Polycystic Ovarian Syndrome

Gavin Sacks
MA BM BCh PhD MRCOG FRANZCOG CREI (UK)

Fertility Specialist IVFAustralia, Sydney VMO Prince of Wales Private and RHW Director of Gynaecology, St George Hospital Conjoint Senior Lecturer UNSW

PCOS - past and present

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Stein-Leventhal Syndrome 1935 PCO Hirsutism Amenorrhoea

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PCOS - past and present

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PCOS - past and present

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Only 50% of women with PCOS are overweight

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Key Learning Objectives

To be able to recognise and diagnose PCOS To understand the lifelong manifestations of PCOS To understand management options for:
longterm health hirsutism infertility

Causes
Syndrome = a collection of symptoms and signs. There is no single cause but multiple predisposing factors. Genetic
Family linkage studies Over 70 candidate genes investigated
Steroidogenic & insulin pathways, ovarian follicle development

Environmental

Fetal programming/ thrifty gene hypothesis Obesity

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Important causal factors

Genetic Central (LH/FSH ratio) Ovarian (Testosterone) Metabolic (Insulin)

PCOS definition
Chronic Anovulation and Hyperandrogenism 5-10% reproductive age women
Diagnosis: 2/3 criteria * 1. Oligo-ovulation &/or anovulation 2. Hyperandrogenism (clinical or biochemical) 3. Polycystic ovaries on ultrasound (PCO) * other causes for hyperandrogenism excluded
ESHRE/ASRM PCOS Consensus Workshop May 2003

How to make a diagnosis

Clinical suspicion
Primary or secondary amenorrhoea Oligomenorrhoea Unexplained infertility Obesity Acne/ hirsutism

Investigations
Serum (early follicular phase):
LH/FSH Total testosterone, Free androgen index (FAI) Exclude other endocrinopathies *TSH, Prolactin, DHEAS, 17-OH progesterone
to look for PCO and endometrial abnormalities

Pelvic ultrasound (follicular phase)

Fasting insulin level testing is not required.

Screening for metabolic syndrome in PCOS may be warranted: Diabetes screen, lipid profile, BP check.

Diagnosis: PCO on ultrasound

At least 1 ovary with 12+ follicles 29mm &/or ovarian volume > 10mls NB: US picture on 1 occasion suffices for diagnosis

25% of women have PCO, but only 5% have PCOS

ESHRE/ASRM PCOS Consensus Workshop May 2003

PCOS is a life-long condition

Hirsutism
? Pronounced adrenarche ? IUGR 0
Longterm health

Cancer (uterine; ?breast) Hypercholesterolaemia Diabetes Hypertension Coronary heart disease

Menstrual irregularities

Infertility, miscarriage Gestational hypertension Gestational diabetes 10 20 30 40 50

60

70 Age (years)

Precocious puberty

Reproductive disorder

Metabolic syndrome

Long-term health risks

Established:

Reproductive: Endometrial Cancer Metabolic: Diabetes, Dyslipidaemias, Hypertension, Obesity

Unproven: Cardiovascular Disease Breast cancer

Cancer risk
Endometrial
Protection from withdrawal bleed at least every 3/12

Breast
Weak association (RR 1.2) Women often concerned and try to avoid the pill (NB. The pill protects against ovarian Ca)

Metabolic problems
Hypertension Dyslipidaemia
TC, LDL-C, TGs

HDL-C

Future diabetes ? Cardiovascular disease (CVD)

coronary disease myocardial infarction

Management of long-term health

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Weight loss (BMI > 25) Lifestyle (diet, exercise)

The Lifestyle Clinic (UNSW; tel 9385 3352)

Orlistat (Xenical); Sibutramine (Reductil)

Protect the endometrium OCP Other progestogens Ovulation induction / pregnancy

Longterm hormone therapy: OCP or metformin ?

The pill versus metformin

OCP Cycle control Contraceptive Side effects Contraindications Reduce ovarian cancer Metformin Induce ovulation 70% No contraception Well tolerated No contraindications ?? Only use if proven hyperinsulinaemia

OCP - metabolic concerns

glucose tolerance insulin resistance lipid levels

Diabetes Cardiovascular disease

OCP use in PCOS women

Outcome Glucose tolerance Improvement
Pasquali 1999

No effect
Korythowski 1995 Morin-Papunen 2003a & b Cagnacci 2003 Guido 2004

Worsening
Nader 1997 Morin-Papunen 2000

Insulin resistance & sensitivity Lipid levels

Pasquali 1999

Morin-Papunen 2003b Armstrong 2001 Cibula 2002 Guido 2004

Korythowski 1995 Dahlgren 1998 Vrbikova 2004 Mastorakos 2006

Falsetti 1995 Mastorakos 2002 Guido 2004 Pasquali 1999

Prelevic 1990 Mastorakos 2002 Guido 2004 Pasquali 1999

Prelevic 1990 Falsetti 1995 Mastorakos 2002 Guido 2004

Vrbikova 2005

The pill is safe in PCOS women

Insulin Resistance

Insulin resistance (IR):

is a prominent feature in both obese (65-90%) and lean (25-45%) women with PCOS is unique to PCOS as occurs independently to obesity, but is aggravated by obesity

