OVULATION
INDUCTION
Professor Homburg is an obstetrician and
gynaecologist who specialises in reproductive
medicine.
He has held posts as Professor of Obstetrics and
Gynaecology at Tel Aviv University Medical
School, as Professor of Reproductive Medicine
at the Free University Medical Centre in
Amsterdam, The Netherlands and, presently, as
Professor of Reproductive Medicine at Queen
Mary, University of London.
Professor Homburg now consults in both the UK, as Head
of Research at the Homerton Fertility Centre, Homerton
University Hospital in London, at the Hewitt Fertility
Centre at the Liverpool Womens Hospital and in Malta, as
an advisor to the Ministry of Health.
As a fertility specialist, Professor Homburg has a worldwide reputation
having published 200 research articles and chapters in books and has
written or edited seven books.
He has been invited to lecture in all five continents at frequent intervals
and has won prizes for his research at the British Fertility Society (twice),
the American Society of Reproductive Medicine, the European Society of
Human Reproduction and Embryology (ESHRE) and the Israel Fertility
Society (3 times).
He has served as an associate editor for Human Reproduction and
presently for Human Reproduction Update.
Professor Homburg’s main
interests and speciality are the
treatment of infertility in
general, polycystic ovary
syndrome, ovulation induction,
ovarian stimulation and IVF.
Age, occupation, previous pregnancies
Duration of infertility
Medical history, alcohol, drugs
Family history
Contraception, treatment of infertility
Menarche, cycle regularity
Menstrual loss/pain/LMP
Hirsutism, acne, galactorrhea
Sexual activity/problems
Body build
Weight, height, BMI
General physical examination
Distribution of hair growth/hirsutism
Breasts, galactorrhea
Acne
Gynaecological examination
Anovulation
prolactin normal
high Prog test No bleeding
bleeding
HYPER- Combined No bleeding
PROLACTINEMIA pill
bleeding OUTFLOW
TRACT
HYPOTHALAMIC DEFECT
-PITUITARY FSH
DYSFUNCTION
low high
HYPOTHALAMIC OVARIAN
PITUITARY FAILURE
FAILURE
CLASSIFICATION OF
AMENORRHEA
I Hypothalamic-pituitary failure
II Hypothalamic pituitary dysfunction
III Ovarian failure
IV Hyperprolactinemia
V Outflow tract defect
PRAGMATIC PROTOCOL
History, examination
Beta-hCG
FSH, LH
E2, prog
Prolactin
Testosterone
U/S
OVULATION INDUCTION
FOR WHO GROUP I:
HYPOGONADOTROPHIC
HYPOGONADISM
Pulsatile GnRH
Gonadotrophin stimulation
WHO GROUP I (HYPOG-HYPOG)
- HMG VS FSH ALONE
Follicular development achieved with both hMG and FSH
alone
BUT with FSH alone:-
inadequate E2
reduced occurrence of ovulation
decreased endometrial thickness
lower oocyte fertilization rates
HYPOG-HYPOG
Some exogenous LH is
necessary to optimize
ovulation induction for good
clinical results.
EFFECT OF R-HLH ON FOLLICULAR
RESPONSE IN WHO I ANOVULATORY
INFERTILE WOMAN
30
1500 r-hFSH 150 I.U./day
LH 75 I.U./day
folliclediameter (mm)
1250 20
oestradiol (pmol/l)
1000
750
10
500
250 r-hFSH 150 I.U./day
0
0
1 5 10 15
days
DT Baird as part of the EU Recomb. LH Group, 1998
HYPOG-HYPOG
LH
Promotes dose related increases in E2
secretion by FSH induced follicles.
A minimum daily dose of 75 IU/day recLH is
needed.
Increases ovarian sensitivity to FSH.
Enhances ability of follicles to luteinize
when exposed to hCG.
THE FIRST STEP
Know the ovary
Can you see follicles on U/S ?
The uterus
Often uterine size is small
Pregnancies do not implant when uterine size is small
GROWTH HORMONE
Growth hormone useful in HP and HA with growth
hormone deficiency
Dose 12 units per day ( IVF - 4 units daily)
Not useful if no growth hormone deficiency
Lower fertility in natural & treatment
cycles (Chong et al, 1986; Zaadstrat et al, 1991,
Crosignani et al, 1994)
Require larger daily and total doses
Higher rate of miscarriages
(Hamilton-Fairley et al, 1992)
80% of obese
PCOS
30-40% of lean
PCOS
Genetic post-
receptor defect
unique to PCO
• Exaggerated by obesity
Kolhapur PCOS study – ‘MAPIN’
study
2007 – 2011
1257 women with PCOS – Rotterdam Criteria
Analysis ready for 492
Clinical
Endocrinology and Metabolism
Ultrasound
(Kulkarni, Gudi, Homburg and Conway)
Kolhapur PCOS study – types of
diet
Indian PCOS study - diet
1 Carb Veg Non Veg Junk
n 50 219 170 51
BMI 17.1 22.3* 25.7* 30.6**
WHR 0.82 0.85 0.84 0.85
LH 10.5 9.3 9.3 9.9
Testo 44 54* 64* 68*
Andro 2.74 2.84 2.61 3.15
SHBG 30 40 32 30
Insulin 5.8 10.7* 12.6* 13.7**
AMH 3.69 3.82* 4.36* 5.11**
symptoms OBESITY
hormones
ultra-
sound
INSULIN
after Dewailly, 2003
symptoms
OBESITY hormones
ultra-
sound WEIGHT
LOSS
INSULIN
after Dewailly, 2003
MULTIPLE CHOICE –
TREATMENT OF
ANOVULATORY INFERTILE
PCOS
FIRST LINE
Weight loss
Clomiphene citrate (CC)
Aromatase inhibitors (AI’s)
Insulin lowering medications
SECOND LINE
Low dose FSH
Laparoscopic ovarian drilling
THIRD LINE
IVF
CLOMIPHENE CITRATE
Spelling – clomiphene or clomifene?
