Tens Secrets to Ovarian Stimulation

PROF.JAIDEEP MALHOTRA
M.D., F.I.C.O.G , F.I.C.M.C.H.
 Managing Director Rainbow Hospitals
 Prof. Dubrovinck International University, Croatia
 President ASPIRE (Asia Pacific Initiative on Reproduction)2014-16
 President Indian Menopause society 2016-17
 Vice President SAFOMS
 Vice President ISPAT
 Editor in Chief Journal of SAFOG
 Member Infertility committee of FIGO
 Editor and Co-editor of many books
 Indumati Jhaveri Award, Jagdishwari Mishra Award three times, Ethicon
Fellowship, Outstanding Achievement Award 1999, Chorion Award.
 Credited with producing firsts of U.P. : IVF birth, ICSI birth, IVF Twins, ICSI
Twins, IVF Triplets, TESA-ICSI Pregnancy .
 Credited for producing first Three hundred Test Tube Babies of Nepal
 Consultant IVF specialist Maulana azad medical college Delhi & SMS medical
College Jaipur.

TEN SECRETS
OF OVARIAN
STIMULATION
 Prof Jaideep Malhotra
 ART Rainbow IVF

VS
CAN YOU TELL THE DIFFERENCE?

UNDERSTANDING THE HYPOTHALAMIC-PITUITARY,
OVARIAN AND UTERINE AXIS

LIFE HISTORY OF OVARIAN FOLLICLES
FSH independent
McGee and Hsueh Endocr Rev 2000;21:200
• Ovarian follicle development is tightly regulated by crosstalk between cell death and survival signals .
• Depletion of the ovarian follicular reserve starts during fetal life and continues throughout a woman’s
life span.
• Only a small proportion of the primordial follicles will reach the ovulatory stage, while the rest follicles
will undergo the degenerative process called atresia

Complete follicular development takes > 220 days &
has three distinct phases:
 (a) initial recruitment of resting primordial follicles,
 (b) development of preantral and early antral follicles,
 (c) cyclic recruitment of a limited cohort of antral follicles
followed by the selection of a single dominant follicle.
Independent of
gonadotropins
The decrease of luteal estradiol and
inhibin A following regression of corpus
luteum leads to a transient rise of serum
FSH, thus, follicle recruitment is induced

FOLLICLES GROW IN WAVES
• Today we understand that multiple (two or
three) antral follicular waves are recruited
during human menstrual cycle.
• The treatment regimens are based on this theory of
follicular waves, to promote increased success with
assisted reproduction technology (ART) and fertility
preservation have been reported.
• Newer options for ovarian stimulation and
oocyte retrieval by making full use of
follicular waves of the patients either with
normal or abnormal ovarian reserve are
changing the standard protocols in ART and
challenging the conventional.

TWO CELL, TWO GONADOTROPHINS
ONLY AT ADVANCED STAGE OF
DEVELOPMENT DO GRANULOSA CELLS
BECOME RESPONSIVE TO FSH AND BECOME
CAPABLE OF CONVERTING THECA CELL
DERIVED ANDROSTENEDIONE TO ESTRADIOL.
CONCEPT THAT STIMULATION OF BOTH
THECA CELL BY LH AND GRANULOSA CELL BY
FSH IS REQUIRED FOR ADEQUATE ESTRADIOL
SYNTHESIS

A PREDOMINANTLY ESTROGENIC INTRA
FOLLICULAR MILIEU WILL PERMIT AND
FAVOUR FOLLICULAR GROWTH AND
DEVELOPMENT
ANDROGENIC MILIEU WILL LEAD TO
DEGENERATION AND ATRESIA

THE FSH THRESHOLD AND WINDOW CONCEPT
Macklon N S et al. Endocrine
Reviews 2006;27:170-207

FOLLICULAR OUTPUT RATE (FORT) Follicle to output indices (FOI)
Alviggi C, Conforti A, Esteves SC, et al. Understanding Ovarian Hypo-Response to Exogenous Gonadotropin in Ovarian
Stimulation and Its New Proposed Marker-The Follicle-To-Oocyte (FOI) Index. Front Endocrinol (Lausanne). 2018;9:589.

Once follicles reach 6-8 mm size there granulosa
cells begin to express LH receptors though at a low
level
Concomitantly, the pulsatile secretion of LH
increases in frequency during the cycle and the
mean LH level increases gradually
Estrogen secretion & follicle development continue
even when FSH is stopped or replaced by rec LH or
low dose hCG suggesting that development of
larger follicles is completely independent of FSH

Understanding the types and
mechanism of action of Ovarian
stimulating Agents

CLOMIPHENE:
MECHANISM OF ACTION
Hypothalamus
Pituitary
CC binds to ER and depletes
receptor concentrations
More smaller follicles are rescued
Multiple follicles develop
estrogen –ve feedback
interrupted
FSH stimulation continues
1
2
3
4
5
 Depletion of ER in pituitary and
hypothalamus due to prolonged
stimulation
 Estrogen feedback loop gets
interrupted
 FSH secretion increased leading
to multiple follicle growth
 Peripheral anti estrogenic effect
 Longer half life

LETRAZOLE:
MECHANISM OF ACTION  Inhibits aromatase in ovaries and
peripheral tissues reducing
estrogen levels
 Negative feed back being active
released, stimulates
hypothalamus-pituitary axis
 GnRH release produces FSH
 FSH-mediated stimulation of
follicle
 Rising estrogen level from follicle
suppresses FSH leaving a single
dominant-follicle
Hypothalamus
Pituitary
Releases off -ve feedback
stimulation
Smaller follicles undergo
atresia
Single follicle develop
estrogen –ve feedback
FSH stimulation
1
2
3
4
6 androstenedione  estrogen
aromatase inhibition
GnRH released
Falling FSH
5

Gonado
tropins
GnRH a
GnRH
anta

VS
 DIFFICULT PROCESS OF URINE COLLECTION
 SOURCE CONTROL NOT ABSOLUTE
 END PRODUCT IS ALWAYS CONTAMINATED WITH
>95% NON FSH HUMAN PROTEINS
 LH CONTAMINATION ,EVEN IN THE PUREST
 BATCH TO BATCH INCONSISTENCY
 LOW SPECIFIC FSH ACTIVITY
 PRESENCE OF FSH INHIBITING SUBSTANCES IN
URINARY FSH
 NO BATCH TO BATCH VARIABILITY
 >99% PURE WITH HIGHLY SPECIFIC BIOLOGICAL
ACTIVITY
 PREG RATES DO NOT DIFFER
 PREG RATES MAY BE HIGHER IF FROZEN THAWED
TRANSFERS INCLUDED
 ROUTE OF ADMINISTRATION
URINARY PRODUCTS VS RECOMBINANT

KEY DIFFERENCES BETWEEN ANTAGONISTS AND AGONIST
 No initial flare effect
 No estrogen deprivation symptoms
 Shorter tt protocol
 Reduced gonadotropin use
 Flexibility
 Rapid reversibility
 Recovery phase is much shorter(2-4 days)
 Patients more inclined to drop out of agonist
regime.

