Could Rapamycin Extend Women's Fertility by Five Years?

More people are choosing to wait before having children. Although there are many reasons to postpone this decision, around one-third of couples experience trouble conceiving when the female partner is older than 35. That is because female fertility starts to decline at about this age.

Researchers running an ongoing clinical trial say that rapamycin, a medicine widely used to stop transplanted organs being rejected, could potentially lengthen a woman's fertile years by as much as five years.

This suggestion comes from an early announcement of findings from a small pilot study, which has not yet undergone peer review.

It remains far too soon to know whether rapamycin could become part of future fertility treatments: the clinical trial will not conclude for another two years. Even so, the results reported so far offer some grounds for optimism.

A substantial number of mouse studies have found that rapamycin benefits several aspects of ageing, fertility among them.

Ovarian reserve and fertility

The foundations of later fertility are laid before birth. In the womb, female gametes, or eggs, become enclosed by specialised ovarian cells to create "primordial follicles". Every follicle holds one egg, which remains dormant until it is selected for use after puberty.

Many follicles are lost before birth. Consequently, every woman is born with the full supply of follicles she will ever possess, known as the "ovarian reserve". Established so early in life, this reserve can influence a person's ability to conceive across their reproductive years.

In each menstrual cycle, several dozen follicles are recruited, or selected, yet just one dominant follicle releases an egg for fertilisation. The ovary breaks down the remaining recruited follicles.

With age, the ovarian reserve shrinks until only a small number of high-quality follicles are left. Levels of certain ovarian hormones circulating in the body then fall, bringing about menopause.

Menopause occurs at an average age of 51 years, although the timing varies considerably between women according to their ovarian reserve. Some women have early menopause, occurring before the age of 45.

Around 1% of women may undergo premature menopause, which occurs before 40. Because menopause has a direct effect on fertility, early menopause can significantly alter a woman's plans for parenthood.

If ovarian ageing could be postponed, however, a woman's fertility might also be extended. Rapamycin may be capable of doing this.

Repurposing rapamycin

Rapamycin is a compound produced by bacteria that enables cells to survive for longer in laboratory conditions.

It is commonly prescribed to organ transplant recipients to suppress their immune systems and prevent rejection of the new organ. It is also used for some vascular conditions, where it slows cell growth, including that of tumours.

An increasing body of research indicates that rapamycin could also offer benefits related to ageing.

Mouse research has shown that it can reduce age-related muscle loss. In older mice, a daily dose of rapamycin has also been found to increase lifespan by 10%.

For fertility, studies have shown that daily rapamycin treatment postpones ovarian ageing and menopause in mice.

Older female mice fed a diet containing rapamycin showed an enlarged pool of primordial follicles: their ovarian reserve.

These mice also produced successful litters later in life. This indicated that rapamycin might be able to delay premature menopause in women.

The rapamycin clinical trial

Whether the medicine can have the same effect in humans is the question a research team is investigating. For its pilot study, the team enrolled 50 perimenopausal women aged 35-45 years.

For three months, participants received either a weekly rapamycin dose or a placebo. Researchers monitored ovarian reserve using transvaginal ultrasound and several blood tests measuring different ovarian hormones.

The researchers say the preliminary findings were highly encouraging. They suggest the drug may reduce ovarian ageing by 20% in women, without causing side-effects. The team hopes this could translate into an extra five years of fertility.

Rapamycin may produce this beneficial effect by limiting how many primordial follicles are recruited and activated during each menstrual cycle.

Women given rapamycin recruited only 15 follicles in each menstrual cycle, compared with 50 among women of a similar age. Recruiting fewer follicles appears to extend the ovarian reserve.

Earlier mouse research found that rapamycin causes fewer follicles to be recruited, potentially helping to conserve ovarian reserve.

Maintaining fertility

The first study involved a relatively small cohort. However, the promising results claimed by the researchers mean they can now proceed to the next phase of the experiment, enrolling 1,000 women.

The hope is that the preliminary results will be replicated and, in a peer-reviewed study, demonstrate that rapamycin is an effective treatment for ovarian ageing. Further research would then be required to determine whether fertility itself is extended.

Should the clinical trial establish that rapamycin is beneficial, it could support women with a low ovarian reserve and those seeking to maintain their fertility for longer.

The study also demonstrates the potential for repurposing existing medicines to address other conditions affecting women's health and wellbeing. My colleagues and I are pursuing this approach at the University of Central Lancashire.

We are currently studying, in cells, whether repurposing widely used diabetes medicines can improve the uterus and help an embryo implant. We are also examining these targets for the treatment of ovarian cancer.

Stéphane Berneau, Lecturer, School of Pharmacy and Biomedical Sciences, University of Central Lancashire

This article is republished from The Conversation under a Creative Commons licence. Read the original article.