Rapamycin in Endometriosis and Fertility: An Old Drug, a New Frontier — and Why It Feels Familiar

By Andrea Vidali, MD • Reproductive Endocrinology, Surgery & Reproductive Immunology

The Buzz Around Rapamycin

Over the past two years, rapamycin has gone from being a niche immunosuppressant — known mostly to transplant physicians and longevity enthusiasts — to one of the most talked-about molecules in reproductive medicine. The Columbia University VIBRANT trial, the 2025 randomized IVF trial published in Cell Reports Medicine, and a wave of mechanistic work in endometriosis have together pushed an unfamiliar drug into very familiar clinical territory: ovarian aging, diminished ovarian reserve, poor ovarian response, recurrent IVF failure, and endometriosis-associated infertility.

In my own practice, however, the excitement does not feel new. As a reproductive immunologist, I have spent years using metformin in IVF, and metformin is — at its core — also an mTOR inhibitor. So while rapamycin is being introduced as a fresh idea, those of us who have followed mTOR biology in fertility have actually been working in this lane for a long time. What is genuinely new is that rapamycin is finally bringing the conversation about mTOR, autophagy, and ovarian aging out of the laboratory and into the clinic.

What Is mTOR, and Why Does Inhibiting It Matter for the Ovary?

mTOR — the mechanistic (originally mammalian) target of rapamycin — is a serine/threonine kinase that sits at the center of how a cell decides between growth and maintenance. When nutrients, insulin, growth factors, and amino acids are abundant, mTOR (and specifically the mTORC1 complex) drives ribosome biogenesis, protein synthesis, lipogenesis, and cell proliferation. When mTOR is inhibited, the cell shifts in the opposite direction: it slows down translation, ramps up autophagy (the cellular recycling system), reduces oxidative stress, and dampens inflammation.

In the ovary, mTOR plays a very specific and consequential role. It is the main signal that activates dormant primordial follicles. Every menstrual cycle, an excess of primordial follicles is recruited from the ovarian reserve — most of them never reach ovulation and are simply lost. Sustained mTOR activation accelerates this attrition, which is why mTOR inhibition has been proposed as a way to slow the depletion of the ovarian reserve and, in essence, slow ovarian aging.

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Figure 1. mTOR integrates nutrient and growth-factor signaling. Both rapamycin and metformin converge on this pathway — rapamycin directly on mTORC1, metformin indirectly through AMPK activation.

Rapamycin: From Easter Island to the IVF Clinic

Rapamycin (sirolimus) was originally isolated from a soil bacterium on Easter Island in the 1970s. It is FDA-approved as an immunosuppressant for kidney transplantation and is used in drug-eluting coronary stents. Over the past decade, it has emerged as one of the most reproducible interventions in geroscience — capable of extending lifespan and healthspan in multiple animal models — and human studies have generally confirmed that low, intermittent dosing is well tolerated.

The reproductive interest in rapamycin started with mouse work showing that short-term treatment can preserve the primordial follicle pool, delay ovarian senescence, and improve oocyte quality in aged animals. Two clinical lines of evidence have now extended these findings into humans:

1. The VIBRANT trial (Columbia University)

The VIBRANT (Validating Benefits of Rapamycin for Reproductive Aging Treatment) study, led by Dr. Zev Williams and Dr. Yousin Suh, enrolled 50 healthy women aged 35–45 in late stage 3a reproductive aging — the window just before perimenopause. Participants were randomized to oral rapamycin 5 mg weekly or placebo for 12 weeks, with follow-up at 9 months. Early data suggested a roughly 20% reduction in the rate of monthly follicular loss — translating, the Columbia group has argued, to a potential extension of the reproductive window of approximately five years if the effect proves durable. A multicenter follow-up, VIBRANT II, is enrolling about 200 women.

2. The Li et al. randomized IVF trial (Cell Reports Medicine, 2025)

The other landmark study is the randomized controlled trial by Li and colleagues, published online ahead of print in Cell Reports Medicine in October 2025. The investigators first used multi-omics on oocytes and cumulus cells from 100 IVF patients aged 23–48 and identified a clear inflection point around age 34, at which oocytes and cumulus cells begin to show ribosome dysregulation, excessive protein translation, accumulation of misfolded protein aggregates, and impaired autophagy.