 Age,
 Ovarian volume,
 Number of antral follicles,
 Ovarian stromal blood flow,
 Serum FSH, LH, estradiol and inhibin
B,AMH
 Cigarette smoking
 Body mass index.
FACTORS AFFECTING FERTILITY OUTCOMES

Age
Biochemical parameters (basal FSH levels
in the early follicular phase, serum anti
mullerian hormone [AMH])
Morphological characteristics (antral
follicular count [AFC] and ovarian volume)
BIOMARKERS OF
OVARIAN RESERVE

WHAT DO I DEPEND ON ?
 Age
 AMH
 Antral Follicle count
Age is the Best Predictor of Quality AMH and AFC good for Quantity

P4, FSH, FOLLICULAR GROWTH
Zonnefeld et al. Hum Reprod 2003;18:495

EGG SUPPLY DICTATES OVARIAN RESERVE
0 5 10 15 20 25 30 35 40 45 50
# Total Eggs
# Recruitable Eggs
0.001% of 100,000 =
100
0.001% of 10,000 =
10
0.001% of 1,000 =
1
Log
(# eggs)
age

STIMULATION DEPENDS ON RESERVE
Ideal
for IUI
0
0.2
0.4
0.6
0.8
1
1.2
0 5 10 15 20 25 30 35 40 45 50
# eggs recruitable
StimStrength
Ideal
For IVF
Low reserve:
-soft / hi dose
Average reserve:
--Antag / mid dose High reserve:
low dose /Anta
NOTE: inverse correlation between dose and response across patients

Choose the right approach for the right patient
Correct number of oocytes to maximize CLBR
We have to predict ovarian response
A moderating approach in high responding women
A maximizing approach in normal responding women
A “creative” approach in reduced responding women

VS
DIFFERENCE BETWEEN VARIOUS PROTOCOLS
 These systematic reviews did not directly
address costs, but there was evidence to
suggest that mild stimulation was more cost
effective than standard IVF, based on a reduced
number of ampoules and total dose of
gonadotropins used.
 Mild stimulation was also associated with a
reduced number of oocytes retrieved, which
may have implications for the number of
surplus embryos eligible for cryopreservation.2017

Clinical common sense of AFC: let’s use AFC with
a pragmatic approach to choose the correct starting dose of gonadotropins
Number of follicles
a little normal a lot
< about 10 about 10 – about 15 > 15
… but let’s take also into consideration age and if possible AMH
r-FSH 300 IUI + r-LH 150 IU r-FSH 225 IUI r-FSH 150 IUI

FUNCTIONAL OVARIAN CYSTS
 There be no functional ovarian cysts at the time
ovarian stimulation commences.
 Day 2 Serum estradiol (E2) <50 pg/ml)
 Aspiration doesnot improve the results of
stimulation.
There is currently insufficient data to clarify whether
the endometrioma-related damage to ovarian
responsiveness precedes or follows surgery
Surgery should be envisaged only in presence of large
cysts (balancing the threshold to operate with the cyst
location within the ovary), or to treat concomitant pain
symptoms which are refractory to medical treatments,
or when malignancy cannot reliably be ruled out
Balkan Med J 2012; 29:197-200.
Hum Reprod. 2009 Mar;24(3):496-501.

SELECTION OF A PROTOCOL FOR A PATIENT
The Journal of Obstetrics and Gynecology of India (November–December 2015) 65(6):357–361.
The
answer is
NO !!!!!
Time to
individualize
Protocols !!!!!

AIMS OF STIMULATION
Terminology Aim Methodology
Natural Single oocyte No medication
Modified natural Single oocyte
hCG only
Antagonist/ FSH addback
Mild stimulation 6-7 oocytes Softer protocols
Conventional More than 8 oocytes Conventional protocols
VALORACIÓN DE LA FUNCIÓN
OVARICA CON 4D

PROFILE OF PATIENTS REQUIRING OI
YOUNG COUPLE---MALE FACTOR
YOUNG COUPLE –FEMALE FACTOR
Middle age group male /female factor
Poor responders
PCOS
High responders
Treatment intended
IUI or IVF

 Uniform cohort
 Synchronous growth
 Avoidance of follicular dominance
 Good quality Oocytes
 Timely induction of ovulation
 Adequate endometrial development
 Cost effective
 Safe
CONTROLLED OVARIAN
STIMULATION

Number of oocyte to obtain an
euploid blastocyst and maternal age
<35 39-40 42-43
Euploidy rate 60% Euploidy rate 30% Euploidy rate 20%
2 blastocysts≈
4 fertilized
oocytes
≈
5 MII oocytes≈
6 COCs≈
Age
3 blastocysts≈
6 fertilized
oocytes
≈
8 MII oocytes≈
10 COCs≈
5 blastocysts≈
10 fertilized
oocytes
≈
13 MII oocytes≈
16 COCs≈

HOW MANY OOCYTES ARE REQUIRED FOR GOOD OUTCOME

The more oocytes, the higher chance to
complete an average-sized family
LBR / Fresh ET Cumulative LBR/OPU
Conclusion(s): We demonstrate that one fresh cycle with high
oocyte yield is an optimal way to plan IVF treatment. With modern
cryopreservation methods, the concept of “one-and-done” could safely
achieve > 2 live births with just one stimulation cycle in almost a quarter
of our patients.
Vaughan DA et al. Fertil Steril. 2017 Feb;107(2):397-404

TYPES OF GONADOTROPINS
Clinics. 2014;69(4):279-293.
The overall conclusion is that both urinary gonadotropins, mainly hMG preparations, and
recombinant FSH have similar efficacy in terms of achieving a pregnancy or live birth per
treatment cycle

OVARIAN RESPONSE PREDICTION INDEX
 ORPI = (AMHxAFC)/ Patient age
 Multiple Marker Model Ovarian Response Prediction
Hum Reprod Update. 2013;20(1):124-140.

