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| EDITORIAL |
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| Year : 2021 | Volume
: 2
| Issue : 1 | Page : 1-4 |
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Letrozole: The ovulogen of first choice
Mayoukh Kumar Chakraborty1, Gautam Khastgir2
1 Department of Obstetrics and Gynaecology, KPC Medical College and Hospital, Kolkata, West Bengal, India
2 BIRTH Fertility Clinic, Kolkata, West Bengal, India
| Date of Submission | 27-Dec-2020 |
| Date of Acceptance | 16-Feb-2021 |
| Date of Web Publication | 28-May-2021 |
Correspondence Address:
Mayoukh Kumar Chakraborty
Department of Obstetrics and Gynaecology, KPC Medical College and Hospital, Kolkata, West Bengal
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jssrp.jssrp_9_20
How to cite this article:
Chakraborty MK, Khastgir G. Letrozole: The ovulogen of first choice. J Surg Spec Rural Pract 2021;2:1-4 |
Polycystic ovarian syndrome (PCOS) is common and complex metabolic disorder, which affects about 9%–18% of females in the reproductive age group and nearly about 80% among women with anovulatory infertility.[1] PCOS is categorized as Group II ovulation disorder according to the World Health Organization (WHO).
In women with normally functioning hypothalamic-pituitary-ovarian axis (HPO) the major cause of anovulatory infertility is PCOS. The fundamental mechanism in PCOS is elevated or normal but static level of estrogen (E2), which through a negative feedback mechanism on the HPO axis inhibits the adequate release of follicle-stimulating hormone (FSH) by the pituitary. As a result, there is inadequate growth and development of ovarian follicles. In addition, the elevated level of E2 by positive feedback mechanism on the HPO axis results in tonic increased state of luteinizing hormone (LH) also from the pituitary. Therefore, no LH surge occurs which results in anovulation [Figure 1]. According to the “two triangle hypothesis” for folliculogenesis in PCOS, preantral follicle growth is excessive due to intrinsic androgen excess that renders granulose cells hypersensitive to FSH, with consequently excessive anti-MüRllerian hormone expression.[2]
The main aim of any ovulation induction drug is to result in monofollicular development with minimal risk of multiple pregnancies and without any chance of resistance. Clomiphene citrate (CC) had been the first-line drug for ovulation initiation over the past five decades. However, about 20%–25% of females do not ovulate with CC resulting in its resistance. In these cases, gonadotrophins are highly effective but with the possibility of multiple pregnancies and ovarian hyperstimulation syndrome. However, supraphysiological levels of E2 are an unwelcome side effect with both CC and gonadotrophins. Elevated E2 levels can lead to asynchrony between the endometrium and maturation of the embryo during the “implantation window” period. Laparoscopic ovarian drilling (LOD) is also advocated as option in CC-resistant cases, but it requires skill and adequate infrastructure with probable threat of lowering the ovarian reserve by damaging healthy ovarian tissue.
CC remains bound with estrogen receptors for 60 days due to its longer half-life. If CC does not result in ovulation, any other ovulation-inducing drug cannot be administered during this period. Although CC induces ovulation in 70%–85% of patients, only about 20%–40% of patients get pregnant, with a success rate of about 10%–20% per treatment cycle. In addition, almost 20%–25% of anovulatory females are resistant to CC. Moreover, CC has unfavorable effects on cervical mucous and endometrial thickness because of its anti-estrogenic property.[3] Furthermore, the prevalence of miscarriage after CC treatment is around 23.6%. This can be explained by the fact that extended use of CC leads to reduced uterine blood-flow during peri-implantation and luteal phase. Supra-physiological increased serum LH levels, collectively with premature luteinization and high serum E2 state during the cycle may result in miscarriage or nonconception [Figure 2].
Letrozole is an aromatase inhibitor, which inhibits estrogen synthesis thereby relieving the HPO block and release of pituitary FSH. This helps to restore ovulation and thereby normal ovulatory cycle. It is a third-generation aromatase inhibitor and repress estrogen synthesis by reducing the conversion of androgens to estrogen. As a result, there is increased secretion of FSH and accumulation of androgens within ovaries.
Letrozole is currently the first-line ovulogen in women with PCOS, particularly in CC-resistant cases. For the activation of folliculogenesis, letrozole causes temporary inhibition of estrogen synthesis thus allowing increased release of FSH.[4] Hypoestrogenic level is fast reversible because of the small half-life of letrozole (45 h). In addition, there is no anti-estrogenic effect on the endometrium and cervix. Moreover, increase in testosterone level is helpful as it increases follicular sensitivity to gonadotrophin [Figure 3].
