LETROZOLE FOR OVULATION INDUCTION

1. LETROZOLE FOR OVULATION INDUCTION PROF.AbdouSaeedAit-Allah Abdel-hafez Prof. and head of GYN&OBS.dept., Sohag University

2. LETROZOLE

4. WHAT ? • These are antiestrogenic agents, which exert their action by inhibiting aromatase enzyme. • Aromatase enzyme is a cytochrome p 450 enzyme present in the ovaries, skin, liver, breast tissues, malignant breast tumors, brain and adipose tissues. Its function is to convert testosterone to estradiol and androstenedione to estrone.

5. WHAT ? Types: (1) Initial aromatase inhibitors: They include 2 types: Type І inhibitors : (steroidal inhibitors) Those are derivatives of androstenedione, they bind irreversibly to androgen-binding sites with continuing treatment so that, and they are called, suicide inhibitors. Type П inhibitors : (non- steroidal inhibitors) They act by binding to the hememoity of the cytochrome p 450 enzyme.Aminoglutethimide, was the first of these inhibitors to be used clinically. Disadvantages: 1- Lack of specificity. 2- Unfavorable toxicity.

6. WHAT ? (2)Present day aromatase inhibitors :( 3rd generation aromatas inhibitors) They include, letrozole, anastrozole, and verozole, which are highly potent and selective. They are available for clinical use for treatment of breast cancer,andrepresent the first improvement for oral ovulation induction in recent decades as they provide an effective, inexpensive and safe alternative to clomiphene citrate .

8. MECHANISM OF ACTION • The use of third-generation AI is recommended owing to their greater selectivity, greater potency, and lesser adverse effects (Holzer, 2006). Of the third-generation AI, both letrozole and anastrozole are available. • Letrozole works by inhibiting aromatization, leading to a decrease in estrogen production. As a result, FSH secretion increases, stimulating the development of ovarian follicles.

9. MWCHANISM OF ACTION • In addition, androgens that are normally converted to estrogens accumulate in the ovary and these androgens increase follicular sensitivity to FSH. As the ovaries from women with PCOS produce high amounts of estrogen, the effects of aromatase inhibitors in these women are more pronounced .

12. (1) Letrozole as first-step treatment: • Aromataseinhibitors can replace clomiphene citrate as ovulation-inducing drugs. The most widely use aromatase inhibitor for this purpose is letrozole • Advantages of letrozole over clomiphene citrate: 1- Greater selectivity, greater potency, and lesser adverse effects . 2- It avoids peripheral antiestrogenic effects on the endometrium, while stimulating monofollicular growth .

13. (1) Letrozole as first-step treatment: 3- Its selectivity of action which is produced only at gonadal level without affecting other organs such as the brain, while avoiding the adverse effects produced by reduced estrogen in the system. 4- Compared to clomiphene citrate, its use is associated with better endometriumand a trend towards higher pregnancy rates (letrozole 16.7%, clomiphene citrate 5.6%)

14. 5- Clomiphenecitrate has a longer half-life (5–7 days) that results in prolonged central estrogen receptor depletion .The half-life is now known to be approximately 45 hours and letrozole is completely eliminated at 17 days 6- Study reported a lower incidence of both minor and major congenital anomalies in a large group of women who conceived using letrozole compared with those who used CC

15. (1) Letrozole as first-step treatment: 7- Aromatase inhibitors have not been formally investigated as an adjunct for limiting the development of OHSS as part of a formal trial. They may well be of benefit in preventing the high oestradiol- induced cascade of vasoactivesubstances promoting OHSS . Treatment with letrozole is associated with higher pregnancy rate and a better uterine environment including, increased uterine flow (as determined by Doppler ultrasound) and increased endometrial thickness; compared with clomiphene citrate (Level I)

16. (2) Letrozole as second-step treatment: Letrozole succeeded in ovulation-induction in anovulatory PCOS patients resistant to clomiphene citrate or with inadequate endometrial thickness during clomiphene treatment

17. (2) Letrozole as second-step treatment: • Letrozole vs.metformin: Meta-analyses of six RCTs demonstrated that letrozole improved the ovulation rate per patient; and there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates compared with placebo or with CC plus metformin in women with CC-resistant PCOS.

18. (2) Letrozole as second-step treatment: • Letrozole vs. gonadotrophins: In women with unexplained infertility, it appears that letrozole has similar efficacy with injectablegonadotropins when considering ovulation, endometrial thickness, and pregnancy rates, The randomized controlled trials are showing similar pregnancy rates but with significantly reduced costs in the letrozole group when compared with gonadotropins.

19. (2) Letrozole as second-step treatment: • In one of the largest randomized clinical trials ever reported [including 1387 PCOS patients with CC failure] where the efficacy of letrozole as an ovulation inducing agent has been compared with CC-rFSH and continuous rFSH protocols. Letrozole appears to be a suitable ovulation inducing agent in PCOS women who fail to conceive with CC.

