Presentation given in Tirupati, India in 2018 on Ovulation Induction for assisted reproductive technologies. Dealing with infertility using Intra uterine insemination (IUI) and In vitro fertilization (IVF)

1. OVULATION
INDUCTION
Optimal
protocols
Dr. K. Anuradha,
F.R.C.O.G.

2. Ovulation Induction
Causes of anovulation
Treatment Choices
To arrive at algorithms
Goals & Objectives

3. Infertility
Highly prevalent, 15 % of reproductive age couples.
World: 60-80 million couples

4. After 12 months of regular inter course
After 6 months over 35 yrs. age.
What Is The Right Time

5. Ovulatory
dysfunction
Uterine
Male factor
Unexplained
Tubal
Infertility Diagnosis
Based on Etiology

6. Basic
Evaluation
Thorough
History
Uterus &
Fallopian
tubes
SEMEN
ANALYSIS
Ov.
Reserve &
Ovulation

7. ‘ Anovulation contributes
infertility in one-quarter of
couples ’

8. Ovulation Induction
• etiological diagnosis
– Right patient
– Right treatment
– Whether or not IUI is needed
• Most anovulatory patients –
Ideal candidates for OI

9. Treatment Options
 Certain types of Infertility
– Severe male factor ART
– Complete tubal obstruction
– Hypergonadotropic anovulation
 Most types (initially)
– Ov. Disorders – 27 % OI
– Mild male factor– 25 % OI + IUI
– Unexplained infertility – 17 %

10. Folliculogenesis
Unknown
factor
± 3 months 14 days
Recruitement Selection Dominance
Menses OVULATION
Hypophysal gonadotrophins
2-4 days
Ovulation Induction
Resting phase

11. Folliculogenesis
D-3 D5 D6 D8 D9 D14
Recruitement Selection Dominance
FSH -
FSH +
FSH -
Ovulation Induction
‘Gate Mehanism’ ‘Mature by chance’

12. Process Of Ovulation
‘LH surge’
maturation
Luteinisation
Ovulation

13. Indications:-
• To stimulate ovulation in anovulatory infertility
• To augment ovulation in ovulatory infertility
• To stimulate production of several mature follicles
(cos) in conjunction with ART
Ovarian Stimulation

14. Duration of FSH secretion
limited by negative feedback
from estrogen produced by
larger follicles
Smaller follicles with fewer
FSH receptors no longer
stimulated to grow by
decreasing FSH levels
undergo atresia
Therefore a single follicle
reaches maturation stage
FSH
estrogen
atresia
mature follicle
Mono follicular
ovulation
negative feedback
reduced stimulation
Single follicle development in natural cycles
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

15. Duration of FSH
secretion increased
by exogenous FSH
injections
Smaller follicles
stimulated to grow by
continued FSH
support
Multiple follicles
develop to mature
state
Increased risk of
hyperstimulation &
multiple pregnancies
Exogenous FSH
Estrogen feedback does not
work with exogenous FSH
More smaller follicles
are rescued
Multiple follicle develop
stimulation continues
 Risk of hyperstimulation
& multiple pregnancies
Multiple follicle development in
ART cycles
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

16. Strategies to improve outcome
(sequential steps)
I II III IV
Select
&
prepare
Optimize
Ov. Stim.
protocols
Adjuvant
medical
therapies
Management
Of luteal
phase
Age
&
duration
Cause
- endometriosis
- tubal dysfunction
Life style factors
- concurrent
medical conditions

18. PAO
Normal Decline 25000
Accelerated
Decline
Early
Menopause
• 37 – 38 yrs –
25,000 follicles
• 51 yrs –
menopause, 1000
follicles
Accelerated
decline in
fertility at
age
• Approx
13.5yrs
Time period
between
accelerated
decline in fertility
is fixed at
Normal Decline
25000
Accelerated
Decline
Early
Menopause

19. Ovarian Reserve Markers
• AMH
 3 – 5 ng/ml (normal)
 More reliable
 No cyclical variation
• AFC
 > 5 – 2-6 mm follicles
 Good predictor,
 cost effective
• FSH
 > 10 m IU / ml - low
reserve
 Less reliable
 Rise when Function deeply
compromised

