgical weight loss, these patients havean important opportunity. Bariatric surgery mayactually provide primary prevention of coronary arterydisease, eliminate MS and cause meaningful, longterm reduction in morbidity and mortality. Youngwomen with PCOS show evidence of atherosclerosisby abnormal carotid intima media thicknessmeasurement and the prevalence of diabetes mellitusbefore the age of 50 is exceptionally high andestimated at 3-4 times the general populationprevalence8.
Reproductive concerns may also lead PCOS womenwith MS to consider bariatric surgery. The relationshipbetween PCOS, obesity and infertility has beendocumented for many years. Known effects includeanovulation, miscarriage, impairment infolliculogenesis and altered endometrial receptivity.Risks in pregnant woman with PCOS & MS are high,namely diabetes, pre-eclampsia, growth disorders,higher rates of cesarean delivery, higher maternalmortality and increase risks of metabolic disease intheir children. Bariatric surgery in reproductive agewomen has been shown to decrease menstrualirregularities. PCOS women have less hyper-androgenism post. LH and FSH levels have beenreported to increase after surgery. On a morefunctional level, ovulatory function measured byluteal LH and progesterone secretion improvedpostoperatively, although levels were still belownormal values. Additionally, leptin levels decreaseafter bariatric surgery, reflecting improvedreproductive metabolic status. These changescertainly would suggest improved reproductivefunction. Women already take pregnancy intoconsideration when electing for bariatric surgery.Although women tend to seek medical care formenstrual irregularities and hirsutism, this encounteroffers a chance for evaluation, education and riskprevention of MS. Lifestyle modification andtreatment of risk factors are appropriate and evennecessary for long term control. Bariatric surgery isa powerful tool that should not be overlooked simplybecause a woman is young or presents with PCOSand MS rather than diabetes mellitus, myocardial
4. PCOS treatment requires combination of medicaltherapy, psychological support, lifestylemodifications and should include bariatric surgeryas a firm treatment modality, wherever indicated.
Bariatric surgeries help obese women in terms ofimproved fertility index, improved interpersonalrelationships & sexual behavior, prevention ofGestational Diabetes & Pregnancy InducedHypertension.
Women with morbid obesity, who are infertilesecondary to PCOS, may have a new surgical optionin the form of bariatric surgery. Studies report that100 % of the morbidly obese women who werediagnosed with PCOS-related infertility becamepregnant within three years following BariatricSurgery.
Methods of Bariatric SurgeryBariatric surgery has been available for decades. Mostprocedures are now performed laparoscopically.Three most common procedures performed are:1. Laparoscopic adjustable gastric banding (LAGB)2. Laparoscopic roux-en-Y gastric bypass (LRYGB)3. Laparoscopic sleeve gastrectomy (LSG)
Weight loss for each procedure increasessubsequently in each of the first 3 years post-operatively.
Decreased surgical time, shorter hospital stay andquicker recovery are the advantages of latestadvances in techniques of laparoscopic surgery.
Metabolic improvements after bariatric surgery:
■ BMI and excess body weight decrease substantiallyafter surgery.
Events & Updates
11
infarction and severe chronic hypertension. In ourexperience of Bariatric surgery since 2003, we havetreated more than 60% women patients foroverweight/ Obesity and related co morbidities. Outof this population, around 70% belonged to thereproductive age. The BMI range was between 28to 70 kg/m2. 42% of these women had PCOS andinfertility as the primary concern. All of them showedimproved ovulatory function and fertility index afterBariatric surgery.
References1. Legro RS, Driscoll D, Strauss JF 3rd, et al. Evidence for a genetic basis for
hyperandrogenemia in polycystic ovary syndrome. ProcNatlAcadSci U S A1998;95:14956-14960
2. Tsilchorozidou, T., Overton, C., Conway, G.S. The pathophysiology ofpolycystic ovary syndrome. ClinEndocrinol (Oxf). 2004;60:1-17
3. Alvarez-Blasco F, Botella-Carretero JI, San Millan JL, et al. Prevalence andcharacteristics of the polycystic ovary syndrome in overweight and obesewomen. Arch Intern Med 2006;166:2081-2086.
4. Conway, G.S., Dewailly, D., Diamanti-Kandarakis, E. et al, The polycysticovary syndrome: an endocrinological perspective from the European Societyof Endocrinology. Eur J Endocrinol. 2014;171:489-498.
5. Plascencia Gomez, A., Vega Memije, M.E., Torres Tamayo, M. et al, Skindisorders in overweight and obese patients and their relationship withinsulin. ActasDermosifiliogr. 2014;105:178-185
6. Vgontzas, A.N., Legro, R.S., Bixler, E.O. et al, Polycystic ovary syndrome isassociated with obstructive sleep apnea and daytime sleepiness: role ofinsulin resistance. J ClinEndocrinolMetab. 2001;86:517-520.
7. Domecq JP, Prutsky G, Mullan RJ, et al. Lifestyle modification programs inpolycystic ovary syndrome: systematic review and meta-analysis. JClinEndocrinolMetab 2013;98:4655-4663.
8. McCartney, C.R., Eagleson, C.A., Marshall, J.C. Regulation of gonadotropinsecretion: implications for polycystic ovary syndrome. SeminReprod Med.2002;20:317-326.
Symposium on PCOS – Science to Practice
One day Symposium on "PCOS –Science to Practice" was organized bythe Guwahati Obstetrics &Gynaecological Society under the aegisof PCOS Society of India on the 11th
December 2016 at Hotel Landmark,Guwahati . Dr. R. K. Talukdar was thechief conevenor, & Dr. Gitanjali Deka wasthe organizing secretary.
