PCOS - Ovulation Induction 1 - Dr Bharati Dhorepatil

Greetings from PUNE!
President POGS
Dr.Bharati Dhorepatil
Dr.Bharati Dhorepatil Ferticon2017 2

PCOS:Ovulation Induction

PCOS
• Heterogeneous, reproductive-metabolic,pathological disorder
• Primary cause: Ovarian androgen overproduction
• Associated with insulin resistance and obesity
1. Allahabadia GN et al. Polycystic Ovary Syndrome in the Indian
Subcontinent. Semin Reprod Med 2008;26:22–34.
2. Badawy A et al. Treatment options for polycystic ovary syndrome. Inter J
Women’s Health 2011:3 25–35
3. Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility
Science & Research. Jan-Jun 2014; 1(1): 23-4
Major symptoms
• Menstrual disorders
• Hyperandrogenaemia
• Metabolic syndrome
• Infertility
Dr.Bharati Dhorepatil Ferticon2017
4

• 31yrs old, married 7yrs, wt 50.5, BMI 23.37
• Semen parameter..80 millions,80% motility
• Hormonal Parameters…FSH 6.82,LH 13.45,TSH
0.64,Prolactin 16ng/ml, Free Testesteron 45.72,
AMH 13ng/ml
• TVS findings…PCOM…with Rt AFC 20 and Lt.25
follicles
• Clinical side.. H/0 irregular cycles.(3 to 4 /yrs)
Acne gr III, Hirsutism FG Score 8

ROTTERDERM CRITERIA
HA
PCOM
IM
IM+ HA+ PCOM
IM+HA
IM+PCOM
HA+PCOM

7
IM+PCOM+HA
PCOM+HA
IM+HA
IM+PCOM

Predicting Ovarian Response
• Poor Responder
• Normoresponder
• Hyperresponder

Two Patterns are seem most commonly…
1.Peripheral Cystic Pattern
2.General Cystic Pattern
2 to 8 mm 8to 10 mm

• General cystic pattern is associated with an
ovarian steroidogenesis disorder whereas
• The peripheral cystic pattern is associated
with abnormal gonadotropin secretion
Ultrasound Obstet Gynecol 1998;11:332–336

• Hypersecretion of LH during the follicular phase of the
menstrual cycle in PCOS is associated with hyperplasia
of the ovarian theca and stromal cells.
• Increased vascularity has been demonstrated by color
Doppler imaging and pulsed Doppler spectral analysis
within the ovary probably because of Elevated LH
levels may be responsible for increased stromal
vascularization by influencing neoangiogenesis,
catecholaminergic stimulation and leukocyte and
cytokine activation

What investigations would you like to do
prior to COS ?
Tests for ovarian reserve ?
12

 Hormones-Day 2 FSH, LH, E2
 TSH,PROLACTIN
 AMH
 USG FOR AFC AND OTHER PATHOLOGIES.
 HSA
 Tubal Patency
13

• Why is there an Abnormal
Response of polycystic ovaries to
COS?
14

Why Abnormal Response of polycystic ovary to COS?
Extremely difficult to find GT threshold
 Recruitable pool of follicles is increased
 Stromal hyperplasia contributes to larger than normal amounts
of androgens to the follicular microenvironment
 Granulosa cell aromatase activity is normally decreased
however, it is readily stimulated by exogenous FSH
 Follicular response initially slow, but explosive at later stages
of stimulation

Could we elaborate ovulation induction
protocols in PCOS ?
What is your first line of treatment ?
16

The management of anovulatory infertility in women with PCOS: an
analysis of the evidence to support the development of global WHO
guidance.
• Management includes lifestyle changes, bariatric surgery,
pharmacotherapy (including clomiphene citrate (CC),
aromatase inhibitors, metformin and gonadotropins), as
well as laparoscopic surgery.
• CC should be first-line pharmacotherapy for ovulation induction and
letrozole can also be used as first-line therapy.
• Metformin alone has limited benefits in improving live birth rates.
• Gonadotropins and laparoscopic surgery can be used as second-line
treatment. There is no clear evidence for efficacy of acupuncture or
herbal mixtures in women with PCOS.
failed.