20.  ART required in tubal problems and poor semen quality
 Best results obtained by timely release of mature ovum
 Extensive Counselling
 Side effects, risks
 Expenses
 Logistics of Treatment and
 Prognosis
Points To Remember

21. Anovulatory Infertility
• MH
• Age of menarche
• Frequency of I.C.
• Medical, surgical, drug history
• BMI – (kg / m²)
HISTORY &
EXAMINATION
INVESTIGATIONS
• FSH, LH (N – 5-10 mIu/ml)
• Estradiol (20-400 pg/ml)
• Prolactin (1-20 ng/ml)
• TSH
• Testosterone / SHBG
• Midluteal progesterone
• Rubella immunity
• Pelvic ultrasound
• Tubal patency test
• Semen Analysis

22. WHO Classification
Group I
(5 – 10%)
Hypogonado-
trophic
Hypogonadism
(Hypothalamic
pit. Failure)
Group II
(75 – 85%)
Hypothalamic-
Pituitary
dysfunction
Group III
(10 – 20%)
Hypergonado-
trophic
anovulation
Group IV
(5 – 10 %)
Hyper-
prolactinaemic
anovulation
Usually caused by
microadenoma
FSH/LH
production
FSH / LH / E2 FSH - N
LH / E2
FSH / LH
E2
PRL

23. Group – I (5 – 10 %)
Hypogonadotrophic Hypogonadism (Hypothalamic pit. Failure)
Selective failure of pit. – to produce FSH & LH
• prim. or sec.
amenorrhoea
• neg. prog.
Challenge
• FSH / E2
Causes
Absent / abnormal
Hypothalamic GnRH sec.
Pit. Insensitive to GnRH
Physical,
Nutritional
or
Emotional
stress
Wt. loss
Kallman
syndrome
Sheehan’s
syndrome
Isolated
Gonado-
trophin
deficiency
• excessive
exercise
• anorexia
nervosa
May need
Hypothalamic-pit.
Imaging-to exclude
Mass lesion

24. Management – hypothalamic-pit. failure
Correction of
• underwt.
• malnutrition &
• exercise
Pulsatile GnRH
(pit. Failure sec.
to hypothalamic
dysfunction)
Gonadotrophins
(primary pit. Failure)
• pure FSH –
not indicated
• antiestrogens
not effective
Group I

25. WHO group - III
Hypergonadotrophic hypogonadism
• Indicates
POF < 40 yrs
• End-organ
deficiency
• Neg. prog.
challenge
• FSH / AMH
& E2
• ov. Induction-
not indicated
• long term HRT
Genetic abnormalities
• turner’s syndrome (45 XO)
commonest
• translocations & deletions
of X chromosome
• Androgen insensitivity
syndrome-46XY
with intrabdominal
gonads
- surgical removal
Oocyte donation
- realistic treat.

26. WHO group - IV
Hyperprolactinaemic anovulation (5-10 %)
Inhibits
Gonadotrophin
Secretion
• low / low normal
FSH & E2
• Commonest presentation
sec.amenorrhoea
• may have oligomenorrhoea,
Galactorrhoea,
• headaches, disturbed vision-
may indicate macroadenoma
Etiology
• pit.prolactin
secreting
adenoma
• primary
hypothyroidism
• drugs
30% of women with irregular cycles
Prolactin
Levels
• euestrogenic
women –
30 – 40 ng/ml
• hypoestrogenic -
20 – 25 ng/ml

27. Hyperprolactinaemia - management
Etiology
Hypothalamic
pituitary imaging –
to exclude
mass lesion
Dopamine
agonists
• Bromocriptine –
2.5 mg/d
• other drugs
- Lisuride
- Pergolide
• cabergoline
(long acting)
Results
• normalizes
prl levels
- 60 – 85 %
• Cyclic menses
- 70 – 90 %
• ovulatory cycles
- 50 – 75 %
These drugs are given in combination with Anti-estrogens,
Gonadotrophins or pulsatile GnRH.

