Polycystic Ovarian Syndrome

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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
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PCOS - past and present
Stein-Leventhal Syndrome 1935 PCO Hirsutism Ameno
rrhoea
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PCOS - past and present
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PCOS - past and present
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

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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)

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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
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How to make a diagnosis

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

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Investigations

• Serum (early follicular phase)
• LH/FSH
• Total testosterone, Free androgen index (FAI)
• Exclude other endocrinopathies
• TSH, Prolactin, DHEAS, 17-OH progesterone
• Pelvic ultrasound (follicular phase)
• to look for PCO and endometrial abnormalities
• Fasting insulin level testing is not required.
• Screening for metabolic syndrome in PCOS may be
  warranted Diabetes screen, lipid profile, BP
  check.

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Diagnosis PCO on ultrasound

• At least 1 ovary with 12 follicles 2-9mm /or
  ovarian volume gt 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
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PCOS is a life-long condition
Cancer (uterine ?breast)
Hirsutism
Hypercholesterolaemia
Menstrual irregularities
Diabetes Hypertension
? Pronounced adrenarche
Infertility, miscarriage Gestational
hypertension Gestational diabetes
Coronary heart disease
? IUGR
0 10 20 30 40 50 60 70
Age (years)
Long-term health
Precocious puberty
Reproductive disorder
Metabolic syndrome
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Long-term health risks
Established
Reproductive Endometrial Cancer
Metabolic Diabetes, Dyslipidaemias,
Hypertension, Obesity
Unproven
Cardiovascular Disease
Breast cancer
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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)

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Metabolic problems

• Hypertension
• Dyslipidaemia
• TC, LDL-C, TGs
• HDL-C
• Future diabetes
• ? Cardiovascular disease (CVD)
• coronary disease
• myocardial infarction

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Management of long-term health

• Weight loss (BMI gt 25)
• Lifestyle (diet, exercise)
• The Lifestyle Clinic (UNSW tel [phone])
• Orlistat (Xenical) Sibutramine (Reductil)
• Protect the endometrium
• OCP
• Other progestogens
• Ovulation induction / pregnancy
• Longterm hormone therapy OCP or metformin ?

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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

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OCP - metabolic concerns

• glucose tolerance
• insulin resistance
• lipid levels

• Diabetes
• Cardiovascular disease

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OCP use in PCOS women
The pill is safe in PCOS women
Vrbikova 2005
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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)

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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

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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

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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

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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

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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)

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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

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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 gt25 (diet/ exercise)
• Clomid (50 - 150mg) versus metformin
• Clomid and metformin combined
• FSH stimulation
• Ovarian drilling
• IVF
• IVM

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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

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FSH stimulation (OI IUI)

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

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Ovarian drilling

• As effective as OI
• natural conception
• No multiples
• Laparoscopy
• Risk of adhesions (unproven)

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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

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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
• 400 babies born (versus gt2 million IVF)

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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

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PCOS, miscarriage and metformin

• Glueck 01
• reduced miscarriage rate from 73 to 10 (n22)
• Jakubowicz 02
• reduced miscarriage rate from 42 (n31
  untreated) to 8.8 (n37 treated)
• Thatcher 06
• decreased miscarriage rate with no increased
  anomalies (n188 237 pregnancies)

RCTs awaited (NB. RCT Suppression LH not
effective)
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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
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Conclusions

• PCOS is common.
• Always focus on presenting problem, but also
  educate patients about the long-term sequellae.
• Life-style modification is a very effective
  treatment option in PCOS.
• Do not be scared of using the OCP.
• Ongoing trials for metformin in IVF and
  miscarriage.