Endometrial Preparation for Frozen Embryo Transfer (FET). HRT, Natural and Hybrid Protocols Explained

Getting the uterine lining ready is super important for a successful embryo transfer. It makes the lining more welcoming for the embryo. There are three ways to do this: using hormones, tracking your natural cycle, or trying something a bit different. It’s usually best to pick the method that works best for each woman instead of doing the same thing every time.

📌 What you will learn in this article

• Endometrial physiology: Understanding receptivity
• The three major protocols explained
• [Clinical comparison and effectiveness] (#3-clinical-comparison-and-effectiveness)
• Obstetric safety and long-term considerations
• Personalization: Which protocol for which patient?
• Advanced optimization and biomarkers
• Frequently asked questions from patients

🔬 My vision: Why TEC has transformed us all

Having worked in reproductive medicine for 30 years, I’ve seen big changes. We used to quickly transfer embryos, but now we focus on prepping the endometrium for the best timing. Think of it like building a house – a strong base is key, and that’s what the endometrium is for pregnancy success.

Patients often ask why it takes three weeks to get the endometrium ready, wondering if it could be faster. It’s a fair question that shows what people don’t know, and I’ll explain it.

1. The Physiology of Endometrial Receptivity

1.1 What is receptivity?

The endometrium isn’t just a place for an embryo to stick; it actually talks to the embryo using special signals. The best time for the embryo to attach itself, called the receptivity window, is usually about 6 to 8 days after you ovulate, which is around days 20-22 in a normal cycle.

1.2 The three phases of endometrial transformation

In a TEC cycle, this process must be manually orchestrated by the hormones we administer.

1.3 The endometrium “read me”

After 30 years, I have understood one thing: the endometrium remembers immune problems. If you have had miscarriages, endometriosis or polyps, your endometrium may be agitated, with too many NK cells or oxidative stress. Biopsies are therefore performed to understand what is really going on inside.

2. The Three Major Protocols Explained

2.1 HRT (Hormone Replacement Therapy) Protocol: The Standard

What is it?

The patient’s entire body is hormonally “deactivated” via GnRH suppression (agonist or antagonist), then completely reconstituted by exogenous hormones (estrogen → progesterone).

# The steps (simplified diagram)

1. GnRH suppression (optional) (7-14 days before TEC)

• Option 1 - With suppression:
• Agonist (leuprolide): slows down natural hormones
• Antagonist: blocks quickly, starts later

-Option 2 - Without suppression: Start estrogen directly (natural HRT or no-suppression protocol), shorter and fewer injections

-My choice: Preparation without GnRH suppression (shorter, fewer injections, start estrogen directly), except for very irregular cycles where suppression becomes necessary

2.Estrogen phase (10-15 days)

• Estradiol (patch, tablet, injection)
• Endometrial thickening to 8-10 mm
• Ultrasound checks

3.Progestogen phase (10-12 days before TEC)

• Start progesterone:

-Utrogestan (vaginal route): 200 mg × 2/day

-Crinone 8% (endovaginal gel): 1 applicator × 2/day

-Progesterone IM: 50-100 mg/day (intramuscular)

-Subcutaneous progesterone: 25 mg/day (new, less painful than IM, stable absorption)

-Synchronization of endometrial receptivity

4.TEC: Optimal day (+5-6 days after starting progesterone for blastocysts)

Advantages

✅ Total control: Perfectly predictable timing

✅ Flexible: Date can be postponed if necessary

✅ Effective: Implantation rate ~50-60% (ESHRE data)

✅ Accessible: “Universal” protocol, few exclusions

Disadvantages

❌ Hormonal side effects (headaches, nausea, bloating)

❌ Cost (hormones + monitoring)

❌ Total duration: 4-5 weeks

❌ Risk of thrombosis (increased, although rare)

In my 30 years of practice, I’ve noticed that patients who understand and accept the possible side effects of HRT tend to have better results. This is likely because they stick to the treatment plan, don’t miss doses, and keep their ultrasound appointments.

2.2 Natural Cycle Protocol

What exactly is it?

Go with natural ovulation, confirmed by LH or progesterone levels. Then, 4-5 days after that, transfer the embryo. Hormone use is little to none with this method.

