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. Treatment extension to 6 months is indicated if any of the following criteria are met at month 3: uterine volume reduction <20% from baseline, JZ maximum ≥12 mm, JZ difference ≥5 mm, or serum estradiol >40 pg/ml indicating incomplete hypothalamic-pituitary-ovarian axis suppression. 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 (ref. 26/769-O_M_SP, October 13, 2026)."

• Linzagolix 200 mg (Yselty) (Drug), also known as Yselty, GnRH receptor antagonist: Linzagolix 200 mg orally once daily for a minimum of 3 months, extendable to 6 months based on morphological response (uterine volume and junctional zone assessment) and serum estradiol levels (>40 pg/ml) at the month-3 visit.O ff-label use for adenomyosis prior to embryo transfer.

Primary outcomes

• Live Birth Rate (LBR) per embryo transfer [Up to 12 months after embryo transfer]: Proportion of embryo transfers resulting in the birth of a live neonate at or beyond 24 weeks of gestation.

Secondary outcomes

• Clinical Pregnancy Rate [6-7 weeks after embryo transfer]: Proportion of embryo transfers resulting in the presence of an intrauterine gestational sac with fetal heartbeat on transvaginal ultrasound at 6-7 weeks of gestation.
• Miscarriage Rate [Up to 22 weeks of gestation]: Proportion of clinical pregnancies ending in spontaneous pregnancy loss before 22 weeks of gestation.
• Change in Uterine Volume [Baseline, month 3, month 6 (if applicable) and pre-transfer (approximately 3-7 months from baseline)]: Change in uterine volume (cm3) measured by transvaginal ultrasound using the ellipsoid formula (L x AP x T x 0.523) from baseline to post-treatment.
• Change in Junctional Zone Maximum Thickness [Baseline, month 3, month 6 (if applicable) and pre-transfer (approximately 3-7 months from baseline)]: Change in junctional zone (JZ) maximum thickness (mm) measured by standardised transvaginal ultrasound in strict sagittal plane from baseline to post-treatment.
• Incidence of Vasomotor Adverse Events [Monthly during treatment period (up to 6 months)]: Proportion of patients reporting hot flushes, insomnia or other vasomotor symptoms, assessed using a visual analogue scale (EVA 0-10) at each visit.
• Serum estradiol levels [Baseline, month 1, month 3, month 6 (if applicable).]: Serum estradiol levels (pg/ml) measured at baseline, month 1, month 3 and month 6 to assess degree of hypothalamic-pituitary-ovarian axis suppression during linzagolix treatment.
• Hepatic safety [Baseline, month 3, month 6 (if applicable).]: Hepatic function parameters (ALT, AST, GGT and total bilirubin) measured at baseline, month 3 and month 6 to assess liver safety during linzagolix treatment.

Sex: Female, ages: 18 Years to 50 Years

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)