Limitations of prolonged down-regulation compel clinicians to avoid using this protocol too often. On one side it is time consuming and delays IVF by 3 to 6 months and on the other side it may over suppress ovaries leading to diminished ovarian response especially in poor responders. Therefore, other medical methods are being explored to minimize negative effect of endometriosis on oocytes.
- Dienogest for 3 months prior to COS
- Oral contraceptive pills for 6 to 8 weeks prior to COS
- Two monthly doses of injectable GnRH agonist depot with letrozole for 2 months as pre-treatment
Dienogest as pre-treatment:
Dienogest is a progestogen with no estrogenic activity. In addition, it also has anti-inflammatory and anti-angiogenic activity, and it is felt that its prolonged use may lead to better implantation rates. To see the benefit of this drug as a pre-treatment agent before COS in women with advanced endometriosis undergoing IVF, retrospective analysis of prospectively collected database of 151 women was done. These women had failed a previous IVF cycle and all subsequent embryo transfers and had an imaging diagnosis of endometriosis. Patients either underwent IVF without receiving hormonal treatment or received 3 months of treatment with DNG (2 mg/daily) before COS for IVF. All patients receiving DNG were assigned to long protocol with 21 days of daily GnRH agonist administration in the last 3 weeks of the 3-month pre-treatment and were also kept dienogest free in last 2 weeks before starting COH.
The results showed that the largest diameter of endometriomas significantly decreased after DNG pre-treatment (P < 0.001). The use of DNG also increased the number of oocytes retrieved significantly (P= 0.031), two-pronuclear embryos (P = 0.039) and blastocysts (P = 0.005) in women with endometriomas of diameter ≥4 cm.
This study suggests that in patients with endometriosis, IVF outcomes can be improved by pre-treatment with DNG. In particular, the use of DNG allows for better oocyte retrieval and blastocysts conversion in patients with large endometriomas. The cumulative implantation, clinical pregnancy and live birth rates were significantly higher in the DNG-treated group.
Oral contraceptive pills for 6 to 8 prior to COS:
It has been speculated that long-term pituitary desensitization with a GnRH agonist for 3-6 months prior to IVF/ICSI improves clinical pregnancy rates in women suffering from endometriosis. Alternatively, IVF/ICSI pre-treatment with continuously administered oral contraceptives may offer fewer side-effects and lower indirect costs, as well as encouraging IVF outcomes in women with endometriosis. To date, these two different IVF/ICSI pre-treatment strategies in women with endometriosis have not been directly compared.
A study has been designed with the title ‘Continuous oral contraceptives versus long term pituitary desensitization prior to IVF-ICSI in moderate to severe endometriosis: A non-inferiority randomised controlled trial’. in an open access publication in Human Reproduction Open. pp 1 to 8. 2019. The sample size calculation is rounded off to 165 patients per group; 330 patients in total will be included. After informed consent, web-based block randomization will be stratified per centre. The protocol for this study has been laid down which is expected to be complete in 3-5 years. This study aims to see and compare the effectivity of OCP pre-treatment in an open-label, parallel two-arm randomized controlled. multicentre trial, which will only include patients with moderate to severe endometriosis.
GnRh agonist with letrozole:
The use of 2 drugs has been analysed in a trial titled ‘A comparison of 2 months of pre-treatment with GnRh agonist depot with or without the addition of letrozole in women undergoing IVF with ultrasound diagnosed endometrioma’ by Arielle Cantor and published in volume 38 issue 4 in RBMO 2019.
To answer the question that, does the addition of an aromatase inhibitor improve IVF outcomes in women with endometriomas when pre-treating them with gonadotrophin-releasing hormone agonists’, a retrospective two-centre cohort study was analysed. This analysis was done for 126 women aged 21–39 years who failed a previous IVF cycle and all subsequent embryo transfers and had sonographic evidence of endometriomas. Women were non-randomly assigned to either 3.75 mg intramuscular depo-leuprolide treatment alone or in combination with 5 mg of oral letrozole daily for 60 days prior to undergoing a fresh IVF cycle. Main outcome measures included clinical pregnancy rate and ongoing pregnancy rate after 24 weeks’ gestation. Prior to treatment, antral follicle count (AFC), basal serum FSH and endometrioma diameter did not differ between groups. After treatment, AFC differed between letrozole and non-letrozole-treated groups (10.3 ± 2.0 versus 6.4 ± 2.5; P = 0.0001), as did mean endometrioma maximum diameter (1.8 ± 0.4 cm versus 3.2 ± 0.8 cm; P = 0.0001). At IVF, the gonadotrophin dose used was significantly lower in letrozole-treated subjects (2079 ± 1119 versus 3716 ± 1314; P = 0.0001), the number of mature oocytes collected was greater (9.1 ± 2.4 versus 4.0 ± 1.7; P = 0.0001), as were the number of two-pronuclear embryos and number of blastocysts. The clinical pregnancy rate was significantly higher in the letrozole-treated group (50% versus 22%, P = 0.003), as was the live birth rate (40% versus 17%, P = 0.008).
Therefore, it looks worthwhile to try the combination of depo-leuprolide acetate monthly for 60 days with daily letrozole for the same duration in women with endometriomas rather than depo-leuprolide acetate treatment alone for 2 months.