Adenomyosis is associated with impaired endometrial receptivity and reduced implantation rates in assisted reproduction, even when using high-quality embryos. Linzagolix (Yselty, 200 mg) is an oral GnRH receptor antagonist approved for uterine fibroids with a favourable tolerability profile and rapid elimination half-life (18-20 hours) compared to GnRH agonists.

This prospective case series evaluates the efficacy of linzagolix 200 mg administered for 3 to 6 months prior to embryo transfer in patients with confirmed adenomyosis and recurrent implantation failure (RIF), defined as ≥2 failed transfers with high-quality blastocysts (≥BB Gardner in oocyte donation, or PGT-A confirmed euploid in autologous cycles).

The primary endpoint is the live birth rate (LBR) per embryo transfer. Secondary endpoints include clinical pregnancy rate, miscarriage rate, morphological response of adenomyosis (uterine volume and junctional zone [JZ] thickness assessed by standardised transvaginal ultrasound), and tolerability profile. The study also explores the optimal treatment duration (3 vs 6 months) as a sub-analysis based on morphological response at the month-3 visit.

The study is conducted at three centres of Vida Fertility Institute (Madrid, Alicante and San Sebastián, Spain). Sample size: n=35 patients. Study duration: 24 months.

BACKGROUND:

Current standard of care for adenomyosis prior to embryo transfer in RIF patients consists of GnRH agonist therapy (triptorelin depot) for 1-3 months, with or without letrozole. This approach requires intramuscular administration, is associated with intense vasomotor symptoms, and has a prolonged pharmacological residual effect (4-6 weeks) that complicates cycle planning. No prospective study has evaluated linzagolix in this specific clinical scenario.

DESIGN:

Prospective before-after case series. Each patient serves as her own historical control (prior failed transfers under standard care vs outcome after linzagolix treatment). Treatment duration (3 or 6 months) is determined by morphological response at the month-3 ultrasound visit. Endometrial preparation is initiated 7 days after the last dose of linzagolix.

ULTRASOUND PROTOCOL:

Standardised transvaginal ultrasound measurements at each visit: uterine volume (L x AP x T x 0.523 cm3), junctional zone maximum (mm), junctional zone minimum (mm) and junctional zone difference (mm). All measurements performed in strict sagittal plane with ≥7 MHz transvaginal probe.

VASOMOTOR SYMPTOM MANAGEMENT:

Standardised non-estrogenic supplementation protocol (Cimicifuga racemosa 20 mg, Remifemin) if EVA score ≥4 for hot flushes or insomnia. Suspended simultaneously with the last dose of linzagolix.

REGULATORY FRAMEWORK:

Observational study with medicinal products (EOMF) under Spanish Royal Decree 957/2020. Use of linzagolix in this indication is off-label. Study approved by CEIm del Hospital Clinico San Carlos, Madrid.

Inclusion Criteria:

• Age 18 to 50 years
• Confirmed adenomyosis by transvaginal ultrasound or MRI
• Recurrent implantation failure defined as 2 or more failed embryo transfers with high-quality blastocysts: oocyte donation recipients (blastocyst grade BB or above, Gardner classification) OR autologous IVF cycles with PGT-A confirmed euploid blastocysts
• Normal uterine cavity with no submucosal distortion
• At least 1 suitable embryo available for transfer (blastocyst grade BB or above, or PGT-A euploid)
• Signed written informed consent including explicit acknowledgement of off-label use of linzagolix

Exclusion Criteria:

• Untreated hydrosalpinx
• Untreated stage III-IV endometriosis
• Major uterine anomaly (uterine septum, bicornuate uterus)
• Known contraindication to linzagolix including known hepatopathy
• Prior treatment with linzagolix
• GnRH analogue treatment within 6 months prior to enrolment
• BMI greater than 35 kg/m2
• Prior failed transfers exclusively with embryos below the quality threshold (below BB grade, non-euploid)

Female only. The study population consists exclusively of women undergoing assisted reproduction treatment for infertility associated with adenomyosis.

Women aged 18 to 50 years with confirmed adenomyosis (transvaginal ultrasound or MRI) and recurrent implantation failure, defined as 2 or more failed embryo transfers with high-quality blastocysts (grade BB or above in oocyte donation cycles, or PGT-A confirmed euploid blastocysts in autologous cycles), attending Vida Fertility Institute centres in Madrid, Alicante and San Sebastian, Spain.

Individual participant data will not be shared at this stage due to the small sample size and the need to protect patient privacy in accordance with the General Data Protection Regulation (GDPR, EU 2016/679) and Spanish Organic Law 3/2018 on Personal Data Protection. Anonymised aggregate data may be made available upon reasonable request following publication of the primary results.