A well-designed double-blind multicenter randomized controlled trial evaluating letrozole versus CC for infertile women with PCOS showed that Letrozole was superior along with a better ovulation rate and high live birth rate.[5] A meta-analysis of 4999 cycles of ovulation (2455 with letrozole, 2544 with CC) also revealed high pregnancy rate and live birth in the letrozole arm.[6] When CC-resistant PCOS women were compared between letrozole therapy and LOD treatment, the results were very similar between two groups.[7] Hence, letrozole could be first-line treatment in women with PCOS in general and definitely for CC-resistant cases. Letrozole outcomes are superior due to synchronized follicular and endometrial growth.
A network meta-analysis compared available first-line treatment options for women with PCOS with infertility and found that letrozole and combined CC– metformin were superior to other ovulation induction medications in terms of clinical pregnancy and that letrozole resulted in more live births than other interventions, including CC.[8]
The recent evidence-based guidelines for PCOS patients, developed by an international collaboration between three partners: Australian CRE-PCOS, ESHRE, and ASRM, have suggested pharmacological therapy for ovulation induction in infertile women with PCOS. This evidence-based review clearly states that letrozole should be used as first-line pharmacological treatment for ovulation induction [Figure 4] to increase ovulation, pregnancy, and live birth rates.[9]  | Figure 4: Algorithm for organization of infertility in polycystic ovarian syndrome[9]
Click here to view |
An individual participant data (IPD) meta-analysis is considered as the gold standard for evidence analysis by providing accurate assessments of outcomes and allows additional analysis of time-to-event outcomes. It also facilitates treatment– covariate interaction analyses and therefore offers an opportunity for personalized medicine.
A recent IPD meta-analysis of infertile women with PCOS showed that letrozole when compared to CC improved both live birth and clinical pregnancy rates [Figure 5] as well as reduced time to pregnancy [Figure 6]. Therefore, it can be recommended as the preferred first-line treatment for women with PCOS and infertility.[10] It was also evident that the treatment effects of letrozole were influenced by baseline serum levels of total testosterone [Figure 7]. | Figure 5: Meta-analyses of letrozole versus clomiphene citrate on live birth and clinical pregnancy
Click here to view |
 | Figure 6: Summary of Kaplan–Meier curve for time-to-event outcome on letrozole versus clomiphene citrate
Click here to view |
 | Figure 7: Forest plot of interaction between baseline serum, total testosterone level, and effect of letrozole versus clomiphene citrate on live birth
Click here to view |
Several studies have now concluded that letrozole improves live birth and clinical pregnancy rates as well as reduces time to pregnancy compared to CC alone in infertile women with PCOS. The treatment effects of letrozole are influenced by baseline serum levels of total testosterone and such findings provide further insights into a personalized approach toward the clinical management of anovulatory infertility related to PCOS and therefore should be confirmed in future studies. At present, letrozole is the “wonder drug” for ovulation induction in anovulatory PCOS, considering its advantages of mono follicular growth and considerably minimal effect on the endometrium. It has also been confirmed that letrozole is as efficacious as LOD in CC-resistant PCOS. Therefore, what can be better than taking an oral medication with minimum side effects for infertile women with PCOS.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | |  |
| 1. | Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: An analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update 2016;22:687-708.  |
| 2. | Dewailly D, Robin G, Peigne M, Decanter C, Pigny P, Catteau-Jonard S. Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary. Hum Reprod Update 2016;22:709-24. |
| 3. | Gadalla MA, Huang S, Wang R, Norman RJ, Abdullah SA, El Saman AM, et al. Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: Systematic review and meta-analysis. Ultrasound Obstet Gynecol 2018;51:64-76. |
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| 7. | Liu W, Dong S, Li Y, Shi L, Zhou W, Liu Y, et al. Randomised control trial comparing Letrozole with laparoscopic ovarian drilling in women with clomiphene citrate-resistant polycystic ovary syndrome. Exp Ther Med 2015;10:1297-302. |
| 8. | Wang R, Kim BV, van Wely M, Johnson NP, Costello MF, Zhang H, et al. Treatment strategies for women with WHO Group II anovulation: Systematic review and network meta-analysis. BMJ 2017;356:j138. |
| 9. | Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod 2018;33:1602-18. |
| 10. | Wang R, Li W, Bordewijk EM, Legro RS, Zhang H, Wu X, et al. First-line ovulation induction for polycystic ovary syndrome: An individual participant data meta-analysis. Hum Reprod Update 2019;25:717-32. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
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