Polycystic ovarian syndrome: an Polycystic ovarian syndrome: an Asian phenomenon?Asian phenomenon?

Premila Jeevan Kollipara MD FRCOGPremila Jeevan Kollipara MD FRCOG

Clinical Director & Consultant in Obstetrics and GynaecologyClinical Director & Consultant in Obstetrics and GynaecologyQueen’s Hospital, London, England Queen’s Hospital, London, England

Defining polycystic ovarian Defining polycystic ovarian syndrome (PCOS)syndrome (PCOS)

Identified by Slein & Leventhal (1935)Identified by Slein & Leventhal (1935) Oligo/amenorrhoeaOligo/amenorrhoea Bilateral polycystic ovaries on surgeryBilateral polycystic ovaries on surgery

NIH definition (1990)NIH definition (1990) HyperandrogenismHyperandrogenism Ovarian dysfunctionOvarian dysfunction Presence of PCO morphology not requiredPresence of PCO morphology not required

Rotterdam Consensus Workshop (2003)Rotterdam Consensus Workshop (2003) HyperandrogenismHyperandrogenism Ovarian dysfunctionOvarian dysfunction Presence of PCO morphologyPresence of PCO morphology

Any 2 of these 3 could lead to a diagnosis Any 2 of these 3 could lead to a diagnosis

IncidenceIncidence

Reported incidence ranges from 10% to Reported incidence ranges from 10% to 80% across epidemiological studies80% across epidemiological studies

Seen in women of all races and Seen in women of all races and nationalitiesnationalities

Very common in the South Asian Very common in the South Asian population, including many from the Indian population, including many from the Indian subcontinentsubcontinent

SymptomsSymptoms

Oligomenorrhea (>35 day cycle) / Amenorrhoea (>6 Oligomenorrhea (>35 day cycle) / Amenorrhoea (>6 months)months) Either may be associated with heavy bleedingEither may be associated with heavy bleeding

Difficulty in losing weightDifficulty in losing weight InfertilityInfertility HirsutismHirsutism DyspareuniaDyspareunia Androgenic alopeciaAndrogenic alopecia AcneAcne SeborrheaSeborrhea Acanthosis nigricansAcanthosis nigricans AcrochordonsAcrochordons Prolonged periods of PMS like symptoms (bleeding, Prolonged periods of PMS like symptoms (bleeding,

mood swings, pelvic pain, backache)mood swings, pelvic pain, backache) Obstructive sleep apnoeaObstructive sleep apnoea

PresentationPresentation

Women may present with these Women may present with these symptoms:symptoms:

at any age at any age

to a gynaecologist, dermatologist or to a gynaecologist, dermatologist or endocrinologistendocrinologist

SignsSigns

On biochemical tests:On biochemical tests: LH to FSH ratio greater than 1 on day 3 of the menstrual cycleLH to FSH ratio greater than 1 on day 3 of the menstrual cycle High level of testosteroneHigh level of testosterone High level of sex hormone binding globulin High level of sex hormone binding globulin HyperinsulinaemiaHyperinsulinaemia

On scan:On scan: 10 or more peripherally located small follicles in ovary (echogenic 10 or more peripherally located small follicles in ovary (echogenic

‘string of pearls’ appearance)‘string of pearls’ appearance) Ovary enlarged 1.5 to 3 times normalOvary enlarged 1.5 to 3 times normal

On laparascopy:On laparascopy: Multiple smooth, thickened, pearl-white areas on the outer surface Multiple smooth, thickened, pearl-white areas on the outer surface

of the ovaryof the ovary

RisksRisks Endometrial hyperplasia and cancerEndometrial hyperplasia and cancer

Insulin resistance and type II diabetesInsulin resistance and type II diabetes Gestational diabetesGestational diabetes Weight gainWeight gain

Infertility Infertility MiscarriageMiscarriage

HypertensionHypertension DyslipidaemiaDyslipidaemia Cardiovascular diseaseCardiovascular disease StrokeStroke

Diagnosing PCOSDiagnosing PCOS

Difficult and therefore characterised as a syndrome and Difficult and therefore characterised as a syndrome and not as a diseasenot as a disease

Standard diagnostic assessments:Standard diagnostic assessments: History – 4 key questions:History – 4 key questions:

Menstrual patternsMenstrual patterns ObesityObesity HirsutismHirsutism Absence of breast dischargeAbsence of breast discharge Sensitivity 77.1% and specificity 93.8%Sensitivity 77.1% and specificity 93.8%

Transvaginal ultrasound scanTransvaginal ultrasound scan

Serum testosterone levelSerum testosterone level Free more sensitive than totalFree more sensitive than total Free androgen index = free testosterone/SHBG x 100Free androgen index = free testosterone/SHBG x 100

Diagnosing PCOS (continued)Diagnosing PCOS (continued)

Common assessments for associated conditions Common assessments for associated conditions or risks:or risks: Fasting biochemical screenFasting biochemical screen Lipid profileLipid profile 2 hour oral GTT2 hour oral GTT

