Ovarian stimulation

Ovulation
Induction
AHMED ELBOHOTY
MSc, MD, MRCOG, MIGSC
Reproductive Endocrinology & Infertility
consultant
Assistant professor in Ain Shams University

ILOs
• To Understand the basic endocrinology of ovulation
• To identify the indications of ovulation inductions
• To be able to use ovulation induction medicines in an effective
and safe way
• To individualize protocol of induction according to patient
parameters
• To use luteal phase support in an effective way
• To highlight the potential complications of ovulation induction.
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Physiology
of
Ovulation
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ELBOHOTY

Follicular growth and selection
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Why do we use ovulation induction?
!Treatment of Chronic Anovulation
!IUI
!IVF/ICSI
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Is ovulation induction alone an effective
treatment of unexplained infertility ?
No
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Elbohoty et al., 2017; Crosignani et al., 1991; Guzick et al., 1999; Goverde et al., 2000; Aboulghar et al., 2003
ELBOHOTY

Aim Of Ovarian stimulation
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For Anovulation or IUI For IVF-ICSI Freeze all
Monofollicular Multifollicular
ELBOHOTY

Management
of Anovulation
(NICE, 2013)
Anovulation
accounts for 25%
of all cases of
infertility.
ELBOHOTY

Diagnosis of
anovulation:
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• Irregular cycle, amenorrhea, excessive
hair,…History:
• Mid-luteal serum progesterone phase
• For irregular cycle & Amenorrhea:
Gonadotrophins level, Prolactin
• Excessive Hair: Androgens
Blood
tests:
• FolliculometryUS:
ELBOHOTY

Anovulation Types
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WHO Type I
WHO Type II
WHO Type III
WHO Type IV
Criteria/Tests
Mid-luteal serum progesterone
EtiologyClassification
↓ ↓ ↓ ↓ FSH, LH, E2.
LH <1.2 IU/L
Normal prolactin
hypothalamic
pituitary failure
Group I
10%
2 out of 3 after exclusion of other
endorcinopathy
• Oligo or anovulation.
• Hyperandrogenism
• PCOM
hypothalamic-
pituitary-ovarian
dysfunction
PCOS
Group II
75-80%
High FSH, LH
Low E2
Premature
ovarian
insufficiency.
Group III
5-10 %
prolactin> 500 mU/L
↓ ↓ ↓ ↓ FSH, LH, E2
Hyperprolactinemia
CAHGroup IV
5-10%ELBOHOTY

Aim of the treatment of chronic
anovulation:
!Management of any associated
health problem
!Monoovulation.
3/18/20(ESHRE Capri Workshop Group, 2003). ELBOHOTY

Causes
Weight loss
Exercise
Psychological stress
Pituitary damage:Sheehan's
syndrome,Hemosiderosis (Thalathemia)
Tumours, Cranial irradiation Head injuries
Chronic illness
Genetic, e.g. Kallmans syndrome
Idiopathic
Hypogonadotropic Anovulation
WHO I
↓ ↓ ↓ ↓ FSH, LH, E2
Normal prolactin
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Management
• Identifying the cause, exclude intracranial lesion e.g. MRI.
• Increasing the BMI if it is ≤19
• Moderating exercise levels if they undertake high levels of exercise.
• HMG versus rFSH+rLH (STEP UP Approach) aiming for monofollicular development
• GnRH analouges ?!
• Long term care of bone
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75 IU HMG or rFSH+rLH
/day
Cycle
D
112.5 IU
250 μg hCG21th D
14th D2nd day
>18 mm
150 IU
TVUS
TVUS
TVUS
TVUS
Luteal support
ELBOHOTY

Diagnosis & Management
Before the age of 40 years
Two FSH levels > 30 iu/ml at an interval of at least 1
month.
Search for the cause: Karyotyping, …
Spontaneous resumption of ovulation in 5 %
Egg donation
Manage consequences: HRT
Causes
Idiopathic 88%
Chromosomal abnormalities 9%
Iatrogenic causes 2.1 %
Autoimmune causes 0.8%
Bachelot et al., 2009
WHO Type III
Premature Ovarian Insufficiency
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WHO Type IV:
Hyperprolactinemia
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ELBOHOTY

