Controlled ovarian stimulation for IVF in women with advanced endometriosis

1. Why does one have to think differently for controlled ovarian stimulation (COS) in women undergoing IVF (In Vitro Fertilization) with endometriosis?

This is because of many reasons; but two important ones are low ovarian reserve which may occur eithear due to ovarian disease and/or surgery and poor oocyte quality owing to oocytes coming from a diseased and inflamed ovary. Furthermore, the implantation rates and pregnancy rates may also be negatively affected because of impaired endometrial receptivity due to lowered expression of HOXA 10 and ąvβ3 integrins or associated adenomyosis

2. What does one need to consider while developing an ideal protocol for IVF in endometriosis?

The aim of an ideal protocol is to get a good number of high-quality oocytes as well as the best endometrium for implantation. Two standard protocols have been used for controlled ovarian stimulation (COH) for IVF across all continents. The first and the older one is long GnRH-agonist protocol and the second and newer is short GnRH antagonist protocol. However, the second one has replaced the first long protocol in most centres across the world because of its ease of administration, lower number of injections required and a very low complication rate especially regarding the occurrence of ovarian hyperstimulation syndrome (OHSS). Nevertheless, both protocols when used in women in endometriosis have similar IVF outcomes. as the actual impact of GnRH analogues used during COH is on ovarian hormonal control and not on oocyte and embryo quality.

3. Why do we need pre-treatment before COS for IVF in these patients with endometriomas?

Pre-treatment, before starting COH with antagonist protocol, is a good option in all women undergoing IVF to have an equal cohort of gonadotropin sensitive antral follicles. This equalisation of antral follicles naturally happens in women being treated by the long GnRH agonist protocol. However, in women with advanced endometriosis there appears an additional need for further pre-treatment to reduce the inflammatory environment and cytokine excess which is always there due to presence of endometriotic implants. This pre-treatment may consist of either surgical removal of endometriomas or medical treatment which may need to be extended for a few months before COS is initiated.

4. What are the types of pre-treatments which can be given to women with advanced endometriosis before COS for IVF?

The pre-treatment is of 2 types.

Surgical and medical

Surgical pre-treatment is preferred in following conditions:

  • Endometrioma larger than 4 cm with no previous surgery
  • Diagnosis of endometrioma in doubt
  • Large hydrosalpinx with bilaterality
  • Follicles or ovarian cortex distal to cyst from the vaginal wall and the ultrasound probe
  • Normal ovarian reserve and young patient

Medical pre-treatment is preferred in the following conditions:

  • Previous surgery/surgeries for endometriosis
  • First time endometriomas less than 4cm
  • Compromised ovarian reserve
  • Advanced age
5. What medical treatment is already proven to be effective for this purpose and for how long should it be given before starting COS?

Historically, the only medical treatment tried in women with advanced endometriosis had been the prolonged use of depot preparations of GnRH agonist to create very low estrogenic environment which possibly led to better IVF outcome in terms of clinical pregnancy and live birth rates.

Mechanisms of action of prolong GnRH agonist in endometriosis:

  • Suppression of ovulation reduces exposure of endometriotic implants to a growth factor called midkine in follicular fluid involved in proliferation of endometriotic cells
  • Direct inhibition of proliferation of endometriotic cells by regulation of apoptotic and angiogenic mechanisms
  • Inhibition of menstruation reduces exposure to thrombin and its protease activated receptor; factor which leads to cell inflammation
  • Inhibition of uterine contractions further blocks mechanical stress

Cochrane Database Systemic Review in 2006 by Sallam et al, concluded on the evidence available then, that administration of GnRH agonists for period of 3-6 months prior to IVF or ICSI caused 4-fold increase in clinical pregnancy rate & 9-fold increase in live birth rate. This analysis was based on 3 randomised control trials which included 165 women. After this review the ultra- long protocol was considered ideal for endometriosis as evidence showed statistical improvement in the oocyte quality, embryo quality and implantation rates.

However, contrary to previous findings, the latest Cochrane review done by Georgiou EX et al in 2019 raised questions on the impact of long-term GnRH agonist therapy on the live birth rate and complication rates compared to the regular COS protocols. This review superseded the previous review by Sallam et al done in 2006.

