AGE, AMH And Reality
Despite Hollywood myths to the contrary, women are faced with the harsh reality that as they age their chances of having a genetic child become less and less. And, if the pages of People Magazine and other tabloids are to be called in question, this occurs at the relatively young age of 41, when as much as 50% of Caucasian females with are unable to have their own child.
So, why does reality not follow reality TV? The underlying physiology starts with the fact that women stop producing eggs (oocytes) when they reach the 5 month mark…that is while they are still gestating inside their mothers. And although, they produce 6-7 million oocytes in total, by the time they are born, that number has depleted to 2-3 million oocytes. This quick regression continues and by age 20, women are left with 300,000 – 400,000 oocytes.
Yet, for all intents and purposes, this still seems to be an impressive number, considering the popular idea that ‘all you need is one.’ Time for more math. Each month, the ovary recruits a large number of oocytes. 20 year old recruits approximately 1000 oocytes per month, of which only one is actually ‘selected’ while the rest die off. This recruitment goes on incessantly until there are no more oocytes to recruit. The pool of oocytes has been called a reserve. Since oocytes are not created, this pool of oocytes represents the reproductive potential. Age decreases the pool, or reserve, and thus there is a constant reduction in the ovarian reserve.
WHAT TO DO, WHAT TO DO?!
How best to use technology then to address this issue? Women would be best served if there was a way to track the status of the reserve. If the number of eggs remaining became dangerously low, she could elect to undergo fertility preservation. In this process, also known now as Egg Freezing, multiple oocytes are simulated to develop and then these are removed and frozen for use in the future, freezing the eggs in time. But, a subtly of this process is that the pool of oocytes is really composed of two groups of oocytes: one group is structurally normal and can create embryos with the correct number of chromosomes. The other group of oocytes are structurally damaged and cannot create embryos with the correct number of oocytes. The ovary has a nasty tendency to use the normal oocytes first. As a woman ages her pool of oocytes diminishes but unfortunately the ovary uses the normal oocytes first. At some point, all oocytes are structurally abnormal even though there are still oocytes present in the ovary. This explains why women may continue to menstruate through and into their 50’s but are incapable, in most cases, of conceiving a chromosomally normal child.
From all of this, a concept called “reduced ovarian reserve” has evolved. Reduced ovarian reserve is used to describe the effect of age on the ability of the oocytes in the ovary to create embryos with the correct number of oocytes. While this seems like a logical concept, a subtle problem exists. Suppose that 10 oocytes are retrieved from a fertile, 20 year old female. Testing embryos from oocyte donors has demonstrated that as much as 30% of these oocytes will create embryos with the incorrect number of oocytes. From 10 oocytes, 7 would be normal. Now consider 10 oocytes from a 40 year old female. Studies have demonstrated that up to 90% of these oocytes will be abnormal. However, both the 10 oocytes from the 20 year old and the 10 oocytes from the 40 year old, contain at least one oocyte that can potentially create normal. Thus, knowing the number of oocytes would not help identify which woman is at risk of soon having no more normal oocytes and will be functionally sterile. Thus, age alone warns a woman that her reserve is being reduced. If a woman wants to freeze some of her oocytes for fertility preservation, she needs to do that at a young age. She may never need the use the frozen oocytes but if she wait too long, fertility preservation through oocyte freezing will be too late. Freezing oocytes at a young age (< 35 years old) provides an insurance policy that she may never need to use.
IS THE ANSWER IN THE AMH?
A number of tests have been proposed as a test to identify this at- risk group of young women. One such test is to measure the hormone AMH (anti-mullerian hormone). AMH is produced by the cells that develop around the oocyte in the oocyte unit termed a follicle. Thus the more oocytes, the more follicles, and by corollary, the higher the AMH. If the AMH is low, it implies that there are fewer follicles and common sense would say that the woman had less of a chance for achieving a pregnancy which has been termed a reduced ovarian reserve. AMH has been advertised as a way to decide if oocyte freezing for fertility preservation would help. Nothing is that easy and the AMH story is exemplar of a situation where the theory does not match the reality. AMH was proposed to help decide the chance of having a success if the woman chooses to use IVF. The higher the AMH, the more oocytes, and thus a better chance of having at least one oocyte that can produce a child. But as has been suggested, the number of oocytes may not correlate with the number of functionally normal oocytes. AMH has been used in IVF and has not been adequately studied to determine if it does identify the group of women who have a reduced functional ovarian reserve.
A number of studies have evaluated the ability of AMH to predict the probability of pregnancy in IVF cycles. This body of work has spawned at least three meta-analyses as a way to statistically summarize the information contained in many smaller studies. A study by Tai R ( 2015 Fertil. Steril 101: 119) identified 19 studies which were comprised of data from 5,373 women. The women were grouped into three groups: unspecified ovarian reserve, diminished ovarian reserve, and polycystic ovarian syndrome. AMH had no predictive value for the PCOS group. The analysis concluded that AMH had a weak association with the clinical pregnancy rate. It was a poor predictor for the women with PCOS. AMH was most predictive for women with a reduced ovarian reserve. Wang et al (2010) demonstrated that AMH was least predictive of pregnancy in younger women completely. To further muddy the waters, AMH levels are depressed by as much as 30% when a woman is using oral contraceptives. AMH can be used to predict the time of menopause, but assessing the time to menopause generally starts with women in their 40’s, past the point where egg freezing should be considered a reasonable option.
The conclusion from a large number of studies and three meta- analyses suggest the AMH does correlate with fertility potential based upon the concept of reduced ovarian reserve. Unfortunately the correlation is weak. Therefore, the use of AMH to determine if oocyte freezing as a form of ovarian preservation is not predictive enough to be clinically useful, The older a woman is when she considers freezing her oocytes, the lower the chance that the oocytes will provide the woman with a chance to achieve a pregnancy using her own oocytes. For young women, the AMH does not help because it is less predictive in younger women.
Unfortunately, people are being offered AMH testing with the intention to help in the decision concerning oocyte freezing. The decision to freeze or not is not aided by the AMH. Freezing oocytes acts as an insurance which most people will never need. But like most insurance policies, it is extremely useful when needed. If a young woman freezes her oocytes, the chance of being able to achieve a pregnancy can be quite high with some estimates bring as high as 80-90% chance with more than 15 oocytes. The rates are much lower for women freezing oocytes if the woman is over the age of 37.
So what is the clinical usefulness for AMH? Unfortunately, just as the aforementioned Hollywood baby miracles, AMH does not live up to its reviews. The decision to cryopreserve oocytes, similar to the realization of fertility being a finite process that ends sooner rather than later, is dependent upon age alone.