Polycystic Ovary Syndrome Polycystic Ovarian Syndrome Gavin Sacks

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Polycystic Ovary Syndrome Polycystic Ovarian Syndrome Gavin Sacks Powered By Docstoc
					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                             QuickTime™ and a
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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                                              QuickTime™ and a
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  – 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
 •   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.
  Diagnosis: PCO on ultrasound

 • At least 1 ovary with 12+ follicles 2-
   9mm &/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

                                Cancer (uterine; ?breast)
               Hirsutism
                                     Hypercholesterolaemia
         Menstrual irregularities
                                         Diabetes
  ? Pronounced adrenarche                Hypertension
                       Infertility, miscarriage   Coronary heart disease
? IUGR                 Gestational hypertension
                       Gestational diabetes

  0       10      20       30       40     50     60        70
                                                             Age (years)
Long-      Precocious        Reproductive         Metabolic syndrome
term       puberty           disorder
health
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, TG’s

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



       glucose tolerance

       insulin resistance

       lipid levels




       Diabetes

       Cardiovascular disease
     OCP use in PCOS women

     Outcome        Improvement       No effect                 Worsening
     Glucose        Pasquali 1999     Korythowski 1995          Nader 1997
                                      Morin-Papunen 2003a & b   Morin-Papunen 2000
     tolerance                        Cagnacci 2003
                                      Guido 2004


     Insulin        Pasquali 1999     Morin-Papunen 2003b       Korythowski 1995
                                      Armstrong 2001            Dahlgren 1998
     resistance &                     Cibula 2002               Vrbikova 2004
     sensitivity                      Guido 2004                Mastorakos 2006


     Lipid levels   Falsetti 1995     Prelevic 1990             Prelevic 1990
                    Mastorakos 2002   Mastorakos 2002           Falsetti 1995
                    Guido 2004        Guido 2004                Mastorakos 2002
                    Pasquali 1999     Pasquali 1999             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                       QuickTime™ and a
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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
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• Fertilise and transfer
  embryos

• Few centres worldwide
  – Recently reported 1st success in UK
     • Twins as 2 embryos transferred
  – 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.

				
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posted:12/22/2011
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