20. (2) Letrozole as second-step treatment: • This protocol was found to be most effective in women with high baseline estradiol level (>60 pg/ml). An interesting finding has also emerged from this study which opens up the possibility of considering baseline estradiol level as a potential marker for selecting the most suitable ovarian stimulation protocol for achieving best outcome in women after failure of CC treatment

21. (2) Letrozole as second-step treatment: • Letrozole &gonadotrophinsvsgonadotrophins alone : RCT showed that the combined regimen of letrozole and HMG is more effective and lesser cost than HMG alone .

22. (2) Letrozole as second-step treatment: • Letrozole vs. laparoscopic ovarian drilling: in the Cochrane database review, There was not difference in effectiveness between letrozole and laparoscopic ovarian drilling.

23. Letrozole & ART: • IUI: The recommended regimen in ovarian stimulation for IUI includes the use of letrozole 2.5 mg/day (from Day 3 to Day 7 of the cycle) plus FSH (usually 100 IU/day, although doses can vary depending on the characteristics of the patients) 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), minimizing the effect of letrozole on the endometrium(Level I).

24. Letrozole & ART: • Letrozole is also an effective ovulation inducing agent in women with higher-BMI undergoing IUI trial . • In a recent study, minimum 40 years of age infertile women (n = 159) undergoing controlled ovarian stimulation and artificial insemination, treated with aromatase inhibitor, letrozole in combination with FSH, exhibited comparable pregnancy rates with less cancelled cycles and less FSH required for stimulation compared to FSH-treated patients alone

25. Letrozole & ART: (2) In IVF treatment: • Though the ovarian stimulation and assisted reproductive technologies have improved to a great extent, there has not been a corresponding increase in implantation rate.supraphysiological levels of estrogen attained during ovarian stimulation may explain the lower pregnancy rate than expected by different mechanisms including deleterious effects on the endometrium.

26. Letrozole & ART: • In IVF treatment, letrozole may improve implantation rate and reduce the requirements of exogenous gonadotrophins and, consequently, the cost of an IVF treatment cycle. This is particularly important in poor responders.

27. Letrozole & ART: • Garcia-Velasco et al. was compared rFSH and highly purified hMG along with antagonist in one group, then added 2.5 mg letrozole to create a second group for comparison. Testosterone and androstenedionewere significantly increased in the follicular fluid of the experimental group, compared with the controls.

28. Letrozole & ART: . Interestingly, E2 levels of follicular fluid were similar with controls. These findings are consistent with the hypothesis that aromatase inhibition, by blocking androgen to convert into estrogen, increases intraovarianandrogens and follicular FSH receptor expression and sensitivity to FSH administration

29. Letrozole & ART: Also this inhibition can be rapidly reversed. The implantation rate was higher in the letrozole group than gonadotropins alone group (25% and 9.4% respectively). The pregnancy rate was higher (41.6% versus 28.9%) in letrozole group. These two results were not statistically significant .

30. Letrozole & ART: • Reduced ovarian reserve: letrozole is the promising agent to enhance the follicular response in women with diminished ovarian reserve. Due to inhibition of aromatization, androgens that normally converted to estrogens accumulate in the ovary, and these androgens increase follicular sensitivitytoFSH by increasing follicular FSH receptors. HOW

31. Letrozole & ART: The effect of remaining FSH, accelerates follicular development. Also, androgen accumulation in the follicle, stimulates insulin-like growth factor I (IGF-I) which may synergize with FSH to promote folliculogenesis. The improved response was clearly shown by the significantly higher number of mature follicles and significantly lower amount of FSH needed to achieve an adequate number of preovulatory follicles.

32. Letrozole & ART: LETROZOLE&ENDOMETRIOSIS: AIs are thought to be useful in treatment of infertility associated with endometriosis. combined letrozole and goserelindownregulation reduces endometriomal volume and serum Ca125 which is in accordance with pregnancy and delivery but a high pregnancy loss was noted

33. Letrozole & ART: LETROZOLE & FERTILITY PRESRVATION STRATEGY: Further treatment for breast cancer often involves chemotherapy with alkylating agents that can damage ovarian follicle reserve leading to diminished ovarian reserve. For future fertility, oocyte cryopreservation is recommended before chemotherapy.

34. Letrozole & ART: Oktayet al. compared, that use of tamoxifen alone or letrozole combined with low-dose FSH in women with breast cancer who desired embryo cryopreservation. The combination therapy was associated with lower peak E2 levels and a higher number of embryos . Adjunctive use of letrozole may also considered as a cost/effective IVF protocol in these patients .

35. DOSAGE

36. Dose of letrozole for ovulation-induction: Letrozole is given in a dose of 2.5–5 mg/day for 5 days starting on Day 2, 3, 4 or 5 of the cycle . There is no advantage to the use of 7.5 mg/day over 5 mg/day dose of Letrozole for induction of ovulation in women with PCOS.

37. SIDE EFFECTS

38. Side Effects • Side effects from letrozole are uncommon and related to suppression of the production of estrogens as a result of aromatase inhibition induced by the drug. • Side effects include hot flashes (11%), nausea (7%), fatigue (5%), alopecia and vaginal bleeding, which occur more frequently in breast cancer patients than in women treated for ovulation induction due to differences in the duration of treatment (Level I).