A Life of PCOS

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A Life of PCOS

• Roy Homburg
• Barzili Medical Centre, Ashkelon and Maccabi
  Medical Services, Israel
• Homerton Fertility Centre, London
• 
  
  
• 
  

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PCOS A typical case history
A life in 25 minutes of ..
Polly Sistik
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Age 16, schoolgirl. c/o irregular periods, acne,
hirsutism. All symptoms started age 13.5 when had
first period, since then 3-4 periods/year.
o/e Obese BMI 31.5 Abdo circ. 92cm Acne face
and back Mild hirsutism
Polly Sistik
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PCOS revised diagnostic criteria 2003 Rotterdam
consensus 2 out of 3 criteria required

• Oligo- and/or anovulation
• Hyperandrogenism (clinical and/or
• biochemical)
• Polycystic ovaries
• Exclusion of other aetiologies

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symptoms
OBESITY
hormones
ultra- sound
INSULIN
after Dewailly, 2003
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Treatment aims options
Cure acne and hirsutism Regulate menstruation

• Life-style changes

• Anti-androgens / OC pill

• ? metformin

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symptoms
hormones
OBESITY
ultra- sound
WEIGHT LOSS
INSULIN
after Dewailly, 2003
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HIRSUTISM/ACNETREATMENT
- Contraceptive pills
- Cyproterone acetate ethinyl estradiol
- Drosperinone ethinyl estradiol


- Cosmetic treatment
- Metformin not recommended as first line
treatment
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Polly Sistik age 24

• Engaged to be married.
• BMI now 28
• Amenorrhea for the last 6 months.
• Wants to know her chances of conceiving.

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72
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Polly Sistik age 25

• Married.
• Trying to conceive for 6 months.
• 4 periods in the last year.
• Examinations
• Treatment

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Multiple Choice

• Weight loss
• Clomiphene citrate (CC)
• Aromatase inhibitors
• Insulin lowering medications
• Low dose FSH
• Laparoscopic ovarian drilling
• IVF/IVM

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Clomiphene

• Homburg, Hum Reprod, 2005
  
• n 5268 patients
• Ovulation - 3858 (73)
• Pregnancies - 1909 (36)
• Miscarriage - 827 (20)
• Multiple pregnancy rate - 8
• Single live-birth rate 25

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Should we give hCG in CC cycles?
NO NO Maybe Yes NO

• Agarwal Buyalos, 1995
• No improvement in conception rates
• Deaton et al, 1997
• No difference
• Viahos et al, 2005
• hCG may be beneficial
• Kosmas et al, 2007 Meta-analysis
• Favoured hCG but no significant difference
• Brown et al, 2009, Cochrane review
• No difference

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Should we monitor clomiphene cycles with
ultrasound?
No U/S or hCG With U/S hCG
150 150 105 n
34.7 34.7 48 Cumulative pregnancy rate
26.7 26.7 35.6 Deliveries
1 1 0 Multiple pregnancies

• Konig, Homburg et al, ESHRE, 2009
  

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Reasons for Clomiphene Failure

• Failure to ovulate
• FAI
• BMI
• LH
• Insulin

• Ovulation
• but no conception
• Anti-estrogen effects
• - Cervical mucus
• - Endometrium
• High LH

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Clomiphene Citrate Treatment
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Anti-estrogen effect on endometrium

• Endometrial thinning in 15-50
• (Gonen Casper,
  1990Dickey et al, 1993)
• Causes ER downregulation and depletion.
• Suppresses pinopode formation
• 
  (Creus et al, 2003)
• No pregnancies when endometrial thickness at
  midcycle lt 7mm
• Not dose related and recurs in repeat cycles
  
• (Homburg et
  al, 1999)
• 
  

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Aromatase Inhibitor Treatment Day 3-7 of Cycle
ER
ER
ER
ER
E2
FSH
AI
Casper Mitwally
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Aromatase InhibitorsTheoretical Advantages

• Do not block estrogen receptors
• No detrimental effect on endometrium
• or cervical mucus
• Negative feedback mechanism not
• turned offless chance of multiple
• follicular development

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Clomiphene Citrate Treatment
CC
CC
ER
ER
ER
ER
ER
ER
E2
FSH
Day 10
Casper Mitwally
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Aromatase Inhibitor Treatment
ER
ER
ER
ER
ER
ER
E2
FSH
AI
Day 5
Casper Mitwally
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Aromatase InhibitorQuestions

• Do they work?
• Better than CC for first-line treatment?
• Safety?