Scott M. Nelson, Ph.D
Fertility and Sterility 2013
AMH and AFC stratified
treatment
for choosing the GnRH
analogue for generating
customized individualized
stimulation protocols
pmol/l
Ng/ml
5.6
2.8
1
0.14

Gynecological Endocrinology. 2019. 35:12, 1027-1036.
SELECTION OF A PROTOCOL FOR A PATIENT
Proposed treatment algorithm for
controlled ovarian stimulation
according to (predicted) ovarian
response

Cochrane Databaseof SystematicReviews
Individualised gonadotropin dose selection usingmarkersof
ovarian reserve for women undergoingIVF/ICSI (Protocol)
Lensen SF, Wilkinson J, Mol BWJ, LaMarcaA, Torrance H, BroekmansFJ
2017
2016
2017
2019
Fixed Dose verses Individualized dose for COS in IVF

UNDERSTANDING THE
PHARMACOECONOMICS
OF GONADOTROPINS

MONEY MATTERS?
 Higher dose higher cost
 Higher dose higher number of follicles
 Higher dose higher pregnancy rates???
 Higher dose higher stimulation related
problems
 Higher dose higher multiple
pregnancies
 Higher multiple pregnancies higher
perinatal morbidity and mortality.
And everything costs
money and health
implications

MINIMAL-MILDER STIMULATION
Increased safety
for both the
woman and the
offspring
Decreased cost Better embryos
Hohmann, Macklon, Fauser (Rotterdam) JCEM 2003.
Broekman, Weima and te Velde (Utrecht). JCEM 2003.

Cost
Measuring
Success in
IVF/ART
• Time to birth encompasses the critical components of
cost, time and outcomes
• It is patient-centric
• It acknowledges all clinical and social issues that are
critical to managing fertility
• It facilitates openness and transparency in conversations
related to fertility treatments
‘Time’ in time to birth: how to define it?
New approach: Time to birth in IVF / ART

DO TYPE AND DOSE OF GONADOTROPINS MAKE A
DIFFERENCE?

DOSE OF HCG FOR FINAL MATURATION

In both procedures of IUI and IVF
what we would like to avoid is
cost of multiple pregnancies and
related procedures:
Embryo reduction
Perinatal morbidity and mortality
related to multiple pregnancies

OVULATION INDUCTION FOR PCOS PATIENTS
BMI < 27
PCOS and Chronic Anovulation
Ovul. (-)
BMI  27
Insulin
Sensitizer
OvulationObservation &
F/U every 3 ~
6 mths
Desire (+) for pregnancy
Desire (-) for pregnancy
Weight Reduction
at least for 8 ~ 12 wks

METFORMIN
 Ever changing role and understanding
 Insulin-resistant PCOS patients with low BMI more likely to respond to
metformin, whereas CC treatment was more effective in less
hyperandrogenic and more insulin-sensitive patients.
Evanthia Diamanti-Kandarakis et al
European Journal of Endocrinology 2010

OHSS FREE CLINICS
SEGMENTATION OF IVF TREATMENT
 The strategy to obtain an OHSS-Free Clinic is closely related to the segmentation concept.
 Segment It consists of optimization of the ovarian stimulation, including GnRH agonist triggering in a GnRH
antagonist cycle.
 Segment B then consists of optimum cryopreservation methods for oocyte or embryo vitrification.
 Segment C includes embryo replacement in a receptive, non-stimulated endometrium in a natural cycle or with
artificial endometrial preparation.

FREEZE ALL OR FREEZE FOR ALL
 Compared with a ‘fresh-transfer’ strategy,
the ‘freeze-all’ strategy resulted in a
similar cumulative live birth rate among
high responders but significantly lower
cumulative live birth rates among normal
and suboptimal responders.
 This suggests that a universal ‘freeze-all’
strategy is not warranted.

Reprod Biol Endocrinol. 2018;16(1):20.
POOR OVARIAN RESPONSE/ POOR RESPONDERS

Folic acid is generally accepted as a necessary
periconceptual supplement to reduce the risk spina
bifida.
Vitamin D A recent systematic review live birth was
found to be more likely in women replete in vitamin D
when compared with women with deficient or
insufficient vitamin D status (OR, 1.33; 95% CI, 1.08–
1.65); and recommendations for dietary intake have
been established.
Chu J, Gallos I, Tobias A, et al. Vitamin D and assisted reproductive treatment
outcome: a systematic review and meta-analysis. Hum Reprod 2018;33:65–80.
ADJUVANTS in ART
Currently the evidence does not support the routine use of
Aspirin as an adjuvant to ART.
Dentali et al 2012
Androgens play an important role in reproductive processes
and intrafollicular physiology and their use
as adjuvants in ART, especially in poor ovarian responders
has been advocated. Three reviews have concluded there
was insufficient evidence to recommend DHEA as routine
supplementation in poor responders.
Lin LT et al 2015, Sunkara et al 2012

LUTEAL SUPPORT
Is a must in all stimulated cycles.
Could be progesterone or hCG
Micronised vaginal progesterone is most accepted form.
Dose between 400-800mg vaginally individed doses.

NEWER LUTEAL SUPPORTS
• The meta-analysis results indicated significantly higher rates
of ongoing pregnancy or live birth per transfer, clinical
pregnancy per transfer (and multiple pregnancy per
pregnancy (P=0.020) in the GnRHa group compared with
those in the control group.
• Meta-analysis of a subgroup of trials with long-acting GnRH-a
ovarian treatment protocols indicated that the rate of
ongoing pregnancy or live birth and multiple pregnancy per
pregnancy were not significantly different between the two
groups.
• The results from trials that had used a multi-dose GnRH
antagonist ovarian treatment protocol indicated a
significantly higher ongoing pregnancy or live birth rate per
transfer (P=0.010), CPR per transfer (P<0.0001) and multiple
pregnancy rate per pregnancy (P=0.003) compared with those
in the control group.
Exp Ther Med 2020

CHANGING APPROACH
YESTERDAY
TODAY
TOMORROW
CONVENTIONAL
MILD/MINIMAL
INDIVIUALISED
More Oocytes Supraphysiological E2
Agonist protocols More embryos/OHSS
Multiple pregnancies Cryopreservation
Less Oocytes Optimal E2
Antagonist protocols No OHSS
No multiple pregnancies Lower cost
Optimal Oocytes/Embryos
No OHSS No Multiple pregnancies
Lower cost PATIENT FRIENDLY

CONSTANT UPDATING AND EXPERIMENTING RATIONALLY
Evidence changes practice
Practice changes evidence

LEARNING CURVE
There is a learning curve for
understanding of the factors responsible
for good outcome
Be Persistent

