Serdar Bulun, MD George H Gardner Professor of Clinical Gynecology

1. Aromatase Inhibitors and PCOS Serdar Bulun, MD George H Gardner Professor of Clinical Gynecology Chief, Division of Reproductive Biology ResearchDepartment of Obstetrics and Gynecology Northwestern University, Chicago, IL

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

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

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

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

6. Aromatase Deficiency

7. Aromatase knockout (ArKO) mice

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

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

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

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 (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

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.