28. WHO gp.II - Hypothalamic pit.dysfunction
(Eugonadotrophic Euestrogenic anovulation)
• Largest gp – 75 – 85%
• Prog. Challenge test +ve
• S. FSH/E2 – normal
• LH – normal or elevated
• 90% women – PCO
• Most common endocrinopathy
• 5 – 10% of fertile age women
• Irregular cycles
• clinical / biochemical
hyperandrogenism
U/S – PCO
• 12 ≥ follicles (2-9 mm. diam.)
• Ov. Volume > 10 cm³

29. PCOS-spectrum of clinical
manifestations
SYMPTOMS
• Hyperandrogenism
(hirsutism, acne,
alopecia)
• Infertility
• Obesity
POSSIBLE LATE SEQUELAE
• Type II diabetes
mellitus
• Dyslipidaemia
• Hypertension
• Cardiovascular disease
• Endometrial
carcinoma

31. Definition Of Pcos
• Much debated
• Refined definition of PCOS by
‘The Rotterdam, ESHRE / ASRM PCOS
consensus work shop group, 2004’
Presence of 2 out of 3 criteria :
i. Oligo and or anovulation
ii. Hyperandrogenism (clinical, Biochemical)
iii. Polycystic ovaries
 Ovary with 12 or more follicles
 Measuring 2-9 mm. diam.
 & / or increased ovarian volume > 10 cm³

34. PCOS - Serum Endocrinology
• LH / Testosterone / Androstenedione
• or normal FSH
• Normal or high E2
• or normal fasting insulin

36. PCOS – Main features
• Hyperandrogenism
• Hyperinsulinism
• Driven by LH
Slim PCO
• By insulin, which acts as ‘co-
Gonadotrophin’ &
• Amplifies effect of LH
Obese PCO

37. Insulin resistance - PCO
• common feature in –
Obese & to a lesser extent in lean PCO
• Overall prevalence 50 – 75 %
• PCOS
– 35 % exhibit impaired glucose tolerance
(140-199 mg/d1)
– 7-10 % meet criteria for type II diabetes
mellitus (≥ 200 mg/d1)

39. PCOS – menstrual problems
• Likely to benefit from cyclical hormone therapy
– In unpredictable, irregular and heavy bleeding
• ed risk of endometrial hyperplasia and adeno
ca.-
– Risk factors – obesity,
long term unopposed est.,
nulliparity and
infertility
• Important to shed endometrium
at least every 3 months.

40. Supra-physiologic
synthesis of estrogen
Strong negative
feedback signals to
hypothalamus &
pituitary
Low GnRH
production, with +ve
feedback on LH
Low FSH & high LH
No ovulation
Hypothalamus/Pituita
ry
Strong estrogen -ve
feedback
Low FSH
Follicle does not
develop
Low GnRH
Anovulation
Very high levels of
estrogen
High LH
1
2
3
4
5
6
Anovulation in PCOS patients
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

41. WHO group II – management
Life style
changes
• 50% PCOS - ≥ 30 BMI
• Loss of 5% body wt.
- 30% reduction in
visceral fat.
oral anti-
estrogens
injectable
gonadotrophins
laparoscopic
ov. drilling

42. Principles of O.I
Life Style Changes
• Fertility adversely affected by an individual
being overweight,
hyperandrogenism and
elevated serum LH
• Optimize health before OI
induce regular unifollicular ovulation,
minimize risk of OHSS and
multiple pregnancy

43. Life Style Management
• Weight reduction ‘first-best’ treatment
• Weight loss or prevention of weight gain
recommended (diet, exercise and
behavioral interventions)
• Should be the ‘first–line therapy’ for 3–6 m.,
arbitrarily aiming for a 5-7 % weight
reduction

44. Bariatric Surgery
• In women with BMI > 35 kg/m² after failed
attempts at weight loss for >than 1 yr.
• Risks of surgery and p-o nutritional
deficiencies to be informed
• Pregnancy to be avoided for at least 6-12 m.
after surgery

45. Normogonadotropic normogonadism –
medical treatment
oral anti-
estrogens
• CC
• Tamoxifen
insulin
sensitizing
agents
• metformin
Aromatase
inhibitors
• letrozole
• anastrazole
injectable
gonadotrophins
alone
With GnRH-a,
GnRH-ant.

