Aboubakr Elnashar lecture

1. Ovarian stimulation
Prof. Aboubakr Elnashar
Benha university, Egypt
ABOUBAKR ELNASHAR

2. CONTENTS
1.TYPES OF OVARIAN STIMULATION
2.TYPES OF ANOVULATION
3.HYPOGONADOTROPHIC HYPOESTROGENIC,
TYPE I
4.NORMOGONADOTROPHIC NORMOESTROGENIC,
TYPE II
5.HYPERGONADOTROPHIC HYPOESTROGENIC,
TYPE III
6.HYPERPROLACTINAEMIA, TYPE IV
ABOUBAKR ELNASHAR

3. TYPES OF OVARIAN STIMULATION
Controlled
ovarian
stimulation
Super
ovulation
Induction of
ovulation
Anovulatory or ovulatoryAnovulatoryPatient
Multiple> oneOne mature
follicle
Objective
IVFIUI
Unexp inf
Example
Down regulation
Stimulation
Prevent premature
LH surge
StimulationStimulationMethod
ABOUBAKR ELNASHAR

4. TYPES OF ANOVULATION
% Type Hormonal profile
5-10%
WHO type I
(Hypogonadotropic
Hypoestrogenic)
E2
FSH
75-80%
WHO type II
Normogenadotrophic
Normoestrogenic
Normal E2
Normal FSH
10-20%
WHO type III
(Hypergonadotropic
Hypoestrogenic)
E2
FSH
5-10%
WHO type IV
(Hyperprolactinemia) prolactin
WHO Scientific group, Geneva 1976, Report 514, Rowe et al, 1993ABOUBAKR ELNASHAR

5. Amenorrhea or severe oligomenorrhea
FSH & LH: low
Prolactin: normal
I. HYPOGONADOTROPHIC
HYPOESTROGENIC
TYPE I
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6. 1. Reverse the life style factors:
Increase wt if BMI <19
When the metabolic state is normalized reflected
by a normal BMI (>20 kg/m2), a regular menstrual
cycle will be restored in the majority of patients.
(Stafford, 2005)
Moderating exercise if high levels of exercise.
Treat stress
CC:
not effective
ABOUBAKR ELNASHAR

7. 2. Gonadotrphins with LH activity or
Pulsatile GnRH (pump)
3. luteal support
hCG or progesterone from time of ovulation induction
until sufficient hCG production by trophoblast
cells is necessary.
(Beckers et al., 2006)
ABOUBAKR ELNASHAR

8. II. NORMOGONADOTROPHIC
NORMOESTROGENIC
TYPE II
PCOS
2 of 3 (Noterdam definition,2003):
•U/S PCO
•Hyperandrogenism (Clinical or Laboratory)
•Irregular or absent ovulation
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9. Life style modification
Letrozole or CC
Obese &overweight
Normal weight &No weight loss & No ovulation
Laparoscopic ovarian drilling (LOD)Gonadotropins (FSH)
No ovulation after 3 cycles.
No pregnancy after 6 cycles.
No pregnancy
after 6 cycles.
No pregnancy after spontaneous,
Clomiphene, FSH ovulation
Assisted reproductive technology (IVF/ICSI)
Other surgical indication
Difficult follow up
Less aggressive
No desire for
surgery
Add metformin
IGT &IR
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10. WHO, 2016
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11. 1.Weight reduction
 The treatment of obesity includes:
 Lifestyle modifications.
 Pharmacological treatment.
 Bariatric surgery.
1st -line therapy in obese PCOS patients seeking pregnancy.
Wt loss of 5% :restore reproductive function in PCOS.
(The Thessaloniki ESHRE/ASRM workshop, 2008)
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12. 1. Lifestyle modifications
Include:
1.Dietary modification:
2.Exercise:
3.Behavioral modification:
 Moderate-intensity aerobic activity (30 min & 5 days ).
 Vigorous-intensity aerobic activity (20 min & 3 days ).
 Resistance training (2 days).
 Hypocaloric diet (500–1,000 kcal/day reduction) .
 Rich in fiber, fruits, and vegetables.
 Calories: 50 % carbohydrates ,30 % fat and 20 % proteins.
 Correction of abnormal eating behaviors .
 Daily tracking of food intake and physical activity.
 Modify the patient’s environment to reduce stimuli leading to food
intake.
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13. 2. Pharmacological treatment
 Anti-obesity drugs (Orlistat - Sibutramine –Rimonabant )
Inhibition of gastric and pancreatic lipase .
120 mg t.d.s during or within 1 h of a fat meal.
 Mechanism of action:
 Dose:
 Comparison of orlistat with metformin:
 significant reduction in total testosterone, cholesterol and triglycerides
with orlistat, but ovulation rate was higher in metformin group.
(Ghandi et al., 2011)
Orlistat
 Fatty stool, headache, abdominal pain and back pain.
 It increases the anticoagulant effect of warfarin.
 Side effects:
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14. 3.Bariatric surgery
 Bariatric surgery includes:
 Gastric bypass.
 Sleeve gastrectomy.
 Gastric banding.
2nd -line treatment in obese PCOS (BMI ≥35 kg/m2) who are
anovulatory after lifestyle management at least for 6 months.
(Australian evidence-based guidelines for the management of PCOS)
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15. 2.Insulin sensitizers
Insulin-sensitizing drugs include:
 Biguanides (Metformin).
 Thiazolidinediones (Pioglitazone, Rosiglitazone, and Troglitazone).
Metformin
 enhances insulin sensitivity through :
 Liver: inhibition of glucose production.
 Peripheral tissue: increases glucose uptake and utilization in muscle
 Dose:
 Mechanism of action :
should not be used as 1st choice or as an adjuvant to CC.
restricted in patients with glucose intolerance.
(The Thessaloniki ESHRE/ASRM workshop, 2008)
Immediate release metformin: begin with 500 mg at dinner for 3–4 days,
and then increasing by 500 mg every 3–4 days up to a maximal dosage of
1000 mg twice daily.
Immediate release: 500, 850, and 1000 mg
Extended release: 1000 and 2000 mg
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16.  Results:
1. improved PR but there is no evidence that it improves LBR (used
alone or in combination with CC).
(Cochrane review 2012)
2.Addition of metformin to CC improved ovulation in CC resistant
patients with insulin resistance and hyperandrogenism.
(Systematic review 2006)
3.It increases pregnancy and live birth rate, and reduces the
cancellation rate in PCOS treated with Gnt for ovulation induction.
(Palomba et al., 2014)
 Side effects:
 Gastrointestinal distress
 Lactic acidosis
ABOUBAKR ELNASHAR

