What does bleeding on day 14 indicate in a fertility treatment cycle with Letrozole (letrozole) from day 3 to 7, a corpus luteum seen on day 12 scan, and prescribed progesterone support for luteal phase support?

Bleeding on Day 14 in Letrozole Fertility Cycle

Day 14 bleeding in a letrozole ovulation induction cycle with confirmed corpus luteum on day 12 most likely represents breakthrough bleeding from inadequate luteal phase support, and you should ensure progesterone supplementation is adequate and rule out early pregnancy loss or ectopic pregnancy.

Understanding the Clinical Scenario

Your patient has:

• Completed letrozole stimulation (days 3-7)
• Confirmed ovulation occurred (corpus luteum visible on day 12 scan) 1
• Bleeding started on day 14 (approximately 7-9 days post-ovulation)

Most Likely Explanations (in order of probability)

1. Inadequate Luteal Phase Support

• The corpus luteum may not be producing sufficient progesterone despite its presence on ultrasound, as structural presence does not guarantee adequate hormonal output 2
• Letrozole cycles can result in corpus luteum dysfunction requiring exogenous progesterone support, particularly when peak estradiol levels were suppressed during stimulation 1, 3
• Midluteal progesterone levels in letrozole cycles can be variable, and bleeding suggests insufficient endometrial support 3

2. Early Pregnancy-Related Bleeding

• You must rule out early pregnancy before attributing bleeding to luteal insufficiency, as implantation bleeding or threatened miscarriage can occur at this timeframe 4
• Obtain serum hCG immediately - if positive, this changes management entirely 4
• If hCG is positive with bleeding, perform transvaginal ultrasound to confirm intrauterine pregnancy and rule out ectopic pregnancy, as ectopic pregnancies occur ipsilateral to the corpus luteum in 70-80% of cases 4

3. Anovulation Despite Corpus Luteum Appearance

• A corpus luteum-like structure can occasionally represent a luteinized unruptured follicle rather than true ovulation 1
• However, this is less likely given the day 12 scan showed a corpus luteum (not a persistent follicle)

Immediate Management Algorithm

Step 1: Rule Out Pregnancy (ALWAYS FIRST)

• Obtain serum hCG immediately - this is non-negotiable before any other intervention 4, 5
• If hCG positive: Perform transvaginal ultrasound to confirm intrauterine pregnancy location and viability 4

Step 2: Assess Progesterone Support

• If hCG is negative and patient is on progesterone: Verify compliance and adequacy of dosing 2
• If hCG is negative and patient is NOT on progesterone: This is the likely cause - inadequate corpus luteum function in letrozole cycles often requires supplementation 2, 1
• Consider checking midluteal progesterone level (though treatment should not be delayed for results) 3

Step 3: Optimize Luteal Support for Current Cycle

• If pregnancy test is negative: Increase or initiate progesterone supplementation immediately (vaginal progesterone 200mg twice daily or intramuscular progesterone 50mg daily) 2
• Continue progesterone through expected menses or until pregnancy test date 2

Step 4: Plan for Next Cycle

• For subsequent letrozole cycles: Initiate progesterone supplementation routinely starting 2-3 days after documented ovulation, as letrozole-induced corpus luteum function may be suboptimal despite increased progesterone levels reported in some studies 1, 3
• The paradox is that while some research shows elevated midluteal progesterone in letrozole cycles 1, 3, clinical bleeding suggests functional inadequacy in your patient's case

Critical Pitfalls to Avoid

• Never assume bleeding is benign without checking hCG - early pregnancy complications must be excluded first 4, 5
• Do not confuse corpus luteum with ectopic pregnancy on ultrasound - they appear similar and occur on the same side in 70-80% of ectopic cases; the key is determining if the mass is intraovarian or extraovarian 4
• Do not wait for "next cycle" to address luteal support - if pregnancy is ruled out, optimize progesterone now to salvage this cycle if conception occurred 2
• Do not assume visible corpus luteum equals adequate function - structural presence does not guarantee sufficient progesterone production 2

Evidence Considerations

The evidence shows conflicting data on luteal phase adequacy in letrozole cycles:

• Research demonstrates letrozole can increase corpus luteum progesterone output and improve luteal function 1, 3
• However, clinical practice recognizes that individual patients may still have inadequate luteal support despite these general findings 2
• Your patient's bleeding is clinical evidence of inadequacy regardless of what average study results show 2