Polycystic Ovary SyndromePolycystic Ovary SyndromePCOSPCOS

Talia Eldar-Geva, MD, PhD

Director Reproductive Endocrinology and Genetics Unit, IVF Unit

Shaare-Zedek Medical Center

5th year Medical Students, 2014

אז מה זה??

“Stein-Leventhal Syndrome”

Stein, Leventhal. Am J Obstet Gynecol 1935:

Amenorrhea associated with bilateral polycystic ovaries.

Seven women with amenorrhea, hirsutism, obesity, and a characteristic polycystic appearance of their ovaries.

Ovarian Morphology

Vaginal US 12 follicles of 2-9 mm in diameter in one ovary and/or

ovarian volume > 10cm3

Hyperandrogenism

• Hirsutism

• Acne

• Male-pattern alopecia

HirsutismFerriman-Gallwey scoring system

0-36mild

Moderate

severe

Diagnostic criteria ESHRE/ASRM PCOS Consensus

(Rotterdam, July 2003)

• Two out of three:Two out of three:–Ovarian morphology

–Hyperandrogenism (biochemical or clinical)

–Chronic Oligo/anovulation

Range of clinical manifestations of PCOS

Mensrual disturbence two thirds Oligomenorrhoea 50% Amenorrhoea 20% Regular cycles 30% Infertility (~75% of anovulatory

infertility)

Hyperandrogenism 50%

Obesity 30-75%Insulin resistance >50%

Asymptomatic (20% of those with PCO)

Pathogenesis

• No single etiologic factor fully accounts for the spectrum of abnormalities in PCOS

• GnRH pulse frequencyGnRH pulse frequency• Pituitary responsePituitary response

– LH LH/FSHLH LH/FSH – stimulate androgens secretion by theca cells

• Cytochrome P-450c17Cytochrome P-450c17– ovarian theca cells of PCOS women are more efficient at

converting androgenic precursors to testosterone than are normal theca cells.

• InsulinInsulin

• ??

Weight increase

Genetic defects ininsulin action

Insulin receptor disorders

INSULINincreases

IGFBP-1decreases

SHBP decreases

LH THECA

Androstenedioneincreases

Testosteroneincreases

+

Free Testosteroneincreases

Free E2increases

Free IGF-Iincreases

Acanthosis Nigricans

INSULIN RESISTANCE: DIAGNOSIS & SCREENING

•OGTT (75 gr)– Glucose response, Insulin response – area under curves– Glucose Insulin (G:I) ratio

Fasting G:I ratio < 4.5 is the single best screening measure for detecting Insulin Resistance in PCOS

Differential Diagnosis

• Hyperprolactinemia• Nonclassic congenital adrenal hyperplasia• Cushing’s syndrome• Androgen-secreting neoplasm• Acromegaly• Hypothyroidism• Drugs-related (androgens, valproic acid,

cyclosporine, or other drugs).

Hormones profile

• Testosterone– SHBG– Free Androgen Index

• Androstenedione

• DHEA-S• 17-OH-Progesterone

• LH• LH/FSH

• Lipids profile• Glucose• Insulin

Dermatologist

Disorder of hair growth, Acne

Fertility problem Menstrual dysfunctionGynecologyst

Obesity problem pseudo Cushing’s diseaseInternist General

practitioner

?

Frequency: 5-10% of females

Long-Term Disease Risks in PCOS (Independent of Obesity)

Increased risk very likely• Type 2 diabetes mellitus• Dyslipidemia• Endometrial cancerIncreased risk possible• Hypertension• Cardiovascular disease• Gestational diabetes

mellitus• Pregnancy-induced

hypertensionIncreased risk unlikely • Ovarian cancer• Breast ca.

TOPIC: Summary of Disease Risks

לו הייתם שטיין ולוונטלאיך הייתם מטפלים?

