Transcript No Slide Title

Aromatase Inhibitors and PCOS
Serdar Bulun, MD
George H Gardner Professor of Clinical Gynecology
Chief, Division of Reproductive Biology Research
Department of Obstetrics and Gynecology
Northwestern University, Chicago, IL
21
18
11
cholesterol
19
StAR
2
3
P450scc
CH3
C
12
1
10
4
5
13
14
9
20
17
22
24
23
25
16
15
26
27
8
6
7
CH3
O
MITOCHONDRION
C
O
3b-HSD-II
nmol/L
pregnenolone
P450c17
PROGESTERONE
P450c17
CH3
C
O
OH
CH3
C
O
OH
3b-HSD-II
17-hydroxyprogesterone
17-hydroxypregnenolone
P450c17
P450c17
O
O
3b-HSD-II
dehydroepiandrosterone
17b-HSD-1
androstenedione
testosterone
aromatase
aromatase
O
17b-HSD-1
estrone
pmol/L
ESTRADIOL
CYP19A1 gene, human
~90 kb
GENE:
I.1
~30 kb
UNTRANSLATED FIRST EXONS ATG
I.7
I.4
I.f I.2
I.6 I.3 PII
CODING EXONS
X
II
Common Splice Site (in Exon II)
mRNA:
Placenta:
I.1 Arom Coding Region
Brain:
I.f Arom Coding Region
Adipose Tissue:
I.4 Arom Coding Region
Breast cancer:
I.3 Arom Coding Region
Ovary/endometriosis:
PII Arom Coding Region
PII Arom Coding Region
I.7 Arom Coding Region
REGULATION OF AROMATASE EXPRESSION
FSH
aromatase
E2
SF1/LRH1
gene
promoter II
P450arom
mRNA PII P450arom
ovary
cytokines, cortisol
aromatase
STAT GR
E1
E2
promoter I.4
73 kb
gene
P450arom
mRNA I.4 P450arom
adipose tissue, skin
BRAIN AROMATASE
E2
HYPOTHALAMUS
promoter I.f
T
A
ERa
aromatase aromatase
E2
E1
P450arom
mRNA I.f P450arom
+
LIBIDO
GnRH
a
FSHb
LHb
FSH
c-jun
LH
Aromatase Deficiency
Aromatase knockout (ArKO) mice
AROMATASE INHIBITORS
PSt
E
aromatization
No inhibitor
Arom
CI
PSt
Anastrozole
Letrozole
Arom+Pr
Arom+PSt
PSt
E
aromatization
Arom+CI
PSt
IAc
PSt
x
Arom+CI
Arom
E
aromatization
Exemestane
Arom
Arom+IAc
x
Arom+IAc
Suppression of peripheral aromatization and circulating E 1, E2, E1S by 90-99%
Hypothalamus
Postmenopausal on AI
Prememopausal on AI
Ovary
Aromatase
E2
Aromatase
E2
Aromatase
Pituitary
Premenopausal on AI
+ OC or P
FSH
LH
FSH
LH
No Follicular
Aromatase
FSH
LH
OC
P
GnRHa
Aromatase
Aromatase
Follicle Development
AI
AI
AI
Endometriosis
Peripheral Tissues
Peripheral
Aromatase
Peripheral
Aromatase
Takayama et al, Fertil Steril, 1998; Ailawadi et al, Fertil Steril, 2004; Soysal et al, Human
Reproduction, 2004; Amsterdam et al, Fertil Steril, 2005; Attar and Bulun Fertil Steril, 2006
Peripheral
Aromatase
ultrasound
ultrasound
AI
once daily
for 5 days
LH surge
or
hCG injection
menses
1
2
3
4
5
6
intercourse
check
pregnancy
(urine hCG)
7
8
9 10 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1
cycle days
2
3
Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to
clomiphene citrate
Mohamed F. M. Mitwally, M.D., and Robert F. Casper, M.D.
Fertility and Sterility 2001
12 patients with anovulatory PCOS and 10 patients with ovulatory infertility
previously received CC with an inadequate outcome (no ovulation or endometrial
thickness <0.5 cm).
letrozole was given orally in a dose of 2.5 mg on days 3–7 after menses
PCOS tx’d with CC: ovulation in 8 of 18 cycles (44.4%), endometrial thickness <0.5 cm.
Ovulatory tx’d with CC: 15 cycles, mean number of 2.5 mature follicles, endometrial thickness <0.5 cm on
the day of hCG administration.