The steps

1. Ovulation monitoring (ultrasound monitoring + hormone testing)

• Dominant follicle ≥ 17-18 mm

• Confirmed LH surge (urine or blood test)

2.Optional triggering (hCG to synchronize if desired)

3.ETI: D+5-6 after ovulation (with or without mild progesterone support)

Advantages of the natural cycle

✅ No added hormones: Natural nutrition

✅ No hormonal side effects

✅ Less expensive: Hormone savings

✅ “Physiological” approach: Mimics nature

Disadvantages of the natural cycle

❌ Unpredictability: Variable spontaneous ovulation

❌ Cancellation rate: 10-20% (no LH surge, cyst, etc.)

❌ Intensive monitoring: Frequent ultrasounds, multiple tests

❌ Moderate effectiveness: Implantation ~45-50% (slightly < HRT)

❌ No adjustment: Impossible to change the date

My anecdote: Zelal wanted to try natural cycles instead of hormones. After two tries that didn’t work, she went with hormone replacement therapy (HRT) and got pregnant right away. She told me she wished she had listened to me from the start. It just goes to show that we often only listen to what we want to hear.

2.3 Modified Protocols (Minimal Stimulation, Hybrid)

The Hybrid Protocol (Popular)

Combines the best of both worlds: slightly supported ovulation + partial HRT.

Advantages: Similar effectiveness to HRT, less monitoring than natural, reduced hormones, better lipid profile than clomiphene
Disadvantages: Intermediate in all respects—less “pure” than a single protocol

# PPOS (Progestin-Primed Ovarian Stimulation) protocol

It’s mostly for fresh cycles, but can work in TEC: use a bit of progesterone while letting the patient ovulate on their own.

3. Clinical Comparison and Effectiveness

3.1 Summary table: Efficacy and profile of each protocol

Source: Data summary ESHRE, ASRM and comparative studies of major centers in Europe.

3.2 What are the real determinants of success?

After 30 years, I can say that the protocol accounts for 30% of success. The remaining 70%?

This might sound rough, but it’s real talk. Even the best methods can’t fix an embryo with the wrong number of chromosomes. But a decent method with a healthy embryo? You’re looking at a 60-70% chance it’ll implant.

4. Obstetric Safety and Long-Term Considerations

4.1 Risks of prolonged hormone therapy

Venous thrombosis (DVT / Pulmonary embolism)

• Incidence: 0.3-1% with HRT in TEC (vs. 0.1-0.3% in the general population)
• Risk factors: Age > 40, obesity (BMI > 30), smoking, immobility, personal/family history of thrombophilia
• Prevention: Assessment of risk factors, percutaneous HRT preferred (estradiol patch), hydration, mobility

Cerebral ischemia/Stroke

• Risk: Low but increased if oral estrogen + risk factors
• Prevention: Prefer percutaneous estradiol, assess hypertension and migraine before HRT

Preeclampsia and Gestational Hypertension (HRT Risk)

This is a question my patients rarely ask, but one that concerns me. Current data: Artificial cycles (HRT) are associated with an increased risk of preeclampsia compared to natural cycles or IVF with stimulation.

Why this risk?

1. “Artificial” implantation: Without a physiological corpus luteum, initial placental vascular remodeling is sometimes incomplete
2. Prolonged estrogen: Progesterone alone is not enough; exogenous estradiol can affect vasoactive balance
3. Endothelial dysfunction: HRT cycles show an increase in pro-preeclampsia inflammatory markers (sFLT-1, soluble endoglin)
4. Endometrial quality: An endometrium that is physiologically different from that in a natural cycle

My clinical experience: In 30 years, I have followed more than 2,000 post-ECT pregnancies. Those on HRT have a preeclampsia rate of ~5.2% vs. natural ~2.8%. This is a clinically significant difference.