FOR FERTILITY PRESERVATION
Sometimes the time frames are very short in these cases .
 Dual stimulation
 Random start protocols
 There are many protocols
available and individual clinics can follow.
1.Baerwald, A., Adams, G., and Pierson, Characteristics of ovarian follicular wave
dynamics in women. Biol Reprod. 2003.
3.Cardoso MCA, et al .JBRA Assist Reprod. 2017 Sep
2.Li, Y., Yang, W., Chen, X., Li, L., Zhang, Q., and Yang, D.
Gynecol Endocrinol. 2016;

THE END OF INFERTILITY MAY BE IN SIGHT

"I know that serving others has been a source of inspiration, a source of strength, a
reinforcement of faith, and an illustration of my life’s purpose."
Dr. Rachel Talton

SHORTLY YOU WILL RECEIVE
FOGSI FOCUS
Birth defects

Ectopic pregnancy
MINIMISE SIDE EFFECTS
MULTIPLE GESTATIONS ,O.H.S.S ,Ectopic pregnancy
DISADVANTAGES
COST,INJECTIONS,MONITORINGS,FAILURES

CONCLUSION
CC is first line drug for ov stimulation
If pronounced antiestrogenic effect seen with CC switch to aromatase inhibitors.
Present data favours analogues in IVF and antagonists in IUI
Antagonists ideal for PCOS & poor responders
Efforts must be made to use it as a first line drug rather than replacement for GnRH-a

100 patients >40 y randomized, serum FSH<14, Inhibin>30 pg/ml
All long GnRH agonist protocol
450 IU rFSH+150 IU hMG
Same protocol + 8 IU hGH start on day 7 of stim to day after hCG
HUMAN
GROWTH
HORMONE

HGH RESULTS
Tesarik et al Hum Reprod 2005;20:2536

Poor responder,high responders

CHANGING OF DOSE AND TYPE
OF GONADOTROPHINS
FREQUENTLY IN THE SAME CYCLE

FEMALE AGE, TYPE OF PROTOCOL, BASAL FSH AND TOTAL
NUMBER OF ANTRAL FOLLICLES, WITH ALL OTHER PARAMETERS
BEING EXCLUDED FROM THE EQUATION.

Antagonists were significantly associated with lower length and total dose of GnRH,
lower length of rFSH, and higher numbers of oocytes and high quality embryos, whereas
the agonist presented a higher fertilization rate and probability of pregnancy.
Significant predictors of retrieved oocytes and high quality embryos were the antagonist
protocol, lower female age, lower serum levels of basal FSH and higher total number of
antral follicles.
Significant predictors of clinical pregnancy were the agonist protocol, reduced number
of attempts, increased endometrial thickness and lower female age. The probability of
pregnancy increased until 30 years-old, with a decline after that age and with a sharp
decline after 40 years-old.

Ten predictor variables were considered with the dependent variable being the number of retrieved
oocytes (age, type of protocol, basal estradiol and FSH levels, total number of antral follicles, ovarian
volume, BMI, smoking status, number of attempts, cause of infertility, male or male+female). Only five
factors were found significant in the univariable analysis: female age and basal FSH were variables inversely
related to the number of retrieved oocytes, whereas the total ovarian volume and total number of antral
follicles had a positive correlation to the ovarian response. The patients from the antagonist protocol had a
larger number of oocytes retrieved than patients treated with the agonist protocol (Table 2).

BENEFIT OF HIGH OVARIAN RESPONSE OFTEN
NOT APPARENT IN FRESH CYCLE
0%
10%
20%
30%
40%
50%
60%
%
delivered
1 - 5 6 - 10 > 10
# mature eggs
Frozen
Fresh
Toner et al., Hum Reprod 6:284, 1991

GNRH
AGONIST TO
TRIGGER
OVULATION
 OHSS remains a significant complication of controlled ovarian hyperstimulation.
 'GnRH' agonists are able to induce an endogenous surge of LH and FSH.
 Its effect may be more physiological than that of exogenous hCG.
 It can prevent OHSS in high responders (like PCOS).
 Hum Fertil 2002;5:G35-G39
 In agonists groups the progesterone levels were “normal luteal values” as we observe in
natural, unstimulated cucles.
 However hCG induced enormous increase in progesterone levels at the time of ET.
 The luteotrophic effect gives rise to such elevated progesterone levels.
 75th international Symposium on GnRH anologues in Cancer & Human Reproduction, 2003

Holds promise for the PCOS
Reduction in the incidence of OHSS
• More physiological
• Lower half life (60 mins vs 32 – 34 hrs)
• Lower incidence of OHSS
Agonist can be used as a trigger instead of hCG to drastically reduce risk of OHSS
ANTAGONIST

OC pill for programming and LH suppression
rFSH 75 / 100 / 112.5 / 125 / 150 starting doses with antagonist after 14 mm
hCG 5000 / 10000 / Agonist trigger@ E2 levels
Fresh transfer in hCG cycles
Cryothawed ET in agonist trigger cycles
WHAT SHOULD BE THE IDEAL PROTOCOL?

DOSE OF HCG FOR FINAL MATURATION IN PCO

Craft et al
 CC/Gn with antagonist in
poor responders & PCOS
USG
E2
USG
E2
USG
E2
HCG
5000
10,000
ET
D2
ET
D3
ET
D5
Blastocyst
OPU
IUI
35-37
hr
1 2 3 4 5 6 7 8 9 10 11 12
Progesterone
IM
Oral
Vaginal
CC
GnRH antagonist
FSH/HMG
SOFT OVARIAN STIMULATION:POOR RESPONDERS

ALL PROTOCOLS ARE TAILOR MADE FOR EACH PT
ONE OF THE MOST HEATED DEBATE IS THE CHOICE OF GONADOTROPHIN
BETTER UNDERSTANDING AND USE OF PHYSIOLOGIC PRINCIPLES AND
COST MAY PROVIDE USEFUL ANSWERS

KEEP YOUR GOALS WITH OVARIAN
STIMULATION ON THE TABLE

MINIMAL STIMULATION
COMPARABLE PREGNANCY RATES PER ET CYCLE
Weghofer et al F &S 2004

ESTROGEN PRE-TREATMENT
Smulders et al Cochrane Database Sys Rev 2010, Issue 1

E2 PRIMING IN POOR RESPONDERS
Agonist/antagonist conversion with E2 priming with 600 or 750 IU r-FSH, poor
responders, DOR, advanced age, <43y/o : Case series, OPR 25-28%
• Fisch et al Fertil Steril 2008;89:342
Luteal Estrace 2mg bid added to microflare or flexible antagonist protocols with r-FSH
and micro-hCG (60) vs without (60): Retrospective, former with more oocytes more D3
embryos but no LB 1st cycle, 2nd cycle LBR higher in the former but NS; 2009 larger
report LBR NS, longer stim, more FSH use with E2 priming
• Frattarelli et al Fertil Steril 2008:89:1118
• Hill et al. Fertil Steril 2009;91:739

E2 PRIMING ANTAGONIST VS POOR RESPONDER PROTOCOL
• Weitzman et al. Fertil Steril 2009;92:226
E2 patch 0.1mg qod with precycle and flexible antagonist (n:45) vs ocp followed by micro agonist (80mcg) flare
(n:76); retrospective,mean age around 38 y, OPR 30 vs 26% NS.

