Serdar Bulun, MD

George H Gardner Professor of Clinical Gynecology

Chief, Division of Reproductive Biology ResearchDepartment of Obstetrics and Gynecology

Northwestern University, Chicago, IL

Aromatase Inhibitors and PCOS

HO

O

O

O

OH

HO

O

HO

C

CH3

O

OH

HO

O

O

C

CH3

O

O

C

CH3

OOH

HO

C

CH3

O

HO

OH

cholesterol

MITOCHONDRION

pregnenolone

17-hydroxypregnenolone

dehydroepiandrosterone

StAR

P450scc

P450c17

P450c17

androstenedione testosterone

estrone ESTRADIOL

17-hydroxyprogesterone

PROGESTERONE

P450c17

P450c17

aromatase aromatase

3HSD-II

3HSD-II

3HSD-II 17HSD-1

17HSD-1

6

12

34

5

9

7

810

1112

13

14 1516

17

18

19

21 2022

23

252427

26

nmol/L

pmol/L

Arom Coding RegionI.1

Arom Coding RegionI.4

Arom Coding RegionI.f

Arom Coding RegionI.3

Arom Coding RegionPII

Placenta:

Adipose Tissue:

Ovary/endometriosis:Arom Coding RegionPII

Brain:

Breast cancer:

GENE:

mRNA:

Arom Coding RegionI.7

CODING EXONSCODING EXONS

Common Splice Site (in Exon II)

ATGUNTRANSLATED FIRST EXONSUNTRANSLATED FIRST EXONSI.1 I.4 I.2 I.6 I.3 PIII.f

II X

~90 kb ~30 kb

I.7

CYP19A1 gene, human

REGULATION OF AROMATASE EXPRESSION

ovary

FSH

aromatase E2

adipose tissue, skin

aromatase

cytokines, cortisol

E1 E2

P450arom

promoter II

promoter I.4

P450arom

androstenedione

P450aromPII

P450aromI.4

gene

mRNA

gene

mRNA

STAT GR

SF1/LRH1

73 kb

GnRH

FSH

LH

FSH LH

HYPOTHALAMUS

E1 E2

T

aromatase

BRAIN AROMATASE

Apromoter I.f

P450arom

P450aromI.fmRNA

c-junER

E2

aromatase

+LIBIDO

Aromatase Deficiency

Aromatase knockout (ArKO) mice

aromatizationArom

PSt

Arom

Arom

E

Arom+Pr

Arom+PSt

Arom+IAc

Arom+CI

PSt

CI

aromatization

E

Arom+CI

PSt

PSt

IAc

aromatization

E

Arom+IAc

PSt

x

x

x

x

x

xAnastrozoleLetrozole

Exemestane

No inhibitor

AROMATASE INHIBITORS

Suppression of peripheral aromatization and circulating E1, E2, E1S by 90-99%

Hypothalamus

Pituitary FSHLH

Postmenopausal on AI

Ovary

Peripheral Tissues

Endometriosis

Peripheral

Aromatase

No FollicularAromatas

e

AI

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

Follicle Development

Prememopausal on AI

Aromatase

AromataseE2

AI

Peripheral

Aromatase

FSHLH

Premenopausal on AI+ OC or P

Aromatase

Peripheral

Aromatase

AI

OC P

GnRHa

FSHLH

AromataseE2

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

menses

AIonce daily for 5 days

ultrasound ultrasound

LH surge or

hCG injection

checkpregnancy(urine hCG)intercourse

cycle days

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 infertilitypreviously 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.

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.

Atay V, Cam C, Muhcu M, Cam M, Karateke A.

J Int Med Res. 2006

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

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

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.