P-324 Effectiveness of letrozole in symptomatic women with adenomyosis undergoing IVF: An overview of clinical features, sonographic characteristics, and reproductive outcome
Authors: Sharma S , RoyChoudhury S , Bhattacharya M.P , Mitra I , Hazra S , Chakraborty P , Chaudhury K , Majhi A.K , Baidyanath C 
Published: June 2022

Abstract

Study question
Is letrozole pre-treatment a cost-effective option in improving symptoms, sonographic features, and reproductive outcomes in women with adenomyosis, undergoing IVF treatment?

Summary answer
Only two months of low dose letrozole pre-treatment is as effective as GnRH-agonist in symptomatic adenomyosis while significantly reducing the cost of treatment.

What is known already
About 20%–25% of women undergoing IVF present with adenomyosis and many of them suffer from dysmenorrhea and menorrhagia. Adenomyosis is often underdiagnosed and neglected uterine pathology which has a major bearing on the quality of life and fertility. Since adenomyosis is an estrogen-dependent disorder, letrozole, an aromatase inhibitor (controls estrogen production) is reported to be effective in improving symptoms of adenomyosis similar to GnRH-agonist but its role as before treatment IVF is unclear. Although GnRH-agonist is an established and effective pre-treatment option, is expensive and comes with the concerns like menopausal symptoms, increased gonadotropin doses, and duration of stimulation.

Study design, size, duration
This longitudinal, randomized cohort study was conducted at a tertiary-care hospital during June-2019 and November-2021. 194 adenomyosis women with symptoms undergoing fresh-cycle IVF, were screened and 147 recruited. These women were resistant to OCPs/progestins for symptomatic relief. 72 patients were treated with letrozole and 75 with GnRH-agonist for 2 months, and changes in their sonographic features and symptoms were evaluated before and after treatment. Reproductive outcomes were also compared between the treatment groups after IVF.

Participants/materials, setting, methods
Adenomyosis was diagnosed on 2D-TVS according to MUSA criteria. Among them, 72 patients were treated with 2.5 mg letrozole (only thrice weekly instead of conventional 2.5mg/daily) and 75 women were treated with GnRH-agonist depot (3.6mg/month) for 2 months. Patients were evaluated before and after 2 months of treatment for improvements in dysmenorrhea (VAS score) and menorrhagia (PBAC score), and quantitative scoring of sonographic features. Reproductive outcomes were also compared after both treatment.

Main results and the role of chance
The majority of women had 3-4 sonographic criteria on TVS (median of 3), such as irregular or interrupted junctional zone (79.49%), asymmetrical thickening of the myometrium (71.15%), globular uterus (43.59%), and myometrial cyst (33.33%). Significant reductions in the sonographic severity scores for diffuse adenomyosis, adenomyoma, and asymmetry in myometrial thickness were observed following both the treatment (p &lt; 0.05). The effects of both the treatments were comparable in terms of severity of sonographic features (p &gt; 0.05). Significant decreases in dysmenorrhea (letrozole: pre-7.76±1.6, post-1.74±0.58; GnRH-agonist: pre-7.92±2.1, post-0) and menorrhagia (letrozole: pre-169±31, post-73±18; GnRH-agonist: pre-171±25, post-12±6) were observed after 2 months in both the treatment (p &lt; 0.05). Since GnRH-agonist treated women experienced cessation of menstruation, the VAS and PBAC scores were not directly comparable between the groups after treatment. All fresh cycle IVF women were included to understand the effect of pre-treatment of these women. Following fresh cycle IVF, clinical pregnancy (23.61%, 25.33%), miscarriage rate (35.29%, 36.84%), and live birth rate (12.5%, 13.33%), respectively for letrozole and GnRH-agonist groups were comparable (p &gt; 0.05). The cost of the treatment was 19 times less with letrozole pre-treatment when compared with GnRH-agonist, while a comparable reduction in symptoms and IVF outcome parameters were observed.

Limitations, reasons for caution
A possible limitation is the lack of a proper blinding due to different routes of administration of the therapies. In the absence of a standardized classification of severity, we have used the TVS based scoring proposed by Lazzeri et al (2018), which is not universally accepted or independently validated.

Wider implications of the findings
Low-dose letrozole pre-treatment for 2 months is an attractive option before IVF for symptoms relief and comparable reproductive outcome to that of GnRH-agonist but with lower cost and without over-suppression of pituitary. This protocol may also be extended to women in general who are suffering from symptomatic adenomyosis.

Trial registration number
CTRI/2019/01/016919 [04/01/2019]