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A Life of PCOS
Roy Homburg
Barzili Medical Centre, Ashkelon and Maccabi Medical
Services, Israel
Homerton Fertility Centre, London
PCOS – A typical case history
A life in 25 minutes of ………..
Polly Sistik
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.
Polly Sistik
o/e
Obese – BMI 31.5
Abdo circ. 92cm
Acne face and back
Mild hirsutism
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
symptoms
OBESITY
hormones
ultrasound
INSULIN
after Dewailly, 2003
Treatment aims & options
Cure acne and hirsutism
Regulate menstruation
• Life-style changes
• Anti-androgens / OC pill
•? metformin
symptoms
OBESITY
hormones
ultrasound
WEIGHT
LOSS
INSULIN
after Dewailly, 2003
HIRSUTISM/ACNE
TREATMENT
- Contraceptive pills
- Cyproterone acetate + ethinyl estradiol
- Drosperinone + ethinyl estradiol
- Cosmetic
treatment
- Metformin not recommended as first line treatment
Polly Sistik – age 24
• Engaged to be married.
• BMI now 28
• Amenorrhea for the last 6 months.
• Wants to know her chances of conceiving.
72%
Polly Sistik – age 25
• Married.
• Trying to conceive for 6 months.
• 4 periods in the last year.
• Examinations
• Treatment
Multiple Choice
•
•
•
•
Weight loss
Clomiphene citrate (CC)
Aromatase inhibitors
Insulin lowering medications
• Low dose FSH
• Laparoscopic ovarian drilling
• IVF/IVM
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%
Should we give hCG in CC cycles?
Agarwal & Buyalos, 1995
NO
No improvement in conception rates
Deaton et al, 1997
NO
No difference
Viahos et al, 2005
hCG may be beneficial
Kosmas et al, 2007 Meta-analysis
Maybe
Yes
Favoured hCG but no significant difference
Brown et al, 2009, Cochrane review
No difference
NO
Should we monitor clomiphene
cycles with ultrasound?
With U/S + hCG
No U/S or hCG
n
105
150
Cumulative
pregnancy rate
48%
34.7%
Deliveries
35.6%
26.7%
Multiple
pregnancies
0
1
Konig, Homburg et al, ESHRE, 2009
Reasons for Clomiphene Failure
Failure to ovulate
•
•
•
•
FAI
BMI
LH
Insulin
Ovulation
but no conception
• Anti-estrogen effects
- Cervical mucus
- Endometrium
• High LH
Clomiphene Citrate Treatment
CC
ER
ER
ER
ER
E2
FSH
Day 5
Anti-estrogen effect on endometrium
• Endometrial thinning in 15-50%
(Gonen &Casper, 1990;Dickey et al, 1993)
• Causes ER downregulation and depletion.
• Suppresses pinopode formation
(Creus et al, 2003)
• No pregnancies when endometrial thickness at
midcycle < 7mm
• Not dose related and recurs in repeat cycles
(Homburg et al, 1999)
Aromatase Inhibitor Treatment:
Day 3-7 of Cycle
ER
ER
ER
ER
E2
FSH
AI
Casper & Mitwally
Aromatase Inhibitors:
Theoretical Advantages
• Do not block estrogen receptors
• No detrimental effect on endometrium
or cervical mucus
• Negative feedback mechanism not
turned off—less chance of multiple
follicular development
Clomiphene Citrate Treatment
CC
CC
ER
ER
ER
ER
ER
ER
ER
ER
E2
FSH
E2
FSH
Day 5
Day 10
Casper & Mitwally
Aromatase Inhibitor Treatment
ER
ER
ER
ER
ER
ER
ER
E2
E2
FSH
FSH
AI
Day 5
Day 10
Casper & Mitwally
Aromatase Inhibitor
Questions
• Do they work?
• Better than CC for first-line treatment?
• Safety?
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
Letrozole vs CC
• 911 newborns in 5 centers
CC
Letrozole
Pregnancies
397
Congenital
19 (4.8%)
malformations
Major malformations 12 (3%)
Total cardiac anomalies 1.8%
514
14 (2.7%)
6 (1.2%)
0.2%
Tulandi et al, 2006
Aromatase Inhibitors
• Letrozole 2.5-10 mg/day, n=1102
• 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)
Metformin for ovulation
induction?
Live birth rates
CC
22.5%
Metformin
7.2%
CC+metformin
26.8%
Legro et al, NEJM, 2007
15.4%
7.9%
21.1%
Zain et al, Fertil Steril, 2009
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.
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 CC+Maitake
CONVENTIONAL REGIMEN
WITH GONADOTROPHINS
75
75
75
5
5
5
DAYS
5
Results of Conventional Therapy
14 series, 1966-1984, WHO I & II
Conceived
46% (16-78)
Multiple pregs.
34% (22-50)
Miscarriages
23% (12-30)
Severe OHSS
4.6% (1.3-9.4)
Hamilton-Fairley & Franks, 1990
Low dose rec-FSH
100-150 IU
75-112.5 IU
50-75 IU
14
7
Days
7
Low dose gonadotropins
Summary of results
Patients - 841, Cycles 1556
Pregnancies
320 (40%)
Fecundity/cycle
20%
Uniovulation
70%
OHSS
0.14%
Multiple pregs.
5.7%
Updated from Homburg & Howles, 1999
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.
Duration of Initial Dose: 14 or 7 Days?
N=50, 107 cycles
FSH required
- Amps
- Days
1 large follicle/cycle
14 days
22
17.4
74%
E2 (pmol/L)
1659
Pregnancies
10 (40%)
OHSS
0
Multiple pregnancies 0
7 days
17
13
60%
2072
14 (56%)
0
2/14
Homburg, 1999
Extended Study
Multiple pregnancies
14 days
0/10
7 days
6/29
Homburg, 1999
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 hCG
within 14 days
Homburg & Howles, 1999
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 < 3 years infertility, thin and high LH
Maternal PCOS in pregnancy
Increased prevalence of:
•
•
•
•
Early pregnancy loss
Gestational diabetes
Pregnancy induced hypertension
SGA babies
Polly Sistik – age 44
• Happy mother with 2 kids.
• The future
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
Sleep Disorders in PCOS
PCOS n=53, controls n=452
90
80
70
60
50
40
30
20
10
0
Risk of Sleep
Apnea in PCOS
PCOS N
=53
Controls N
=452
Odds Ratio 29
(95% CI 5-294)
Sleep
Apnea
Daytime
Sleepiness
Adjusted for
differences in
BMI
Vgontzas et al,
JCEM, 2001
PCOS - Late sequelae
Hyperinsulinemia / hyperandrogenism / obesity
•Diabetes mellitus x7
•Hypertension x4
•Low HDL/high LDL
*All are risk factors for
cardiovascular disease and CVA
Polly Gone