Impact of Ultra-long Versus Long Down-regulation Protocol on IVF/ICSI in Adenomyosis

Adenomyosis is a benign condition defined as the invasion of ectopic endometrium into the myometrium, resulting in smooth muscle hyperplasia and endometrial inflammation, commonly associated with endometriosis and uterine fibroids.

Heterogeneity among studies regarding diagnostic criteria and therapeutic management has fed the debate surrounding the impact of adenomyosis on assisted reproductive therapy outcomes. Nevertheless, recent data support that adenomyosis impairs reproductive outcomes associated with in vitro fertilization (IVF). According to several experimental data, prolonged exposure to gonadotropin releasing hormone (GnRH) agonists may overcome part of the detrimental impact of adenomyosis on fertility outcome. Overall, GnRH agonist treatment resulted in decreased local production of cytochrome P450 aromatase, decreased intrauterine concentration of free radicals and reduced inflammatory response and angiogenesis in endometrium, myometrium and adenomyosis lesions. At the same time, GnRH agonists affect neither endometrial capacity to support invasion nor invasive potential of the blastocyst in the early stages of implantation.

For IVF, 2 main protocols based on GnRH agonist pituitary down-regulation are available:

* the long protocol involving a 15 days pituitary down-regulation;
* the ultra-long protocol involving a 3 months pituitary down-regulation. Most studies using ultra-long protocol reported similar IVF outcomes in adenomyosis patients and control groups. Conversely, studies involving long or GnRH antagonist protocols demonstrated a significant reduction in clinical and ongoing pregnancy rates in adenomyosis patients compared to control subjects. Thus supporting that ultra-long protocol may be beneficial to improve IVF outcomes in the setting of adenomyosis.This is what investigators would like to demonstrate in this study


Eligibility Criteria:
Inclusion Criteria:

1. suspected adenomyosis on high quality transvaginal ultrasound or focal or diffuse adenomyosis defined as a thickening of the junctional zone to more than 12mm on previous magnetic resonance Imaging (\<6 months)
2. infertility of any cause requiring IVF or ICSI
3. infertility period of at least 1 year except for women with history of deep infiltrating endometriosis or bilateral salpingectomy
4. age \>18 and \< 40 years
5. complete fertility workup comprising for women hormone serum measurement (anti-mullerian hormone (AMH), estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH)), high quality transvaginal ultrasound and, when applicable, hysterosalpingography, diagnostic laparoscopy or hysteroscopy
6. first or second IVF or ICSI attempt
7. absence of severe premature ovarian insufficiency defined by antral follicle count \< 8 and AMH \< 1ng/ml
8. meet the criteria from the French law to be included in an assisted reproductive technique program
9. informed written consent for both women and men
10. social security cover for both women and men

Exclusion Criteria:

1. absence of adenomyosis (defined as a thickening of the junctional zone to more than 12mm) on pelvic MRI
2. other potential causes of implantation failure: leiomyoma, endometrial polyp, not removed hydrosalpinx, malformed uterus (unicornis, bicornis, septate, duplex), antiphospholipid syndrome
3. medical contraindication to study treatments (GnRH agonist and add-back therapy)
4. women taking prohibited concomitant treatments and not able to stop them for the study period
5. medical contraindication to assisted reproductive technique and/or pregnancy including: uncontrolled type I and II diabetes; undiagnosed liver disease or dysfunction; renal insufficiency; history of deep venous thrombosis, pulmonary embolism or cerebrovascular accident; uncontrolled hypertension; known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial carcinoma, ovarian carcinoma or breast carcinoma; undiagnosed vaginal bleeding; genetic abnormalities
6. positive plasma viral load for human immunodeficiency virus(HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) for one (or both) in the couple during the year before inclusion
7. participation in another research study including an exclusion period which has not expired at the time of screening
8. patients subject to a judicial safeguard order, guardianship or trusteeship.