•Repeat Prolactin level.
Exclude pregnancy, check
medicines hypothyroidism, ….
•Treat the cause
•S.prolactin>1000mIU/L: MRI
•Micro or Macroadenoma:
Dopamine agonists:
Cabergoline 0.25 - 1 mg twice
weekly
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Management
ELBOHOTY

WHO Type II
The most common form of
ovulatory dysfunction.
80% are due to polycystic
ovarian Syndrome
(Broekmans et al., 2006; NEJM, 2016).
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Diagnosis of PCOs
• Two of the following criteria requested:
1) Oligo or anovulation.
2) Clinical and/or biochemical signs of hyperandrogenism
3) PCOM :
• Using TVS with a frequency ≥ 8MHz: a follicle number per ovary of > 20 and/or an ovarian volume ≥ 10ml
• Using older technology or TAS: an ovarian volume ≥ 10ml on either ovary.
3/18/20 (ESHRE, 2018; ESHRE/ASRM, 2004)
Other causes of menstrual cycle disturbance or androgen excess should be excluded.
ELBOHOTY

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Different phenotypes
Type 1,2 & 4 are anovulatory
Phenotype 1 (classic PCOS) 62.4%
• Clinical and/or biochemical evidence of hyperandrogenism
• Evidence of oligo-anovulation
• Ultrasonographic evidence of a polycystic ovary
Phenotype 2 (Essential NIH Criteria) 8.6%
Phenotype 3 (ovulatory PCOS) 11 %
Phenotype 4 (nonhyperandrogenic PCOS) 18 %
ELBOHOTY

Induction of ovulation in PCOs women
3/18/20 ESHRE, 2018ELBOHOTY

Risks of women
with PCOS
should be part of
the management
• Metabolic consequences of PCOS
• NIDM
• Hypertension
• Obstructive sleep apnoea
• Developing cardiovascular disease (CVD)
• Endometrial cancer
• Anxiety and depression
• Psychosexual dysfunction
• Eating disorders and disordered eating
• During pregnancy:
• Miscarriage
• Gestational diabetes
• Preclampsia

Weight reduction in PCOS
• Dietary intervention:
• An energy deficit of 30% or 500 - 750 kcal/day
• Exercise intervention:
• A minimum of 250 min/week of moderate
intensity activities or
• 150 min/week of vigorous intensity
• Bariatric surgery:
• Women with a BMI> 40 Kg/m2 with no other
morbidities
• >35 kg/m2 with comorbidities, such as diabetes,
hypertension, OSA,…..
ELBOHOTY

FSH
(+++)
FSH=Follicle Stimulating Hormone
AI or CCE2
(-)
E2=Estradiol
Developing follicle
Inhibit –ve feedback
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1st line medicines
ELBOHOTY

AI (letrozole) versus CC
Gadalla et al., UOG 2018, Legro et al., N Engl J Med 2014: Casper et al,. Hum Reprod Update. 2008; Sharma et al.,
PLoS One. 2014
• No statistically differences in side effects or congenital malformations
• Many trials are reassuring about its safety towards the unborn babies
• Letrozole is a reasonable first-line agent for ovulation induction in PCOS
patients (World Health Organization guidance and ASRM 2017, ESHRE 2018)
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Forest plot for comparison of live birth between CC and letrozole
ELBOHOTY

