Transcript PCOS revised diagnostic criteria ~ 2003 Rotterdam

Treatment strategies for the infertile PCO patient
Shahar Kol
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 etiologies
Multiple Choice
 Lifestyle modification: Weight loss
 Clomiphene citrate (CC)
 Aromatase inhibitors (AI’s)
 Insulin lowering medications
 Low dose FSH
 Laparoscopic ovarian drilling
 IVF: new options
Lifestyle modification
Obesity associated with:



Anovulation
Pregnancy loss, late pregnancy complications
Failure or delayed response to CC, FSH, LOD.
Weight loss recommended as 1st line therapy in obese
PCOS women seeking pregnancy
OBESE PCOS - LOSS OF WEIGHT
 Loss of >5% of body weight 
Reduces - insulin levels
- ovarian androgen production
- circulating free testosterone
 Induces ovulation
 Facilitates ovulation induction
 Reduces miscarriage rates
Kiddy et al,1992;Hamilton-Fairley et al,1992
Lifestyle modification
Behavioural counselling
Diet (caloric restriction) & exercise
Bariatric surgery
Lifestyle changes in women with
polycystic ovary syndrome 2011
 There was no evidence of effect for lifestyle intervention
on improving glucose tolerance or lipid profiles and no
literature assessing clinical reproductive outcomes.
 Long term complicated studies, dropout rates, fertility
seeking patients are impatient…
Clomiphene Citrate Treatment
CC
ER
ER
ER
ER
E2
FSH
Day 5
Clomiphene Citrate
 Starting on day 2,3,4 or 5 makes no difference
 Dose 50-150 mg/day
 6 Ovulatory cycles recommended
 75% of pregnancies in first 3 cycles
Response to clomiphene
Ovulation
& pregnancy36%
Ovulation
-No pregnancy
37%
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%
35.6%
26.7%
0
1
Deliveries
Multiple
pregnancies
Non-Response to Clomiphene
Failure to ovulate
Androgens
BMI
LH
Insulin
Reasons for Clomiphene Failure
Ovulation but no conception
 Anti-estrogen effects
- cervical mucus
- endometrium
 Fetal toxicity: category X
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)
AI’s
Original Article
Letrozole versus Clomiphene for Infertility in the
Polycystic Ovary Syndrome
Richard S. Legro, M.D., Robert G. Brzyski, M.D., Ph.D., Michael P. Diamond, M.D.,
Christos Coutifaris, M.D., Ph.D., William D. Schlaff, M.D., Peter Casson, M.D.,
Gregory M. Christman, M.D., Hao Huang, M.D., M.P.H., Qingshang Yan, Ph.D.,
Ruben Alvero, M.D., Daniel J. Haisenleder, Ph.D., Kurt T. Barnhart, M.D., G. Wright
Bates, M.D., Rebecca Usadi, M.D., Scott Lucidi, M.D., Valerie Baker, M.D., J.C.
Trussell, M.D., Stephen A. Krawetz, Ph.D., Peter Snyder, M.D., Dana Ohl, M.D.,
Nanette Santoro, M.D., Esther Eisenberg, M.D., M.P.H., Heping Zhang, Ph.D., for the
NICHD Reproductive Medicine Network
N Engl J Med
Volume 371(2):119-129
July 10, 2014
Study Overview
 This double-blind, multicenter, randomized trial showed
that letrozole, as compared with clomiphene, was
associated with higher live-birth and ovulation rates
among infertile women with the polycystic ovary
syndrome.
Kaplan–Meier Curves for Live Birth.
Legro RS et al. N Engl J Med 2014;371:119-129
Outcomes with Regard to
Live Birth, Ovulation,
Pregnancy, Pregnancy
Loss, and Fecundity.
All Serious Adverse Events, plus Other Adverse Events with
Significant Differences between the Treatment Groups.
Congenital malformations
 Letrozole: imperforate anus + spina bifida, Dandy
walker, CP, VSD
 CC: VSD+pul stenosis
 In 2005, some concern was raised as a result of an
abstract (Biljan et al) of a study that compared 150 babies
born to women who had used letrozole with 36,005 babies
born to low-risk pregnant women.
 The results of this study, which had several
methodological issues, suggested that letrozole might
increase the risk of cardiac and bone anomalies; however,
the overall rate of major malformations did not differ
between the 2 groups.
 Following the publication of this abstract, the
manufacturer of letrozole (Novartis) issued a statement to
physicians contraindicating the use of letrozole in premenopausal women.
COCHRANE September 2014
Letrozole appears to improve live birth and
pregnancy rates in subfertile women with
anovulatory PCOS, compared to clomiphene citrate.
Due to the short halflife elimination time of letrozole
it should be completely cleared out of the system
before implantation takes place.
OHSS was a very rare event, with no occurrences in
most studies.
Letrozole vs. CC
Treatment timing is the same, but…
Letrozole: Half life: 2 days. Pregnancy category D
CC: Half life: 5-7 days. Pregnancy category X
CC is used routinely for 60+ years…Letrozole is
off-label?
GONADOTROPHIN STIMULATION
Complications
Multiple folliculogenesis
- OHSS
- Multiple pregnancies
High miscarriage rate
CONVENTIONAL REGIMEN (IU)
300
225
150
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 rFSH (“low-slow”)
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
Summary – low-dose FSH
Only a low-dose protocol should be used for
ovulation induction in PCOS.
Step-up more efficient and safer than step-down.
Small starting and incremental dose increases
recommended with no dose change for 14 days.
