IUI INDICATIONS,
OVARIAN STIMULATION PROTOCOLS
CC, AROMATASE INHIBITORS, GONADOTROPINS
Hakan Özörnek, MD
EUROFERTIL
İstanbul
Indications
• Male subfertility
• Unexplained infertility
• Endometriosis (mild)
• Cervical factor
• Ejaculatory dysfunction
• Immunologic infertility
Contrindications
• Tubal infertility
• Severe male infertility
• Severe endometriosis
• Decreased ovarian reserv
• Age > 40
ART in Europe, 2006: results generated from European registers by ESHRE
J. de Mouzon*, V. Goossens, S. Bhattacharya, J.A. Castilla, A.P. Ferraretti, V. Korsak, M. Kupka, K.G. Nygren, A. Nyboe Andersenand
The European IVF-monitoring (EIM) Consortium, for the (ESHRE)
Cycles
Deliveries
Deliveries
(%)
Singleton
(%)
Twin (%)
Triplet (%)
134261
11 052
8.5
88.4
10.6
0.8
ÜYTE yönetmeliği
MADDE 18 –
(8) İstenmeyen durum olan, anne ve çocuk sağlığını riske
eden çoğul gebeliklerin önlenmesi esastır. Bu kapsamda;
a) ÜYTE yöntemlerinden biri olan klasik ovulasyon
indiksiyonu ile 2 (iki) den fazla folikül gelişmemesi
hedeflenmelidir. Çoğul gebeliklerin önlenmesi için üç veya
daha fazla folikül gelişmesi halinde artifisyel inseminasyon
işlemi yapılması yasaktır.
Male subfertility
Unexplained subfertility
Cervical factor
CC/Letrazol protocol
E2 control
LH control
Ovulation
induction
Gonadotropin protocol
E2 control
50-75 IU/day
LH control
Ovulation
induction
Advantages of oral drugs
• Low incidence of multiple pregnancies
• Low incidence of OHSS
• Low cost
• Less need for cycle monitoring
• More comfortable
CC
• Competitive antagonist of ovarian estrogen
• Requires an intact hypothalamic-pituitary-ovarian axis and
serum estradiol > 50 pg/ml.
• Endometrial thickness is initially decreased, but is later
increased compared to natural cycles as rising estrogen
concentration overcomes the antiestrogen effect. [Randall
JM, F&S, 1991]
Letrazol
• Third generation aromatase inhibitor
• Act directly to the ovary to decrease production of
estrogen
• Intraovarian androgens accumulate mid sized follicles
become atretic
• Multiple follicular ovulation are reduced compared to CC
• Used «off label»
CC IUI
Dickey RP, et al., Fertil Steril, 2002
CC IUI
Dickey RP, et al., Fertil Steril, 2002
CC IUI
Dickey RP, et al., Fertil Steril, 2002
CC IUI
Dickey RP, et al., Fertil Steril, 2002
Cumulative pregnancy rate
Dickey RP, et al., Fertil Steril, 2002
Cumulative pregnancy rate
Dickey RP, et al., Fertil Steril, 2002
Cumulative pregnancy rate
Dickey RP, et al., Fertil Steril, 2002
CC for unexplained subfertility in women
Objectives
Clomiphene citrate in improving pregnancy outcomes in
women with unexplained subfertility, dose range of 50 to
250 mg for up to 10 days. The primary outcome was live
births.
Selection criteria
Only randomised controlled trials were included.
Data collection and analysis
Seven trials were included in this review.
Hughes E, et al., Cochrane Database of Systematic Reviews 2010
CC for unexplained subfertility in women
Main results
1159 participants from seven trials were collated. There
was no evidence that CC was more effective than no
treatment or placebo for live birth (odds ratio (OR) 0.79,
95% CI 0.45 to 1.38; P = 0.41) or for clinical pregnancy per
woman with intrauterine insemination (IUI) (OR 2.40, 95%
CI 0.70 to 8.19; P = 0.16).
Authors' conclusions
There is no evidence of clinical benefit of clomiphene
citrate for unexplained fertility. .
