Rapamycin for Perimenopause

(Rapamycin Trial)

Overseen By Stephanie Morgan

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: Columbia University

Disqualifiers: Irregular cycles, Severe ovarian deficiency, Kidney or liver disease, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether a small dose of rapamycin can delay ovarian aging in women. Rapamycin has shown potential for preserving ovarian health, but using it for an extended period can have negative effects. The goal is to extend the time women remain fertile and delay menopause. This could reduce health risks and improve quality of life for women as they age.

Do I need to stop my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more information.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the idea that Rapamycin for Perimenopause is an effective drug?

The available research does not provide direct evidence that Rapamycin is effective for treating perimenopause. However, some studies suggest that Rapamycin may help preserve ovarian function during chemotherapy, which could be relevant for women experiencing perimenopause. For example, one study found that Rapamycin helps protect the ovarian reserve, which is important for fertility, during chemotherapy. Another study showed that Rapamycin, similar to caloric restriction, can preserve the ovarian reserve in mice, potentially delaying menopause. While these findings are promising, they are not directly related to perimenopause treatment. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug Rapamycin for perimenopause?

Research shows that Rapamycin can help preserve ovarian function and delay menopause by protecting the ovarian reserve, similar to the effects of caloric restriction. It has been effective in preserving fertility during chemotherapy by maintaining the number of primordial follicles in the ovaries. ^{1 2 3 4 5}

What safety data is available for Rapamycin treatment?

Rapamycin, also known as Sirolimus, has been studied for safety in various contexts. In pediatric patients with chronic renal failure, it was found to be safe with some adverse events reported, such as changes in blood sirolimus levels. In renal transplant patients, sirolimus was associated with reversible decreases in platelet and white blood cell counts and increased cholesterol levels. However, it did not significantly affect blood pressure, kidney function, or liver enzyme levels. Additionally, sirolimus has been shown to increase lipid levels, particularly in patients with pre-existing hyperlipidemia. Overall, while sirolimus has some side effects, it is considered safe when used under medical supervision. ^{1 2 6 7 8}

Is rapamycin generally safe for human use?

Rapamycin, also known as sirolimus, has been shown to be generally safe in humans, particularly in kidney transplant patients, though it can cause some side effects like increased cholesterol levels and reduced blood cell counts. It has been used safely in both adults and children, but monitoring for side effects is important. ^{1 2 6 7 8}

Is rapamycin a promising drug for perimenopause?

Rapamycin shows promise as it helps preserve ovarian follicles, which could delay menopause. It also supports ovarian health by promoting follicle growth and protecting against damage from chemotherapy. ^{1 2 3 5 8}

How does the drug rapamycin differ from other treatments for perimenopause?

Rapamycin is unique because it targets the mTOR pathway, which is involved in cell growth and metabolism, and has shown potential in preserving ovarian follicles, potentially delaying menopause. This mechanism is different from traditional hormone replacement therapies used for perimenopause. ^{1 2 3 5 8}

Research Team

Samuel Z. Williams, MD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for women aged 38-45 in the early stages of menopause, who have struggled with fertility due to diminished ovarian reserve. They should still have regular menstrual cycles and specific hormone levels within a set range. It's not suitable for those outside this age group or stage of menopause.

Inclusion Criteria

Anti-müllerian hormone (AMH) levels of >0.1 ng/mL

Antral Follicle Counts (AFC) of >3

I am a woman aged between 38 and 45.

Exclusion Criteria

My menstrual cycles are irregular.

Severe ovarian deficiency, or with no evidence of remaining follicles

I cannot take rapamycin due to health reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 5mg/week of rapamycin or placebo orally for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including measurement of ovarian reserve and hormone levels

Up to 1 year

Treatment Details

Interventions

• Placebo
• Rapamycin

Trial Overview The study tests if low-dose Rapamycin can delay the process of ovarian aging compared to a placebo. Participants won't know which one they're getting as it's a double-blind study, meaning neither the participants nor the researchers know who receives Rapamycin or placebo until after the results are collected.