17. 2. Oral anti-estrogens
1. Clomiphene citrate
 binds to estrogen receptors in hypothalamus and pituitary gland:
release of hypothalamus from negative feedback effect of
estradiol: increasing production of endogenous Gnt from the
pituitary gland.
 Mechanism of action:
 Dose:
 50-150 mg for 5 days starting on 2nd to 5th day of cycle.
 Duration of Treatment:
 A course of 6 ovulatory cycles is sufficient as:
 75% of the pregnancies occur in the first 3 cycles.
 Pregnancies are rare after 6 ovulatory cycles.
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18.  Results :
 Ovulation rate: 75% and PR: 35- 40%.
 The large gap between ovulation and pregnancy is due to anti-
estrogenic effects on endometrium and cervical mucus.
 Monitoring:
Objective evidence of ovulation is key to successful treatment.
1. Urinary ovulation kits: detect midcycle LH surge.
2. TVS: sudden collapse of the preovulatory follicle: increase in cul-de-
sac fluid volume
3. Mid-luteal progesterone: 3 ng/ml.
 Failure:
 CC treatment failure is divided into two groups:
1. CC-resistance: failure of ovulation after 150 mg of CC for at least
3 cycles.
2. CC- failure: failure to achieve pregnancy after 6-12 cycles despite
ovulation.
ABOUBAKR ELNASHAR

19.  Adjuvant treatments to CC:
1. Pre-treatment with COC: in cycle before taking CC increased ovulation
rates and PR. (Cochrane review , 2009)
2. Addition of metformin: improved ovulation in CC resistant patients with
insulin resistance and hyperandrogenism. (systematic review , 2006)
3. Addition of dexamethasone: (high dose 2 mg, short course 3-12 D of
the cycle): no adverse anti-estrogenic effect on endometrium and higher
ovulation and PR. (Elnashar et al., 2006)
4. Addition of coenzyme Q10 : improves ovulation and PR .
(El Refaeey et al., 2014)
 Side effects of CC:
 Mood swings :64%
 Hot flashes: 10%
 Visual disturbances: <2%
 Less specific side effects: breast tenderness, pelvic discomfort.
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20.  Dose:
2. Tamoxifen
20–40 mg daily for 5 days .
 Results:
 Tamoxifen and CC are equally effective in inducing ovulation.
(Meta-analysis , Steiner et al., 2005)
 Combination of tamoxifen and CC improved ovulation and PR than CC
alone .
(Ghafourzadeh et al., 2004)
ABOUBAKR ELNASHAR