Experts in the fields of gnaecology, infertility, dermatology and endocrinology spoke on thevarious aspect of the multifaceted condition of PCOS. Drs. Rekha Sheth, Saswati S. Chaudhary,Uma Kaima Saikia & Ashok Bhuyan were the keynote speakers. The symposium was attendedby 140 gynaecologists and was spread over 6 sessions, which focused on Basics in PCOS,Infertility & PCOS, Evidence Based treatment, PCOS & Pregnancy, Health risks of PCOS andDrugs in PCOS.
The attendees expressed their interest to seek more information through CMEs in the diagnosis& phenotypes of PCOS, IVF in PCOS and etiopathogenesis of PCOS.
Such effects are mediated by specific changes inplacenta pathways that improve intrauterineenvironment in humans and mouse, resulting finallyin the interruption of the epigenetic vicious cyclewhich transfer maternal metabolic andcardiovascular diseases to the offspring.
Moreover, inositol counteracts the downstreamconsequences of insulin resistance in womenaffected by PCOS, ameliorating the fertility bydecreasing the need of ovarian hyper stimulation andincreasing the pregnancy rate.
Lastly, inositol supplementation from the firsttrimester of pregnancy demonstrated to have a rolein reducing the incidence of GDM in overweight andobese women.
However, larger studies, in double-blind trials,including a more heterogeneous population wouldbe necessary, to confirm the previous results forwomen with GDM, PCOS or post-menopausal and
Continued from page 6
Insulin Sensitizing Properties of Inositol: Experimental Studiesto test a possible application for a more generalizedpopulation of subjects already presenting an insulinresistance or at risk of developing one because ofgenetic predisposition.
References1. Micheal J B, Robin F I. Inositol triphosphate, a novelsecond messenger in
cellular signal transduction. Nature. 1984;308(22):339.
2. Ferrari F, Facchinetti F, Ontiveros AE, Roberts RP, Saade MM, Blackwell SC,et al. The effect of combined inositol supplementation on maternalmetabolic profile in pregnancies complicated by metabolic syndrome andobesity. Am J Obstet Gynecol. 2016;215(4):503.e1-503.e8.
3. Harry E, Vance I O, Mina L, Aaron F. Myo-Inositol as an Essential GrowthFactor for Normal and Malignant Human Cells in Tissue Culture. Sci NewSer. 1956;123(3202):845-7.
4. Jenny F L C, M K L, Janice W S L, Sookja K C, Stephen S M C. Sodium/myo-inositol cotransporter-1 is essential for the development and function ofthe peripheral nerves. FASEB J. 2005;19(5).
5. Dai Z, Chung SK, Miao D, Lau KS, Chan AWH, Kung AWC. Sodium/myo-inositol cotransporter 1 and myo-inositol are essential for osteogenesisand bone formation. J Bone Miner Res. 2011;26(3):582-90.
6. Carlomagno G, Nordio M, Chiu TT, Unfer V. Contribution of myo-inositoland melatonin to human reproduction. Eur J Obstet Gynecol Reprod Biol.2011;159(2):267-72.
7. Coady M, Wallendorff B, Gagnon D, Lapointe J. Identification of a novelNa+/myo-inositol cotransporter. J Biol Chem. 2002;277(38):35219-24.
8. Croze ML, Soulage CO. Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie. 2013;95(10):1811-27.
9. Winegrad A. Does a common mechanism induce the diverse complicationsof diabetes? Diabetes. 1987;36:396-406.
10.Allison S K, Cynthia R H, James C, Clifton B, Itmar R, Heidi K O, et al. Lowurinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus.N Engl J Med. 1990;323:373-8.
11.Sun TH, Heimark DB, Nguygen T, Nadler JL, Larner J. Both myo-inositol tochiro-inositol epimerase activities and chiro-inositol to myo-inositol ratiosare decreased in tissues of GK type 2 diabetic rats compared to Wistarcontrols. Biochem Biophys Res Commun. 2002;293(3):1092-8.
12.Asplin I, Galasko G, Larner J. chiro-inositol deficiency and insulin resistance:a comparison of the chiro-inositol and the myo-inositol containing insulinmediators isolated from urine, hemodialysate, and muscle of control andtype II diabetic subjects. Proc Natl Acad Sci U S A. 1993;90(13):5924-8.
13.Antony PJ, Gandhi GR, Stalin A, Balakrishna K, Toppo E, Sivasankaran K,et al. Myoinositol ameliorates high-fat diet and streptozotocin-induceddiabetes in rats through promoting insulin receptor signaling. BiomedPharmacother. 2017;88:1098-113.
14.Santamaria A, Di Benedetto A, Petrella E, Pintaudi B, Corrado F, D'Anna R,et al. Myo-inositol may prevent gestational diabetes onset in overweightwomen: a randomized, controlled trial. J Matern Fetal Neonatal Med[Internet]. 2015;7058(March 2017):1-4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26698911
15.Monastra G, Unfer V, Harrath A, Bizzarri M. Combining treatment withmyo-inositol and D-chiro-inositol (40:1) is effective in restoring ovaryfunction and metabolic balance in PCOS patients. Gynecol Endocrinol.2017;33(1):1-9.
16.Emekçi Özay Ö, Özay A, Ça?l?yan E, Okyay R, Gülekli B. Myo-inositoladministration positively effects ovulation induction and intrauterineinsemination in patients with polycystic ovary syndrome: a prospective,controlled, randomized trial. Gynecol Endocrinol. 2017;3:1-5.
