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