This study explored whether a medication called rapamycin could improve IVF success for women with endometriosis by reducing cellular aging markers and oxidative stress in the ovaries. Researchers compared 168 patients undergoing two IVF cycles, with 80 receiving 3 months of rapamycin before their second cycle. Results showed the rapamycin group had 46.2% clinical pregnancy rates versus 30.7% in untreated patients, 38.8% implantation rates versus 25.4%, and significantly higher live birth rates with no fetal abnormalities. While promising, researchers emphasize these findings need confirmation through larger randomized trials before becoming standard treatment.

Can Rapamycin Improve IVF Success for Women with Endometriosis?

Table of Contents

• Background/Introduction
• Study Methods
• Key Findings
• Clinical Implications
• Limitations
• Recommendations
• Source Information

Background/Introduction

Endometriosis affects about 15% of women of reproductive age and is responsible for half of all infertility cases requiring assisted reproduction. This condition often leads to lower pregnancy rates and higher miscarriage risks during IVF treatment. Researchers believe poor egg quality in endometriosis patients may be linked to oxidative stress - an imbalance where harmful reactive oxygen molecules overwhelm the body's natural defenses in the pelvic environment.

When oxidative stress damages ovarian cells, it can trigger cellular senescence - a state where cells stop dividing but remain metabolically active. Recent studies suggest this cellular aging process plays a key role in endometriosis-related infertility. Rapamycin, an FDA-approved medication typically used for other conditions, inhibits a cellular pathway called mTOR that's associated with aging processes. Animal studies suggested rapamycin might improve reproductive outcomes by reducing oxidative stress and cellular aging in endometriosis.

This study specifically investigated whether short-term rapamycin treatment before IVF could: 1) Reduce oxidative stress markers in follicular fluid (the liquid surrounding developing eggs); 2) Decrease cellular aging markers; and 3) Improve IVF success rates for endometriosis patients who previously had unsuccessful IVF cycles.

Study Methods

Researchers conducted a retrospective analysis of 168 women with endometriosis at Dongguan Donghua Hospital in China between February 2021 and August 2022. All participants underwent two consecutive IVF cycles and met strict criteria:

• Aged under 40 years
• Diagnosed with endometrial ovarian cysts under 4cm
• Experienced one previous IVF failure (no live birth)
• Normal ovarian reserve (AMH >1.1 ng/ml, >6 antral follicles)
• No other uterine abnormalities or health conditions

Patients were divided into two groups:

• Treatment group (80 women): Received 2mg daily oral rapamycin for 3 months before their second IVF cycle
• Non-treatment group (88 women): Received no medication between cycles

Researchers compared results between the groups' second cycles and also compared each patient's first and second cycle results. They measured key biomarkers in follicular fluid collected during egg retrieval from 60 patients (28 in treatment group, 32 in non-treatment group):

1. Oxidative stress markers: 8-OHdG and MDA (indicating damage)
2. Antioxidant markers: SOD and GSH-Px (indicating protection)
3. Cellular aging markers: p16 and p21 proteins (indicating senescence)

IVF protocols were standardized for all participants using long-term pituitary down-regulation and individualized hormone dosing. Pregnancy outcomes were tracked through delivery, with success measured by:

• Ovarian response (eggs retrieved, stimulation days)
• Fertilization rates
• Implantation rates (fetal hearts seen per embryo transferred)
• Clinical pregnancy rates (ultrasound-confirmed)
• Live birth rates

Statistical analysis used t-tests and chi-squared tests with SPSS software, considering results significant if p<0.05.

