"There is Hope for Women with Declining Ovarian Reserve"
published in RESOLVE Newsletter

By: Michael Mersol-Barg, MD

A couple’s opportunity to have a child in large part depends on their ability to produce good gametes: the egg and the sperm. Reproductive reserve describes both quantity and quality of gametes and such reserve is affected by gender, genetics, time, and exposure to environmental conditions. The duration, peak and decline of reproductive reserve differ by gender. This article will focus on how impaired reproductive reserve affects a woman’s fertility and ways in which to overcome this condition. 

What is ovarian reserve?

Ovarian reserve describes both the quantity and quality of eggs in the ovary.

To better understand how ovarian reserve changes in adulthood, it may help to review the developmental production process of gametes and the factors that influence egg quantity and egg quality. There are stem cells within the ovary and testicle from which eggs and sperm are produced. There are gender differences that place greater limitations on a woman’s reproductive reserve. In men, stem cells within the testicle continue to produce new sperm over their entire lifetime with gradual decline. In women, the stem cells stop producing eggs at about 5 months in fetal development. It has been estimated that about 7 million eggs are created by that time and this amount constitutes all the eggs a woman will have in her lifetime.  The eggs undergo substantial attrition with estimates of 2 million total eggs present by birth and four hundred thousand eggs present by the start of puberty. The average age of puberty is 12 years old.  The average age of menopause is 52 years old. If we assume that over a woman’s 40 year reproductive range she releases one egg per month, 12 eggs per year and 480 eggs over 40 years, then four hundred thousand eggs available at puberty seem more than sufficient. However, the real math is not straightforward.  In reality, the egg that is released in any given month represents the tip of a pyramid of eggs that were recruited 6 months earlier. The base of the pyramid may represent several hundred to nearly a thousand eggs of which only the one at the very top will successfully develop and the others will not survive to ovulation. When we add this egg attrition constant to the equation, we have to add 2 to 3 zeros to the end of 480. Four hundred thousand eggs no longer looks like a vast number.  

Each woman has her own unique ovarian pyramid. When fertility drugs are used, we go deeper into the pyramid of activated eggs. That is, we are able to supply more follicle stimulating hormone than a woman normally makes and rescue eggs that would otherwise have lost the competition for dominance in that month and would have undergone attrition. The number of additional eggs recruited depends on the breadth and depth of the pyramid. If a woman has a broad pyramid like those in Egypt, then many eggs are recruited. If her pyramid is narrow like the Washington Monument, then few eggs will be recruited. This also explains why use of fertility drugs does not shorten the time to menopause. We are recruiting eggs within that month’s pyramid that would have otherwise been lost rather than borrowing from future months’ pyramids.

Egg quality works through a different equation. Not all eggs are of good quality. For example, at puberty, assume fifty thousand of the four hundred thousand eggs are not normal and are more resistant to being recruited. Also, assume the good quality eggs are most responsive and will be easiest to recruit. Over the 40 years to menopause, the best eggs would have been recruited earlier while the poor quality eggs, resistant to recruitment, would still be present. By age 40, there may be sixty thousand eggs left of which the original fifty thousand poor quality eggs are still present. Thus, five of six eggs may be poor at age 40 compared to one of eight eggs at puberty.

How do you know if you have diminished ovarian reserve?

Unlike the assessment of a man’s reserve by directly seeing the sperm with microscopic semen analysis, methods to assess a woman’s reserve are less tangible and mostly indirect due the difficult task of accessing eggs and the limited insight gained by just looking at them under a microscope during IVF therapy.

Tests for ovarian reserve include:

What are my chances of having a baby if I have diminished ovarian reserve?

Among women less than 40 years of age, it appears that FSH levels are more closely related with the potential number of eggs to be recruited and not so much with reduced egg quality. Exceptions to this rule include women with very high FSH levels, perhaps greater than 20. For these women less than 40 years of age, the overall prognosis for pregnancy per cycle is estimated at 15-25%. High FSH levels are related to reproductive aging rather than chronologic aging.

Among women age 40 or greater with elevated FSH levels, pregnancy per cycle is estimated at less than 10%.  Even with normal FSH levels, their age is more related with reduced implantation, pregnancy and live birth rates per embryo transferred because of decreased egg quality. Therefore, the appearance of normal reserve in women age 40 or greater does not eliminate the age effect. An estimate of pregnancy per cycle among women age 40 or greater with IVF therapy and normal FSH levels is 10%. This includes women greater than age 42. A higher estimate would be expected if the upper limit of age were 42 years old.

What is the best treatment?

In making the best effort to have a mutually biologic child, I recommend IVF therapy. For younger women with diminished ovarian reserve, an aggressive dose of FSH medication assists in follicle recruitment. If eggs are collected, the prognosis is good. The challenge is getting eggs.  For women 40 years of age and over, we hope that pressing the ovaries to provide a greater number of eggs will present the opportunity for at least one good egg leading to success. The consensus for maximum dose of FSH medication is 450 units per day. Microdose Lupron Flare Protocol has commonly been prescribed since the mid-1980’s. However, growing experience in the use of the GnRH antagonist protocol over the past 3 years (with pretreatment of oral contraceptive pills) demonstrates at least an equivalent ovarian response, implantation and pregnancy rate when compared to the Microdose Lupron Flare Protocol (with some reporting improved pregnancy rates with the GnRH antagonist protocol). I have found improved outcome and simplicity of treatment with the GnRH antagonist protocol. 

Many physicians have a minimum follicle number of four that must be recruited in order to proceed to IVF egg retrieval.  Women with diminished ovarian reserve commonly have fewer than four follicles, which result in a high IVF cycle cancellation rate. The number of four follicles is not written in stone. If at least one follicle develops, then there is hope for success. For many women and their partners, cancellation of a cycle with at least one follicle can be devastating. There are many instances in which a child is born from an IVF cycle with 1-3 follicles are present. As long as the couple is clearly aware of the low prognosis for success and the alternative consideration of donor egg IVF therapy, I support their choice to proceed to egg retrieval. Many couples need to know they have made every effort to have a mutually biologic child before embarking towards use of donor eggs. Discussion of donor egg IVF therapy is beyond the scope of this article.

It is understandable that a woman is frustrated when faced with the paradoxical discovery that although she is physically strong and healthy, her reproductive aging has exceeded her chronologic aging. The key to success is identifying this problem as early as possible and proceeding directly to an aggressive level of IVF therapy.

What does the future hold?

We cannot turn back time, but soon we may be able to freeze its forward progression. In the near future, technology of egg cryopreservation will become sufficiently reliable to enable women to have more control over their reproductive health. Freezing eggs at a young age such as her early 20’s and storing them for future use will change the apprehension and frustration women feel under pressure of the biological clock. This technology will afford women the freedom to choose a wider range of social, family and career planning options.  Until that day comes, we have to work with the eggs one has and make the best effort to overcome diminished ovarian reserve.