This is NOT the case, provided that the BCP is overlapped with administration of a gnrh agonist (e.G. Lupron,
buserelin) for several days leading up to the start of menstruation and the initiation of ovarian stimulation cycle with
fertility drugs. If the latter precaution is not taken, and the cycle of stimulation is initiated coming directly off the BCP
the response will often be blunted and subsequent egg quality could be adversely affected. The explanation for this
is that in natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability to properly respond to
FSH stimulation is dependent on the recruited follicles having reached the antral phase of development by the time
the cycle begins (or similarly, stimulation with fertility dugs is initiated).

Unfortunately, this approach represents “a double edged sword” as the resulting increased release of FSH is likely to
be accompanied by a concomitant (excessive) rise in LH levels that could evoke excessive production of male
hormone by the ovarian stroma. The latter in turn could potentially compromise egg quality, especially in women
over 39 years of age, women with diminished ovarian reserve, and in women with polycystic ovarian syndrome
(PCOS) - all of whose ovaries have increased sensitivity to LH. In this way, “microflare protocols” can potentially
hinder egg/embryo development and reduce IVF success rates. While microflare protocols usually are not harmful in
younger women and those with normal ovarian reserve, I personally avoid this approach altogether for safety sake.

The use of GnRH antagonists as currently prescribed in ovarian stimulation cycles (i.e. the administration of 250mcg
daily starting on the 6th or 7th day of stimulation with gonadotropins) may be problematic, especially in women over
39 yrs., women with diminished ovarian reserve (i.e. “poor responders” to gonadotropins), and women with PCOS.
Such women tend to have higher levels of LH to start with and as such the initiation of LH suppression with GnRH
antagonists so late in the cycle (usually on day 6-7) of stimulation fails to suppress LH early enough to avoid
compromising egg development. This can adversely influence egg/embryo quality and endometrial development. As
is the case with the “microflare”approach (see above) the use of GnRH antagonist protocols in younger women who
have normal ovarian reserve, is acceptable. Again, for reasons of caution, and because I see no benefit in doing so, I
personally never prescribe this approach for my patients.

Long protocol (or A/ACP) with estrogen priming: women who have a significant degree of diminished ovarian reserve
are first given gnrh agonist for a number of days to effect pituitary down-regulation. Upon post-bcp/agonist-induced
menstruation, the dosage of gnrh agonist is drastically lowered (or commonly is supplanted by 125mg daily of an
antagonist) and the woman is given twice-weekly injections of 2-4mg of estradiol valerate (E2V) for a period of 7-10
days. Ovarian stimulation is then initiated using a relatively high dosage of an fsh-dominant gonadotropins such as
folistim, puregon or gonal F for a few days, whereupon the dosage is reduced and a small amount of dna-
recombinant LH (luveris) is added daily. Both the FSH and the LH are then continued along with daily administration
of gnrh agonist (or antagonist) until the “hcg trigger”. The reason for the “estrogen priming” is because it enhances
follicle response to FSH and also helps optimize the uterine lining.

There is one potential drawback to the use of the A/ACP. We have learned that prolonged use of a gnrh antagonist
throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2 measurements
to evaluate follicle growth and development. It appears that when the antagonist is given throughout stimulation,
the blood E2 levels tend to be significantly lower than when the agonist alone is used or where antagonist treatment
is only commenced 5-7 days into the ovarian stimulation process. The reason for this is presently unclear.
Accordingly, when the A/ACP is employed, we rely more on follicle size monitoring than on serial blood E2 trends to
assess progress. Also, younger women (under 30 years) and women with absent, irregular or dysfunctional ovulation,
and those with polycystic ovarian syndrome are at risk of developing life-threatening severe ovarian
hyperstimulation. The prediction of this condition requires daily access to accurate blood E2 levels. Accordingly we
currently tend to refrain from prescribing the A/ACP in such cases, preferring instead use the “standard long-
protocol” approach.

3 D STIMULATED OVARY
3D CONTROLLED OVARIAN HYPERSTIMULATION FOR IVF

The transition of early primary follicles to develop into antral follicles (AF) takes a 3-6 day period of a sustained rise in
blood FSH prior to the onset of menstruation.. The BCP (as well as prolonged administration of
estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH
levels to rise otherwise development will not take place. GnRH agonists (e.g. Lupron, Buserelin, Nafarelin and
Synarel) do this by triggering a rapid increase in FSH production. Thus, by overlapping the BCP with an agonist for a
few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF
stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing
of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of
time that the woman is on the BCP.

The intent is to deliberately allow Lupron to affect an initial surge (“flare”) in pituitary FSH release so as to augment
ovarian response to the gonadotropin medication. Unfortunately, this approach represents “a double edged sword”
as the resulting increased release of FSH is likely to be accompanied by a concomitant (excessive) rise in LH levels
that could evoke excessive production of male hormone by the ovarian stroma. The latter in turn could potentially
compromise egg quality, especially in women over 39 years of age, women with diminished ovarian reserve, and in
women with polycystic ovarian syndrome (PCOS) - all of whose ovaries have increased sensitivity to LH. In this way,
“microflare protocols” can potentially hinder egg/embryo development and reduce IVF success rates

the event is the culmination (end point) of the progressive escalation in LH (“a staircase effect”) which results in
increasing ovarian stromal activation with commensurate growing androgen production. Trying to improve ovarian
response and protect against follicular exhaustion by administering GnRH antagonists during the final few days of
ovarian stimulation is like trying to prevent a shipwreck by by removing the tip of an iceberg.