Metformin for ovulation induction?
Screening for insulin resistance in PCOS
Should we make a formal assessment of
insulin resistance in all women with PCOS?
NO
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
Metformin alone
Obese PCOS
N=143 PCOS, BMI>30
Placebo vs metformin (1700 mg) for 6 months
All on diet and exercise
No difference - Placebo and metformin improved
menstrual function and weight loss equally
Menstrual regularity correlated with weight loss
Insulin-sensitising drugs for women with PCOS,
oligo/amenorrhea and subfertility
Tang et al. Cochrane Database, 2012
The use of medications to lower insulin levels,
such as metformin alone or in combination with
drugs to induce ovulation (for example
clomiphene citrate), does not increase the chance
of having a live birth.
Metformin was also associated with increased
gastrointestinal symptoms such as nausea and
diarrhea.
LOD for PCOS
Factors affecting outcome of LOD for PCOS
111 patients, CC resistant
CPR: 54% after 12 months
75% after 30 months
Diathermy > Argon laser
Best if < 3 years infertility, thin and high LH
Li et al Br J Obstet Gynaecol 1998; 105: 338
Laparoscopic 'drilling' by diathermy or laser for
ovulation induction in anovulatory polycystic
ovary syndrome, 2012.
Ovarian drilling with/out ovulation induction, was as
effective as medical ovulation induction alone in inducing
ovulation, but the risk of multiple pregnancies was lower
in the group of women who had laparoscopic ovarian
drilling.
Approximately 37% of women will have a live birth and
7% will have a miscarriage with either procedure.
IVF
2012
Main concern: OHSS
Keep the option of agonist trigger
Individual patient-based decision: Freeze all? Fresh
transfer?
If fresh transfer: how to handle luteal phase?
OHSS PREVENTION: WHAT REALLY WORKS?
 GnRH agonist versus hCG for oocyte triggering in GnRH
antagonist ART cycles
Total events 0 (GnRH)
21 (hCG)
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A safe and OHSS-free clinical environment
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LUTEAL PHASE: INTENSIVE E+P
OHSS high-risk patients
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Engmann et al, 2008
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HCG-BASED LUTEAL SUPPORT: FIXED
TIME POINTS
1,000 IU with trigger (Griffin)
1,500 IU with OPU (Humaidan)
1,500 IU 3 days post OPU (Haas)
Can we be more patient specific???
Can we tailor hCG support to a specific
patient endocrine response???
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COASTING
A popular OHSS prevention strategy.
So far, follicular phase only.
In OHSS high risk situation: stop gonadotropin.
Follow E2 level daily. Individualized approach.
Trigger with hCG when E2 drops below a cutoff level.
Mechanism: partial follicular demise.
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CASE #1
30 year old, mechanical + male factors, AFC=15
Short antagonist protocol, starting dose Menopur 112.5 daily,
last 3 days 75.
On trigger (0.2 mg triptorelin) day E2=19017 pmol/l, P=2.5
nmol/l, LH=2.1 IU, >20 follicles >11 mm
OPU=20 oocytes, 12 injected, 4 normal fertilization, 2
embryos transferred on day 2, 2 frozen.
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CASE #1, P POST AGONIST TRIGGER
BETA=316
ET
P levels
hCG 1,500 IU
200
100
0
trigger
OPU+2
OPU+3
OPU+17
P
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OUTCOME
Moderate OHSS
Ongoing singleton pregnancy
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CASE #2
 A 27 year old patient, severe OTA syndrome.
 A previous IVF cycle 7 years ago resulted in live birth.
 Three IVF trials failed during the last 4 years.
 Stimulation: antagonist-based, 150 IU Menopur.
 A day before trigger E2=15768 P=3.2 LH=1.2, with >30 follicles >11 mm.
 Trigger with triptorelin 0.2 mg
 25 oocytes were retrieved, 23 injected with sperm, 11 normal 2pn
fertilizations.
 2 embryos transferred 48 hours post retrieval, 8 were frozen.
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CASE #2, P POST AGONIST TRIGGER
BETA=174
P
200
ET
150
hCG 1,500 IU
100
P
50
0
OPU
OPU+1
OPU+2
OPU+7
OPU+14
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OUTCOME
No OHSS
Ongoing twin pregnancy
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THE QUESTION OF IMPLANTATION POTENTIAL POST
EXCESSIVE OVARIAN RESPONSE
Clinical evidence for a detrimental effect on uterine receptivity
of high serum oestradiol concentrations in high and normal
responder patients. Simon et al, 1995
Lower implantation rates in high responders: evidence for an
altered endocrine milieu during the preimplantation period.
Pellicer et al, 1996
Is it secondary to insufficient P during implantation window?
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CONCLUSION
Luteal coasting in high responders is a viable
option if fresh transfer is desirable.
Cutoff P levels yet to be determined.
LH activity –dependent luteal support does not
require additional E2 and/or P : patient comfort.
Despite extreme E2 levels, good clinical outcome is
possible if endogenous P secretion is high enough
during implantation window.
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PUTTING IT ALL TOGETHER FOR THE PCOS IVF PATIENT
 Always choose antagonist protocol so agonist trigger can be
used.
 Mild stimulation is the aim.
 Assess risk: age, BMI, previous history, number of
follicles>12 mm, estradiol level.
 If in doubt – freeze all.
 If low risk: agonist trigger followed by hCG 1500 IU on
retrieval day, progesterone to follow.
 Consider luteal coasting
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Thank You