This study investigates the presence of a possible link between treatment with danazol and expression of endometrial αvβ3 integrin which might allow tailoring of danazol treatment to the subset of repeated IVF/ET failure that might benefit most from it.

38 eligible ovulatory women were recruited aged 20 - 38 years with unexplained recurrent implantation failure (RIF). Timed suction endometrial biopsy was obtained from participants during the implantation window of the pretreatment cycle, followed by immunohistochemical staining for endometrial αvβ3 integrin expression, scored using H-score.

Participants were treated with danazol (Danol® 200mg capsules, Sanofi, Guildford, UK) in daily dosage of 400 mg for 12 weeks. Post-treatment suction endometrial biopsy was obtained during the implantation window following the first ovulation after danazol treatment and endometrial αvβ3 integrin expression was compared to the pretreatment cycle.

Inclusion Criteria:

• Age: 20-38 yrs
• Unexplained recurrent implantation failure (RIF), defined as failure to achieve an intrauterine gestational sac recognized by ultrasonography after transfer of at least four good-quality embryos (defined as those with four or five blastomeres on day 2, seven or more cells on day 3, ≤ 20% anucleated fragments and absence multinucleated blastomeres) in a minimum of three fresh or frozen IVF cycles after exclusion of other causes of RIF (as depicted by normal transvaginal ultrasonography, hysteroscopy, hysterosalpingography, laparoscopic findings, male and female karyotypic examination, endocrinological profile during ovarian stimulation and negative anti-cardiolipin antibody IgM/IgG, lupus anticoagulant, thrombophilia screening (including protein C, protein S, anti thrombin III and factor V leiden) and normal male semen analysis as depicted by 2010 WHO criteria for semen analysis and sperm DNA fragmentation testing).

Exclusion Criteria:

• Anovulation
• Contraindications to treatment with danazol (including chronic liver disease, congestive heart failure, dyslipidemia or history/current thrombo-embolic disease)
• Medical comorbidities (e.g. autoimmune disorders, diabetes mellitus, etc)
• Patients who underwent induction of ovulation / received hormonal treatment during the previous three months