Explainer: what causes women’s fertility to decline with age?

It all comes down to egg supply. Image from shutterstock.com

We’ve known for over 50 years that reproductive ageing results in a gradual loss of fertility until about age 37, when the rate of decline accelerates dramatically. The loss of fertility is accompanied by increased risks of miscarriage and of conceiving babies with Down syndrome.

But we have not been clear on the precise mechanism by which this occurs – until now.

All of a woman’s eggs are produced before she is born and remain in a preserved state within structures called primordial follicles for several decades.

Follicles are gradually recruited to grow; this process begins soon after they are formed and continues throughout the woman’s reproductive life. Once a follicle is triggered to re-initiate development, it enters into the pool of growing follicles, most of which will disintegrate along the way.

Hundreds of thousands of follicles are lost before puberty but once puberty occurs, follicles go through an extra phase of maturation so that each month, one follicle (usually) is ovulated and a single egg released. The majority of follicles are still lost along the way.

The last three months of growth and maturation of recruited follicles are critical for normal development and this is when the ageing environment causes problems. Strangely enough, having a low number of remaining follicles causes the problem. Such a lot of follicles have been wasted during the woman’s life that as she ages there just isn’t the critical mass remaining to give out the correct hormonal signals.

The size of the pool can be measured by the AMH (anti-muellarian hormone) test or slightly less accurately by the FSH (follicle stimulating hormone) test. A low AMH or a high FSH result is a sign that the pool is near or at a critically low level.

Some younger women have a condition known as reduced ovarian reserve, which has similar outcomes to ageing. This is caused by several different genes, the best known of which is the Fragile X gene, which causes learning difficulties in affected males. Women carrying this gene have low ovarian reserves and higher risks of having Down syndrome babies, as well as of sons with fragile X.

Blood tests can measure AMH and FSH. Image from shutterstock.com

Anyone who is experiencing reduced fertility, however young, would be wise to have FSH or AMH testing before undertaking any fertility treatment.

When the follicle number is below the critical mass, the levels of a hormone inhibin B become very low. This in turn reduces the synthesis of a hormone called DHEA dehydroepiandrosterone, which is produced both by the ovarian theca cells and the adrenal gland.

DHEA controls critical elements of the ovarian environment at the earliest stage of maturation of the follicles, some 70 days before ovulation. DHEA is the precursor of hormones (both androgens and oestrogens) that are necessary for many aspects of follicle development.

However, normal levels of DHEA are also required for the activation of another hormone called PPAR alpha which controls over 200 genes, especially those regulating mitochondria (the powerhouse of the cell) and fat metabolism.

Oddly enough, the reduced fat metabolism caused by low follicle number not only changes the metabolism of the developing follicle but causes more follicles to self-destruct. So as well as improving egg quality, DHEA also stops the rapid loss of follicles and reduces the rate of ageing.

Many clinics in Europe and the United States now are treating women with DHEA supplementation and clinics report that taking pharmaceutical DHEA for about three months may restore the quality of the eggs so that women can conceive normally. Age of about 40 may be the upper limit.

But to date, the published results on DHEA treatment have been mixed, possibly because IVF clinics have treated women who have a range of different reasons for their infertility. As such it’s not routinely prescribed in Australia.

DHEA supplementation may also be dangerous for some women, especially those with polycystic ovarian syndrome where there is often already excess DHEA. It is vital that DHEA levels are measured before any supplements are taken.

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