PCOS tx’d with letrozole: ovulation in 9 of 12 cycles (75%), pregnancy in 3 patients (25%).
Ovulatory tx’d with letrozole: mean number of 2.3 mature, endometrial thickness 0.8 cm, pregnancy in 1
patient (10%).
Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing
ovarian stimulation.
Atay V, Cam C, Muhcu M, Cam M, Karateke A.
J Int Med Res. 2006
106 women with primary infertility and a diagnosis of PCOs were randomized to receive either 100
mg CC (n = 55) or 2.5 mg letrozole (n = 51) daily for 5 days.
hCG was administered when at least one follicle >18 mm was observed
number of mature follicles was significantly lower, but endometrial thickness and ovulation and
pregnancy rates were significantly higher in the letrozole group than in the CC group.
Clomiphene citrate or anastrozole for ovulation induction in women with PCOS? A prospective
controlled trial
Ahmed Badawy, M.D., Ibrahim Abdel Aal, M.D., and Mohamed Abulatta, M.D.
Fertility and Sterility 2008
Ovulation in 165 (67.9%) of 243 cycles in the anastrozole group and in 150 (68.6%) of 226 cycles in
the CC group without significant difference.
Anastrozole was associated with significantly fewer mature and growing follicles, thicker
endometrium, and slightly higher pregnancy rate but not significant. Anastrozole may be helpful in
situations in which multiple pregnancy is not desirable or the risk of ovarian hyperstimulation
syndrome is high.
Clomiphene citrate or letrozole for ovulation induction in women with PCOS: a prospective randomized
trial
Ahmed Badawy, M.D., Ibrahim Abdel Aal, M.D., and Mohamed Abulatta, M.D.
Fertility and Sterility 2008
randomized to letrozole 5 mg daily (218 patients, 545 cycles) or CC 100 mg daily (220 patients, 518
cycles) for 5 days starting on day 3 of menses; timed intercourse 24 to 36 hours after hCG injection.
endometrial thickness at hCG administration was statistically significantly greater in the CC group
(9.2 + 0.7 mm versus 8.1 + 0.2 mm).
pregnancy rate per cycle 15.1% in the letrozole group and 17.9% in the C group, no significant difference
Anastrozole or letrozole for ovulation induction in clomiphene-resistant women with PCOS: a
prospective randomized trial
Ahmed Badawy, M.D., Abeer Mosbah, M.D., and Magda Shady, M.D.
Fertility and Sterility 2008
Ovulation in 183/295 cycles (62%) in the letrozole group and 177/279 cycles (63.4%) in the
anastrozole group, whereas pregnancy occurred in 36/295 cycles (12.2%) in the letrozole group
and 42/279 cycles (15.1%) in the anastrozole group
No significant difference
Congenital malformations among 911 newborns conceived after infertility treatment with
letrozole or clomiphene citrate.Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J,
Librach C, Greenblatt E, Casper
Fertility and Sterility 2006
Retrospective study
Examination of medical files of both mother and newborn, and cross-checked with the parents by
telephone calls.
Identified major and minor congenital malformations, birth weight, age of the mother, and type of
treatment that led to the conception.
Congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in
the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major
malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397).
The rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group
(1.8%) compared to the letrozole group (0.2%).
The SERM, clomiphene citrate (CC), has been the principal drug used for
induction of ovulation in women with PCOS.
Theoretically, CC is associated with adverse side effects and low pregnancy rates
attributed to long-lasting estrogen receptor antagonism.
AIs mimic the action of CC in reducing estrogen negative feedback on follicle
stimulating hormone (FSH) secretion.
AIs, in fact, induce ovulation in anovulatory women with PCOS.
Concomitant use of AIs resulted in a significant reduction of the FSH dose
needed for controlled ovarian hyperstimulation.
A retrospective study showed that AIs were safe in pregnancy outcome with
respect to spontaneous pregnancy loss, multiple pregnancy rates and congenital
anomalies compared to a control group of infertility patients treated with CC.
BOTTOMLINE
No clear difference between CC and AIs with respect to ovulation,
pregnancy or safety.
Theoretical advantages of AIs (endometrial development) have not
translate into clinical benefit yet.
AIs may be used in CC-resistant PCOS patients or as adjuvant agents to
reduce the injectable FSH dose.
AIs may be used as first-line inducers of ovulation, since they are
equivalent to CC.