Luteal Stimulation vs. Estrogen Priming for Diminished Ovarian Reserve

Overseen By Baruch Abittan, MD

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: Northwell Health

Must be taking: Gonadotropins

Must not be taking: Aromatase inhibitors

Disqualifiers: Ovarian cyst, Anovulation, Breast cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

142 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you plan to use aromatase inhibitors during the ovarian stimulation or if you've had ovarian stimulating therapy in the past month.

What data supports the effectiveness of the treatment Estradiol Priming Protocol for Diminished Ovarian Reserve?

Research suggests that using luteal estradiol pre-treatment in poor ovarian responders undergoing IVF may have potential advantages over standard protocols, such as higher serum estradiol levels and a higher number of fertilized eggs and good quality embryos, which could indicate improved outcomes. ^{1 2 3 4 5}

Is the Luteal Stimulation or Estrogen Priming Protocol safe for humans?

The 17beta-estradiol/levonorgestrel transdermal system, which is similar to the estrogen priming protocol, has been shown to be safe in managing menopausal symptoms without causing endometrial hyperplasia (abnormal thickening of the uterus lining) or adverse impacts on cholesterol levels. However, hormone replacement treatments, in general, may increase the risk of high blood pressure and other pregnancy-related complications. ^{1 3 4 6 7}

How is the luteal stimulation and estrogen priming treatment different for diminished ovarian reserve?

The luteal stimulation and estrogen priming treatment is unique because it uses a combination of hormone patches and medications to prepare the ovaries and improve the chances of successful IVF (in vitro fertilization) in women with diminished ovarian reserve. This approach may lead to higher levels of key hormones and better embryo quality compared to standard protocols. ^{1 2 3 5 8}

What is the purpose of this trial?

Ovarian reserve defines the quantity and quality of the ovarian primordial follicular pool. Diminished ovarian reserve (DOR) indicates a reduction in the quantity of ovarian follicular pool to less than expected for age. It is an important cause of infertility in many couples. To date, there is no clear consensus in the literature on the definition of diminished ovarian reserve, and it is unclear whether low oocyte yield results from an abnormal atresia rate of the follicle pool, or from a lower follicle pool at birth or whether it can just occur as a normal variation in the population. The ovarian response to controlled ovarian stimulation with gonadotropins (for example, for in vitro fertilization) is largely determined by the ovarian reserve, and there are numerous different ovarian stimulation protocols that are employed to try and increase the oocyte yield of a particular cycle. There is no consensus on which, if any, of these protocols are superior and preferred for patient with DOR. Luteal gonadotropin stimulation is a protocol of controlled ovarian stimulation (COS) for use in assisted reproductive technologies (ART) that has emerged over the past decade as an acceptable alternative to the classic follicular gonadotropin stimulation. The luteal estradiol patch protocol was introduced in 2005 in patients with poor response to controlled ovarian stimulation (COS) and to address the phenomenon of early follicle recruitment in patients with diminished ovarian reserve (DOR). Luteal gonadotropin stimulation can potentially achieve the same effect by initiating follicular recruitment for IVF prior to the body's own premature recruitment. Our hypothesis is that the luteal stimulation protocol and estradiol priming protocol are equivalent with regard to the outcome of number of mature oocytes retrieved. Patients who will be undergoing controlled ovarian stimulation and who have a diagnosis of diminished ovarian reserve will be considered for this trial, and enrolled if meeting all inclusion and no exclusion criteria.

Eligibility Criteria

Women aged 20-45 with diminished ovarian reserve (DOR) who are undergoing in vitro fertilization can join this trial. They must have both ovaries, an AMH value less than 1 ng/mL, and a history of poor response to IVF stimulation or specific hormone levels indicating DOR. Participants need regular menstrual cycles and willingness to follow the study procedures.

Inclusion Criteria

I have both of my ovaries.

I am a woman aged between 20 and 45.

Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria

I have or had breast cancer.

My cancer is thought to grow with estrogen.

I have experienced unexplained bleeding from my genitals.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Luteal Phase Ovarian Stimulation

Patients undergo controlled ovarian stimulation with gonadotropins and Clomiphene citrate, followed by monitoring and ovulation trigger.

2-3 weeks

Multiple visits for monitoring and blood tests

Luteal Estradiol Priming Protocol

Patients begin Estradiol patches and GnRH antagonist, followed by gonadotropin injections and monitoring.