AGONIST/ANTAGONIST PROTOCOL
With the A/ACP, as with the long protocol (see above) the woman again prepares to launch her stimulation cycle by
taking a BCP for at least ten days before overlapping with an agonist such as Lupron. However, when about 5-7 days
later her menstruation starts, she supplants the agonist with a half dosage (125mg) of an antagonist (e.g. Ganirelix,
Orgalutron or Cetrotide).Within a few days of this switch-over, gonadotropin stimulation is commenced. Both the
antagonist and the gonadotropins are then continued until the hCG trigger. The purpose in switching from agonist to
antagonist is to intentionally allow only a very small amount of the woman's own pituitary LH to enter her blood and
reach her ovaries, while at the same time preventing a large amount of LH from reaching her ovaries. This is because
while a small amount of LH is essential to promote and optimize FSH-induced follicular growth and egg maturation, a
large concentration of LH can trigger over-production of ovarian stromal testosterone, with an adverse effect of
follicle/egg/embryo quality. Moreover, since testosterone also down-regulates estrogen receptors in the
endometrium, an excess of testosterone can also have an adverse effect on endometrial growth. Also, since agonists
might suppress some ovarian response to the gonadotropin stimulation, antagonists do not do so. It is for this reason
that the A/ACP is so well suited to older women and those with some degree of diminished ovarian reserve.

ESTROGEN PRIMING IN POOR RESPONDERS
The reason for the “estrogen priming” is because it enhances follicle response to FSH and also helps
optimize the uterine lining.
We recently reported in a prestigious medical Journal on results using the A/ACP with estrogen
priming in older women and women with diminished ovarian reserve where the approach has proven
to be most advantageous.

There is one potential drawback to the use of the A/ACP. We have learned that prolonged use of a gnrh antagonist
throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2
measurements to evaluate follicle growth and development. It appears that when the antagonist is given
throughout stimulation, the blood E2 levels tend to be significantly lower than when the agonist alone is used or
where antagonist treatment is only commenced 5-7 days into the ovarian stimulation process. The reason for this
is presently unclear. Accordingly, when the A/ACP is employed, we rely more on follicle size monitoring than on
serial blood E2 trends to assess progress. Also, younger women (under 30 years) and women with absent,
irregular or dysfunctional ovulation, and those with polycystic ovarian syndrome are at risk of developing life-
threatening severe ovarian hyperstimulation. The prediction of this condition requires daily access to accurate
blood E2 levels. Accordingly we currently tend to refrain from prescribing the A/ACP in such cases, preferring
instead use the “standard long-protocol”

There is a progressive increase in the incidence in egg/embryo aneuploidy with advancing age. To put numbers to
the equation; by time a woman reaches 35 yrs; approximately 60% of her eggs are likely to be aneuploid. By the
time she reaches her mid 40’s the incidence will be greater than 85%.

For example, a woman of 43 years would be fortunate if six (6) or eight (8), of her eggs would upon being
fertilized, result in one (1) “competent” embryo. As the woman gets older, the inevitable decline in egg/embryo
quality results in her having a reduced ability to conceive naturally, a declining IVF success rates, an increase in
miscarriages, and a rising incidence of having her baby affected by chromosomal birth defects such as Trisomy 21
(Down's syndrome). This is why for such a woman, the anticipated IVF birth rate per egg retrieval is less than 10%
(i.e. 60% lower than at age 35), the miscarriage rate rises almost by 300% to about 60% and why her risk of having
a baby with Down’s syndrome is about 2% (as compared to 0.1% ).

Combined Clomiphene or Letrazole) /Gonadotropin Stimulation:
This approach when used in older women and women with diminished ovarian reserve is also potentially harmful
to egg/embryo quality. The reason is that like GnRHa, clomiphene and Letrazole also cause LH to be released in
large amounts. Since these medications are given at the start of ovarian stimulation they, as with “flare protocols”
can elicit ovarian over-production of testosterone. As such this approach is in my opinion far less than ideal for
older women and women who have diminished ovarian reserve.

The initial administration of agonist serves to rapidly expunge pituitary FSH and LH causing an immediate rise in
the blood levels of both hormones. Then, within a few days, having virtually exhausted/depleted pituitary
gonadotropin stores, the blood levels of FSH and LH both rapidly decline, such that by the time menstruation
occurs, the levels are very low. The initial premenstrual GnRHa-induced rise in FSH helps recruit ovarian antral
follicles for the upcoming cycle, while the ultimate virtual depletion of LH serves to prevent excessive ovarian
testosterone production and protects egg quality.

Proper development as well as precise timing in the initiation of egg maturation with LH or hcg is no less crucial to
optimal egg maturation, fertilization and ultimately to embryo quality.

Antagonists were significantly associated with lower length and total dose of GnRH, lower length of rFSH, and higher
numbers of oocytes and high quality embryos, whereas the agonist presented a higher fertilization rate and
probability of pregnancy. Significant predictors of retrieved oocytes and high quality embryos were the antagonist
protocol, lower female age, lower serum levels of basal FSH and higher total number of antral follicles. Significant
predictors of clinical pregnancy were the agonist protocol, reduced number of attempts, increased endometrial
thickness and lower female age. The probability of pregnancy increased until 30 years-old, with a decline after that
age and with a sharp decline after 40 years-old.

During the normal ovulation cycle, ovarian hormonal changes are orchestrated to avoid irregularities in
production and interaction that could adversely influence follicle development and egg quality

As an example, while small amounts of ovarian male hormones (predominantly testosterone) are essential to
enhance egg and follicle development, over-exposure to excessive amounts of the same hormones can seriously
compromise egg (and subsequently, also embryo) quality. It follows that protocols for ovarian stimulation should
be geared towards optimizing follicle and egg development while avoiding overexposure to ovarian male
hormones. The fulfillment of these objectives requires a very strategic and individualized approach to ovarian
stimulation and precise timing of the human chorionic gonadotropin (hcg) “trigger.”

It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in
follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed at
the cells that line the inside of the follicles (i.E. Granulosa cells). LH, on the other hand, acts primarily on the
connective tissue that surrounds the follicles (i.E. The ovarian stroma or theca) to compel the production of male
hormones. Only a small amount of these hormones (predominantly testosterone) is necessary for optimal
estrogen production. Overproduction has a deleterious effect on granulosa cell activity, follicle
growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore,
excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.

In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels,
there is also an increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo
quality” and inadequate endometrial development are often features of this condition. The use of lh-containing
preparations such as repronex might further aggravate this effect. Thus we strongly recommend against the
exclusive use of such products, in PCOS patients, preferring fsh-dominant products such as folistim and gonal F.
While it would seem prudent to limit LH exposure in all cases of ovarian stimulation, this appears to be more
relevant in older women, who tend to be more sensitive to LH

Preparing for ovarian stimulation:
Before embarking on ovarian stimulation it is essential to try and define the woman’s ovarian reserve (i.E., The
number of eggs still available in her ovaries). Determination of the ovarian reserve will assist in defining the
protocol of ovarian stimulation that would most safely yield the optimum number and quality of follicles/eggs in
a given case. The ovarian reserve can best be assessed by determining the woman’s blood FSH and estradiol (E2)
measurement on the 3rd day of a spontaneous menstrual cycle and by evaluating the manner in which she
responded to a most recent cycle of treatment. Other blood tests that can also be selectively used to assist in
assessing ovarian reserve are measurement of blood antimullerian hormone and inhibin B levels.