46. Aromatase Inhibitors
• Letrozole – (2.5 – 7.5 mg/d)
• Anastrazole – (1mg/bd)
• 3rd generation AI
• Non-steroidal, potent and
selective

47.  Ovaries
 Brain
 Adipose tissue
 Muscle
 Liver
 Breast tissue
 Malignant breast
cancers
Androstenedione
Testosterone
Estrogen
Estradiol
Aromatase
Role of aromatase enzyme
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771

48. Inhibits aromatase in ovaries &
peripheral tissues reducing
estrogen levels
Negative feed back being active
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
-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
Letrozole: Mechanism of action
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

49.  Rapid clearance of drug from body
 Reversible aromatase inhibition
 Elevated FSH supports more
aromatase synthesis
androstenedion
e
 estrogen
aromatas
e
Will it affect oocyte and
pregnancy results?
 androstenedione
Will limit androgen accumulation in
ovaries
Estrogen production should be
relatively normal at time of
ovulation
increased
follicular
sensitivity to FSH
Testosterone
augments FSH
receptors in
follicle
Testosterone
augments IGF in
follicle

folliculogenesis
Would low estrogen/high androgen levels
be harmful?
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

50. Prescribing information; Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771; Harriet et al. Drugs 1998; 56(6):1125-1140;
Bhatnagar AS. Breast Cancer Res Treat 2007;105:7–17
Letrozole: Pharmacokinetics
Parameter Data
Absorption Rapid & complete (Cmax within 1 h)
Bioavailability 99.9%
Food Absorption not affected by food
Metabolism Inactive metabolite, by CYP 2A6 & 3A4
Elimination T1/2 ~2 days (45 h)
Excretion Renal (90%), rapid clearance, no
accumulation
Safety Well tolerated
Letrozole: Pharmacokinetics

51. Advantages of AI over CC
–Does not deplete ERS throughout the body
–Keeps H-P axis intact
–Short acting
• Improved endometrial thickness and cervical
mucus
• Monofollicular and better folliculogenesis

52. Current evidence supporting ‘Letrozole’
for ovulation induction
The need for an alternative to CC for ovulation induction was
realised since 1990.
Robert casper and mohamed F-M mitally proposed
concept of aromatase inhibitors as an alternative
to O.I.
A pilot study was initiated to test Letrozole for O.I in
women with CC failure, 2001.
An oral abstract in 2005, reported congenital anomalies in
150 babies born from infertile women with
Letrozole
since then large studies with better design have
been published comparing safety of Letrozole &
CC in infertile group
Available medical data shows that Letrozole is at least as
effective as CC

53. Legro RS, et al. N Engl J Med. 2014 Jul 10;371(2):119-29.
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., and Heping Zhang, Ph.D., for the NICHD Reproductive Medicine Network*
2012-2017
Recent Clinical Evidence
Conclusions
LTZ was associated with higher live-birth & ovulation rates
LTZ was superior to CC as a treatment for anovulatory infertility
in women with PCOS

54. Latest evidence...2017!
Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.

55. LTZ
stimulation
Reduces risk of
miscarriage
No increase in risk of
Major congenital
anomalies
Adverse pregnancy
outcomes
Adverse neonatal
outcomes
Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.
Conclusions
Safer option for mild
ovarian stimulation

56. Society Year Recommendation
American College
of Obstetricians
and
Gynaecologists
2016 LTZ should be considered as 1st-line therapy for OI in patients
with PCOS & BMI > 30 because of increased LBR compared to
CC
WHO guideline 2016 CC or LTZ (when available & permissible) should be 1st line
pharmacological therapy to improve fertility outcomes in
women with PCOS & anovulatory infertility, with no other
infertility factors
Australian
National Health
and Medical
Research Council
(NHMRC)
guideline
2015 LTZ, under caution, could be offered as pharmacological
treatment for OI indicated for infertile anovulatory women
with PCOS with no other infertility factors
-Considered as 1st line pharmacological treatment for OI in
therapy naive, infertile anovulatory women with PCOS with
no other infertility factors
AACE/ACE/Androg
en Excess and
PCOS Society
Disease State
Clinical Review
2015 Treatment for women with PCOS & anovulatory infertility
should begin with oral agent such as CC or LTZ
Guidelines