(Franks S 1989; Dunaif A 1994)

PCOS and glucose intolerance

Increased prevalence of glucose intolerance (35%) and type 2 diabetes (10%)
Also increased in non-obese PCOS (10%, 1.5%)

Increased risk (x3-7) of developing type 2 diabetes PCOS women develop glucose intolerance at an early age (3rd-4th decade) PCO is risk factor for gestational diabetes

The case for metformin

Women with PCOS: over 6 years:
9% develop impaired glucose tolerance 8% develop diabetes

Metformin can reduce progression to diabetes by 31% in non-PCOS populations

Metformin

Direct intracellular effects to reduce hepatic gluconeogenesis, improve glucose metabolism Target dose: 1500 2550mg daily with meals Most common side effects are GI (diarrhea, nausea/vomiting, flatulence, indigestion, abdo discomfort) Rare problem of lactic acidosis: never been reported in PCOS

Metformin in PCOS

Lifestyle 1st line treatment if overweight

Some advocate lifelong metformin from puberty Currently no long-term data on metformin use

Uncertain advantage adding metformin to OCP

OCP versus metformin: RCTs

Cochrane review: Costello et al 2007 OCP more effective in improving menstrual pattern OCP more effective in reducing serum androgens

No difference between OCP & metformin in effect on hirsutism or acne

No adverse metabolic risk with the use of the OCP compared to metformin for both clinical and surrogate metabolic outcomes. Possible benefit of adding metformin to OCP (improved hirsutism)

Hirsutism
Cosmetic measures Waxing, shaving, laser Oral contraceptive Any (often diane/ yasmin) Metformin Need contraception Anti-androgens Spironolactone (very weak) Cyproterone acetate (need to use 50mg for effect) 5-alpha-reductase inhibitors Finasteride Effective but potentially teratogenic Must counsel carefully and use oral contraceptive

Infertility: ovulatory
Essentially unexplained infertility Exclude other causes (male/ tubal etc) Small but proven benefit from clomid

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Infertility: anovulatory
Weight loss if BMI >25 (diet/ exercise) Clomid (50 - 150mg) versus metformin Clomid and metformin combined FSH stimulation Ovarian drilling IVF IVM

Clomiphene citrate
Used since 1960s Safe to use for 9-12 months continuously Oestrogen receptor antagonist: boost natural FSH release Can have detrimental effect on endometrium Try tamoxifen alternative

FSH stimulation (OI + IUI)

Low doses Need cycle monitoring Pregnancy rates 15-20% Multiple rate 20-25%

Ovarian drilling
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As effective as OI natural conception No multiples

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Laparoscopy Risk of adhesions (unproven)

IVF
Best way to achieve singleton pregnancy in PCOS infertility Main risk is OHSS (ovarian hyperstimulation syndrome)
Low doses of stimulation Careful and frequent monitoring Co-treatment with metformin unproven benefit: ongoing trial at IVFA Blastocyst transfer Sometimes freeze all embryos

IVM (in vitro maturation)

Collect immature eggs Culture in vitro Fertilise and transfer embryos
Few centres worldwide
Recently reported 1st success in UK
Twins as 2 embryos transferred

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400 babies born (versus >2 million IVF)

Miscarriage
40% of women with recurrent miscarriage have PCO (general population 25%) Miscarriage rate increased in women with PCO
High insulin levels can affect the endometrium and implantation Metformin has no known teratogenic effect

PCOS, miscarriage and metformin

Glueck 01
reduced miscarriage rate from 73% to 10% (n=22)

Jakubowicz 02
reduced miscarriage rate from 42% (n=31 untreated) to 8.8% (n=37 treated)

Thatcher 06
decreased miscarriage rate with no increased anomalies (n=188; 237 pregnancies)

RCTs awaited (NB. RCT Suppression LH not effective)

Pregnancy
Outcomes:
Maternal:
Gestational Diabetes (OR 2.94) Pregnancy induced hypertension (OR 3.67) Cesarean sections Acne

Neonatal:
Admission to ICU Premature delivery (OR 1.75)

Metformin still considered experimental

Conclusions
1. PCOS is common.
2. Always focus on presenting problem, but also educate patients about the long-term sequellae. 3. Life-style modification is a very effective treatment option in PCOS.

4. Do not be scared of using the OCP.

5. Ongoing trials for metformin in IVF and miscarriage.