They then ran a separate randomized controlled trial in 100 infertile women with at least one prior failed IVF cycle (mean age ≈ 36, mean AMH ≈ 1 ng/mL, AFC ≈ 5). Patients received either a standard GnRH-agonist long protocol or the same protocol plus rapamycin 1 mg orally daily for 21–28 days, from pituitary downregulation through oocyte retrieval.

Table 1. IVF outcomes — Li et al. 2025 randomized trial (n = 100)

Outcome	Control (median)	Rapamycin (median)	p-value
Mature eggs retrieved	2	3	NS
Fertilized eggs	2	3	0.012
Day-3 embryos	1	2	0.001
Blastocysts	1	2	0.012
Top-quality blastocysts	0	1	0.043
Clinical pregnancy rate (overall)	28.2%	50.0%	0.047
Clinical pregnancy after Day 5–6 transfer	7.7%	27.5%	0.021

(Note: Trial was not blinded and was underpowered for live-birth rates. Adapted from Li et al., Cell Reports Medicine 2025.)

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(Li et al., 2025)

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The benefit was driven primarily by patients reaching the blastocyst stage. The interpretation: rapamycin did not increase the number of eggs retrieved, but it improved what came out of those eggs — fertilization rates, embryo numbers, blastocyst numbers, top-quality blastocysts, and ultimately clinical pregnancy. This is exactly the pattern one would predict from a drug that improves oocyte proteostasis rather than one that affects follicle recruitment in the same cycle. The signal is biologically coherent.

Why This Feels Familiar: The Metformin Connection

For those of us who have used metformin systematically in IVF, none of this is surprising. Metformin is conventionally classified as an insulin-sensitizer, but its core mechanism is mitochondrial: it inhibits respiratory chain complex 1, which raises the intracellular AMP:ATP ratio and activates AMP-activated protein kinase (AMPK). AMPK, in turn, is the principal upstream brake on mTORC1. So metformin is, functionally, an indirect mTOR inhibitor.

The biology has been documented repeatedly. In PCOS, metformin lowers mTOR phosphorylation in pathological B cells and reduces TNF-α production through mTOR-dependent metabolic reprogramming. In ovarian theca-interstitial cells, metformin inhibits proliferation in an AMPK-dependent fashion. In animal models of PCOS, metformin restores AMPK/mTOR balance and reduces ovarian ferroptosis. In other words, the same anti-inflammatory, anti-senescence, autophagy-promoting biology that everyone now ascribes to rapamycin has been quietly attributable to metformin for years.

Table 2. Rapamycin vs. metformin — convergence on the mTOR pathway

Feature	Rapamycin (sirolimus)	Metformin
Primary mechanism	Direct allosteric inhibitor of mTORC1	Inhibits mitochondrial complex 1 → activates AMPK → inhibits mTORC1
Effect on autophagy	Increases	Increases
Effect on ribosomal translation	Decreases (4E-BP1, S6K1)	Decreases (indirect, via AMPK)
Anti-inflammatory effect	↓ TNF-α, ↓ IL-6, ↓ Th17	↓ TNF-α, ↓ Th17, ↓ NF-κB
Effect on primordial follicle activation	Suppresses (preserves reserve)	Modulates (less direct)
FDA-approved indications	Transplant immunosuppression; coronary stents	Type 2 diabetes; off-label PCOS, GDM
Pregnancy use	Stopped at conception (teratogenic concern)	Considered safe (Category B)
Years of clinical experience in reproductive medicine	< 5 (emerging)	> 25 (established)

The Immunology Angle: Th17/Treg, Recurrent Implantation Failure, and Why This Sits in My Wheelhouse

I want to spend a moment on the part of this story that is most directly in my lane as a reproductive immunologist, because it is the part that gets the least airtime in the consumer-facing rapamycin coverage.

mTOR is not just a metabolic switch — it is also one of the most important regulators of T-cell differentiation. When mTOR is active, naive CD4+ T cells preferentially differentiate into Th1 and Th17 effectors. When mTOR is inhibited, the same precursors are pushed toward regulatory T cells (Tregs). In other words, rapamycin is one of the few drugs we have that can pharmacologically tip the Th17/Treg balance toward tolerance — which is exactly the balance that needs to be right for an embryo to implant and for a pregnancy to continue.

This is not theoretical. In 2019, Ahmadi and colleagues published a double-blind, phase II randomized trial of sirolimus in women with recurrent implantation failure (≥ 3 prior failed transfers) and an elevated Th17/Treg ratio. The treatment arm received sirolimus 2 mg orally daily for 17 days. The results were striking: a significant decrease in Th17/Treg ratio, a clinical pregnancy rate of 55.8% in the sirolimus group versus 24.2% in controls, and a live-birth rate of 48.8% versus 21.2%.