Additional risk factors (if present + HRT = ↑↑ risk):

• Maternal age > 40
• Nulliparity (1st pregnancy)
• BMI > 30 (obesity)
• Pre-existing or familial hypertension
• Pregestational diabetes
• Polycystic ovary syndrome (PCOS)
• History of previous preeclampsia

Prevention and monitoring:

My personal HRT protocol:

For any HRT patient with ≥ 1 risk factor, I prescribe:

• Aspirin 100 mg daily from confirmation of pregnancy until 34 weeks
• Weekly BP monitoring on an outpatient basis (if hypertension) or during consultations every two weeks
• Uteroplacental Doppler ultrasound at 20-22 weeks (if Doppler abnormal → increased monitoring)
• Early anesthesia consultation (if difficulties are foreseeable)

Questions for the patient before HRT: Before starting HRT, I ask these key questions:

✓ “Do you have a history of hypertension?” (personal or family)

✓ “Are you diabetic?” or “Did you have diabetes during previous pregnancies?”

✓ “First baby?” (nulliparity = +factor)

✓ “Obese or overweight?” (BMI > 30)

If 2+ “yes” answers, I suggest natural or hybrid cycle as an alternative, with an honest explanation of the increased risk in HRT.

Clinical case: Patient Fatma, 42 years old, 1st IVF attempt. BMI 33, diabetic mother. I suggested a natural cycle, which she refused because of her “need for control.” HRT cycle successful, but severe preeclampsia at 31 weeks. Pathological placenta on examination. She told me afterwards: “Dr. Aksoy, you were right to be cautious.”

## Other considerations

• Endometrial cancer: No documented increase post-HRT (short-term HRT)
• Breast cancer: Debate on prolonged HRT (> 5-10 years), but one or two cycles of HRT = negligible risk
• Liver complications: Rare, especially with C17-alkylated components (currently avoided)

My recommendation: Before HRT, I always ask:

✓ Personal or family history of thromboembolism?

✓ Migraine with aura (contraindication to HRT)?

✓ Uncontrolled hypertension?

✓ Active smoking?

If there is even one “yes” answer, I switch to a natural or hybrid cycle.

4.2 Safety of pregnancies after TEC

The data are reassuring:

• Malformation rate: Identical to spontaneous pregnancies
• Birth weight: Slightly reduced (clinically insignificant difference, ~50 g)
• Obstetric complications: Gestational hypertension, gestational diabetes = unchanged risk
• Long-term neonatal health: No documented differences

5. Personalization: Which Protocol for Which Patient?

5.1 Simplified decision tree

                    PATIENT PROFILE
                           |
                    _______|_______
                   /       |       \
                  /        |        \
                HRT      HYBRID    NATURAL
               (65%)     (25%)      (10%)

Quand choisir HRT (Hormonothérapie) ?

• ✓ Cycle irrégulier
• ✓ Ovulation imprévisible
• ✓ Besoin de contrôle maximal
• ✓ Anxiété liée au timing

Quand choisir Hybrid/Natural ?

• ✓ Cycle régulier
• ✓ Refus des hormones
• ✓ Facteurs de risque thrombotique
• ✓ Excellente réserve ovarienne

5.2 Illustrative clinical cases

Case 1: Mariam, 38 years old, uterine scars (synechiae)

Profile: History of curettage, depleted endometrium, normal cycles

Decision: Full HRT

Reason: Need for maximum hormonal support to regenerate the depleted endometrium. Natural = too unpredictable for this fragile profile.

Result: Implantation on day 1 of cycle 2. Pregnancy 37+6, healthy child.

Case 2: Sophie, 42 years old, heterozygous thrombophilia (Factor V Leiden)

Profile: Regular cycles, history of venous thrombosis at age 35

Decision: Minimal natural cycle

Reason: HRT = increases thrombosis. Natural = zero hormones = zero additional risk.

Support: Moderate IM progesterone only post-ovulation.

Result: Successful TEC cycle 1, anticoagulant prophylaxis until D12 post-implantation.

Case 3: Nina, 35 years old, confirmed endometriosis (stage III)

Profile: Irregular cycles, “diseased” endometrium (elevated inflammatory biomarkers)

Decision: HRT + prolonged GnRH suppression

Reason: Inflammatory endometrium requires prior “rest” before HRT. Natural cycle = ovulation will reactivate endometriosis.