Hughes E, et al., Cochrane Database of Systematic Reviews 2010
Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained
infertility undergoing intrauterine insemination: a prospective randomized trial
Ahmed Badawy, et al., Fertil Steril, 2009
Letrazol vs CC
• A meta-analysis of four published randomized controlled
trials for ovulation induction in a total 662 patients with
PCOS now provides strong evidence that letrozole is at
least as effective as CC, the present gold standard, for
ovulation induction with similar pregnancy rates ([RR]
1.02; 95% CI 0.83, 1.26).
• Letrazole is equally effective in inducing ovulation, but
without antiestrogenic adverse effects, as a first-line
therapy.
Casper RF, Fertil &Steril, 2009
Letrazol vs CC
• 5 fertility centers in Canada.
• 911 newborns from women who conceived following CC or
letrozole treatment.
• Congenital malformations and chromosomal
abnormalities in the letrozole group 2.4% and in the CC
group 4.8%.
• The major malformation rate in the letrozole group was
1.2% and in the CC group was 3.0%.
Tulandi T, et al. Fertil Steril, 2006
Gonadotropins IUI
Dickey RP, et al., Fertil Steril, 2002
Gonadotropins IUI
Dickey RP, et al., Fertil Steril, 2002
Gonadotropins IUI
Dickey RP, et al., Fertil Steril, 2002
Gonadotropins IUI
Dickey RP, et al., Fertil Steril, 2002
Gonadotropins IUI
Dickey RP, et al., Fertil Steril, 2002
Cumulative pregnancy rate
Dickey RP, et al., Fertil Steril, 2002
Cumulative pregnancy rate
Dickey RP, et al., Fertil Steril, 2002
Cumulative pregnancy rate
Dickey RP, et al., Fertil Steril, 2002
Effect of age
Dickey RP, et al., Fertil Steril, 2001
Pregnancy rates following IUI
Cantineau et al., Cochrane, 2007
Letrazol vs FSH
Baysoy A, et al. RBM Online, 2006
Letrazol vs FSH
Baysoy A, et al. RBM Online, 2006
Letrazol vs FSH
Odysseas, et al., Fertil Steril, 2008
Pregnancy rate FSH vs FSH+Letrazol
Requena, et al. Hum Reprod Update, 2008
CC-FSH vs FSH alone vs Letrazol
Ganesh, et al. J Assist Reprod Genet, 2009
CC-FSH vs FSH alone vs Letrazol
Ganesh, et al. J Assist Reprod Genet, 2009
Premature LH surge during mild FSH
stimulation (203 cycles)
Lambalk et al.,
Hum Reprod,2006
OPR with or without antagonist
A randomized clinical trial to evaluate optimal treatment for unexplained infertility:
the fast track and standard treatment (FASTT) trial
Richard H. Reindollar, et al FS 2010
• 3 x CC/IUI + 3 x FSH/IUI + 6 x IVF (n= 247)
• 3 x CC/IUI + 6 x IVF (n= 256)
A randomized clinical trial to evaluate optimal treatment for unexplained infertility:
the fast track and standard treatment (FASTT) trial
Richard H. Reindollar, et al FS 2010
A randomized clinical trial to evaluate optimal treatment for unexplained infertility:
the fast track and standard treatment (FASTT) trial
Richard H. Reindollar, et al FS 2010
A randomized clinical trial to evaluate optimal treatment for unexplained infertility:
the fast track and standard treatment (FASTT) trial
Richard H. Reindollar, et al FS 2010
Conclusion
• IUI is the first choise particularly in male subfertility and
•
•
•
•
•
unexplained infertility
Letrazol is as effective and safe as CC. Absence of
antiöstrogenic effect of Letrazol is an advantage
Adding of oral drugs to gonadotropins reduce the cost of
the therapy but the pregnancy rate is not differ
In a subgroup of patients whose basal E2 < 30 pg/ml is
gonadotropins preferable
Adding GnRH antagonist to a gonadotropin stimulation
bevor IUI increase the pregnancy rates
Due to new regulation of ministery of health oral
drugs are more cost effective than the gonadotropins
F A K A T !!!
Thank you