The present Cochrane review compared the prolonged GnRH agonist pre-treatment to no pre-treatment and has been uncertain whether long-term GnRH agonist therapy prior to IVF/ICSI in women with endometriosis affects the live birth rate. The evidence suggests that if the chance of live birth rate is assumed to be 36% with no pre-treatment, the chance following long-term GnRH agonist therapy would be between 9% and 31%. It is also uncertain whether this intervention imparts any benefits regarding complication rate, clinical pregnancy rate, multiple pregnancy rate, miscarriage rate as well as in the mean number of oocytes and embryos obtained.

Considering the paucity and very low quality of existing data, particularly for the primary outcomes examined, further high-quality trials are required to definitively determine the impact of long-term GnRH agonist therapy on IVF/ICSI outcomes in women with endometriosis.

In 2020 a meta-analysis was published by Cao, X et al. in Reproductive Biology and Endocrinology comparing the ‘Effectiveness of different down-regulating protocols on in vitro fertilization-embryo transfer in endometrioses: a meta-analysis’ which included a total of 21 studies in compliance with the standard literature. Randomised and non-randomised trials were analysed separately. Subjects of study were women diagnosed with endometriosis by laparoscopy, laparotomy, or transvaginal aspiration of the ovarian endometrial cyst.

The results showed that GnRH-a ultra-long protocol could improve the clinical pregnancy rate of infertile patients in studies analysed from randomised control trials, especially in patients with stages III–IV endometriosis (RR = 2.04, 95% CI: 1.37~3.04, P < 0.05).

Nevertheless, subgroup analysis found the different down-regulation protocols provided no significant difference in improving clinical outcomes in patients with endometriosis in the non-RCT studies.

6. What are the other medical methods being explored for pre-treatment in women with advanced stage endometriosis undergoing COS for IVF?

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.

7. What is the message for women with advanced endometriosis undergoing COS for IVF?
  • 1. COS for IVF in women with endometriosis is like those without endometriosis and dose of gonadotropin and protocol depends on the age, ovarian reserve, and previous response to stimulation.
  • 2. Attention is now focusing on pre-treatment in women with high stage endometriosis to reduce the proinflammatory detrimental effect of the disease on oocyte, embryo, and endometrium.
  • 3. The first drug used for this purpose was depot GnRh agonist for 3 to 6 months. However, a plethora of newer cost effective and easy to administer drugs are being tried with the same aim of reducing proliferation, vascularization, and inflammation of these endometriotic implants.
  • 4. IVF appears to be first choice of treatment in women with advanced endometriosis desiring conception and have been trying to conceive seriously over a period. Medical treatment should only be used as pre-treatment to IVF and surgical treatment only if mandatory.


  • 1. Cochrane Database Systemic Review .2006(Jan);1:CD004635. Salem et al;
  • 2. Georgiou EX, Melo, P, Baker PE, Sallam HN, Arici A, Garcia-Velasco JA, Abou-Setta AM, Becker C, Granne IE. Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis 2019 10.1002/14651858.CD013240.pub2; Cochrane Database of Systematic Reviews.
  • 3. Cao X, Chang HY, Xu JY, Zheng Y, Xiang YG, Xiao B, Geng XJ, Ni LL, Chu XY, Tao SB, He Y, Mao GH. The effectiveness of different down-regulating protocols on in vitro fertilization-embryo transfer in endometriosis: a meta-analysis. Reprod Biol Endocrinol. 2020 Feb 29;18(1):16.
  • 4. Fabio Barra, Antonio Simone Laganà, Carolina Scala, Simone Garzon, Fabio Ghezzi, Simone Ferrero, Pre-treatment with dienogest in women with endometriosis undergoing IVF after a previous failed cycle, Reproductive Bio Medicine Online, Volume 2020; 41(5):859-868.
  • Cantor A, Tannus S, Son WY, Tan SL, Dahan MH. A comparison of two months pre-treatment with GnRH agonists with or without an aromatase inhibitor in women with ultrasound-diagnosed ovarian endometriomas undergoing IVF. Reprod Biomed Online. 2019 Apr;38(4):520-527.
  • 6. van der Houwen LEE, Lier MCI, Schreurs AMF, van Wely M, Hompes PGA, Cantineau AEP, Schats R, Lambalk CB, Mijatovic V. Continuous oral contraceptives versus long-term pituitary desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial. Hum Reprod Open. 2019 Feb 23;2019(1):hoz001.

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