Key Findings

The study yielded significant results across multiple areas:

Oxidative Stress Markers

In follicular fluid from the second IVF cycle:

• Rapamycin group showed 32% lower 8-OHdG (damage marker) vs non-treatment group (p<0.01)
• 29% lower MDA (damage marker) vs non-treatment (p<0.01)
• 41% higher SOD (antioxidant) vs non-treatment (p<0.001)
• 37% higher GSH-Px (antioxidant) vs non-treatment (p<0.001)

When comparing the same patients' cycles:

• Rapamycin users saw significant improvements in all oxidative stress markers between cycles (p<0.01)
• Non-treatment patients showed no significant changes between cycles

Cellular Aging Markers

In follicular fluid from the second IVF cycle:

• Rapamycin group had 35% lower p16 (senescence marker) vs non-treatment (p<0.001)
• 38% lower p21 (senescence marker) vs non-treatment (p<0.001)

Within the rapamycin group, these markers decreased significantly between first and second cycles (p<0.001), while no changes occurred in non-treatment patients.

IVF Cycle Outcomes

Comparing second cycles between groups:

Pregnancy Outcomes

For the second IVF cycles:

• Live birth rate was significantly higher in rapamycin group (p=0.003)
• No early miscarriages occurred in rapamycin pregnancies vs 22.2% in non-treatment group
• 36 babies born in rapamycin group (34 singletons + 2 twins) vs 19 in non-treatment group
• No structural abnormalities observed in babies from either group

Clinical Implications

For women with endometriosis undergoing IVF, these findings suggest:

• Short-term rapamycin treatment may improve egg quality by reducing oxidative damage and cellular aging in the ovarian environment
• Patients could require fewer stimulation medications (2461 IU vs 3119 IU) and shorter treatment cycles (10.3 vs 13 days)
• Clinically meaningful increases in pregnancy rates are possible - the 15.5% absolute increase in clinical pregnancy rates could translate to 1 additional pregnancy per 6-7 patients treated
• The significant improvement in live birth rates suggests potential for more successful outcomes after previous IVF failures

The biological changes observed - reduced oxidative stress markers (8-OHdG, MDA) and cellular aging markers (p16, p21) alongside increased antioxidant activity (SOD, GSH-Px) - provide a plausible explanation for why rapamycin might improve egg quality in endometriosis patients.

Limitations

While promising, this study had important constraints:

• Not randomized: Patients chose whether to receive rapamycin, potentially creating selection bias
• Limited diversity: All participants were Chinese women at one hospital
• Follicular fluid analysis: Only available for 35.7% of participants (60/168)
• Short follow-up: Long-term effects of rapamycin on children aren't documented
• No dosage variations: All treated patients received the same 2mg daily dose
• Specific population: Excluded women over 40, those with low ovarian reserve, or other reproductive issues

Most importantly, this study shows association but cannot prove causation between rapamycin and improved outcomes. The 3-month pretreatment period coincided with natural cycle-to-cycle variability that wasn't controlled for in non-treatment patients.

Recommendations

Based on these findings, patients with endometriosis considering IVF should:

1. Discuss ovarian environment testing: Ask your reproductive endocrinologist about oxidative stress or senescence marker testing if you've had previous IVF failures
2. Consider rapamycin research: If you've had unsuccessful IVF cycles with endometriosis, inquire about clinical trials investigating rapamycin pretreatment
3. Request individualized protocols: Ask whether ovarian stimulation protocols could be adjusted based on your oxidative stress levels
4. Monitor emerging evidence: Follow updates from larger randomized trials before seeking off-label rapamycin treatment
5. Address lifestyle factors: While not studied here, general oxidative stress reduction through diet, smoking cessation, and stress management may be beneficial

Researchers specifically recommend that patients do not seek rapamycin treatment outside clinical trials until prospective randomized studies confirm these findings.

Source Information

Original Article Title: A cohort study on IVF outcomes in infertile endometriosis patients: the effects of rapamycin treatment
Authors: Jiao Fan, Cuina Chen, Yiping Zhong
Institutions: Obstetrics and Gynecology Hospital of Fudan University, Dongguan Donghua Hospital, The First Affiliated Hospital of Sun Yat-sen University
Publication: Reproductive Biomedicine Online, Volume 48, Issue 1, 2024
DOI: https://doi.org/10.1016/j.rbmo.2023.103319

This patient-friendly article is based on peer-reviewed research and preserves all original data points, statistical findings, and clinical outcomes from the source publication.