Linzagolix in Adenomyosis and Recurrent Implantation Failure

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)