For women who require a repeated cycle it is advisable that at least one-month be allowed to elapse (“resting
cycle”) between IVF treatments, in order to allow the ovaries to fully recover from the preceding stimulation.

One often hears the expressed opinion that the BCP suppresses response to ovarian stimulation. This is NOT the
case, provided that the BCP is overlapped with administration of a gnrh agonist (e.G. Lupron, buserelin) for
several days leading up to the start of menstruation and the initiation of ovarian stimulation cycle with fertility
drugs. If the latter precaution is not taken, and the cycle of stimulation is initiated coming directly off the BCP the
response will often be blunted and subsequent egg quality could be adversely affected. The explanation for this is
that in natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability to properly respond to
FSH stimulation is dependent on the recruited follicles having reached the antral phase of development by the
time the cycle begins (or similarly, stimulation with fertility dugs is initiated).

The transition of early primary follicles to develop into antral follicles (AF) takes a 3-6 day period of a sustained
rise in blood FSH prior to the onset of menstruation.. The BCP (as well as prolonged administration of
estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH
levels to rise otherwise development will not take place. GnRH agonists (e.g. Lupron, Buserelin, Nafarelin and
Synarel) do this by triggering a rapid increase in FSH production. Thus, by overlapping the BCP with an agonist for
a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to
the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach,
the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by
varying the length of time that the woman is on the BCP.

At the onset of bleeding a measurement of blood estradiol (E2) is done to insure that it is low enough (under 70
pg/ml) to start administering the fertility drugs. The commonest cause of an elevated blood E2 level around this
time is the existence of one or more ovarian follicular cysts. These should be allowed to absorb, or be aspirated as
soon as possible (I personally prefer to aspirate cysts under local anesthesia, on the spot COH.

Unlike GnRH agonists that exert their LH (and FSH) lowering effect by exhausting the pituitary gland of its over 4-7
days GnRH antagonists (such as Ganirelix, Orgalutron, Cetrotide ) do so directly and immediately (within a few hours
of administration).Thus both agonists and antagonists of GnRH both serve to establish a “low LH environment” in
which follicular and egg development can proceed optimally.

There is also (in my opinion) little advantage in using combined FSH/LH urinary-derived products where the
additional LH contained in the preparation might in some cases compromise rather than enhance follicle and egg
development. Accordingly, with few exceptions

With the A/ACP, as with the long protocol (see above) the woman again prepares to launch her stimulation cycle by taking a BCP for
at least ten days before overlapping with an agonist such as Lupron. However, when about 5-7 days later her menstruation starts,
she supplants the agonist with a half dosage (125mg) of an antagonist (e.g. Ganirelix, Orgalutron or Cetrotide).Within a few days of
this switch-over, gonadotropin stimulation is commenced. Both the antagonist and the gonadotropins are then continued until the
hCG trigger. The purpose in switching from agonist to antagonist is to intentionally allow only a very small amount of the woman's
own pituitary LH to enter her blood and reach her ovaries, while at the same time preventing a large amount of LH from reaching
her ovaries. This is because while a small amount of LH is essential to promote and optimize FSH-induced follicular growth and egg
maturation, a large concentration of LH can trigger over-production of ovarian stromal testosterone, with an adverse effect of
follicle/egg/embryo quality. Moreover, since testosterone also down-regulates estrogen receptors in the endometrium, an excess of
testosterone can also have an adverse effect on endometrial growth. Also, since agonists might suppress some ovarian response to
the gonadotropin stimulation, antagonists do not do so. It is for this reason that the A/ACP is so well suited to older women and
those with some degree of diminished ovarian reserve.
AGONIST/ANTAGONIST PROTOCOL

The reason for the “estrogen priming” is because it enhances follicle response to FSH and also helps optimize the uterine lining.
We recently reported in a prestigious medical Journal on results using the A/ACP with estrogen priming in older women and
women with diminished ovarian reserve where the approach has proven to be most advantageous.
ESTROGEN PRIMING IN POOR RESPONDERS

There is one potential drawback to the use of the A/ACP. We have learned that prolonged use of a GnRH antagonist
throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2 measurements to
evaluate follicle growth and development. It appears that when the antagonist is given throughout stimulation, the blood
E2 levels tend to be significantly lower than when the agonist alone is used or where antagonist treatment is only
commenced 5-7 days into the ovarian stimulation process. The reason for this is presently unclear. Accordingly, when the
A/ACP is employed, we rely more on follicle size monitoring than on serial blood E2 trends to assess progress. Also, younger
women (under 30 years) and women with absent, irregular or dysfunctional ovulation, and those with polycystic ovarian
syndrome are at risk of developing life-threatening severe ovarian hyperstimulation. The prediction of this condition
requires daily access to accurate blood E2 levels. Accordingly we currently tend to refrain from prescribing the A/ACP in such
cases, preferring instead use the “standard long-protocol”

There is a progressive increase in the incidence in egg/embryo aneuploidy with advancing age. To put numbers to the
equation; by time a woman reaches 35 yrs; approximately 60% of her eggs are likely to be aneuploid. By the time she
reaches her mid 40’s the incidence will be greater than 85%.

For example, a woman of 43 years would be fortunate if six (6) or eight (8), of her eggs would upon being fertilized,
result in one (1) “competent” embryo. As the woman gets older, the inevitable decline in egg/embryo quality results
in her having a reduced ability to conceive naturally, a declining IVF success rates, an increase in miscarriages, and a
rising incidence of having her baby affected by chromosomal birth defects such as Trisomy 21 (Down's syndrome).
This is why for such a woman, the anticipated IVF birth rate per egg retrieval is less than 10% (i.e. 60% lower than at
age 35), the miscarriage rate rises almost by 300% to about 60% and why her risk of having a baby with Down’s
syndrome is about 2% (as compared to 0.1% ).

