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Aromatase inhibitors

Aromatase inhibitors. Human M.Fatemi, MD, PhD Centre For Reproductive Medicine UZ BRUSSEL. Presentation:. AI’s: The physiology AI’s: Different types AI’s: Ovulation induction AI’s: IVF AI’s: Safety AI’s: Fertility preservation in cancer patients AI’s: The ideal regimen

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Aromatase inhibitors

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  1. Aromatase inhibitors • Human M.Fatemi, MD, PhD • Centre For Reproductive Medicine • UZ BRUSSEL

  2. Presentation: • AI’s: The physiology • AI’s: Different types • AI’s: Ovulation induction • AI’s: IVF • AI’s: Safety • AI’s: Fertility preservation in cancer patients • AI’s: The ideal regimen • AI’s: Conclusions 2 titel 08/17/2007

  3. Aromatase inhibitors • Aromatase • is a member of the cytochrome P450 hemoprotein-containing enzyme complex superfamily (P450arom, the product of the CYP19 gene) • synthesizes estrogens by catalyzing three consecutive hydroxylation reactions converting C19 androgens to aromatic C18 estrogenic steroids. • converts androstenedione to estrone and testosterone to estradiol. 4 titel 08/17/2007

  4. AI AI 5 titel 08/17/2007

  5. Mechanism of action of AI’s 6 titel 08/17/2007

  6. Aromatase Enzyme • Sources: • Granulosa cells of Ovary • Placenta • Subcutaneous fat • Liver • Muscle • Brain • Normal breast • Breast cancer • Endometriosis • Premenopausal women • Ovarian source • Postmenopausal women • Adipose tissue 7 titel 08/17/2007

  7. Evolution of Aromatase Inhibitors • Aminoglutethimide • 1st generation • Developed anitconvulsant • Adrenal suppression • low potency and lack of specificity, side-effects (Holzer et al., 2006) • Formestane • 2nd generation, Type 1 • IM injection • Fadrozole • 2nd generation, Type 2 • Aldosterone suppresion 8 titel 08/17/2007

  8. Classifications of AI 9 titel 08/17/2007

  9. Biochemical structurs 10 titel 08/17/2007

  10. 3rd Generation Aromatase Inhibitors • Type 1: Exemestane • t½= 27h • Type 2: Anastrozole and Letrozole • t½= 48h, once daily dosing • 99% inhibition of aromatase enzyme • Oral administration • More selective for aromatase • No effect on aldosterone or corticosterone level 11 titel 08/17/2007

  11. 3rd Generation Aromatase Inhibitors • Differnce between Type 1&2? • type 1 steroidal (noncompetitive, irreversible): known as a suicide inhibitor. • type 2 nonsteroidal (competitive, bind reversibly to aromatase) 12 titel 08/17/2007

  12. AI’s for ovulation induction? 13 titel 08/17/2007

  13. AI: The physiology behind • Estradiol: produced by the ovarian granulosa cells • exerts a negative feedback effect on FSH release • aromatization of androgens to estrogens is inhibited, causing a reduction of circulating estrogens: modifications in the hypothalamic–pituitary–ovary axis, including: • FSH secretion,resultant stimulating effect on the growth of ovarian follicles. • increase of intraovarian androgens,augmenting follicular sensitivity to FSH. The concept that androgens actually enhance early follicular growth is becoming increasingly important (Weil et al., 1998) • AIs do not antagonized estrogen receptors in the brain and, therefore, feedback central mechanisms remain intact. (Casper and Mitwally, 2006) 14 titel 08/17/2007

  14. AI’s For Induction of Ovulation? • Letrozole has been evaluated most in fertility research (Requena et al., 2008) • Dose: between 2.5-5 mg (Fatemi et al., 2004) • AIs do not deplete estrogen receptors, as does CC. • Normal central feedback mechanisms remain intact. • As the dominant follicle grows and estrogen levels rise, normal negative feedback occurs centrally, resulting in suppression of FSH and atresia of the smaller growing follicles. • A single dominant follicle, and mono-ovulation occur in most cases (Casper and Mitwally, 2006). 15 titel 08/17/2007

  15. AI’s For Induction of Ovulation? • Temporary accumulation of intraovarian androgens • because conversion of androgen substrate to estrogen is blocked by aromatase inhibition (Weil et al., 1999 • Testosterone was found to augment follicular FSH receptor expression • androgens promote follicular growth and estrogen biosynthesis indirectly by amplifying FSH effects (Weil et al., 1999). 16 titel 08/17/2007

  16. AI’s For Induction of Ovulation? • PCOS patients • already have a aromatase deficiency in the ovary • increased intraovarian androgens • development of multiple small follicles responsible for the polycystic morphology of the ovaries. • The androgens also increase FSH receptors making women with PCOS exquisitely sensitive to an increase in FSH through exogenous administration of gonadotrophins, and hence the high risk of ovarian hyperstimulation syndrome and multiple ovulation (Vendola et al., 1998). 17 titel 08/17/2007

  17. AI’s For Induction of Ovulation? • AI’s have no negative impact on the cervical mucus and endometrial morphology • AIs do not have androgenic, progestagenic or estrogenic activity (Fatemi et al., 2003) • Bur are the efficient for OI or even IVF? 18 titel 08/17/2007