Participant Groups

Group I: Rapamycin Experimental Treatment 1 Intervention

Participants randomized to the treatment arm will receive 5mg/week of rapamycin orally, for 12 weeks (3 months).

Group II: Placebo Placebo Group 1 Intervention

Participants randomized to the placebo arm will receive placebo orally, for 12 weeks (3 months).

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Findings from Research

In a phase III study, everolimus significantly improved progression-free survival in patients with metastatic renal cell carcinoma, showing a median of 4.9 months compared to 1.9 months for placebo, with a strong hazard ratio of 0.33 (P < 0.001).

The treatment had a low discontinuation rate due to adverse events (10%) and maintained health-related quality of life, indicating that everolimus is both effective and well-tolerated in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience and critical evaluation of the role of everolimus in advanced renal cell carcinoma. Sun, M., Abdollah, F., Schmitges, J., et al.[2021]

In a study using 8-week old female mice, rapamycin was found to significantly protect primordial follicles from depletion caused by the chemotherapy drug cyclophosphamide, indicating its potential as a protective treatment for ovarian function during chemotherapy.

The protective effect of rapamycin is linked to its ability to modulate the PI3K/Akt/mTOR signaling pathway, preventing premature activation of primordial follicles and maintaining normal levels of serum anti-Müllerian hormone (AMH) compared to those treated with cyclophosphamide alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo. Zhou, L., Xie, Y., Li, S., et al.[2021]

Nanomolar concentrations of mTOR inhibitors like rapamycin, everolimus, and temsirolimus reduce the proliferation of ovarian granulosa cells and inhibit follicle growth, indicating a potential safety concern at higher doses.

In contrast, picomolar concentrations of rapamycin can accelerate follicle growth, but this effect is dependent on the presence of estradiol, suggesting a complex mechanism of action that could be harnessed for therapeutic purposes in ovarian follicle development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross talk between estradiol and mTOR kinase in the regulation of ovarian granulosa proliferation. Yu, J., Thomson, TC., Johnson, J.[2021]

Blocking the mTOR pathway with inhibitors like everolimus can effectively preserve ovarian function and fertility in premenopausal women undergoing chemotherapy, as demonstrated in a mouse model of chemotherapy-induced gonadotoxicity.

The study showed that mTOR inhibition maintained primordial follicle counts and serum anti-Mullerian hormone levels, leading to normal fertility outcomes, suggesting a promising approach for fertility preservation during cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy. Goldman, KN., Chenette, D., Arju, R., et al.[2018]

Caloric restriction (CR) and rapamycin both significantly increased the number of primordial follicles in female mice, suggesting they can help preserve ovarian reserve and potentially delay menopause.

While CR improved insulin sensitivity and reduced body weight, rapamycin did not affect body weight and induced insulin resistance, indicating that these two interventions have different metabolic effects despite similar benefits on ovarian reserve.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of caloric restriction and rapamycin on ovarian aging in mice. Garcia, DN., Saccon, TD., Pradiee, J., et al.[2020]

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

A 14-day study of sirolimus in renal transplant patients showed that it can be safely combined with cyclosporine and corticosteroids, as it did not significantly affect kidney function or blood pressure.

While sirolimus caused a reversible decrease in platelet and white blood cell counts and increased cholesterol levels, these side effects were manageable and distinct from the nephrotoxic effects of cyclosporine, suggesting a potential for effective immunosuppression without added toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Murgia, MG., Jordan, S., Kahan, BD.[2019]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical experience and critical evaluation of the role of everolimus in advanced renal cell carcinoma. [2021]

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

Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Cross talk between estradiol and mTOR kinase in the regulation of ovarian granulosa proliferation. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Effect of caloric restriction and rapamycin on ovarian aging in mice. [2020]

6. Denmark pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. [2019]