Rapamycin: a new treatment to delay menopause?

The menopause marks the end of the fertility period in women. It occurs when the ovaries cease producing oestrogens, causing the cessation of menstrual cycles. This process, which may seem sudden, begins years earlier. At birth, the ovaries contain about one million oocytes. At puberty, this number falls to 600,000 or 700,000. It declines with each menstrual cycle until fewer than 1,000 remain at menopause. At each cycle, several follicles are recruited but only one reaches ovulation. The others degenerate, reducing ovarian reserve.

Menopause occurs between 45 and 55 years of age, according to World Health Organization data.

Menopause can be unsettling. For some women, it brings symptoms of varying intensity that can affect quality of life. The most common symptoms, such as hot flushes, night sweats, vaginal dryness or sleep disturbances, can persist for several years. The menopause also affects the skin. The decline in oestrogen is accompanied by a sharp reduction in fibroblast activity, the dermal cells producing collagen, elastin, and hyaluronic acid, which results in visible skin laxity and more pronounced wrinkles.

Early menopause, defined as onset before age 45, is linked to an increased risk of osteoporosis, resulting in a higher risk of fractures. Inserm estimates osteoporosis is two to three times more common in menopausal women than in age-matched men. Menopause also carries an increased risk of cardiovascular disease in women. Delaying its onset may therefore offer genuine medical benefits.

Slowing the ovarian biological clock... Is it possible? This is the question raised by rapamycin, also known as sirolimus. This molecule, first isolated in 1975 from the filamentous bacterium Streptomyces hygroscopicus, was first used as an immunosuppressant after organ transplants, before being studied for its effects on longevity. Studies have shown that rapamycin can extend mouse lifespan by 10 to 15%. A 2023 study assessed its safety in 333 participants taking low doses of 1 to 15 mg per week. Few side effects were reported, although there was a higher risk of bacterial infections. Patients noted improvements in symptoms of various conditions, from arthritis to mood disorders, including long Covid. This study, based on participant reports without medical evaluation of benefits or side effects, cannot provide sufficient evidence of rapamycin’s efficacy or safety. However, it supports further research into this molecule’s effects on senescence.

Rapamycin could also preserve ovarian function.

Rapamycin inhibits the mTOR protein (mechanistic target of rapamycin), an enzyme that regulates multiple cellular metabolic pathways. When mTOR is active, it favours cell proliferation and activity. Conversely, inhibiting mTOR with rapamycin slows these processes. This resembles a resting state for cells and may extend their lifespan. In the ovaries, the mTOR pathway plays a key role in the activation of primordial follicles, the structures housing immature oocytes. Over time, some of these follicles activate, mature, then degenerate if they do not lead to ovulation. This monthly cycle accelerates depletion of the ovarian reserve.

A double-blind clinical trial is underway to assess the effects of rapamycin. The treatment is a 5 mg oral dose once a week for 12 weeks, compared with a placebo. Fifty women aged 35 to 45 are enrolled. The study aims to slow primordial follicle activation by blocking the mTOR pathway, to preserve the oocyte reserve and delay menopause. Initial results suggest rapamycin slows ovarian ageing by 20%. The compound lowers the number of eggs released each month to 15 instead of 50.

These initial results are encouraging but warrant caution: the clinical trial remains in progress and is not expected to conclude until September 2026.

We must wait for final data to confirm whether low-dose, short-term rapamycin can slow primordial follicle activation without causing adverse effects. If the final data confirm preliminary observations, the implications could be important: rapamycin could slow follicle reserve depletion and extend female fertility.

It is important to clarify that rapamycin does not appear to act directly on oestrogen secretion. Its main interest lies in its capacity to preserve ovarian follicles, delaying their premature activation. Fertility and menstrual cycle regularity depend on the presence of follicles and the cyclical production of oestrogen and progesterone. If rapamycin preserves follicles that remain endocrinologically inactive, its impact on fertility remains limited. The final study conclusions are needed to determine whether preservation of the follicular reserve also maintains ovarian hormonal function. Without this, the clinical relevance of rapamycin for extending fertility or delaying menopause must be reconsidered.