WEDGE RESECTION

Laparoscopic Ovarian “Drilling”/CauterizationLaparoscopic Ovarian “Drilling”/Cauterization))Stein-Leventhal - wedge resectionStein-Leventhal - wedge resection

הצגת מקרה

45 ימים, וסת אחרון לפני 45-60, וסת אחת ל 32בת •ימים.

ק"ג למ"ר(, BMI 31 ס"מ )165 ק"ג, גובה 82משקל •עודף שיער בפנים.

• LH=IU/L16.טסטוסטרון תקין ,

– SHBGאבל •

נמוך, ולכן...•

האם חסר משהו לאבחנה?•

INDUCTION OF OVULATIONINDUCTION OF OVULATION WHO Group IIWHO Group II

PRINCIPLE - need stimulation with FSHPRINCIPLE - need stimulation with FSH

Clomiphene CitrateClomiphene Citrate

HMGHMG

FSHFSH - -urinaryurinary - -recombinantrecombinant

Pulsatile GnRHPulsatile GnRH

))Ovarian cauterizationOvarian cauterization((

Clomiphene citrate (CC) )Ikaclomin, Clomid(

Synthesized 1956

Clinical use 1960

Approved )US( 1967

Orally active

Non-steroidal

Similar to estrogen

Estrogen agonist / antagonist

1-3 months in serum

CC: Mechanism of ActionPRINCIPLE: Weak ESRM (estrogen receptor modulator)

Binding to Hypothalamic Estrogen receptors

Occupying Estrogen-receptors for long time

Inhibition of receptor replenishment

“mimicking” hypoestrogenism

Increase in GnRH pulse frequency (& amplitude)

FSH & LH levels rise

Treatment cycle with CC

First step –Progesterone

treatment – induce bleeding–decreases LH levels –opposes estrogen-

induced endometrial hyperplasia

Cycle days5 9

CC50-200mg/day

5 days

LH

FSH

Progesterone

CC: Minor EffectsCC: Minor Effects

Directly stimulates FSH secretion from hypophysis

Direct ovarian effect

BUTBUTAnti-estrogenic effect in the

Cervix

Endometrium

Can induce/aggravate luteal-phase defect

Response to clomipheneResponse to clomiphene

No responseNo response20%20%

OvulationOvulation & & pregnancypregnancy

OvulationOvulation - -no pregnancyno pregnancy

45%45%

35%35%

Cumulative 6 cycles pregnancy (75%) rate approaches the normal rate (if no other cause of infertility)

CC: Side Effects

•Vasomotor flushes10-20%

•Abdominal bloating, pain 5.5%

•Breast discomfort 2%

•Nausea, vomiting 3%

•Visual symptoms 1.5%

•Headache 1.3%

•Dryness, loss of hair 0.3%

CC: Complications

• Multiple pregnancy 8-10%

• high-order <1%

• OHSS 5-10%

• mostly mild - moderate• No or slightly increased ectopic pregnancy rate )1%(

• No change in miscarriage rate )15%(

• No change in congenital malformations rate

• Inconclusive data regarding increased cancer rate

What to do with CC failures?• Extended protocols • Add dexamethasone• Add pretreatment suppression )pill, GnRH-a(• Treat obesity• Treat hyperinsulinemia• Add intra-uterine insemination• Ovarian cauterization• Estrogen to improve endometrial factor is ineffective

• Do not treat for more that 6 cycles

GONADOTROPINS TREATMENT

• Human menopausal Gonadotropins )hMG(– FSH 75IU + LH 75IU

• Urinary FSH - FSH 75IU, <1% LH

• Highly purified urinary FSH - < 0.1% LH

• Recombinant FSH

• hCG

• Recombinant LH

• Could be replaced by GnRH / GnRH agonist

Treatment Cycle with Menotropins

++5-75-7 ++55 ++55

Cycle DaysCycle Days55

7575

150150

225225

US & E2 measurement

every 2 -5 days

US for follicular number and size

hCGhCG, 5000-10000IUFSH dailyFSH daily

When follicle 17-20mmand E2 600-1500pmol/L

Complications of Complications of Gonadotropins Gonadotropins StimulationStimulation