  18. Latest review: Requena et al., 2008 19 titel 08/17/2007

  19. what does the meta-analysis conclude?(Requena et al., 2008) • The overall effects of letrozole in comparison with CC in PCOS was • neither significant for ovulatory cycles (OR = 1.17; 95% CI 0.66–2.09) • nor for pregnancy cycle rate (OR = 1.47; 95% CI 0.73–2.96) • or for pregnancy patient rate (OR = 1.37; 95% CI 0.70–2.71) • For all three outcomes, the I2 was above 50% indicating that the studies were not statistically homogeneous. 20 titel 08/17/2007

  20. Aromatase inhibitors plus gonadotrophins in ovarian stimulation for IUI 21 titel 08/17/2007

  21. AI’s for IVF? • Mmaqza Meta analysis 2008: Significant differences in the pregnancy rate per patients between both treatment modalities were not found (OR = 1.40; 95% CI 0.67−2.91). 22 titel 08/17/2007

  22. Safety profile of aromatase inhibitors iovulation induction • Concern related to the inadvertent exposure to letrozole during pregnancy (Tiboni, 2004) • Hu et al. (2002) examined how profound changes in androgen/estrogen ratio would affect mouse in vitro follicular development • Drastic changes in the intrafollicular steroid concentrations did not disrupt meiotic maturation nor compromise early preimplantation development. • The short half-life of AIs and the administration of these drugs during early follicular phase from Day 3 to Day 7 of the cycle leave a sufficient interval for complete washout to occur before fertilization and implantation. • Nevertheless, if AIs are going to be used for ovulation induction, measurement of beta-hCG may be recommended to ensure that candidates to AIs treatment are not pregnant. It is amply demonstrated that neither CC nor AIs including letrozole should be administered in pregnant women. 23 titel 08/17/2007

  23. Safety profile of aromatase inhibitors iovulation induction Safety profile of aromatase inhibitors iovulation induction • In a cohort study by Mitwally et al., 2005,the outcome of pregnancies after letrozole and other ovarian stimulation treatments were compared • 394 pregnancy cycles in 345 infertile couples • The Pregnancies conceived after letrozole treatments were associated with similar miscarriage and ectopic pregnancy rates compared with all other groups. 24 titel 08/17/2007

  24. Safety profile of aromatase inhibitors iovulation induction • However,a study presented at the 2005 ASRM meeting suggested that the AI, letrozole, could cause serious fetal anomalies when used off-label for ovulation induction. • In that study Biljan et al. found • a malformation rate of 4.7% among 150 babies born after the use of letrozole, • compared with a rate of just 1.8% in a database of 36 050 normal conceptions. • An identical number of birth defects in each group was reported • but the incidence of cardiac malformations and malformation of the musculoskeletal system was significantly higher in letrozole-treated group. • As a result Novartis issued global warnings 25 titel 08/17/2007

  25. Safety profile of aromatase inhibitors iovulation induction • However,the study had several methodological problems: • The main criticism : controls were normal deliveries, which are known to have a lower risk of malformations than babies born to women needing assistance to ovulate. • The mean (standard deviation, SD) age of women in the letrozole group was 35.2 (4.7) years compared with 30.5 (1.2) in the control cohort. • cardiac and possibly skeletal abnormalities are likely to be diagnosed before birth, and the mothers transferred to a tertiary care hospital for delivery. Therefore, it is possible that such abnormalities were underrepresented in the control cohort. • In addition, only 110 women treated with letrozole gave birth to singleton infants, and it is well known that congenital malformations are more common in twin births than in singletons. 26 titel 08/17/2007

  26. Safety profile of aromatase inhibitors iovulation induction • Tulandi et al., 2006, analyzed retrospectively the incidence of congenital malformations among offspring of mothers who conceived with CC (n = 397) or with letrozole (n = 514) • Overall, 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) • in the CC group it was 3.0% (12/397). • In addition, the rate of all congenital cardiac anomalies was significantly higher in the CC group (1.8%) compared with the letrozole group (0.2%) (P = 0.02). • On the basis of these data, the concern that letrozole use for ovulation induction could be teratogenic is unfounded. 27 titel 08/17/2007

  27. AI’s and fertility preservation in cancer patient • Fertility preservation options for female patients with malignancy include oocyte or embryo cryopreservation before starting chemotherapy or radiation therapy (Oktay, 2006; Seli and Tangir, 2005). • hypothetically, increasing estradiol levels may have adverse effects in patients with estrogen-dependent tumors. • Ovarian stimulation with letrozole and FSH appears to reduce estrogen exposure compared with standard IVF, without affecting oocyte quality, fecundation rate and the number of embryos obtained. Even in the case of elevated estrogen levels after oocyte retrieval, the use of letrozole could be maintained for some days to obtain reduction of estrogen levels. • oncologists should refer interested and appropriate patients to reproductive specialists 28 titel 08/17/2007

  28. Ideal regimen of the clinical use of AI’s • Letrozole 2.5 mg/day (from Day 3 to Day 7 of the cycle) plus FSH (+/- 100 IU/day, starting on Day 8. • This schedule favors lower consumption of FSH injections and more moderate ovarian responses are obtained (lesser mature follicles and lower levels of estradiol) (Requena et al., 2008) 29 titel 08/17/2007

  29. Coclusions • Letrozole may be as effective as clomiphene citrate in ovulation induction • Use of letrozole for ovulation induction may be considered before gonadotrophin therapy, or when clomiphene citrate is unsuccessful • There is a large potential for expanding the role of aromatase inhibitors in the field of male and female fertility 30 titel 08/17/2007

  30. Coclusions • Cohort studies do not show an increase of congenital malformations among offspring of mothers who conceived with letrozole treatment for infertility. • However, for sure there is need for further prospective randomized trials 31 titel 08/17/2007

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