No need for Luteal support
Letrozole (2.5 mg)
(D2-6)
TVS TVS
Ovulation Trigger
250 Mcg
hCG
D2 D 6
Cochrane Review 2013; holzer H et al 2005. Fertil & sterility: Casper et al., J Clin Endocrinol Metab.
2006; The Practice Committee ASRM 2013. Fertil & Sterile, 100,2,341-348
Letrozole or CC regimen
One follicle >18
mm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
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C C (50 mg)
(D2-6)
Not to use for more than 6 months if ovulation occurs
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Premenstrual use: Clomiphen citrate or
Letrozole
Has a higher probability of ovulation and higher number
of mature follicles than the conventional use.
Elbohoty et al., J. Obstet. Gynaecol. Res. 2016 ; Badawy et al., Fertil Steril 2009
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Menstrual
shedding
TVS TVS
Ovulation Trigger
250 μg hCG
Progesterone
withdrawal One follicle
>17mm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
C C (50 mg) or
Letrozole2.5 MG
Before
menstruation
17
ELBOHOTY

2nd line
Gonadotrophins Or
LOD
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ELBOHOTY

Gonadotrophins
•For women with PCOS who have failed
to ovulate with first line oral ovulation
induction therapy
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low-dose step-up regimen is
recommended
25-37.5-50 IU FSH/day
Cycle
D
37.5- 75
IU FSH
250 μg
hCG
14- 21th D
7-14th D2nd day
>17mm
E2TVS
75- 112.5
IU FSH
TVS
E2
TVUS
TVUS
TVUS
TVUS
Luteal support
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CANCEL THE CYCLE:
more than two follicles greater than 16–18 mm in mean
diameter are observed.
NO trigger and avoid intercourse.
ELBOHOTY

Technique
• NO more than four per
ovary for 4 seconds at 40
watts.
• Avoid the hilum & ovarian
ligament
• The instillation of 500–1000
ml of an isotonic solution
into the pouch of Douglas
cools the ovaries
An alternative: Laproscopic
ovarian drilling
ELBOHOTY

LOD versus OI with rFSH?
• Multicentre RCT in the Netherlands
• In which 168 CC-resistant women
Bayram et al., BMJ 2004
LOD OI with rFSH
Initial cumulative
pregnancy rate after 6
months
34% 67%
Time to conceive Took longer to conceive
and 54% required
additional medical
ovulation induction
therapy.
Less time to conceive
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When to refer PCOS
patient to IVF ?
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•Where first or second line
ovulation induction therapies have
failed.
•If conception has failed to occur
after six to nine ovulatory cycles.
ELBOHOTY

Is there a role for IUI?
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unexplained subfertility that under- went the same ovarian
stimulation in both arms.
mild male subfertility in unstimulated and in stimulated cycles.
Cochrane Database Syst Rev. 2016
NO
ELBOHOTY

AIM
to facilitate retrieval of multiple
oocytes without having complications
Fresh Transfer
+ freeze surpulus embryos
Freeze All
Or
+

Ideal number of retrieved oocytes
• For Fresh LBRs: 7-15.
• For Cumulative LBRs: the more
the better (70% when 25 oocytes
were retrieved)
(Sunkara et al, 2011; Polyzos et al,2018)
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Process of stimulation
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1. Down regulation
• Antagonist
• Agonist
• others
2. Ovarian stimulation
• Dose
• Type
3. Final maturation
• HCG
• GnRH
4. Luteal phase support
• Progesterone
• E+P
• HCG
• GnRH

The ovarian response can be expected by
• AMH or AFC
3/18/20 ELBOHOTY
Hyper
response
the retrieval of more
than 15 oocytes
Normal
response
the retrieval of 10 to
15 oocytes
Suboptimal
response
The retrieval of four to
nine oocytes
Poor
response
the retrieval of less
than four oocytes
• Previous response
In the first IVF cycle

Markers of ovarian response and dose
determination
AFC AMH Ovarian reserve Clinical
application
Gonadotrophin
Dose
0-4 <0.8 ng/ml Very low POR
5-8 0.8-1.5 ng/ml low Low response 225-300
9-19 1.5-4 ng/ml Normal Normal response 150-225 IU
20- > 4 ng/ml High Hyperresponse 112.5-150
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Martins et al.,
2015

Down regulation
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Lambak et al HR 2017
AlInanay etal Cochrane Syst Rev 2016

Antagonist protocol
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
OPU after 36 hours
Start the gonadotrophins till the day of
trigger
Day 2 scan
HCG or
GnRh
ESHRE, 2019
Start Cetrorelix