57. Advantages of letrozole over CC
Parameters Clomiphene citrate Letrozole
MOA SERM Aromatase inhibitor
Half-life Long, 5-7 days Short, 45 h
Anti-estrogenic
effects
Thin endometrium &
altered cervical mucus
Thick endometrium &
favourable cervical
mucus
Uterine blood flow Decreased Increased
Miscarriages Possibly high Less incidence
OHSS risk High Low
Multiple pregnancy High Low
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

58. Aromatase inhibitors
- Endometriosis & adenomyosis
- Uterine fibroids
- Endometrial stromal sarcoma
‘most benefit’
E2 dependent disorders
- Endometriosis
- Breast ca.
- Inherent clotting
abnormality
Luteal phase aromatase inhibitors
- drastically reduces E2 levels
- potential use in egg donors and in high risk of OHSS

59. Oral antiestrogens
CC
Selective estrogen
receptor modulator
(SERM)
Tamoxifen
Mild antiestrogenic
Estrogen Agonist
Reduced negative
est. feed back
Alters GnRH sec.
pattern
Antagonist less desirable peripheral action
thinnning of endomet. & cx mucus
Ov. Women - pulse frequently
PCO – pulse amptitude
pituitary gonadotrophins
ovulation
20 – 40 mg/d • CC resistants
• side effects to CC

60. CC – Non – steroidal triphenyl ethylene
derivative (2-isomers)
En –CC (62%)
• more potent
• relatively short ½ life
Zu – clomiphene (38%)
• clears slowly
• may accumulate gradually
over a series of cycles

61. CC
Dosage
• orally – 25 -100 mg/d
3rd – 7th day
if responds -
ov. occurs with in 5-7 d
of last CC tab.
• extended CC regimen
7 – 10 days
• ‘stair-step protocol’
side effects
• vasomotor disturbances
• visual – 1-2% reversible
• Alopecia
• Ov. enlargement
• U/s before each
new CC cycle

62. CC
Risks
• multiple pregnancy
• approx – 7-10%
• treat with lowest
effective dose
• OHSS – small risk
• Ov. Ca
• ed risk with > 12 cycles
• to recommend for –
no more than 6 cycles
Results
• induces ovulation
- 70 – 85%
• cumulative preg. Rate (6 m)
- 40 – 60%

63.  CC resistant:
If patient fails to ovulate despite 6 CC cycles
 CC failure: CC-resistant plus women who
ovulate, but do not get pregnant or get
pregnant but end in miscarriage
 About 20-25% of anovulatory women are CC-
resistant*
Clomiphene resistant / failure
Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9. *Azargoon A, et al. Iran J Reprod Med. 2012 Jan; 10(1): 33–40.

64. Management of CC-resistant PCOS
Obese women
Lifestyle modifications
=weight loss (Diet +
Exercise): If BMI> 29
kg/m2
Non-obese
women
Metformin + CC (3-6
cycles)
Letrozole (3-6 cycles)
LOD
Gonadotropins
In vitro
fertilization
Failure
Hashim HA (2012). Management of Women with Clomifene Citrate Resistant Polycystic Ovary Syndrome – An Evidence Based Approach,
Polycystic Ovary Syndrome, Dr. Mukherjee S. (Ed.), InTech. LOD: Laparoscopic ovarian drilling.