• Can we individualize CC or letrozole or
gonadotrophins depend on E2 levels Low &
high…
• Low E2..Responds well with CC or
Gonadotrophins
• High E2 ..responds well with letrozole

FSH 2.5
E2 55
LH 7
AMH 4
AFC 15..P P
FSH 6.5
E2 25
LH 10
AMH 3.5
AFC 15..C P
FSH 2.5
E2 45
LH 2
AMH 10
AFC 25..C P
FSH 4.1
E2 75
LH 7
AMH 7.5
AFC 18..P P
19

What modifications of Clomiphene
protocols can be done to improve
outcomes?
Or
Would you shift to aromatse inhibitor as a
first line option or only after CC faliure?
20

Luteal phase clomiphene citrate for ovulation
induction in women with PCOS.
• Patients in Group 1 received 100 mg of CC daily for 5 days starting on day 5 of
menses, and patients in Group 2 received 100 mg of CC daily for 5 days starting the
next day after finishing medroxyprogesterone acetate (MPA) (before withdrawal
bleeding).
RESULTS:
• The total number of follicles and the number of follicles ≥14 mm during stimulation
were significantly greater in Group 2. The endometrial thickness at the time of
(hCG) administration was significantly greater in Group 2 as compared to Group 1.
Pregnancy occurred in 10.3 % in Group 2 and in 8.7 % in Group 1.
CONCLUSION:
Luteal phase administration of CC in patients with PCOS leads to increased follicular
growth and endometrial thickness, which might result in a higher pregnancy rate.
Kosar O1 Arch Gynecol Obstet. 2014 Oct

Clomiphene citrate 'stair-step' protocol vs. traditional protocol in
patients with PCOS: a RCT
• In the stair-step protocol,patients were treated with CC 50 mg/day for 5 days and
then in nonresponsive patients, the dosage was increased to 100 mg/day for
5 days in the same cycle. Patients who failed with 50 mg/day CC in the previous
cycle were stimulated with 100 mg/day CC and were the control group.
• Ovulation and pregnancy rates were similar between the stair-step and the
control group (43.3 vs. 33.3 %, respectively) (16.7 vs. 10 %, respectively). The
duration of treatment was significantly shorter in stair-step compared to
traditional protocol (20.5 ± 2.0 vs. 48.6 ± 2.4 days, respectively). Uterine side
effects were evaluated with endometrial thickness and uterine artery Doppler
ultrasound; no significant differences were observed.
CONCLUSIONS:
• The stair-step protocol has a significantly shorter treatment period without any
detrimental effect on the ovulation and pregnancy rates.
Deveci CD Arch Gynecol Obstet.2015 Jan
22

Case
• 31yrs old, married 7yrs, wt 50.5, BMI 23.37
• Semen parameter..80 millions,80%
• Hormonal Parameters…FSH 6.82,LH 13.45,TSH 0.64,Prolactin
16ng/ml, Free Testesteron 45.72, AMH 13
• USG findings…PCOM.with 20 and 25 follicles on either side
• Clinical side.. H/0 irregular cycles.(3 to 4 /yrs)
Acne gr III, Hirsutism FG Score 8
• Undergone Laparoscopy,Hyestroscopy,Ov.Drilling
• Treatment H/O…she has been received 16 cycles of various
drug regimes like CC,CC+HMG,HMG,FSH with no follicular
growth
• Past h/o of treatment 5yrs back with some oral medication
good response?

• Do you face any group of patients difficulty in
using letrozole?

Estradiol Levels..
• Estradiol levels donot correspond with
maturity of the follicle on the day of HCG….
Lower S.E2 levels
• Thin pts..where levels of E2 already low..
D8-10..leads breakthrough bleeding..
Our unpublished data of 50 pts with BMI 19.5,in
CC resistance group

There is a lot of controversy on the role of Insulin
sensitizers in PCOS patients. Do you still use
metformin ?
27

Lifestyle modification should be the first-line treatment.
• Current evidence - metformin cannot be recommended as first-line
pharmacological treatment for anovulatory infertile women with PCOS.
• Clomiphene citrate still represents the gold standard first line theraphy
• Metformin does not improve the efficacy of clomiphene citrate as a first-step
treatment for ovulation induction in anovulatory infertile women with PCOS.
• Available evidence is insufficient to recommend metformin as a primary treatment
in non-obese PCOS subgroup.
• Metformin plus clomiphene citrate could be considered an effective option in
patients with CCR-PCOS.
• More attempts with metformin plus clomiphene citrate are warranted when there
is limited access to gonadotrophins.
RBM online 2016
28

 In patients with CCR-PCOS undergoing ovulation induction with
gonadotrophins, the addition of metformin increases the rates of clinical
pregnancy and live birth and reduces the cancellation rate.
 In patients with PCOS undergoing assisted reproduction technniques,
metformin co-treatment reduces the OHSS risk and increases the pregnancy
rate.
No evidence exists of reduced spontaneous abortion risk in women with PCOS
who have undergone pre-gestational metformin tretment.
 No evidence exists of increased risk of major anomalies in women with PCOS
undergoing metformin treamtent during the first trimester.
 Adequately powered RCT are needed to evaluate the efficacy of metformin
treatment in different PCOS phenotypes.
RBM online 2016
29

There is a lot of discussion on myoinositol
nowdays. What is your experience with the
drug ?
30

