The goal of this clinical trial is to:

• Prospectively investigate the association of Adenomyosis with fertility outcomes in relation to COH protocols for ART (long or ultra- long protocol) with a preventive high-dose anti-inflammatory progestin such as DNG and to assess their association with pregnancy and neonatal outcomes (preterm delivery,pre-eclampsia,Caesarean section,fetal malpresentation,small for gestational age,low birth weight and postpartum hemorrhage).
• Understand how the endometrial interface by studying the response of progesterone and DNG stimulated decidualization markers, correlating them with the success of ART protocol stimulation and to pregnancy specific outcomes
• Evaluate the immune changes during the implantation period and in the different trimesters of the pregnancies after ART conception.

Adenomyosis (internal endometriosis) may negatively influence fertility and perinatal outcomes. Inflammation, immune modulation, oxidative stress, extracellular matrix remodelling, aberrant angiogenesis have been implicated in altered oocyte development, uterine receptivity, implantation, successful maintenance of pregnancy. An improvement for infertile women could be a longer GnRH(gonadotropin-releasing hormone) agonist protocol with the addition of a preventive high-dose progestin treatment during controlled ovarian hyperstimulation (COH) Infertile women with transvaginal ultrasound (TV-US) based diagnosis of adenomyosis treated will be randomized into 3 different protocols of COH. Study group 1: Long COH, Study group 2: Long COH + high-dose dienogest (DNG), Study Group 3: Ultra-long COH. COH in controls without adenomyosis will be performed using a long GnRH agonist protocol as previous described or using a flexible GnRH antagonist protocol, according to clinical practice. Our aim is to include a total of n=250 women with adenomyosis and n=250 healthy women of a similar age and basal features at the first ART attempt. The primary outcome will be the number of live birth defined as delivery of one or more live-born infant at > 22 weeks of gestation. Many secondary outcomes will be evaluated as well.

Subsequent eventual ongoing pregnancies will be followed as in normal clinical practice, in particular for the risk of preterm delivery, pre-eclampsia, Caesarean section, fetal malpresentation,small for gestational age, low birth weight and postpartum hemorrhage. In a subgroup of randomized women, the role of endometrial decidualization and its mechanisms will be evaluated in endometrial cells in vitro looking at the response to progesterone and DNG stimulated decidualization markers (in particular osteopontin and prolactin). The different responses will be related to the outcome of ARt and pregnancy related outcomes (preterm delivery, pre-eclampsia, Caesarean section, fetal malpresentation, small for gestational age, low birth weight and postpartum hemorrhage).

Another in vitro study will evaluate the immune system contribution in the implantation period and its changes in the different trimesters of pregnancies after ART conception in women with and without adenomyosis. Blood samples will be obtained - Baseline: prior to ovarian stimulation - Post ovarian stimulation (day of HCG, human chorionic gonadotropin, administration) - Post implantation (2 weeks after embryo transfer, the day of first beta HCG measurement -Second (18-24 gestational weeks) and -Third trimester (28-32 gestational week) of eventual subsequent pregnancies).

The aim of this study will be to identify immunological markers such as cellular component and related cytokines in healthy women and women with adenomyosis that undergo ART. In particular the immune system cells population and relative cytokines, the frequency of immune system cells, the interleukins profile, T cells activity and of specific receptors of pregnancy hormone involved in T cell activity will be studied. These results will be linked with estradiol, progesterone and nitric oxide in vivo levels: this will be very important in order to prevent birth losses and to propose new therapies and targets to improve early stages of blastocyst implantation in women with adenomyosis. Forty women with adenomyosis vs. 40 healthy controls will be included in this last part of the study.

Inclusion Criteria:

• Adenomyosis of the uterus defined with at least one of the following features: (1) heterogeneous myometrium; (2) hypoechoic striation in the myometrium; (3) myometrial anechoic lacunae or cysts; (4) asymmetrical myometrial thickening of the uterine walls.
• Couples who are undergoing a cycle of IVF/ICSI, where a cycle is defined as egg collection following ovarian stimulation.
• First or second IVF or ICSI attempt.
• Absence of severe premature ovarian insufficiency defined by antral follicle count < 8 and AMH (anti-mullerian hormone) < 1ng/ml
• Meet the criteria from the Italian law to be included in a ART program.
• The female partner is ≥18 and < 42 years of age.
• The female partner has a BMI <30.
• Both partners are willing and able to provide written informed consent.

Exclusion Criteria:

• Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within the previous 3 months of study enrolment.
• Other potential causes of implantation failure: in situ leiomyoma, hydrosalpinx, malformed uterus (unicornis, bicornis, septate, duplex), antiphospholipid syndrome
• Uterine fibroids (untreated FIGO, International Federation of Gynecology and Obstetrics, Type 0-I-II and type III-IV fibroids > 3 cm)
• Use of GnRH analogues within previous 3 months.
• Extremely severe male factor infertility (sperm count < 1x 10 6 /ml, use o surgically retrieved spermatozoa)
• 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
• Couples unable to give fully informed consent to the study.