• MULTIPLE FOLLICULOGENESISMULTIPLE FOLLICULOGENESIS– MULTIPLE PREGNANCIES – 20%!MULTIPLE PREGNANCIES – 20%!– OHSS – (severe 1-3%)OHSS – (severe 1-3%)

• HIGH MISCARRIAGE RATEHIGH MISCARRIAGE RATE (25%)(25%)

Low dose protocolsLow dose protocols

•Step-down

•Step up

•Sequential

step-up/step-down

LOW DOSE FSHLOW DOSE FSHThe FSH threshold theoryThe FSH threshold theory

1414 77 77

DAYSDAYS

37.537.5

37.537.5

Low dose FSHLow dose FSH

•Monovulation 70%Monovulation 70%

•Fecundity/cycle 20%Fecundity/cycle 20%

• OHSS <0.1%OHSS <0.1%

•Multiple pregnancies 6%Multiple pregnancies 6%

FSH or HMG in PCOS?FSH or HMG in PCOS?Recombinant or urinary FSH?Recombinant or urinary FSH?

• Same pregnancy rates

• Same OHSS rates

• Same multiple pregnancy rate

OBESE PCOS - LOSS OF WEIGHTOBESE PCOS - LOSS OF WEIGHT

Improves signs of hyperandrogenismImproves signs of hyperandrogenismInduces/facilitates ovulationInduces/facilitates ovulation

Loss of >5% of body weight -Loss of >5% of body weight - Reduces - insulin levelsReduces - insulin levels - ovarian androgen production- ovarian androgen production - circulating free testosterone- circulating free testosterone Increases - SHBG, IGFBP-1 Increases - SHBG, IGFBP-1 75% conceived75% conceived

Insulin sensitizing agentsInsulin sensitizing agents Metformin (Glucophage) Metformin (Glucophage)

• Inhibits hepatic glucose production.Inhibits hepatic glucose production.

• Reduces insulin resistance and secretion.Reduces insulin resistance and secretion.

• Causes weigh loss.Causes weigh loss.

• Directly inhibits ovarian steroidogenesis.Directly inhibits ovarian steroidogenesis.

• Reduces T, free T, A4, DHEAS, LH,Reduces T, free T, A4, DHEAS, LH,

Waist to hip ratio, BMI, BP.Waist to hip ratio, BMI, BP.

• Increases FSH, SHBGIncreases FSH, SHBG

• Side effects - gastrointestinal (30%).Side effects - gastrointestinal (30%).

• 1500mg-2500mg/day, at least 3 months.1500mg-2500mg/day, at least 3 months.

Metformin as adjuvant therapy for Metformin as adjuvant therapy for induction of ovulationinduction of ovulation

• Restored menstruation and ovulation Restored menstruation and ovulation

• Improves ovulation rate with CCImproves ovulation rate with CC

• Metformin + FSH = fewer follicles, less Metformin + FSH = fewer follicles, less OHSSOHSS

• Improved quality of mature oocytes, Improved quality of mature oocytes, fertilization & pregnancy ratesfertilization & pregnancy rates

Laparoscopic Ovarian “Drilling”/CauterizationLaparoscopic Ovarian “Drilling”/Cauterization))Stein-Leventhal - wedge resectionStein-Leventhal - wedge resection

Treatment sequence in PCOSTreatment sequence in PCOSWeight loss / change life stileWeight loss / change life stile

ClomipheneClomiphene

Low dose FSHLow dose FSH

Metformin (only if insulin Metformin (only if insulin resistant/obese?)resistant/obese?)

GnRH-agonist (if LH very high)GnRH-agonist (if LH very high)

Laparoscopic ovarian drillingLaparoscopic ovarian drilling

IVFIVF

?