65. Insulin Sensitizing Agents
PCOS
Increased insulin resistance Hyperinsulineamia
- 80% obese
- 20% normal wt. PCOS
LH / Ov. Androgens Hyperandrogeneamia
Follicular atresia

66. • 500 – 2,500 mg/d
- side effects -
G1 symptoms
• ‘caution’
- renal & Hepatic function
- undergoing surgery
- with IV contrast administration
• Metformin + CC combination
better than metformin alone
Indications
• PCOS – resistant to CC
• BMI > 25
• Associated glucose
intolerance
Metformin – widely used
Insulin - Sensitizers

67. Metformin - recommendations
i. ‘Could’ be used alone to improve ovulation
rate and PR in PCOS who are anovulatory
with no other infertility factors, or if facilities
are not available for monitoring of CC or Let,
which are more effective.
ii. Can be combined with CC to improve fertility
outcomes

68. Adjuvant & Combination Treatments
– Glucocorticoids
Follicular phase (D 5-14)
» Predn. 5mg/d or
» Dexamethasone 0.5-2mg/d
– Exogenous HCG
– Metformin
– Deserve consideration
who prove CC resistant
– Before proceeding to ov. Drilling or
treatment with gonadotrophin
– Preliminary suppression; contraceptives

69. Laparoscopic ov. drilling
alternate for
CC resistant PCOS
success rates
comparable with FSH
• risks of surgery / anaesthesia
• adhesion formation
• potential risk of POF
in the future
Favourable
responders
• slim women
• LH > 10 IU/L

71. Contra indications
• Ovarian failure
• untreated Hyperprolactinaemia
• uncontrolled thyroid, adrenal function
• Pituitary tumours
• Ov. Cysts
• Lack of appropriate monitoring, patient
cooperation or trained personnel
2nd line treatment for O.I
Gonadotrophin therapy
Indications
• Hypothalamic pituitary
dysfunction
• Hypogonadtropic
hypogonadism
• CC failures
• ART

72. Gonadotrophins
Increase the no. of follicles recruited
into the growing pool
+
Maintaines their growth until
the stage of ovulation
One or more oocytes are available for
fertilisation

73. Mechanism Of Increased Ovulation
Rate
 Rescuing of follicles undergoing
early atresia
 Recruitment of smaller healthy
follicles
 Reduced follicular atresia

74. Different Gonadotropin prep.
FSH LH
activity content activity content
hMG 75 IU 75 IU
pFSH 75 IU 1 IU
HP FSH 75 IU < 0.1 IU
Recombinant
r-hFSH follitropin-a 75 IU 0
r-hFSH follitropin-b 50-100 IU 0
r-hLH 0 75
Corifollitropin α
r-hCG

75. ‘Which preparation to use’
Recombinant drugs
•  allergic reactions
•  potential risk of
infection
• High specific activity:
less acid isoforms
• Sub-cutaneous
administration
• HMG, purified urinary
FSH & recombinant FSH
- equally effective
• choice depends on
• availability
• user’s convenience
• cost

76. Dilemmas Are :
Consider –
• Wt.
• AFC / PCO
• Previous
responses
What
dosage
5th, 6th & 7th day
7th & 8th day
3rd & 8th day
5th & 7th day
(alt.days)!
When
to start
No set
protocols

77. Pool of recruitable follicles
Follicular response to FSH
Genetic polymorphisms
FSH bioavailability
BMI
DOSE DECISION

78. ‘Which Gonadotrophin To Use’
• FSH – represents
‘primum movens’
of follicle growth
• LH – autonomously
& in synergy with
FSH to
Stimulate support
foll. development
& function
• HMG – Hypogonadotropic
hypogonadism
• FSH – for PCOS
• CC + FSH / HMG – preferably
Regimens
step step combined
up down
• Ovulation trigger
• Luteal support
HCG
GnRH-a

79. Low dose Step-up regimen
• allow the FSH threshold to be reached
gradually,minimizing excessive stimulation
and hence decreasing the risk of
multifollicularresponse
• monofollicularg rowth reported in 69% of
cycles(Hombury& Howles, 1995)
• recommend in PCOS patients who have tendency
for over-response during ovarian stimulation

81. Low dose Step-down regimen
• Induction ovulation protocol which mimic more
closely the FSH threshold and window of the
natural cycle
• Another approach for PCOS patients with
monofollicular growth reported in 56 % of
cycles (van sant brink et al, 1995)
• So far, results compared with step-up approach
are conflicting but some suggestions of
shorter duration of treatment and smaller
conception of gonadotrophin, but lower
monofollicular growth and higher
hyperstimulation rate