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Aromatase Inhibitors vs CC

• Meta-analysis, 4 RCTs
• Clear superiority of aromatase inhibitors in
  pregnancy rates (OR 2.0) and deliveries (OR 2.4)

Polyzos et al, Fertil Steril, 2008
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Letrozole vs CC

• 911 newborns in 5 centers
• CC Letrozole
• Pregnancies 397 514
• Congenital 19 (4.8) 14
  (2.7)
• malformations
• Major malformations 12 (3) 6 (1.2)
• Total cardiac anomalies 1.8
  0.2

Tulandi et al, 2006
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Aromatase Inhibitors

• Letrozole 2.5-10 mg/day, n1102
• Pregnancies 368 (33.4)
• Miscarriages 99 (26.9)
• Twins 2 (0.5)
• Fetal anomalies 1 (0.2)

Aghssa et al, 2007 (PCOS, eds Allahbadia, Agrawal)
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Metformin for ovulation induction?


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Live birth rates
CC Metformin
CCmetformin 22.5 7.2
26.8
Legro et al, NEJM,
2007 15.4 7.9
21.1 Zain
et al, Fertil Steril, 2009
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Insulin-sensitising drugs for women with PCOS,
oligo/amenorrhea and subfertility

• Tang et al. Cochrane Database, 2009
• There is no evidence that metformin improves live
  birth rates whether it is used alone or in
  combination with clomiphene, or when compared
  with clomiphene.
• Therefore, the use of metformin in improving
  reproductive outcomes in women with PCOS appears
  to be limited.

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Maitake mushroom

• Chen JT et al, J Altern Complement Med, 2010
• Maitake mushroom extract improves insulin
  resistance.
• Capable of inducing ovulation in PCOS (77)
• 6/8 CC resistant ovulated with CCMaitake

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CONVENTIONAL REGIMEN WITH GONADOTROPHINS
75
75
75
5
5
5
5
DAYS
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Results of Conventional Therapy14 series,
1966-1984, WHO I II
Hamilton-Fairley Franks, 1990
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Low dose rec-FSH
100-150 IU
75-112.5 IU
50-75 IU
14
7
7
Days
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Low dose gonadotropinsSummary of
resultsPatients - 841, Cycles 1556
Updated from Homburg Howles, 1999
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Low-dose FSH

• Only a low-dose protocol should be used for
  ovulation induction in PCOS.
• Small starting and incremental dose increases
  recommended with no dose change for 14 days.

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Duration of Initial Dose 14 or 7 Days?
14 days 7 days
N50, 107 cycles
FSH required - Amps 22
17 - Days 17.4 13 1 large
follicle/cycle 74 60 E2
(pmol/L) 1659
2072 Pregnancies 10 (40)
14 (56) OHSS 0
0 Multiple pregnancies 0
2/14
Homburg, 1999
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Extended Study
Multiple pregnancies 14
days 0/10 7 days
6/29
Homburg, 1999
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How long does it take?

• With a starting dose of 75 IU FSH, unchanged for
  a minimum of 14 days, 90 will get to the
  criteria for hCGwithin 14 days

Homburg Howles, 1999
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Factors affecting outcome of LOD for PCOS

• CCR 54 after 12 months
• 75 after 30 months
• CC and low-dose FSH may be added if no ovulation
  after 3 months
• One-off treatment with low multiple pregnancy
  rate and no OHSS
• Best if lt 3 years infertility, thin and high LH

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Maternal PCOS in pregnancy

• Increased prevalence of
• Early pregnancy loss
• Gestational diabetes
• Pregnancy induced hypertension
• SGA babies

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Polly Sistik age 44

• Happy mother with 2 kids.
• The future

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Effect of aging on PCOS

• Women with PCOS gain regular menstrual cycles
  when aging
• Menstrual cycle restored in those with a smaller
  follicle count
• Elting et al, 2000, 2003

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Sleep Disorders in PCOSPCOS n53, controls n452
Risk of Sleep Apnea in PCOS Odds Ratio 29 (95
CI 5-294) Adjusted for differences in BMI
Vgontzas et al, JCEM, 2001

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PCOS - Late sequelae
Hyperinsulinemia / hyperandrogenism / obesity

• Diabetes mellitus x7
• Hypertension x4
• Low HDL/high LDL

All are risk factors for
cardiovascular disease and CVA
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Polly Gone
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