Table 3. Ahmadi et al. (2019) — sirolimus in immunologic RIF

Outcome	Control	Sirolimus	Direction
Th17/Treg ratio (post-treatment)	Elevated	Significantly reduced	↓
Treg cell number / function	Low	Increased	↑
Clinical pregnancy rate	24.2%	55.8%	↑↑
Live-birth rate	21.2%	48.8%	↑↑

Two things are worth underlining here. First, this trial used standard sirolimus dosing for a relatively short window — 17 days — not chronic immunosuppression. The intervention is short and finite, and the drug is washed out before any embryo transfer or conception attempt. Second, it works specifically in patients with an immunologic phenotype: an elevated Th17/Treg ratio is the entry criterion.

From a reproductive immunology perspective, then, rapamycin and metformin sit alongside the rest of our toolkit — intralipids, low-molecular-weight heparin, prednisone, IVIG, GCSF, and others — and the question is never “should this patient get rapamycin?” but rather “what is the immunologic phenotype, and which set of tools fits it?”.

My Approach: A Protocol Built Over Years, Now Updated

Over the years, I have put together a protocol that uses metformin in IVF patients who I judge to have poor oocyte quality — particularly the puzzling subset of patients who produce a healthy number of oocytes but consistently end up with few good blastocysts. The metformin-based protocol I have used pre-cycle and during stimulation rests on the same logic the rapamycin trials are now formalizing: dampen mTOR, enhance autophagy, reduce oxidative and inflammatory stress in the follicular microenvironment, and let the oocyte clean house before retrieval.

Given the new data, I have now added GLP-1 receptor agonists (the “GOPs” — semaglutide and tirzepatide-class agents) to the protocol where metabolically appropriate, because they share several of the relevant downstream effects: they lower systemic inflammation, improve insulin sensitivity, and indirectly reduce mTOR drive in metabolically loaded patients.

My current ‘poor-quality oocyte’ framework (illustrative, not a recipe):

• Pre-cycle metabolic and inflammatory workup (HOMA-IR, hs-CRP, vitamin D, thyroid antibodies, immune panel where indicated).

• Metformin started 6–12 weeks before retrieval in patients with insulin resistance, PCOS phenotype, or unexplained poor oocyte quality despite normal AMH/AFC.

• GLP-1 RA added in selected patients with metabolic load, with appropriate washout before stimulation per current safety guidance.

• Adjunctive low-dose pulsed rapamycin in carefully selected, counseled cases — based on the published Cell Reports Medicine schedule (1 mg/day for 21–28 days from downregulation through retrieval) or the lower-dose pulsed schemes described in the literature, always with the drug stopped before embryo transfer.

• Standard supportive ovarian-quality measures (CoQ10, vitamin D repletion, sleep, glycemic control).

The Anti-Inflammatory Side: Endometriosis Comes Into View

The mTOR pathway is hyperactivated in ectopic endometrial tissue. Multiple studies have shown that ectopic endometrium expresses higher levels of phosphorylated mTOR than eutopic endometrium, and that this overactivation contributes to the proliferation, angiogenesis, and progesterone resistance that define the disease.

In mouse models, rapamycin reduces endometriotic lesion size, suppresses VEGF expression and microvessel density, and inhibits the formation of deep infiltrating nodules. A 2024 narrative review in Molecular Human Reproduction concluded that mTOR inhibitors show real promise as a non-endocrine therapeutic option for endometriosis, particularly for women who fail or cannot tolerate hormonal therapy and who wish to preserve fertility.

There is also direct clinical signal. A cohort study in infertile endometriosis patients undergoing IVF examined the effect of adjunctive rapamycin and reported improvements in IVF outcomes, consistent with the idea that quieting mTOR in this population addresses both the lesion biology and the oocyte/follicular environment simultaneously.

