Do patients with adenomyosis respond to Progynova (estradiol) in Hormone Replacement Therapy (HRT) Frozen Embryo Transfer (FET) cycles?

Endometrial Response to Progynova in Adenomyosis Patients During HRT-FET Cycles

Patients with adenomyosis respond to Progynova (estradiol) in HRT-FET cycles with similar endometrial preparation and progesterone requirements as patients without adenomyosis, and do not require higher progesterone levels to achieve live births. 1

Evidence for Normal Estrogen Response

The most recent and highest quality evidence demonstrates that women with adenomyosis achieve comparable live birth rates (32.0% vs 31.2%) in HRT-FET cycles compared to unaffected women, with no difference in progesterone levels required on transfer day (13.6 ± 4.3 ng/ml vs 13.2 ± 4.4 ng/ml, P = 0.302). 1 This finding held true even in subgroups with deep infiltrating endometriosis (13.1 ± 4.1 ng/ml) and adenomyosis specifically (12.6 ± 3.7 ng/ml). 1

The presence of adenomyosis does not impair endometrial response to exogenous estradiol (Progynova) during HRT-FET preparation. 1

Important Caveat for Severe Adenomyosis

However, a critical exception exists for patients with severe adenomyosis:

• Women with severe adenomyosis may present with persistent hyperestrogenism due to local estrogen production from adenomyotic lesions, even after long-term GnRH agonist suppression (≥3 months). 2
• In these cases, standard HRT protocols may be insufficient because the adenomyotic tissue itself produces estrogen independent of exogenous supplementation. 2
• Serum estradiol levels should be measured in patients with severe adenomyosis before proceeding with HRT-FET, particularly if they have experienced previous embryo transfer failures. 2

Clinical Algorithm for HRT-FET in Adenomyosis

For Mild-to-Moderate Adenomyosis:

• Proceed with standard HRT-FET protocol using Progynova for endometrial preparation 1
• Use standard micronized vaginal progesterone dosing 1
• Measure progesterone levels on transfer day (target >10-13 ng/ml based on laboratory standards) 1
• No adjustment in estradiol or progesterone dosing is required compared to unaffected patients 1

For Severe Adenomyosis with Prior FET Failures:

• Consider 3+ months of GnRH agonist pretreatment before HRT-FET cycle 2
• Measure serum estradiol after GnRH agonist treatment but before starting Progynova to assess for persistent local estrogen production 2
• If estradiol remains elevated despite GnRH agonist suppression, add letrozole (aromatase inhibitor) for 21 days to suppress local estrogen production from adenomyotic lesions 2
• Then proceed with standard HRT-FET protocol 2

Progesterone Resistance Considerations

While progesterone resistance is described in the pathophysiology of adenomyosis, this does not translate to requiring higher progesterone levels for successful embryo implantation in HRT-FET cycles. 1 The 2024 study specifically tested this hypothesis and found no association between adenomyosis presence and progesterone requirements (coefficient 0.38; 95% CI: -0.63 to 1.40; P = 0.457). 1

Common Pitfalls to Avoid

• Do not empirically increase progesterone dosing in adenomyosis patients without evidence of inadequate levels, as standard dosing achieves equivalent outcomes 1
• Do not assume all adenomyosis patients need prolonged GnRH agonist pretreatment—reserve this for severe cases with prior failures 2
• Do not skip estradiol level monitoring in severe adenomyosis patients after GnRH agonist treatment, as local production may persist despite pituitary suppression 2
• Recognize that progesterone resistance in adenomyosis primarily affects symptom management (bleeding, pain) rather than embryo receptivity in properly prepared endometrium 3, 1