Clinical evidences with Myoinositol in PCOS
Free & Serum
Testosterone
Myoinositol
IR
Insulin
Sensitivity
Provides Good
quality
Oocytes
Improve
glucose
utilization
Restores
Menstruation &
Normal Ovulation
Improves
pregnancy rates
31

Inositol's and other nutraceuticals' synergistic actions counteract
insulin resistance in polycystic ovarian syndrome and metabolic
syndrome: state-of-the-art and future perspectives.
• MI and DCI have been classified as insulin-sensitizers and seem to
adequately counteract several InsR-related metabolic alterations with a
safe nutraceutical profile.
•
• Supplementation with MI and/or DCI complement each other in their
metabolic actions and act in synergy with other insulin sensitizing drugs
and/or nutraceuticals.
• Considering the possible bias due to different methodologies across
published studies, we conclude that there is a need for further studies on
larger cohorts and with greater statistical power.
Paul C, et al, Gynecol Endocrinol. 2016 Jun

Ovulation induction with myo-inositol alone and in combination
with clomiphene citrate in PCOS patients with insulin resistance.
 50 anovulatory PCOS patients with insulin resistance. All of them received myo-
inositol during 3 cycles. If patients remained anovulatory or no pregnancy was
achieved, combination of myo-inositol and clomiphene citrate was used in the
next 3 cycles.
RESULTS:
 After myo-inositol treatment, ovulation was present in 61.7% and 38.3% were
resistant. Of the ovulatory women, 37.9% became pregnant. Of the 18 myo-
inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of
the 13 ovulatory women, 6 (42.6%) became pregnant.
CONCLUSION:
Myo-inositol treatment ameliorates insulin resistance
and body weight, and improves ovarian activity in PCOS
patients.
Kamenov Z Gynecol Endocrinol. 2015 Feb

When giving Gonadotropins for COS :
Which Gonadotropin do you use ? Does the type
make a difference
34

Can we predict Starting Dose for the stimulation
in IUI or IVF cycle
AGE & AMH,FSH
AGE & AFC,FSH
35

Individualization of OI according to AMH
• Starting Dose
• Maintanence Dose
• Trigger

Which Gonadotrophin to use?
HMG / FSH / Rec FSH
 FSHHMG when combining with CC
 FSHHMG in standard ovulatory IUI /COH
 HMG in Hypogonadotrophic hypogonadism
 HMG in patients with high FSH
 FSH in patients with high LH (PCOS)
37

Comparison between stimulation with highly purified hMG
or recombinant FSH in patients undergoing IVF with GnRH
antagonist protocol.
• Retrospective study : N= 508 cycles
• 320 rFSH , 188 – hp/hmg
• rFSH – had more mature oocytes, more embryoes with
lower dose of Gn
• In subgroup analysis – young pts in rFSH group had better
cyvle outcomes
Conclusion – In antagonist protocol, different gonadotropin
products are equally effective. The choice of one or the
other should depend on the availability, convenience of
use, and cost.
Shavit T, et al, Gynecol Endocrinol. 2016 Mar

When giving Gonadotropins for COS :
What protocol do you use ?
What is your opinion on using
Clomiphene in IVF cycles?

Gonadotrophin Induction
• CC+HMG/FSH
• HMG/FSH
– Standard regime
– Step-up regime
– Chronic low dose step up regime
– Step down regime
• GnRh antagonist+HMG/FSH
40

At what stage would you abort or
convert an IUI cycle into IVF cycle ?
3,4 ,5 or more mature follicles?
41

Is it necessary to wait for menses
before starting ovarian
stimulation?
42

ORPI= AMH (ng/ml) x AFC (2-9 m) and the result was divided by the age
(years) of the patient
ORPI Values Oocyte No expected Protocol
< 0.2 < 3 GnrH Antagonist, Short
GnrHa, CC + Gnrha long
> 0.2 < 0.5 4 - 5 Gnrh antagonist, short
Gnrh, Long Gnrha
0.5 < 0.9 6 – 14 Long Gnrha, Gnrh
Antagonist
0.9 >15 Gnrh Antagonist
Ovarian response prediction index (ORPI) implications for
individualised COS.
Oliveira, et al, reprod biol endocrinol 2012.
43

Gonadotrophin-releasing hormone antagonists for assisted
reproductive technology.
• There is moderate quality evidence that the use of GnRH
antagonist compared with long-course GnRH agonist protocols is
associated with a substantial reduction in OHSS without reducing
the likelihood of achieving live birth.
Al-Inany HG, et al, Cochrane Database Syst Rev. 2016 Apr

Ragni Protocol
USG
E2
USG
E2
USG
E2
HCG
5000
10,000
OPU
IUI
35-37
hr
1 2 3 4 5 6 7 8 9 10 11 12
Progesterone
IM
Oral
Vaginal
GnRH antagonist
Rec FSH 50
45