21.  Mechanism of action:
3. Aromatase inhibitors (AIs)
 At the central level: inhibiting of aromatase enzyme: release of
hypothalamus from the negative feedback effect of estrogen: increasing
production of endogenous Gnt from the pituitary gland.
 At the peripheral level: inhibition of aromatase enzyme: accumulation
of androgens which augment follicular FSH receptor expression and
stimulate IGF-1 which may act with FSH to promote folliculogenesis.
Aromatase inhibitors work both centrally (hypothalamus and pituitary) and
peripherally (ovaries)
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22.  Result of AIs:
 Letrozole improves live birth and PR compared to CC .
 No evidence of difference in CPR between letrozole and LOD.
 No evidence of difference in CPR between
 letrozole and anastrozole.
 5 day and 10 day of letrozole.
 5 mg and 7.5 mg of letrozole.
 No evidence of difference in OHSS rate when letrozole was compared
with placebo , CC, LOD, and anastrozole.
(Cochrane review 2014)
 Letrozole might be associated with a higher risk of congenital
cardiac and bone malformations in newborns: Not proved
(ASRM meeting, 2005)
 Safety of AIs:
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23. 4. Gonadotropins
The main reasons for use of Gnt as 2nd line:
 Lack of an oral formulation.
 Expensive
 Serious side effects (multiple pregnancy and OHSS(
 Close monitoring with ultrasound.
2nd line treatment after CC resistance/failure
(The Thessaloniki ESHRE/ASRM workshop)
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24.  Gonadotropin Preparations
• 3 main preparations: FSH, LH & HCG
• 2 types
I. Urinary
1. HMG
2. Highly purified HMG
3. Purified FSH
4. Highly purified FSH
5. Urinary HCG
II. Recombinant
1. Rec FSH
2. Rec HCG
3. Rec LH
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25. Preparation Trade name Route U.pr FSH LH Price Company
HMG Menogon,
Pergonal,
Humegon,
IM 95% 75 75 66 Ferring
Serono
Organon
H.P.HMG Merional
Menopur
SC <5% 75 75 66
118
Ferring
Purified FSH Metrodine IM <5% 75
Urofillotropin
<0.1 Serono
H.P.FSH Fostimon
Bravelle
Metrodine HP
SC,
IM
<5% 75
Urofillotropin
<0.001 55
70
Ibsa
Ferring
Serono
HCG Pregnyl
Profasi
IM 95% Organon
Serono
H.P.HCG Choriomon SC,
IM
<5% 70 Ibsa
I. Urinary Gonadotropins in Egypt
ABOUBAKR ELNASHAR

26. II. Recombinant Gonadotropins
Preparation Trade name Route U.pr FSH LH company
1. FSH Gonal-f (follitropin)
Gonal-f FbM Pen
Puregon (follitropin)
Puregon pen
SC, IM
SC, IM
SC,IM
SC, Im
-
-
-
-
75,150
300,450,900
50,100
300,600
-
-
-
-
Serono
Serono
Organon
Organon
2. HCG Ovitrelle
Choriogonadotropin
SC - Serono
3. LH Luveris
lutotropin
SC - Serono
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27. CHOICE OF GONADOTROPINS
No difference in outcome
between ovarian stimulation with hMG preparations or
urinary derived FSH, in studies using the long protocol of
GnRH desensitization.
(MA: Agrawal et al. 2000)
No significant clinical differences
between hMG and rFSH.
(Nugent et al., Cochrane Data base Syst Rev 2000; van Wely et al, 2003)
hMG, uFSH, and r-FSH:
equally effective for achieving pregnancy in PCOS.
(Al-lnany et al.,2005)
 Rec FSH make no difference to the incidence of OHSS.
The particular FSH formulation used for ovarian stimulation
does not affect the incidence of OHSS.
(SOGC, (I)
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28.  Gonadotropin regimens:
3. Conventional step-up dose:
 Start with 150 IU of hMG.
 Increase by 50% every 3-5 days until an ovarian response .
 No longer recommended in PCOS ( high OHSS).
150 225
300
450
50-75 IU
14 days 7 days
1. Chronic low dose step-up:
 Start with 50 – 75 IU/day for 14 days.
 Increase by 25–37.5 every 7 days until follicular development is observed
 Maintained until follicular selection is achieved.
 Recommended in PCOS (low OHSS).
2. Low dose step up:
 Start with 75 IU/d for 5-7 d
 Increase by 100%
 Mono-ovulation: 69%
 MP: 5.7%
 OHSS: 0.14%
(Homburg & Howles, 1999)
5 days
3 days
3 days
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29.  Monitoring:
 Serial E2 measurements.
 TVS: to reduce the risk of OHSS and multiple pregnancy.
 Risks:
 Multiple pregnancy :
depends on the number of large mature follicles.
 OHSS:
 The higher risk of OHSS in PCOS {large cohort of FSH sensitive
small antral follicles}
Cycle cancellation by withholding hCG administration and postponing
intercourse when:
 >4 follicles more than 14 mm (U.K. guidelines ), or > 3 follicles > 16 mm
 Serum E2 concentration > 2000 pg/ml (ASRM , 2008)
ABOUBAKR ELNASHAR