Give hCG?
Monitor CC cycles with ultrasound?
SHOULD WE GIVE HCG IN CC
CYCLES?
Agarwal & Buyalos, 1995 NO
No improvement in conception rates
Deaton et al, 1997
No difference
NO
Viahos et al, 2005
hCG may be beneficial
Maybe
Kosmas et al, 2007 Meta-analysis
Favoured hCG but no significant difference
Brown et al, 2009, Cochrane review Yes
No difference
NO
SHOULD WE MONITOR
CLOMIPHENE CYCLES WITH
ULTRASOUND?
With U/S + hCG No U/S or hCG
n 105 150
Cumulative
48% 34.7%
pregnancy rate
Deliveries 35.6% 26.7%
Multiple
0 1
pregnancies
Konig, Homburg et al, ESHRE, 2009
CLOMIPHENE: EXPECTED
RESULTS
n = 5268
Ovulation – 3858 (73%)
Pregnancies – 1909 (36%)
Miscarriage – 20%
Multiple pregnancy rate – 8%
Homburg, Hum Reprod, 2005
NON-RESPONSE TO CLOMIPHENE
Failure to ovulate
FAI
BMI
LH
Insulin
Age
IMPROVEMENT OF RESULTS WITH
CC
Decrease insulin - weight loss
Monitor for anti-estrogen effects
Mucus
Endometrium
POSSIBLE ADJUVANTS
Estrogens
Dexamethasone
Metformin
PROTOCOL
50-150 mg D2-day6 Clomid 50 for 5 days
If no response next cycle Re-assessed on day 11
plan higher dose If no response
100 mg clomid daily and
review after 7 days
Continued till 200 mg
reached
FIXTURE LIST
Clomiphene vs Letrozole
Clomiphene vs Metformin
Clomiphene vs low dose
FSH
FSH vs
laparoscopic ovarian
drilling
Endometrial thinning in 15-50%
(Gonen &Casper, 1990;Dickey et al, 1993)
Causes ER downregulation and depletion.
Suppresses pinopode formation
(Creus et al, 2003)
No pregnancies when endometrial thickness at midcycle <
7mm
Not dose related and recurs in repeat cycles
(Homburg et al, 1999)
Theoretical Advantages:
Do not block estrogen receptors –
No detrimental effect on endometrium
or cervical mucus.
Negative feedback mechanism not
turned off – less chance of multiple
follicular development.
Clomiphene Citrate Treatment
CC CC
ER
ER
ER
ER
ER
ER
ER
ER
E2 E2
FSH
FSH
Day 5 Day 10
Casper & Mitwally
Aromatase Inhibitor Treatment
ER
ER ER
ER
ER ER
ER
E2 E2
FSH
FSH
AI
Day 5 Day 10
Casper & Mitwally
AROMATASE INHIBITOR
QUESTIONS
Do they work?
Better than CC for first-line treatment?
Safety?
N=750 PCOS, RCT
Letrozole CC P
Ovulation 61.4% 48.3% 0.001
Preg loss 31.8% 28.2% NS
Twins 3.2% 7.4% NS
Live births 27.5% 19.5% 0.007
Health Canada Endorsed Important Safety Information on
Femara* (Letrozole)
~November17,2005
Dear Health Care Professional:
Subject: Contraindication of Femara* (letrozole) in premenopausal
women Following discussions with Health Canada, Novartis is
advising you of concerns about the use of the aromatase inhibitor
Femara* (letrozole) for the purpose of ovulation induction in the
treatment of infertility. Novartis is aware that Femara* has been or is
being used to treat infertility even though statements in the Canadian
Product Monographs warn physicians about potential embryo- and
fetotoxicity with or without teratogenicity. There have been post-
market reports of congenital anomalies in infants of mothers exposed
to Femara* for the treatment of infertility. Femara* (letrozole) is
contraindicated in women with premenopausal endocrine
status, in pregnancy, and/or lactation due to the potential for
maternal and fetal toxicity and fetal malformations.
OUTCOME – LETROZOLE VS CC
Tulandi et al, 2006 n=911 newborns in 5 centers
CC Letrozole
Pregnancies 397 514
Congenital
malformations
+ 19 (4.8%) 14 (2.4%)
Chromosomal
abnormalities
OUTCOME – LETROZOLE VS CC
Tulandi et al, 2006
n=911 newborns in 5 centers
CC Letrozole
Pregnancies 397 514
Major malformations 12 (3%) 6 (1.2%)
VSD 4 (1.0%) 1 (0.2%)
Total cardiac anomalies 1.8% 0.2%
OUTCOME – LETROZOLE VS
CC
Casper & Mitwally 2006
CC
Letrozole
Pregnancies 315 428
Major malformations 1.9% 0.5%
Minor malformations 2.2% 1.4%
AROMATASE INHIBITORS
Letrozole 2.5-10 mg/day, n=1102
Pregnancies 368 (33.4%)
Miscarriages 99 (26.9%)
Twins 2 (0.5%)
Fetal anomalies 1 (0.2%)
Aghssa et al, 2007 (PCOS, eds Allahbadia, Agrawal)
© Dr Roy Homburg 2018