Effect of GnRH antagonists on CPR with gonadotropins in IUI
 No significant improvement in clinical pregnancy rates
when GnRH antagonists were used during COH + IUI
cycles, despite a significant increase in the number of
follicles > 16 mm on the HCG trigger day.
Ramazan Dansuk, et al, Singapore Med J. 2015 Jun
46

How do you monitor these cycles ?
Hormones / Usg Scan / Doppler
47

Monitoring starts..
• D7,D8,D9…any day could be a start in IUI cycle if
IVF D5
• Growth pattern to be followed..Day X 2mm
appro.
• Alternate day monitoring is advisable if required
changed according to the need
• Sustained growth…is must
In healthy follicles, genes direct
cytodifferentiation, proliferation, and follicular fluid
formation.
48Dr.Bharati Dhorepatil Ferticon2017

What to achieve before ovulation?

• The large increase in LH inhibits androgen
production, and as a result estradiol
concentrations decrease drastically from the
preovulatory peak.
• Granulosa cells become 'luteinized', and
consequently a small preovulatory rise in
progesterone occurs within one hour of the LH
surge completion

Hormonal Cycles:
LH, FSH, Estradiol,
Progesterone, Inhibin
A & B
europe.obgyn.net/nederland/mp/o
vergang/images/overgang14x.gif
After a248.e.akamai.net/.../pubs/mmanual_home/ illus/i232_1.gif

52
•Assesment of the follicular maturity and endo receptivity
and the time of HCG Is one of the Key factors for the
success of all ART procedures
•Vascular changes are the reflection of the biochemical
changes.
•3D power doppler gives not only qualitative but also
quantitaive idea of the global vasularity

When to give HCG..
• Triple line Endo >7mm,follicle >17mm
• Perifollicular and subendometrial Hallo…oedema
• Cumulus presence..30-40%
• Follicular volume..0.6 to 1.5ml
• Flow Indices…PSV: >10,RI:<0.5
• Perifollicular Vasularity..3/4th
• Sub Endo vasularity..minimum 5 spiral vessels
reaching to zone 4,ant & post,RI<0.6
• Endo peristalsis 3to5/ min
• Uterine A..on dominent sidePI:<3.2

Timeline of ovulation
• Case A..Day 11…DF..18mm,..endo..8mm,triple
line
• but RI<0.48,PSV 6-7,poor flow
Timeline…Wait…HCG next Day or when
parameters improves as PSV low
54

What is the opinion on PCO drilling?
55

Laparoscopic drilling by diathermy or laser for ovulation
induction in anovulatory PCOS
 25 RCT’s
 Noevidence of a significant difference in rates of
a) clinical pregnancy,
b) live birth or
c) miscarriage in women with clomiphene-resistant PCOS
undergoing LOD compared to other medical treatments.
 The reduction in multiple pregnancy rates in women undergoing LOD
makes this option attractive.
 However, there are ongoing concerns about the long-term effects of
LOD on ovarian function.
Farquhar C, Cochrane Database Syst Rev.2012 Jun
56

Drilling: medical indications and surgical
technique.
• Laparoscopic drilling is indicated for patients with polycystic ovary
syndrome with ovulatory resistance to the use of clomiphene
citrate, body mass index less than 30 kg/m2 and preoperative
luteinizing hormone above 10 IU/L & AMH >6 to <10
• The preferred surgical technique should be the realization of 5 to
10 perforations on the surface of each ovary bilaterally using
monopolar energy.
• Hueb CK, et al, Rev Assoc Med Bras (1992). 2015 Nov-Dec

What about the risks of COS – multiple
pregnancy and OHSS. What precautions
do you take ?
58

Strategies to prevent OHSS
 Identify high responders.
 Titration of COS.
 Monitor the ovarian response carefully.
 If more than 5 follicles - abort cycle or convert to
IVF.
 Use GnRH agonists as trigger.
 Use of antagonists, Cabergoline, HES
 Do not use HCG for luteal support
59

OHSS prevention.
The recent implementation of four new modalities:
• the GnRH antagonist protocol,
• GnRH agonist (GnRHa) triggering of ovulation,
• blastocyst transfer and
• embryo/oocyte vitrification,
• renders feasible the elimination of OHSS in connection with ovarian
hyperstimulation for IVF treatment.
Papanikolaou EG , Reprod Biol Endocrinol.2011 Nov

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Debates are productive……
• In any event, conversation, discussion, and
debate are positive.
• They can ignite people's passion, their
creativity, and bring their best ideas to the
table…..
• Thank You all for Active participation

PCOS - Ovulation Induction 1 - Dr Bharati Dhorepatil

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