83. ‘Low-Slow treatment regimens’
• Expense and frustration associated with
canceled cycles usually can be
avoided by;
(involving low doses 37.5 – 75 IU/d)
–Small increments & a longer duration
of treatment
• Most gonadotrophin stimulations span
an interval of 7 – 12 days

84. Cycle Cancellation
OVARIAN OVER- RESPONSE
• Cycle abandoned because of the risk of high multiple
pregnancy
• HCG should be withdrawn and patient should be advised
not to have intercourse
POOR OVARIAN RESPONSE
• Low responders usually encountered in patients with
high basal FSH or patients with characteristics of
more severe PCOS (eg : obesity, hyperandrogenism)
PREMATURE LH SURGE
• Adjuvant use of OC pretreatment or down regulation by
regulation by GnRH before ovarian stimulation
may be considered in subsequent cycle

85. Ovulation Induction – GnRH analogues
+ HMG
(agonists / antagonists)
 As a routine in most IVF centres
 Severe PCOS
 Poor responders to HMG
 Premature LH surges

86. GnRH-agonist & Antagonist
Regimen
A go n i s t
A n t a go n i s t

88. GnRH – analogues &
Gonadotrophins
 in Hyperstimulation rate
 Risk of multiple pregnancy
 Higher cost
 Routine use not justified

89. COMPLICATIONS
 Multiple Pregnancy
 Increased incidence of
heterotopic pregnancies
 OHSS
Gonadotrophin Therapy

90. Ectopic & Heterotopic Pregnancies
• Incidence of ectopic – 1.5 - 2 %
 With Ovulation Induction - 3 %
 With ART - 5 %
• Incidence of Heterotopic Pregnancies – 1 in
30,000
 With Ovulation Induction & ART – 1 %
• Surgical treatment – viable option
 1/3rd spontaneous miscarriages
• A high index of suspicion required

91. Ovarian Hyperstimulation
 Iatrogenic condition ‘epidemic’ caused
by doctors
 Incidence of mod. & severe
OHSS ranges from 0.1 – 4%
 Condition can not be completely
avoided

92.  Mild OHSS is seen 3 - 20% and
severe form in 0.4 - 4%
 Increased risk in younger women
and PCO
 PCO highly sensitive to
Gonadotrophins
OHSS

93. OHSS
‘ Loss of control over COH ’
 Only after overstimulated ovaries
‘ exposed to hCG inj ’
C U L P R I T
HMG HCG

94. AN OHSS – FREE CLINIC
Segmentation –
of –
IVF treatment

95. Segmentation of IVF
OHSS can be ‘erased’ by applying ovarian
stimulation using a combination of
GnRH-antagonist with
GnRH-agonist trigger
- freeze all

96. Gonadotrophin - Risks
OHSS
Mild severe
3-2% 0.4-4%
• strictly speaking – OHSS
can not be prevented
• Adopt low dose regimens
• cycle cancellation
• GnRH–ant. protocols
• cabergoline 0.5 mg/d
- 8 d. from HCG
• GnRH-a triggering
• Luteal support – prog.
High order
Multiple preg.
Ways to aggressive
reduce cancellation
policy
• monovulatory cycles
• normogonadotrophic
• diet & exercise
• insulin sensitizing
agents
• LOD
Heterotopic preg.
• ectopic preg – 1.5 – 2%
- with O.I – 3%
• Heterotopic preg.
- with O.I & ART– 1%

97. Gonadotrophins – strong recommendations
‘could’ be second-line pharmacological
therapy in PCOS with CC resistance and /
or failure
Where appropriate to use gonadotrophins –
provide low dose protocol and appropriate
monitoring –
to minimize risk of multiple pregnancy

98. Gonadotrophins – points to be considered
i. Cost of intervention
ii. Expertise required for use of intervention
iii. Degree of intensive monitoring required
iv. Implications of multiple preg & risk of OHSS
v. The most ‘cost-effective’ gonadotrophin should
be used –
no significant difference in effectiveness
between preparations

