Ovarian Reserve Testing (AMH)
As woman pass age 35, we call them Advanced Maternal Age, since pregnancy rates show a dramatic first decline, and adverse pregnancy outcomes increase. The current state of the art of evaluating potential egg quality and number-translation, the potential likelihood of a successful outcome, is to consider maternal age, cycle day three FSH/estradiol, and antimullerian hormone level, and basal antral follicle count. As with any new testing, AMH has yet to be understood in its role in determining ovarian reserve. The common interpretation of AMH has been to assume it is a better indicator of ovarian reserve and as it declines, so does reserve. This dropping AMH is noted with age, especially over 35, and as this value drops below 1, and becomes 0.8 or 0.54 to 0.24 and ultimately <0.16, patients are routinely counseled to consider donor egg. Why? Well, AMH does correlate with the number of basal astral follicles, and thus in an IVF cycle, fewer eggs correlate with lower rates.
When AMH is very low to undetectable, patients have been stampeded into doing donor eggs or rushing into an IVF before all their eggs are gone. There were a recent Fertility and Sterility article condemning the practice of counseling patients into using donor eggs when they have low AMH since the eggs that are obtained have shown they can grow to viability. Having an AMH below 1.0 is anxiety provoking, and the lower it goes, the higher the tension. Still, patients with very low AMH should be counseled that their per cycle outcomes should be very low, <10% delivery rate under age 40. I would expect an AMH below 0.4 to be considered very low, and for this reason, began looking at these patients to see if I could recruit new basal astral follicles (BAF).
I initially approached only patients with AMH <0.16 and who did not wish to move to donor egg. They understood and had heard from multiple REI doctors that their chance of getting a baby with their own egg would be <1%. From this small group of 6 patients between 36 and 39 years old, all of them made it through super ovulation to egg capture. All of them had at least two mature eggs, and all had two blasts for embryo transfer. Two out of six patients have conceived and gone on to delivery. (33%LBR). What is interesting, is all six had been called poor responders and failed previous IVF attempts. They had failed to make follicles grow, or get mature eggs, or embryos that would not grow past day two.
The difference in my approach was not to simply repeat another futile IVF cycle in these women but to consider recruiting “new” eggs into these depleted ovaries. My approach was to challenge the prevailing anecdotal belief that DHEA was the fountain of youth hormone, and simply having women take this with Co-Q 10 will significantly improve their outcomes. We are all taught that by age 1, woman’s ovaries contain 300,000 eggs in immature primordial follicles. In this stage, the vast majority of them will remain. A woman will convert 3500 primordial follicles into a primary follicle, also known as a primary follicle. It is these primary follicles that are the 4mm or larger follicles that we can see on ultrasound, and constitute the BAF count. It is this BAF count that correlates with AMH. So, if even 10,000 primary follicles are consumed in a women’s reproductive lifetime, what happens to the remaining 290 thousand primordial follicles? Even if we are taught that there is accelerated follicle death with advancing maternal age, there would have to be a few thousand primordial follicles remaining. It is these remaining primordial follicles that I suspected could be recruited. Ovarian biopsies from 50% of women declared to be menopausal have shown to contain primordial follicles with eggs. It is well known that recently menopausal women given estrogen hormone replacement, 20% of them will spontaneously ovulate within the first year.
Given this landscape, I recalled a talk from a Canadian Ph.D., who was looking at why birth control pills failed to suppress ovulation. During his talk, he mentioned that FSH hormone oscillated up and down, and as it dropped, it initiated a new wave of follicle growth. I instantly imagined this to be a supply chain problem. Let’s imagine that the ovary has to contain most of the eggs in microscopic primordial follicles, with a fraction percentage in primary follicles, and one secondary follicle each month. Imaging these eggs are like cookie dough. The primordial follicle is akin to frozen dough, and this has to be taken from the freezer to the kitchen counter to thaw. Once thawed, this becomes a primary follicle and will be put into the oven to bake and grow into a secondary follicle. Once cooked, this is handed out and served, and another thawed cookie dough moves into the oven (primary follicle) and the more frozen dough is removed from the freezer to the counter. (primordial follicle)
This supply chain begins in the first year before menarche, and may account for the accumulation of BAFs that are the hallmark of a young healthy ovary. In nature, we have an experiment in women where they have the ability to recruit primordial follicles into becoming primary follicles, but they are unable or poorly able to move from primary follicle to secondary mature follicles. These women are called polycystic ovarian syndrome (PCOS). The hallmark of this disorder is low circulating FSH and elevated male hormones, androgens. Based on all these observations, and my understanding of inflammation and what I call hormone transmission defect, I started with these initial six women with undetectable AMH and no BAF count. I was not able to get their AMH to change or be detectable, but we got 2-4 quality eggs and 2 expanded blastocysts from all of them and 3 of 6 got pregnant and 2 of 6 delivered, (33% delivery rate). This is not markedly different but is higher than for the best national outcomes for all-comers for this age group. In three women over age 40, (41,42, and 43), all with undetectable AMH, they were able to produce 2-4 mature eggs and each made two good blasts but did not get pregnant.
Over time, I applied this FSH suppression protocol in concert my Inflammation Balancing Protocol to a less severe cohort of a woman having detectable AMH between 0.16 and 0.54. These women have been able to increase their AMH, and examples are 0.33 to 0.94, or 0.54 to 1.74. Recently we took a 38-year-old with 3 failed IVF and poor responder and were able to get 8 mature eggs, and 5 blasts. This approach is nothing short of astounding. Prior to my approach, the 1-2 eggs that she produced did not get past day two growth. Now we have a 62% expanded blast rate. This is almost twice the national average and suggests to me that we are recruiting new BAF eggs, and these are behaving as if they are young 20-year-old eggs. If I am correct, then this may lower the genetic risks that we typically see with advancing maternal age.
When I did my first patient, we held her for 90 days, because that is the amount of time it takes to make primordial sperm into primary spermatozoa. We got two mature eggs. Over time, I discovered that the maturation interval is 120 day, and as I extended this interval, I got 2-3 mature eggs. By moving to 150 days, I got 3-4 mature eggs, and by 180 days, got 6 mature eggs. Trying to keep an aging infertile woman from actively trying to conceive is no small feat. Woman hear their biological clock loudly and can panic and bolt. I have lost many women to this urge as they left me for another center that was all too eager to push them through an IVF cycle, but many do return after no success with 1-2 failed cycles. They all hear me tell them the same advice I told them earlier, and to get back into recruiting new primary follicles.