2-3 weeks

Multiple visits for monitoring and blood tests

Follow-up

Participants are monitored for outcomes such as oocyte retrieval, fertilization, and embryo development.

4-6 weeks

Treatment Details

Interventions

• Estradiol Priming Protocol
• Luteal Stimulation Protocol

Trial Overview The LUTEAL Trial is testing two different timing protocols for injectable gonadotropins in women with DOR: luteal stimulation versus estrogen priming protocol. The goal is to see which method yields more mature oocytes during controlled ovarian stimulation for assisted reproductive technologies.

Participant Groups

Group I: Luteal estradiol priming protocol Active Control 1 Intervention

In the luteal phase, the patient will begin Estradiol patches 0.1mg QOD. She will also take daily Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix, Organon; and cetrorelix, Serono) for three days. With menses, she will begin 150 IU hMG, 300 IU recombinant FSH daily, and oral Clomiphene citrate 100mg qd (for five days). FSH can be titrated per patient response. GnRH antagonist will be started per criteria. 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU) will be administered for ovulation trigger. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.

Group II: Luteal phase ovarian stimulation (LPOS) Active Control 1 Intervention

Patients will present in the luteal phase, and will begin 150 IU hMG and 300 IU recombinant FSH daily, as well as oral Clomiphene citrate 100mg daily for the first five days of the stimulation. FSH can then be titrated per patient response. Gonadotropin releasing hormone antagonist (Ganirelix, Organon; and cetrorelix, Serono) will be started per criteria. Once patients are ready for ovulation trigger, 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU), will be administered. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.

Estradiol Priming Protocol is already approved in European Union, United States for the following indications:

Approved in European Union as Estrogen Priming Protocol for:

• Diminished Ovarian Reserve (DOR)
• Poor Response to Controlled Ovarian Stimulation (COS)

Approved in United States as Estrogen Priming Protocol for:

• Diminished Ovarian Reserve (DOR)
• Poor Response to Controlled Ovarian Stimulation (COS)

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Findings from Research

In a study of 265 IVF cycles involving poor ovarian responders, the luteal estradiol patch/GnRH antagonists priming protocol (LPP) did not show improved outcomes compared to the standard GnRH antagonist protocol.

Both protocols resulted in similar rates of oocyte retrieval, fertilization, and clinical pregnancy, indicating that LPP does not provide a significant advantage in IVF treatment for poor ovarian responders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the standard GnRH antagonist protocol and the luteal phase estradiol/GnRH antagonist priming protocol in poor ovarian responders. Mutlu, MF., Mutlu, İ., Erdem, M., et al.[2018]

In a meta-analysis of 1056 IVF patients, the luteal estradiol pre-treatment protocol led to a higher number of oocytes and mature oocytes retrieved compared to standard protocols, indicating improved efficacy for poor ovarian responders.

The luteal estradiol protocol also resulted in a lower cycle cancellation rate, suggesting it may enhance the overall success of IVF treatments for patients with poor ovarian response, although clinical pregnancy rates remained similar to standard protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of luteal estradiol pre-treatment on the outcome of IVF in poor ovarian responders. Chang, X., Wu, J.[2013]

In a randomized controlled trial involving 90 women undergoing frozen-thawed embryo transfer (FET), the use of 17ß-estradiol transdermal patches resulted in significantly higher estradiol levels compared to oral estradiol, indicating a more effective method of endometrial preparation.

Despite the differences in estradiol levels, both methods showed similar biochemical and clinical pregnancy rates, suggesting that the transdermal patches could be a preferable option due to lower costs, reduced drug dosage, and less emotional stress for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comparison of the Effects of Transdermal Estradiol and Estradiol Valerate on Endometrial Receptivity in Frozen-thawed Embryo Transfer Cycles: A Randomized Clinical Trial. Davar, R., Janati, S., Mohseni, F., et al.[2022]

In a study involving 317 women undergoing frozen-thawed embryo transfer, both transdermal estrogen patches and oral estrogen were found to be equally effective in achieving similar endometrial thickness and clinical outcomes.