99. Ovulation Induction - IUI
Associated male factor
Failure to conceive despite
successful O.I

100. ART / IVF - When
Anovulation – not an indication
Failed 1st & 2nd line treatment
With associated pathology –
Tubal damage
Severe endometriosis
PGD
Male factor
Low ovarian reserve

101. PCOS / IVF – Strong recommendations
i. Increased risk of OHSS; needs careful
monitoring
ii. GnRH-ant. protocol safer to reduce risk of
OHSS
iii. If a long GnRH-a protocol used; addition of
metformin reduces risk of OHSS
iv. Insufficient data to recommend IVM for
anovulatory PCOS

102. Ovulation Induction – Effective Approaches
1. Antiestrogens (with clomiphene)
ovulation – 77 %
Pregnancy – 47 %
Singleton birth rate – 47 %
Multiple live births – 2 %
2. FSH / HMG Induction
Ovulation – 82 %
Pregnancy rate – 56 %
Single birth rate – 43 %
Multiple birth rate – 5 %
3. Remaining group
IVF – 40 % Live birth rate after max. 3 cycles

103. Fertility Treatment – “Futile”
• ASRM defines – “Futile”
when prognosis for desired end ≤ 1 %
• Women at all Ages
with FSH 10 – 15 mIU/ml &
E2 ≥ 40 pg/ml
- unlikely to achieve live birth
after COH - IUI
• Forty & Over
- immediate IVF

104. Questions & Concerns
 Factors determining recruitment
& Selection not defined
 Recruited follicles are also
Susceptible to atresia
 Follicle selection does not
gaurantee ovulation

105. Congenital anomalies
I. CC
• NTD
• Hypospadias
II. OI / IUI
Higher risk with
i. Increasing intensity of treatment
ii. Severity of parental reproductive
morbidity
III. ART
crude total malformation rate –
8.3 % vs 5.8 in background
population

106. Ovarian Cancer
 Persistent Stimulation may increase mitotic
activity of granulosa cells might have
carcinogenic effect
 Increased risk of Border line and invasive tumours
(Mosagard et al,1997)
 Prolonged use of CC may increase risk
 However evidence is unclear and requires prospective
studies

107. Difficult Situations In
Ovarian Stimulation
 Ovarian deficiency
 Obesity
 Polycystic ovaries
 Endometriosis

108. Patients At Risk Of Ov. Deficiency
 Age
 History of ov. Surgery
 Short cycles
 High FSH
 Prior insufficient response
 Severe endometriosis
 Smoking
 Pelvic Infection
 Strong F/H of early menopause

109. Whist women with PCOS
may take longer to become
pregnant their life time
fertility is not impaired
(koivunen et al’, 2008)
May display sustained
fertility with advancing age
as compared with infertile
ovulatory women
(Mellembakken et al, 2011)

110. Diagnosis Of Cause Of Anovulation
Amenorrhoea
Progestogen challenge test
( MPA 20mg x 5days )
Bleeding
+ve -ve
Chronic anovulation E-P challenge test
eg. PCOS
+ve -ve
Gonadotropin assay End organ fault
Pregnancy
>40 mIU / ml < 5 mIU / ml
Ovarian failure Hypogonadotropism

111. Flowchart of diagnosis and treatment
History and examination
FSH and prolactin
prolactin
Pituitary imaging
TSH
Dopamine agonists
Rarely surgery
FSH
Karyotype
Autoantibody
Donor eggs
Normal FSH
Body weight
Pelvic scan
Weight reduction
Anti-oestrogen / letrozole
Insulin sensitizing agents
Gonadotrophins
Ovarian drilling
FSH
Body Weight
Pituitary imaging
Weight gain
Pulsatile GnRH
Gonadotrohpin
Hyperprolactinaemia
Hypergonadotrophic
Hypogonadism
Hypogonadotrophic
Hypogonadism
Normogonadotrophic anovulation

115. Conclusion
 Prescribe only if necessary
 Imitate Physiology as much as possible
 Analyse results carefully
 To consider multiple pregnancies as failure
 Consider newer techniques to increase success
rates and reduce risks

116. Dr. K. Anuradha,
F.R.C.O.G.