Table 4. Documented effects of mTOR inhibition relevant to endometriosis

Domain	Effect of mTOR inhibition (rapamycin / temsirolimus / everolimus)
Lesion proliferation	Dose-dependent reduction in proliferation of deep infiltrating endometriotic stromal cells in vitro and in mouse models
Angiogenesis	Reduced VEGF expression and microvessel density in ectopic tissue after 2 weeks of rapamycin in peritoneal endometriosis models
Progesterone resistance	Restoration of progesterone responsiveness via PI3K/AKT/mTOR axis modulation; synergy with progestins such as dienogest
Inflammation	Reduction in TNF-α, IL-6, and macrophage activation in peritoneal fluid of endometriosis models
Endometrial hyperplasia	Rapamycin suppresses endometrial hyperplasia in aged mice and reduces proliferation of PTEN-null endometrial cancer cells
Fertility preservation potential	Adding rapamycin to ovarian tissue cryopreservation media reduces follicle activation and improves graft fertility in murine orthotopic transplantation

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How Published Rapamycin Protocols Differ

One source of confusion when patients (and clinicians) read about rapamycin in fertility is that the published protocols are not the same. They differ in dose, schedule, treatment duration, and the population they target.

Table 5. Comparison of published rapamycin protocols in reproductive medicine

Study / setting	Dose	Schedule	Duration	Target population
VIBRANT (Williams/Suh, Columbia)	5 mg orally	Weekly (pulsed)	12 weeks	Healthy women 35–45 wishing to slow ovarian aging
Li et al. 2025 (Cell Rep Med)	1 mg orally	Daily	21–28 days (downregulation → retrieval)	Infertile women with ≥ 1 prior failed IVF
Ahmadi et al. 2019 (RIF)	2 mg orally	Daily	17 days pre-transfer	RIF with elevated Th17/Treg ratio
Sills et al. 2023 (DOR + PRP)	3 mg load, then 1 mg × 6 d	Pulsed: 1 week on / 3 weeks off	4 monthly cycles after intraovarian platelet cytokines	Diminished ovarian reserve

It is worth noting that all four protocols use what is, by transplant standards, a low dose. None come close to the chronic, continuous immunosuppressive dosing that produces the more serious side effects in transplant patients.

A Representative Case

To make this concrete, here is a composite case that reflects the kind of patient who I think is the best candidate for combined mTOR-targeted care. (Identifying details have been removed; this is illustrative, not a single specific patient.)

• Presentation: 38 years old, BMI 27, AMH 2.4 ng/mL, AFC 14, regular cycles. Surgically confirmed stage III endometriosis. Four prior antagonist IVF cycles, each yielding 14–18 oocytes but only 1–2 usable blastocysts; two euploid embryo transfers, both negative. Mildly elevated hs-CRP, borderline insulin resistance (HOMA-IR 2.6), elevated peripheral Th17/Treg ratio.

• Interpretation: This is not a quantity problem — she makes plenty of oocytes. It is a quality and tolerance problem on a substrate of low-grade systemic inflammation, endometriosis, and metabolic load. Classically, this is the patient who gets labeled “unexplained poor embryo development” and is told to consider donor eggs prematurely.

• Approach (illustrative): Metformin started 12 weeks before retrieval for the metabolic and mTOR effect; targeted nutritional and lifestyle work to bring hs-CRP down; surgical re-evaluation of endometriosis where indicated; consideration of adjunctive low-dose rapamycin during the stimulation cycle modeled on the Li et al. 2025 schedule, stopped at retrieval; and a pre-transfer immunomodulatory plan informed by the Th17/Treg ratio. Embryo transfer is delayed until the immunologic and metabolic markers have moved.

The point is not that every patient like this gets rapamycin. The point is that the same patient who would have been told “your eggs are old, try donor” three years ago now has a coherent, biologically grounded set of options to try first.

A Few Important Cautions

Rapamycin is not a benign drug, and it is not a candidate for casual prescribing. The known side-effect profile includes stomatitis, glucose and lipid metabolism abnormalities, mild rash, and dose-dependent immune effects. Most events reported in the longevity and fertility studies have been mild (CTCAE grade 1–2), and the lower the dose and the more pulsed the schedule, the more favorable the safety picture.

Table 6. Reported side effects of low-dose / pulsed rapamycin

Side effect	Typical frequency	Practical management
Mouth ulcers / stomatitis	Most common; usually mild	Topical steroid rinses; reduce dose if recurrent
Mild rash / acneiform eruption	Occasional	Typically self-limited; rarely requires intervention
Mild lipid elevation	Common with chronic dosing; uncommon with short courses	Baseline and follow-up lipid panel; usually reversible
Mild glucose elevation	Uncommon at low pulsed doses	Baseline HbA1c; relevant in metabolic patients
Increased infection susceptibility	Rare at fertility-cycle doses	Avoid live vaccines around treatment; defer if active infection
CYP3A4 / P-gp drug interactions	Pharmacologic, not dose-related	Review medication list (azoles, macrolides, grapefruit, certain antiepileptics)

Caution is warranted in particular in:

• Patients with active infection or recent vaccination (live vaccines especially).