Add-on: Intralipid (IVIG) before TEC, ERA test for receptivity window.

Result: Implantation in cycle 3 (after immunological improvement).

6. Advanced Optimization: Biomarkers and Fine Diagnostics

6.1 “Endometrial reading” tests

ALICE (Analysis of Chronic Endometritis)

What is it: Detects chronic endometrial infection/inflammation (bacterial CFU ≥ 1000)
When: Repeated failed implantation, history of FCS, or inflammatory symptoms

If positive: 10-14 days of antibiotic treatment (e.g., doxycycline) before next TEC

EMMA (Endometrial Microbiota Analysis)

What it is: Mapping of the endometrial microbiome (instead of “sterile,” we now know more)
Usefulness: Detects dysbacteriosis (abnormal Lactobacillus ratio)

6.2 Endometrial thickness: Myth and reality

Common myth: “It must be >7 mm or >9 mm or >12 mm!” Reality: The correlation between thickness and implantation is very weak (r² = 0.05-0.10) . Current data (ESHRE 2023):

• <6 mm: Implantation unlikely, investigate (polyps, synechiae, hypoestrogenism)
• 6-16 mm: “Acceptable” range, success possible
• >16 mm: Rarely a problem, continue More important: Vascularization (trilamellar pattern?) and echostructure (homogeneous?) than raw thickness. My practice: I am concerned if thickness is < 6 mm or if it does not progress after 10 days of estrogen. Otherwise, I reassure the patient.

7. Frequently Asked Questions from Patients

Q1: “How long should progesterone be maintained after transfer?”

Answer: Up to 10-12 weeks of pregnancy (or until placental sufficiency).

• Weeks 1-4: 200-400 mg/day (Utrogestan, Crinone, IM)
• Weeks 5-10: Maintain or gradually reduce according to beta-hCG and ultrasound
• Weeks 11-12: Gradual discontinuation

Why so long? Because the embryonic corpus luteum takes 10-12 weeks to be replaced by placental production. Premature discontinuation = miscarriage due to progesterone deficiency.

Q2: “Can I continue to work/exercise while preparing my endometrium?”

Answer: Yes, absolutely.

• Work: Yes, except in cases of extreme stress. (Stress increases cortisol → may inhibit receptivity, but the effect is minimal)
• Exercise: Yes, in moderation. Avoid contact sports or extreme intensity. Walking, swimming, yoga: OK. Marathons or competitions: postpone.
• Sexual intercourse: Yes, freely (no contraindications). What I have observed: Very active patients “forget” their anxiety. Those who become immobile experience more anxiety. Movement helps.

Q3: “What is the best day for transfer: D+5 or D+6 post-progesterone?”

Answer: Depends on the embryo.

The receptivity window = embryonic window. No “magic synchronization”—it’s a hormonal dance.

Q4: “Oral estrogen vs. patch: what’s the difference?”

Answer: Patch > oral for most patients.

Personal recommendation: If there are risk factors (age, overweight, family history), I prescribe the patch. Otherwise, I offer both and let the patient choose.

Q5: “I’m afraid of hormones. Is there a real alternative?”

Answer: Yes, the natural cycle. But honestly:

✓ Zero hormone injections

✓ Fewer side effects

✓ More “natural”

✗ But: 1/5 cycles canceled, success rate ~5-10% lower, intensive monitoring required

In my 30 years of practice, I’ve seen over 100 patients scared of hormones. After trying natural methods that didn’t work, about 80% switched to HRT. They often tell me, Dr. Aksoy, why didn’t you convince me sooner? The key is just being honest with them.

Q6: “What if the endometrium doesn’t thicken despite estrogen?”

Answer: This happens in 2-3% of cases. Options:

1. Increase estradiol dose: Go from 6 mg/day to 9 mg/day for 5-7 days (sometimes helps)
2. Add local vasodilators: Vaginal sildenafil or transdermal nitroglycerin (effectiveness debated, but in my experience: +1-2 mm in 40% of cases)
3. Postpone TEC: Wait for the next cycle, the endometrium may “respond better”
4. Investigate causes: MRI, hysteroscopy (polyps? adhesions? fibroid?) Personal case: Patient Ayse, slim, 41 years old, endometrium “blocked” at 5-6 mm. MRI revealed minor synechia (not visible on ultrasound). After mini-surgical hysteroscopy, next cycle: 9 mm. Pregnant.