Impaired GTT in 15-30%Impaired GTT in 15-30% Frank diabetes in 65-68%Frank diabetes in 65-68% Insulin resistance in both normal and overweightInsulin resistance in both normal and overweight

Exclusions:Exclusions: Prolactin levelProlactin level TSH / Free thyroxineTSH / Free thyroxine 17 hydroxyprogesterone17 hydroxyprogesterone DHEASDHEAS AndrostenedioneAndrostenedione

Diagnosing PCOS (continued)Diagnosing PCOS (continued)

Controversial testsControversial testsFasting insulin levelFasting insulin levelGTT with insulin level – IGTTTGTT with insulin level – IGTTTHOMAI – mathematical derivation calculated HOMAI – mathematical derivation calculated

from the fasting values of glucose and insulin from the fasting values of glucose and insulin allows a direct and moderately accurate allows a direct and moderately accurate measure of insulin sensitivitymeasure of insulin sensitivity

LH/FSH ratio not very specific – present in LH/FSH ratio not very specific – present in less than 50% in 1 studyless than 50% in 1 study

Differential diagnosisDifferential diagnosis

CAHCAHCushing’sCushing’sHyperprolactinaemiaHyperprolactinaemiaOther pulmonary and adrenal disordersOther pulmonary and adrenal disorders

PCOS has been reported in patients with PCOS has been reported in patients with acromegaly, an insulin resistant conditionacromegaly, an insulin resistant condition

PathogenesisPathogenesis

PCOS develops when:PCOS develops when:

Ovaries are stimulated to produce more Ovaries are stimulated to produce more androgens through the release of LH by the androgens through the release of LH by the anterior pituitaryanterior pituitary

Ovaries are stimulated to produce more Ovaries are stimulated to produce more androgens through high levels of insulinandrogens through high levels of insulin

AetiologyAetiology Cause still unknown as it involves a diverse and complex set of symptomsCause still unknown as it involves a diverse and complex set of symptoms However, a number of theories have been put forwardHowever, a number of theories have been put forward

Insulin resistance hypothesis:Insulin resistance hypothesis:

HyperinsulinaemiaHyperinsulinaemia

↓↓↑↑ GHRH pulse frequencyGHRH pulse frequency

↓↓LH over FSH dominanceLH over FSH dominance

↓↓↑↑ovarian androgensovarian androgens

↓↓↓↓ follicular maturationfollicular maturation

↓↓↓↓ SHBG bindingSHBG binding

↓↓PCOSPCOS

Aetiology (continued)Aetiology (continued) Genetic hypothesis:Genetic hypothesis:

Interpopulation variation in the frequency of Interpopulation variation in the frequency of phenotypic expression of PCOSphenotypic expression of PCOS

Disease familialDisease familial

More common in monozygotic twinsMore common in monozygotic twins

Some link to the D193884 dinucleotide repeat marker Some link to the D193884 dinucleotide repeat marker linked to insulin receptor gene on chromosome linked to insulin receptor gene on chromosome 19p13.219p13.2

Aetiology (continued)Aetiology (continued) Environmental hypothesis:Environmental hypothesis:

Low birth weight females have a higher chance of Low birth weight females have a higher chance of precocious pubarche, hyperinsulinaemia and precocious pubarche, hyperinsulinaemia and hyperandrogenismhyperandrogenism

Hypothesized that poor foetal and infant growth can Hypothesized that poor foetal and infant growth can promote development of PCOS in individuals with promote development of PCOS in individuals with genetic susceptibility when exposed to a nutritional genetic susceptibility when exposed to a nutritional environment of excess later in lifeenvironment of excess later in life

Exposure to androgens during pregnancyExposure to androgens during pregnancy Animal studies in rhesus monkeys and sheepAnimal studies in rhesus monkeys and sheep

Aetiology (continued)Aetiology (continued) Evolutionary hypothesis:Evolutionary hypothesis:

At some point in evolution PCOS may have been selectively At some point in evolution PCOS may have been selectively advantageousadvantageous

Women with PCOS have a high chance of being obese and Women with PCOS have a high chance of being obese and anovulatory during times of normal or excess food availability anovulatory during times of normal or excess food availability

During periods of food shortage and weight loss they begin to During periods of food shortage and weight loss they begin to ovulateovulate

Selective advantage in being able to reproduce when other women Selective advantage in being able to reproduce when other women become anovulatorybecome anovulatory

With a modern Westernised lifestyle with abundant food and limited With a modern Westernised lifestyle with abundant food and limited physical activity these thrifty genes have become disadvantageousphysical activity these thrifty genes have become disadvantageous

High waist to hip ratio and carbohydrate intolerance in many hunter-High waist to hip ratio and carbohydrate intolerance in many hunter-gatherer populations throughout the worldgatherer populations throughout the world

The suggestion is that a thrifty gene would code for famine resistant The suggestion is that a thrifty gene would code for famine resistant glucose metabolismglucose metabolism