The results indicate that there is no significant difference in pregnancy rates or endometrial response between the two methods of estrogen administration, suggesting that either option can be safely used in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal versus oral estrogen: clinical outcomes in patients undergoing frozen-thawed single blastocyst transfer cycles without GnRHa suppression, a prospective randomized clinical trial. Kahraman, S., Çetinkaya, CP., Sahin, Y., et al.[2020]

In a study of 162 ovarian stimulation cycles for poor responders, the luteal estrogen priming (LE) protocol resulted in significantly higher serum estradiol levels, longer cycle duration, and more fertilized oocytes and good quality embryos compared to the letrozole (LZ) co-treatment protocol.

Although both protocols showed low clinical pregnancy rates, the LE protocol had a higher clinical pregnancy rate (12.3% vs. 18.2%) and ongoing pregnancy rate (9.6% vs. 12.7%) per embryo transfer, particularly in younger patients under 40 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen or anti-estrogen for Bologna poor responders? Pabuccu, EG., Caglar, GS., Pabuccu, R.[2018]

This study will compare the efficacy and safety of letrozole-stimulated protocols versus hormone replacement treatment (HRT) in 1078 women with polycystic ovary syndrome (PCOS) undergoing their first frozen embryo transfer (FET), focusing on live birth rates as the primary outcome.

Letrozole, a new ovulation induction drug, may offer a safer alternative to HRT, which has been associated with increased risks of hypertensive disorders and obstetric complications, but high-quality trials comparing these methods are currently lacking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Live birth after letrozole-stimulated cycles versus hormone replacement treatment cycles for the first frozen embryo transfer in women with polycystic ovary syndrome: protocol for a multicentre randomised controlled trial. Wang, X., Li, Y., Zhang, C., et al.[2023]

The Women's Health Initiative (WHI) study raised safety concerns about hormone therapy, particularly focusing on a specific oral regimen of conjugated equine estrogen and medroxyprogesterone, which may not represent the broader population's response to hormone therapy.

In contrast, the once-weekly transdermal patch delivering 17beta-estradiol and levonorgestrel has been shown to effectively reduce vasomotor symptoms and improve quality of life without adverse effects like endometrial hyperplasia or negative impacts on cholesterol, making it a safer alternative for managing menopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17Beta-estradiol/levonorgestrel transdermal system for the management of the symptomatic menopausal woman. Shulman, LP.[2019]

In a study of 8010 women undergoing frozen embryo transfer, both hormone replacement therapy (HRT) and letrozole-induced ovulation (L-OI) protocols were found to be safe and effective for endometrial preparation, with no significant differences in clinical pregnancy or live birth rates.

The L-OI group had a higher proportion of women with a thicker endometrium compared to the HRT group, but both protocols showed similar perinatal outcomes, indicating that either method can be used confidently in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Perinatal Outcomes of Letrozole-Induced Ovulation and Hormone Replacement Therapy Protocols in Patients With Abnormal Ovulation Undergoing Frozen-Thawed Embryo Transfer: A Propensity Score Matching Analysis. Zhang, W., Liu, Z., Zhang, J., et al.[2022]

References

1. Turkey pubmed.ncbi.nlm.nih.gov

Comparison of the standard GnRH antagonist protocol and the luteal phase estradiol/GnRH antagonist priming protocol in poor ovarian responders. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Effects of luteal estradiol pre-treatment on the outcome of IVF in poor ovarian responders. [2013]

3. Iran pubmed.ncbi.nlm.nih.gov

A Comparison of the Effects of Transdermal Estradiol and Estradiol Valerate on Endometrial Receptivity in Frozen-thawed Embryo Transfer Cycles: A Randomized Clinical Trial. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Transdermal versus oral estrogen: clinical outcomes in patients undergoing frozen-thawed single blastocyst transfer cycles without GnRHa suppression, a prospective randomized clinical trial. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Estrogen or anti-estrogen for Bologna poor responders? [2018]

6. England pubmed.ncbi.nlm.nih.gov

Live birth after letrozole-stimulated cycles versus hormone replacement treatment cycles for the first frozen embryo transfer in women with polycystic ovary syndrome: protocol for a multicentre randomised controlled trial. [2023]

7. England pubmed.ncbi.nlm.nih.gov

17Beta-estradiol/levonorgestrel transdermal system for the management of the symptomatic menopausal woman. [2019]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Comparison of Perinatal Outcomes of Letrozole-Induced Ovulation and Hormone Replacement Therapy Protocols in Patients With Abnormal Ovulation Undergoing Frozen-Thawed Embryo Transfer: A Propensity Score Matching Analysis. [2022]