• Patients with poorly controlled diabetes or dyslipidemia.

• Patients planning conception during the treatment window — rapamycin should be discontinued before transfer; the existing trials all stopped the drug at retrieval or earlier.

• Patients on medications with significant CYP3A4 interactions.

The Bottom Line

Rapamycin is a meaningful addition to the reproductive medicine toolkit. It is not, however, a paradigm shift on its own — it is the most direct expression of a paradigm we have already been working in. mTOR is the right target, and it sits at the intersection of three things that matter for fertility: ovarian aging, the inflammatory biology of endometriosis, and the Th17/Treg balance that governs implantation.

If you are a patient with poor oocyte quality, recurrent IVF failure, endometriosis-associated infertility, or simply concerns about ovarian reserve and reproductive aging, this conversation is worth having. The science has moved meaningfully in the last 18 months, and the clinical implications are real — but they belong inside a thoughtful, individualized plan, not on a wellness menu.

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Selected References

• Li J, Wang H, Zhu P, et al. Ribosome dysregulation and intervention in age-related infertility. Cell Reports Medicine. 2025.

• Williams Z, Suh Y, et al. Validating Benefits of Rapamycin for Reproductive Aging Treatment (VIBRANT). ClinicalTrials.gov NCT05836025.

• Ahmadi M, Abdolmohammadi-Vahid S, Ghaebi M, et al. Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: a double-blind, phase II randomized clinical trial. Int Immunopharmacol. 2019.

• Wang Y, Zhang X, Yao Y, et al. The efficacy of immunotherapies for pregnancy outcomes of patients with recurrent implantation failure as defined by ESHRE guidelines: a systematic review and network meta-analysis. J Reprod Immunol. 2026.

• Mok-Lin E, Ascano M Jr, Serganov A, Rosenwaks Z, Tuschl T, Williams Z. Premature recruitment of oocyte pool and increased mTOR activity in Fmr1 knockout mice and reversal of phenotype with rapamycin. Sci Rep. 2018.

• Dou X, Sun Y, Li J, et al. Short-term rapamycin treatment increases ovarian lifespan in young and middle-aged female mice. Aging Cell. 2017.

• Yang Q, Hu J, Wang M, et al. Rapamycin improves the quality and developmental competence of in vitro matured oocytes in aged mice and humans. Aging. 2022.

• Lu J, Li J, Liu C, et al. Short-term rapamycin mitigates the senescence of ovaries and somatic stem cells in multiple organs in reproductively aged mice. FASEB J. 2026.

• Bindels J, Squatrito M, Bernet L, et al. Ovarian cryopreservation with rapamycin improves fertility restoration in a murine orthotopic transplantation model. Sci Rep. 2025.

• Sills ES, Harrity C, Wood SH, Tan SL. mTOR inhibition via low-dose, pulsed rapamycin with intraovarian condensed platelet cytokines: an individualized protocol to recover diminished reserve? J Pers Med. 2023.

• Chen X, et al. A cohort study on IVF outcomes in infertile endometriosis patients: the effects of rapamycin treatment. Reprod Biomed Online. 2023.

• Honda T, et al. mTOR inhibitors as potential therapeutics for endometriosis: a narrative review. Mol Hum Reprod. 2024.

• Ren X, Wang Y, Xu G, Dai L. Effect of rapamycin on endometriosis in mice. Exp Ther Med. 2016.

• Leconte M, et al. The mTOR inhibitor temsirolimus reduces deep infiltrating endometriosis in vitro and in vivo. Am J Pathol.

• Guo M, et al. Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice. Sci Rep. 2017.

• Sun L, Lv S, Song T. Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis. Front Endocrinol. 2023.

• Wang H, et al. Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome. eLife. 2022.

• Will M, et al. Metformin: direct inhibition of rat ovarian theca-interstitial cell proliferation. Fertil Steril. 2012.

• Wang Y, et al. Metformin in gynecological disorders: pathogenic insights and therapeutic implications. Front Pharmacol. 2025.

• Guo Z, Yu Q. Role of mTOR signaling in female reproduction. Front Endocrinol. 2019.

• Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012.