30. 4. Laparoscopic ovarian drilling
 Mechanism of action:
2nd line treatment in CC-resistant PCOS patients, being as effective as
Gnt treatment.
(The Thessaloniki ESHRE/ASRM workshop, 2008)
1.Opening of the subcapsular cysts: release of androgen containing
follicular fluid. ( Daniell and Miller 1989)
2.Decreased LH and increased FSH after LOD (normalization of
FSH/LH ratio).
(Gadir et al., 1992)
 Number of punctures and amount of thermal energy:
 4 punctures, each for 4 seconds at a power 40 W, delivering 640
Joules/ovary
( Armar et al., 1993 )
 Adjusted thermal dose (60 J/cm3 of ovarian tissue): better ovulation
and
PR compared with fixed-puncture dosage (600 J/ovary ).
(Zakherah et al., 2011) ABOUBAKR ELNASHAR

31.  Efficacy :
 Ovulation rate: 30 to 90 %
 PR: 50 to 80 % within 1 year.
 Unilateral vs bilateral drilling:
 ULOD is effective as BLOD .
 ULOD: decreasing adhesion.
(Roy et al., 2009)
 Prediction of success:
 Marked obesity ,marked hyperandrogenism and/or longer duration
of infertility: resistant to LOD.
 LH levels >10 IU/L: higher pregnancy rates.
(Amer et al., 2004 )
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32.  Comparison of LOD with other ovulatory drugs:
 No evidence of a difference in rates of LBR ,CPR, or
miscarriage rate between LOD and other medical treatments.
 LBR is low after LOD when compared with CC+ metformin.
 A significant reduction in multiple PR after LOD.
(Cochrane review 2012)
 Complications
1.Intra-operative:
Avulsion of utero-ovarian ligament-Bleeding from punctures
2.Long-term:
 Adhesion formation: high and their extent was not affected by the
number of punctures.
(Mercorio et al .2008)
 Decreased ovarian reserve: No evidence
Most of the changes in the ovarian reserve markers are due to
normalization of ovarian function rather than reduction of
ovarian reserve.
(Api , 2009)
ABOUBAKR ELNASHAR

33. III. HYPERGONADOTROPHIC
HYPOESTROGENIC
Type III
< 40 yr, 2ndry amenorrhea
Repeated FSH > 20 IU/L
Causes
1. Idiopathic.
2. Genetic.
3. Autoimmune
3. Viral/bacterial infection
4. Pelvic surgery, chemotherapy
5. Galactosemia
ABOUBAKR ELNASHAR

34. 1. Oral contraceptive suppression of gonadotrpins
followed by discontinuation
to allow a rebound in gonadotropins & ovarian
function.
2. GnRHa suppression of gonadotropins secretion
followed by high dose gonadotropin injection
3. Glucocorticoids suppression of immune system.
Non of these tts has demonstrated efficacy in RCT
ABOUBAKR ELNASHAR

35. IV. HYPERPROLACTINAEMIA
Type IV
I. Idiopathic
Dopamine agonist (anxiety, pregnancy).
Stop during pregnancy
II. Microadenoma
Dopamine agonist (anxiety, pregnancy).
Stop after 2-3 yr.
Surgery (rapid growth).
III. Macroadenoma
Dopamine agonist: long term
Surgery
(No response, suprasellar extension, pregnancy).ABOUBAKR ELNASHAR

36. In order to induce fertility
1. Maintain the effective PRL lowering dose for
10–12 months
{it takes time to reestablish ovulatory cycles and half of the pregnancies
occur after the first 6 months of therapy}.
2. Monitor ovulation by measurements of plasma
progesterone.
3. If ovulation does not occur despite the
normalized PRL: CC .
ABOUBAKR ELNASHAR

37. Dopaminergic treatments
1st choice tt for both
idiopathic hyperprolactinemia
prolactinomas.
Dopamine receptors:
D1 and D2 subtypes
Binding of dopamine agonists to dopamine D2
receptors on the surface of lactotrophs: reduces adenyl
cyclase activity and inhibits prolactin secretion.
 3 dopamine agonist
ABOUBAKR ELNASHAR

38. Crosignani et al, 2012
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Parlodel
lactodel
Bromocriptin
Dostinox
Cabergoumoun
Cabergolin
Norplac75 ugmQuinagolide
DoperginLisuride

39. You can get this lecture from:
1.My scientific page on Face book:
Aboubakr Elnashar Lectures.
https://www.facebook.com/groups/2
27744884091351/
2.Slide share web site
3.elnashar53@hotmail.com
4.My clinic althwara st. mansura
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