What are the possible causes of a poorly defined endo-myometrial junction (EMJ) in a woman of likely childbearing age with primary infertility, normal hysteroscopy (Hysteroscopic Resection of the Uterus) findings except for a slightly lengthy posterior wall of the uterus, from day 3 of a Hormone Replacement Therapy (HRT) Frozen Embryo Transfer (FET) cycle?

Poorly Defined Endomyometrial Junction in Primary Infertility

The most likely cause of a poorly defined endomyometrial junction (EMJ) in this patient with primary infertility is adenomyosis, which disrupts the normal interface between endometrium and myometrium and is strongly associated with infertility and implantation failure. 1

Primary Differential Diagnosis

Adenomyosis (Most Likely)

• Adenomyosis is the leading cause of poorly defined EMJ on imaging, characterized by disruption of the normal hypoechoic zone between endometrium and myometrium 1
• The condition involves invasion of endometrial tissue into the myometrium, directly disrupting the EMI structure 2
• Adenomyosis is a common structural cause of infertility in premenopausal women and frequently interferes with implantation 1
• The junctional zone (part of the EMI) differs structurally and functionally from outer myometrium, and its disruption is pathognomonic for adenomyosis 2
• A "lengthy posterior wall" noted on hysteroscopy may represent asymmetric myometrial thickening, which is consistent with focal adenomyosis 1

Intramural or Submucosal Fibroids

• Intramural (IM) fibroids significantly reduce pregnancy and implantation rates even without cavity deformation, with implantation rates of only 6.4% compared to 15.7% in patients without fibroids 1
• Fibroids can cause loss of the normal hypoechoic zone between placenta and myometrium, creating a poorly defined EMJ appearance 1
• The presence of uterine fibroids, especially IM and submucosal types, impairs blood supply to the endometrium and causes atrophy, reducing implantation success 1
• Surgical or medical treatment should be considered before proceeding with ART in patients with IM fibroids 1

Endometriosis with Deep Infiltration

• Endometriosis affects at least one-third of women with infertility and can disrupt the EMI through inflammatory processes 1, 3
• Deep infiltrating endometriosis may not be visible on hysteroscopy but can cause EMJ abnormalities on ultrasound 4
• The condition causes endocrine abnormalities and immunological disturbances that affect implantation beyond anatomical distortion 5

Critical Diagnostic Considerations

Why Normal Hysteroscopy Doesn't Rule Out Pathology

• Hysteroscopy only visualizes the endometrial cavity surface and cannot assess myometrial pathology or the EMI itself 1
• Adenomyosis and intramural fibroids exist within the myometrium and are not visible hysteroscopically 1
• Up to 21% of women with surgically confirmed endometriosis have normal hysterosalpingography, demonstrating that cavity-based examinations miss deeper pathology 4

Timing Considerations (Day 3 HRT Cycle)

• Early in an HRT cycle, the endometrium may not yet be adequately thickened, potentially making EMJ assessment more difficult 6
• However, a poorly defined EMJ represents structural pathology rather than hormonal timing issues 1
• The HRT protocol itself is associated with increased risks of implantation complications, with higher rates of hypertensive disorders (aOR 2.00) and preterm birth (aOR 1.78) compared to natural cycles 6

Recommended Diagnostic Algorithm

Step 1: Obtain dedicated pelvic MRI with T2-weighted sequences

• MRI has superior tissue contrast resolution and can visualize the endometrium even in the presence of adenomyosis and fibroids through multiplanar capability 1
• T2-weighted imaging specifically characterizes the junctional zone and identifies adenomyosis with high accuracy 1
• MRI can detect intramural fibroids and assess their impact on the EMI that ultrasound may miss 1

Step 2: If MRI confirms adenomyosis or significant fibroids

• Consider GnRH agonist therapy for 3-6 months before FET to reduce adenomyosis activity 1
• For intramural fibroids >4cm or multiple fibroids, myomectomy should be considered before ART 1
• Hysteroscopic myomectomy is indicated only for submucosal fibroids and will not address intramural disease 1

Step 3: If imaging remains inconclusive

• Diagnostic laparoscopy may be warranted to evaluate for endometriosis, as small endometrial implants are not well detected on imaging 1, 4
• Laparoscopy remains the gold standard for endometriosis diagnosis and staging 4, 3

Critical Pitfalls to Avoid

• Do not assume normal hysteroscopy excludes significant uterine pathology affecting fertility - hysteroscopy cannot visualize myometrial disease 1
• Do not proceed with embryo transfer without addressing a poorly defined EMJ - this finding indicates structural pathology that significantly impairs implantation 1
• Do not rely solely on transvaginal ultrasound - patient body habitus and uterine pathology can cause incomplete visualization, and MRI provides superior assessment 1
• Do not attribute the finding to hormonal timing alone - a poorly defined EMJ on day 3 of HRT represents underlying structural disease 1, 2

Impact on FET Success

• The presence of adenomyosis or intramural fibroids creates an unfavorable environment for implantation through impaired endometrial blood supply and inflammatory mediators 1, 5
• Pregnancy rates are significantly reduced: IM fibroids show 16.4% pregnancy rate per transfer versus 30.1% without fibroids 1
• Treatment of underlying pathology before embryo transfer is essential to optimize outcomes and avoid wasting viable embryos 1