1. 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

2. nmol/L pmol/L aromatase aromatase StAR P450scc 3b-HSD-II PROGESTERONEHO 6 1 2 3 4 5 9 7 8 10 11 12 13 14 15 16 17 18 19 21 20 22 23 25 24 27 26
cholesterol
StAR HO C
CH3 O
P450scc O C
CH3
MITOCHONDRION
3b-HSD-II
nmol/L
pregnenolone
PROGESTERONE
P450c17 HO C
CH3 O OH
P450c17 O C
CH3 OH
3b-HSD-II
17-hydroxypregnenolone
17-hydroxyprogesterone
P450c17
P450c17 HO O O O OH
3b-HSD-II
17b-HSD-1
dehydroepiandrosterone
androstenedione
testosterone
aromatase
aromatase HO O HO OH
17b-HSD-1
pmol/L
estrone
ESTRADIOL

3. CYP19A1 gene, human CODING EXONS X II Common Splice Site (in Exon II)
ATG
UNTRANSLATED FIRST EXONS
I.1
I.4
I.2
I.6
I.3
PII
I.f II X
~90 kb
~30 kb
I.7
CYP19A1 gene, human
GENE:
mRNA:
Placenta:
Brain:
Arom Coding Region
I.1
Arom Coding Region
I.f
Adipose Tissue:
Breast cancer:
Arom Coding Region
I.4
Arom Coding Region
I.3
Arom Coding Region
PII
Ovary/endometriosis:
Arom Coding Region
PII
Arom Coding Region
I.7

4. REGULATION OF AROMATASE EXPRESSION
FSH
promoter II
SF1/LRH1
P450arom E2
gene
aromatase
mRNA
PII
P450arom
ovary
cytokines, cortisol
promoter I.4
STAT GR E1
aromatase
73 kb E2
P450arom
gene
androstenedione
mRNA
I.4
P450arom
adipose tissue, skin

5. BRAIN AROMATASE HYPOTHALAMUS A T E1 E2 + GnRH LIBIDO E2 aromatase
promoter I.f A T
ERa
c-jun
aromatase
aromatase
P450arom E1 E2 +
mRNA
I.f
P450arom
GnRH
LIBIDO a
FSHb
LHb
FSH LH

6. Aromatase Deficiency

7. Aromatase knockout (ArKO) mice

8. x x x x x x AROMATASE INHIBITORS aromatization aromatization
PSt E
aromatization
No inhibitor
Arom
Arom+PSt
Arom+Pr
PSt CI
PSt E x x
aromatization
Anastrozole
Letrozole x
Arom+CI
Arom
Arom+CI
PSt
PSt E
IAc x x
aromatization
Exemestane x
Arom
Arom+IAc
Arom+IAc
Suppression of peripheral aromatization and circulating E1, E2, E1S by 90-99%

9. FSH LH + OC or P FSH LH FSH LH
Postmenopausal on AI
Hypothalamus
Follicle Development
Prememopausal on AI
Aromatase E2 AI
Peripheral
FSH LH
Premenopausal on AI
+ OC or P
Aromatase
Peripheral AI OC P
GnRHa
FSH LH E2
Aromatase
Pituitary
FSH LH
No Follicular
Aromatase
Ovary AI
Endometriosis
Peripheral Tissues
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

10. cycle days check pregnancy (urine hCG) ultrasound ultrasound
intercourse AI
once daily
for 5 days
LH surge or
hCG injection
menses 1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1 2 3
cycle days

11. 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
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%).

12. 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.

13. 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.

14. 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 ( mm versus mm).
pregnancy rate per cycle 15.1% in the letrozole group and 17.9% in the C group, no significant difference

15. 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
No significant difference
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

16. 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%).

17. 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.

18. 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.