Combined Clomiphene or Letrazole) /Gonadotropin Stimulation:
This approach when used in older women and women with diminished ovarian reserve is also potentially harmful to
egg/embryo quality. The reason is that like GnRHa, clomiphene and Letrazole also cause LH to be released in large
amounts. Since these medications are given at the start of ovarian stimulation they, as with “flare protocols” can
elicit ovarian over-production of testosterone. As such this approach is in my opinion far less than ideal for older
women and women who have diminished ovarian reserve.

The initial administration of agonist serves to rapidly expunge pituitary FSH and LH causing an immediate rise in the
blood levels of both hormones. Then, within a few days, having virtually exhausted/depleted pituitary gonadotropin
stores, the blood levels of FSH and LH both rapidly decline, such that by the time menstruation occurs, the levels are
very low. The initial premenstrual GnRHa-induced rise in FSH helps recruit ovarian antral follicles for the upcoming
cycle, while the ultimate virtual depletion of LH serves to prevent excessive ovarian testosterone production and
protects egg quality.

The potential for a woman’s eggs to undergo orderly maturation, successful fertilization, and subsequent progression
to “good quality embryos” that are capable of producing healthy offspring, is in large part, genetically determined.
However, the expression of such potential is profoundly susceptible to numerous extrinsic influences, especially to
intra-ovarian hormonal changes during the pre-ovulatory phase of the cycle.
Sher 2010

Several studies have been performed to identify predictors of ovarian response, such as female age, ovarian volume,
number of antral follicles, ovarian stromal blood flow, serum FSH, LH, estradiol and inhibin B, cigarette smoking and
body mass index. Similarly, predictors of pregnancy achievement were studied regarding female age, serum FSH,
estradiol and inhibin B, ovarian volume, endometrial thickness, embryo quality, smoking status, body mass index and
parity [16-33] .

Ten predictor variables were considered with the dependent variable being the number of retrieved oocytes (age,
type of protocol, basal estradiol and FSH levels, total number of antral follicles, ovarian volume, BMI, smoking status,
number of attempts, cause of infertility, male or male+female). Only five factors were found significant in the
univariable analysis: female age and basal FSH were variables inversely related to the number of retrieved oocytes,
whereas the total ovarian volume and total number of antral follicles had a positive correlation to the ovarian
response. The patients from the antagonist protocol had a larger number of oocytes retrieved than patients treated
with the agonist protocol (Table 2).

ISSUES
Advancement of the dominant follicle maturation in a spontaneouscycle
Increased gonadotropin requirements
Cost-intensive
Low success rates
• Decreased embryo quality
• Low live birth rates
• Increased miscarriage rates

GONADOTROPIN DOSE EFFECTS
Dosage directly affects ovarian response (within a fixed level of Ovarian Reserve)
• Among High responders, stronger stimulation yields more eggs
Dosage chosen is inversely correlated with Ovarian Reserve
• Low responders: Strong stimulation/Soft stimulation
• High responders: Gentle stimulation

Out HJ, Braat DDM, Lintsen BME, Gurgan T, Bukulmez O, Gokmen O, Keles G, Caballero P, Gonzalez JM,
Fabregues, Balasch J, Roulier R
Human Reprod 2000; 15:29-35
0
5
10
15
30-33 34-36 37-39
150 IU
250 IU
Mean # oocytes Mean total dose per patient
0
500
1000
1500
2000
2500
3000
30-33 34-36 37-39
150 IU
250 IU
Increasing the daily dose of recombinant follicle stimulating hormone (Puregon) does not
compensate for the age-related decline in retrievable oocyte after ovarian stimulation

Cochrane Review 2009, issue 1: Ferraretti 2004 included only poor responders
Tarlatsiz 2006 excluded poor responders
LH supplementation
GnRHagonist/rec-LH+rec-FSH: Poor responders or women >35 y may benefit

Mid-follicular 150 IU r-LH (D6 of stimulation) addition long
agonist protocol 35-39 y/o
• PRCT open label
• ICSI
• Non-PCO, both ovaries intact
• ≤2 previous cycles, no cycle cancellation
• FSH≤10
%ITT r-FSH r-FSH+r-LH
(n:68) (n:63)
CPR 14.7 27
IR 11.3 18.1*
LBR/cycle 7.4 19.0*
LBR/ET 9.3 21.4
Matorras et al. RBMOnline 2009;19:879

PRCT open label
ICSI
Non-PCO, both ovaries intact
≤2 previous cycles, no cycle cancellation
FSH≤10
%ITT r-FSH r-FSH+r-LH
(n:68) (n:63)
CPR 14.7 27
IR 11.3 18.1*
LBR/cycle 7.4 19.0*
LBR/ET 9.3 21.4
Matorras et al. RBMOnline 2009;19:879
MID-FOLLICULAR 150 IU R-LH (D6 OF STIMULATION)
ADDITION LONG AGONIST PROTOCOL 35-39 Y/O

Alviggi et al. Reproductive Biology and Endocrinology 2009;7:101

INVERSE CORRELATIONS
Eggs (#) and implantation rates (%)
0
2
4
6
8
10
12
14
16
18
20
25-29 y 30-34 y 35-39 y 40-44 y
Eggs / retrieval
Implantation rate
Stimulation strength
Hull et al., F&S 65:787, 1996

The potential for a woman’s eggs to undergo orderly maturation, successful fertilization, and subsequent
progression to “good quality embryos” that are capable of producing healthy offspring, is in large part,
genetically determined. However, the expression of such potential is profoundly susceptible to numerous
extrinsic influences, especially to intra-ovarian hormonal changes during the pre-ovulatory phase of the
cycle.
Sher 2010

ANTRAL FOLLICLES AND RESPONSE
2-10 mm Follicles on Day 2/3/4
2D/3D
Low count < 5
Number of mature follicles
Number of oocytes retrieved
Number of good embryos
Cancelled Cycles

IS THERE A DIFFERENCE BETWEEN STIMULATION FOR IUI
AND ART?
Aim for ART stimulation is to achieve
8-10 oocytes.
While IUI we want only one to not
more than four follicles
Today all over the world emphasis is on reducing the incidence of multiple pregnancies

A fruit plucked from a tree before having developed fully or a poorly developed fruit might still ripen
(mature) on the shelf and might even appear as enticing as one that had previously undergone proper
development, but it will lack the same quality. The same principles apply to the development and
maturation of human eggs.
Sher 2010

SYNCHRONISING FOLLICLES DO IMPROVE RESULTS
(1) suppressing the natural increase in FSH level during the
luteofollicular transition with medicine; (2) increasing
circulatory FSH concentration with short-acting gonadotrophin-
releasing hormone agonist (GnRHa) or mini dose exogenous
gonadotrophin before initiating ovarian stimulation with
conventional dose of gonadotrophin.

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