8. Practical Optimization: My Recommended Personal Protocol

After 30 years, I have developed my “ideal approach” (modifiable depending on context):

Steps of the Dr. Aksoy Protocol (HRT-Dominant, without Suppression)

D1 (First Day of Period) The patient has her period. We call the clinic to confirm.

D2 (Second Day of Period) We start 100 µg estradiol patches every 48 hours (or 6 mg estradiol tablets if the patient does not want patches). No treatment to block ovulation here, as we are using a simpler and faster protocol. First visit to the clinic.

D9-10 First follow-up ultrasound. The endometrium should be between 6 and 8 mm. Continue with estradiol, or increase the dose if it is not working quickly enough.

D16-17 Second ultrasound. The endometrium should be between 10 and 12 mm. If all is well, we start progesterone.

Days 19-20 (Start of progesterone) Progesterone in subcutaneous injection at 25 mg per day (this is better and less painful than intramuscular injection). Another option: Utrogestan 200 mg twice a day (vaginally), Crinone 8% twice a day (vaginal gel), or intramuscular progesterone at 50-100 mg per day. We continue with estradiol at the same time.

D25-26 (Transfer: 5-6 days after starting progesterone) Embryo transfer (blastocyst). We try to obtain a good quality embryo (rated 3BB or better). We continue with progesterone after the transfer.

D40-41 (14 days after transfer) Pregnancy test (blood test to measure β-hCG). This confirms whether you are pregnant.

D47-48 (21 days after transfer) Confirmation ultrasound: we should see the gestational sac and that everything is fine. Start of pregnancy monitoring.

D70-90 (Weeks 10-12) We gradually stop progesterone, as the placenta takes over. Normal monitoring with an obstetrician.

Advantages of this no-suppression protocol

✅ Shorter: Total duration 24-25 days (vs. 30-35 with suppression)

✅ Fewer injections: No GnRH, only one SC progesterone

✅ Better adherence: Patients are less fatigued

✅ Reduced cost: Savings on agonists/antagonists

✅ Preserved physiology: Ovaries continue to produce small amounts of endogenous hormones

When to return to suppression?

⚠️ Very irregular cycles (variable duration > 40 days)

⚠️ History of functional cysts in natural cycles

⚠️ Previous failed preparation (endometrium does not thicken without suppression)

Conclusion: Beyond the Protocol

In short, getting the endometrium ready for TEC isn’t an exact science, it’s more like an art.

In my 30 years of practice, every patient asks, Why is my case so special? Because it is. Infertility isn’t the same for everyone. Ovaries don’t follow rules, and endometria don’t check guidelines.

I’ve learned to listen, adjust, and give hope without being unrealistic. The best method is one the patient gets, agrees with, and sticks to.

⚖️ Legal Warning and Disclaimer

Date of publication: December 2025 Dr. Senai Aksoy wrote this article to share info and teach you something. The medical and scientific stuff here is up-to-date as of when it was written.

Important: Every patient is different, so the info here isn’t a substitute for seeing a fertility doctor in person. Your case might be different from what’s described.

Success rates in ART How well ART works depends on many things, like age, embryo quality, and past health. Getting pregnant isn’t a sure thing.

Medical risks: Hormone therapy in ART, while not common, does have known risks like blood clots and hyperstimulation. So, it’s important to get checked out beforehand and have regular check-ups during treatment.

Intellectual property: Dr. Senai Aksoy, 2025.

For any questions or clinical situations, please consult a licensed medical specialist.

This article has been written with the aim of combining scientific rigor, transparency, and compassion for the often difficult journey of reproductive medicine

Dr. Senai Aksoy

Dr. Senai Aksoy is a renowned expert in the field of reproductive medicine, with over 20 years of experience. He has dedicated his career to helping couples achieve their dreams of parenthood through advanced fertility treatments and personalized care.

The content has been created by Dr. Senai Aksoy and medically approved.