Long protocol
3/18/20 ELBOHOTY
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
OPU after 36 hours
Confirm down-regulation
Start the gonadotrophins till the day of
trigger
HCG

Other protocols
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Double stimulation and random stimulation regimens
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Progestins instead of antagonist
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HCG or GnRh
(La Marca et al.,2019)

Long antagonist protocol
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(Papanikolaou et al., 2018)

Triggering
3/18/20 ELBOHOTY
• HCG:
• 5000 IU urinary HCG IM or
• 250 μg subcutaneously of
recombinant human chorionic
gonadotrophin (HCG)
OR
• Triptolin 0.2: in hyper responder
women with antagonist protocol + freeze
all or modified luteal support
• LH should be > 0.5 at start of
stimulation and at trigger day.
Criteria to trigger:
• when dominant follicles sizes between 16
and 22 mm in diameter.

Luteal phase support
ELBOHOTY 3/18/20
The luteal phase of all stimulated IVF cycles is abnormal (Edwards et al., 1980; Ubaldi et al., 1997; Macklon and
Fauser, 2000; Kolibianakis et al., 2003).

Should we give Luteal phase
support with simple induction ?
•Ovulation induction with
gonadotropins: YES
•Clomiphene citrate or
clomiphene plus
gonadotropins: NO
Katherine et al., Fertility and Sterility.VOL. 107 NO. 4 / APRIL 2017
3/18/20 ELBOHOTY

LUTEAL PHASE SUPPORT (Progesterone supplementation):
3/18/20 ELBOHOTY
Crinone gel 90 mg
One time per day
Cyclogest 200mg
suppositories
vaginal capules
(2 times per day)
Endometrin 100 mg
vaginal tablet
(3 times per day)
400 mg vaginal
pessary twice daily
Intramuscular 50 mg
One time per day
SC 25 mg daily
ESHRE, 2019

3/18/20 ELBOHOTY
(van der, et al., Cochrane syst review, 2015).

Risks of ovulation induction
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Short term
Multiple
pregnancies
OHSS
Ovarian
torsion
Long term
ELBOHOTY

Risks •Multiple Gestation
• Simple induction:
• With CC treatment, approximately 8% overall
• With gonadotrophins:20 %.
• IVF: according to number of transferred embryos
•Ovarian Hyperstimulation Syndrome
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• Ovarian torsion
• Its incidence is 0.1% and rises significantly with OHSS (2%) and
more rise in IVF pregnant patients with OHSS (16%)
ELBOHOTY

Risk of cancers
• Ovarian:
• Some studies have suggested that the risk of borderline ovarian tumors may be
increased (Kashyap et al., 2004; Liat et al., 2012).
• Other studies showed there is a strong relation to use of progesterone treatment not
ovarian stimulation (Bjørnholt etal., 2016)
• Breast cancer:
• Inconsistent results and more information on the subject is warranted.
• Endometrial cancers:
• Exposure to clomiphene citrate in subfertile women is associated with increased risk of
endometrial cancer, especially at doses greater than 2000 mg and high (more than 7)
number of cycles.
• This may largely be due to underlying risk factors such as polycystic ovary syndrome,
rather than exposure to the drug itself (Skalkidou et al., Cochrane Database Syst Rev
2017)
3/18/20 ELBOHOTY

•In anovular infertility patients; individualize the
intervention according to the cause and patient’s
characteristics
•In PCOS: Letrozole seems to be the 1st line
medication
•Gonadotrophins: 2nd line in PCOS with low dose
step up protocol aiming for monoovulation
•IVF is indicated for who are having ovulation for
more than 6 months without getting pregnancy
3/18/20 ELBOHOTY

•Antagonist protocol is the standard protocol
for ovarian stimulation for IVF.
•Individualized doses of gonadotrophins
according to expected response.
•Luteal phase support is not routine for
simple ovulation induction but is a
mandatory step with ovarian stimulation for
IVF.
3/18/20 ELBOHOTY

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