Genotype leads to anabolic metabolism and fat depositionGenotype leads to anabolic metabolism and fat deposition Traditionally not obese when living in their own lifestyle where food Traditionally not obese when living in their own lifestyle where food

supplies are at or just above subsistence level or seasonally supplies are at or just above subsistence level or seasonally availableavailable

Aetiology (continued)Aetiology (continued)

Food deprivation hypothesis:Food deprivation hypothesis:

Weight loss results in spontaneous medically Weight loss results in spontaneous medically unassisted pregnancies in 33% of casesunassisted pregnancies in 33% of cases

Thus the onset of severe food deprivation, Thus the onset of severe food deprivation, whether incidental or seasonal, might present whether incidental or seasonal, might present reproductive advantage to women with the reproductive advantage to women with the PCOS genotypePCOS genotype

Aetiology (continued)Aetiology (continued)

Re-feeding hypothesis:Re-feeding hypothesis:

Chronic food deprivation leads to famine related Chronic food deprivation leads to famine related amenorrhoeaamenorrhoea

Amenorrhoeic women, when fed, will reach the critical Amenorrhoeic women, when fed, will reach the critical BMIBMI

This will open the leptin gateThis will open the leptin gate

This will favour earlier ovulationThis will favour earlier ovulation

Aetiology (continued)Aetiology (continued)

Trans-generational privation hypothesisTrans-generational privation hypothesis

Nutrition of mothers and grandmothers has a Nutrition of mothers and grandmothers has a profound influence on the health of the profound influence on the health of the offspring in adulthoodoffspring in adulthood

Treatment of PCOSTreatment of PCOS

The mainstay of treatment is:The mainstay of treatment is:

To start the patient on a weight loss dietTo start the patient on a weight loss dietA low glycaemic index (GI) diet is the idealA low glycaemic index (GI) diet is the idealA significant part of carbohydrate should be from A significant part of carbohydrate should be from

fruit, vegetable and wholegrain sourcesfruit, vegetable and wholegrain sources

To ensure good aerobic exercise for 30 To ensure good aerobic exercise for 30 minutes every dayminutes every day

Aims of medical treatmentAims of medical treatment Medical treatment of PCOS should be tailored to Medical treatment of PCOS should be tailored to

the patients’ goals:the patients’ goals:

Restoration of menstruationRestoration of menstruation

Prevention of endometrial hyperplasiaPrevention of endometrial hyperplasia

Prevention of endometrial cancerPrevention of endometrial cancer

Restoration of fertilityRestoration of fertility

Treatment of hirsutism or acneTreatment of hirsutism or acne

Correction of insulin levelsCorrection of insulin levels

Drugs that reduce insulin resistance are Drugs that reduce insulin resistance are helpful:helpful:Metformin hydrochlorideMetformin hydrochlorideProglitazone hydrochlorideProglitazone hydrochlorideRosiglitazone maleateRosiglitazone maleate

Combined with exercise and low GI diet, Combined with exercise and low GI diet, 85% of patients will improve in terms of 85% of patients will improve in terms of menstrual cycle regularity and ovulationmenstrual cycle regularity and ovulation

Restoration of menstruation and Restoration of menstruation and prevention of endometrial prevention of endometrial

hyperplasiahyperplasia Combined contraceptive pillCombined contraceptive pill Mirena IUDMirena IUD Oral progesterone taken every 3 months to Oral progesterone taken every 3 months to

induce a predictable menstrual bleedinduce a predictable menstrual bleed

D-chiro-inositolD-chiro-inositol Naturally occurring human metabolite known to be Naturally occurring human metabolite known to be

involved in insulin metabolisminvolved in insulin metabolism Available as a nutritional supplement in the US Available as a nutritional supplement in the US

Treatment of infertilityTreatment of infertility Clomiphene citrate +/- metforminClomiphene citrate +/- metformin

Drastic increase in ovulation occurs with a Drastic increase in ovulation occurs with a combination of diet, moderate weight loss and the combination of diet, moderate weight loss and the above drugsabove drugs

Controlled ovarian hyperstimulationControlled ovarian hyperstimulation In vitro fertilisationIn vitro fertilisation In vitro maturationIn vitro maturation Ovarian drillingOvarian drilling Laparoscopic electrocauterisationLaparoscopic electrocauterisation Ovarian wedge resectionOvarian wedge resection

Treatment of androgenic symptomsTreatment of androgenic symptoms

Cyproterone acetate (contained in Cyproterone acetate (contained in Dianette)Dianette)

SpiranolactoneSpiranolactone

EflornithineEflornithine

Electrolysis / laser therapyElectrolysis / laser therapy

SummarySummary

PCOS is an enormous problem, with significant PCOS is an enormous problem, with significant effects on both body morphology and fertilityeffects on both body morphology and fertility

Its incidence could be as high as 80% in the Its incidence could be as high as 80% in the Indian female populationIndian female population

Although its aetiology is not fully understood, a Although its aetiology is not fully understood, a low GI diet and regular exercise may help to low GI diet and regular exercise may help to ameliorate symptomsameliorate symptoms

Thank you!Thank you!