An essay by David B. Sable, MD 

The concept I describe most frequently to anyone interested in fertility is that of ovarian reserve, or the “egg factor.” As of this writing we are quite capable of bypassing the problems of poor quality sperm or low sperm count or problems stemming from dysfunction or disease of the female reproductive system such as endometriosis or tubal disease.

Still vexing though are women in the reproductive age group whose eggs do not seem to respond to the tools that we have available. Eggs are not replaceable. Women are born with all of the eggs they will ever have, and the number of eggs rapidly depletes as women age. Even before a first menstrual period, the number has shrunk from the millions present just before birth to the hundreds of thousands, and many more are lost monthly. Each menstrual cycle sees hundreds of eggs start the journey to maturity, a journey that only one or two will successfully complete. Each woman’s ovaries have their own rate of egg depletion, a sort of ovarian career that lasts from puberty to sometime before menopause.

Over time, the chance of conceiving in any particular month drops. For years we debated whether this decline was a result of the aging ovaries or the aging uterus, but the discovery that a woman’s reproductive potential could be greatly increased by the use of donated eggs demonstrated that the eggs, and not the uterus, were the cause of the decreased fertility.

Why would that be so? Think about what an egg is and what it does. Compare an egg to a sperm cell, which is essentially a DNA-filled ziplock bag with a tail. Its job is to deliver DNA to the egg and safely usher it inside. A good sperm cell contains normal DNA and has an effective way to gain entry into the egg. This process is so inefficient that nature sends millions of sperm cells out for each egg, to insure that one individual sperm cell gets the job done. Once the sperm has delivered the male DNA, however, the egg itself has to do the important work. It must provide an environment for the effective combining and replication of the now combined male and female DNA, and must split again and again in an equal fashion.

Looking for Good Eggs

A “good egg” has two functions: it must have good normal chromosomes and it must let those chromosomes combine with those from a sperm cell and subsequently divide in an efficient fashion. Eggs with abnormal chromosomes or eggs with cytoplasm (the non-DNA containing portion of the egg, in a simplified but not entirely accurate view) that cannot foster the effective distribution of chromosomes as it splits are the cause of the difficulty women experience as they age.

Unfortunately, egg quality is not easy to judge. Although egg quality declines as women get older, going by a woman’s age is not enough. Two women at the same age can have vastly different possibilities of conceiving on any given month. Differences seem particularly wide in the 36–41 year old age group. And while we can easily look at sperm, look at its shape and watch it swim, we can directly view eggs only after they have been somehow removed from the ovaries in an unnatural way.

FSH: The Cruelest Number

We have to look for our clues to egg quality in indirect ways. One possible way is by observing the menstrual pattern. As women age, their cycles shorten. Unfortunately this is such a late phenomenon in a woman’s reproductive career and most women’s cycles vary somewhat month to month that observing menstrual patterns is a very imprecise method of determining egg quality. So too are measurements of estrogen levels or follicle sizes on ultrasound scans.

So far, the best simple test we have been able to come up with is an early cycle FSH level. FSH stands for follicle stimulating hormone, and is one of the more important ways in which the brain talks to the ovaries. Simply, the brain releases FSH when it wants the ovaries to mature an egg; as the ovaries choose and mature the egg, hormone products from the ovaries signal the brain to decrease the release of FSH. This is an example of a feedback loop. An important concept to recognize is that the communication between the brain and the ovaries seems to be controlled by the eggs themselves, or by the cells that surround the egg and if the communication seems to be poor, it is an indication that there may be a problem with the eggs themselves. We are not sure what the exact nature of these problems are, whether they are in the DNA or the cytoplasm or just in the eggs’ ability to respond to stimulation, but we know that a breakdown in the communication between the eggs and the brain correlates with very poor pregnancy rates in infertility treatment.

The FSH test is the simplest method we know of in 1998 to test the ability of the eggs to talk back to the brain. If the system is functioning the way it should, then the FSH level early in the cycle should be on the lower end of the scale. How low? That depends on the laboratory doing the testing. Each lab, by nature of the way the test is done there, will report a different level for a given test. One of the great confusions regarding FSH testing is that a similar level means very different things at different places. Also, some clinics characterize their tests very carefully; others less so. FSH is reported in “units” and results from 2 units to 7 are probably normal in just about any lab. Levels above 25 are probably abnormal. The area between 9–24 may represent normal or abnormal levels, depending on how the test is performed.

Adding to the confusion is that FSH bounces around quite a bit. One month the result may be a 7 and the next month may be a 13. For a while we thought that it might be possible to wait for a month with a better level and improve the odds that a given cycle would work. Unfortunately we learned that the intermittent high FSH is as bad a prognostic sign in months where the FSH is normal as in months where it is high.

[INCIID Editor’s Note, 2026: Since Dr. Sable wrote this essay, a newer hormone test — Anti-Müllerian Hormone (AMH) — has largely replaced day 3 FSH as the primary first-line screening tool for ovarian reserve at most fertility clinics. Unlike FSH, AMH can be measured at any point in the menstrual cycle, does not fluctuate as dramatically month to month, and reflects the pool of small developing follicles more directly. FSH testing remains clinically valuable, particularly when interpreted alongside estradiol levels, but AMH is now considered the more reliable single marker of ovarian reserve. See the 2026 Update section below for more detail.]

Pregnant with Decreased Reserve

Now I know someone, somewhere is reading this and saying, “Wait a minute — I know someone who got pregnant after being told she had a high FSH.” Yes, you can get pregnant with a high FSH. But we are virtually incapable of bringing it about. Almost all of the tools we use in infertility care in 1997 need the ovaries to respond to extra stimulation: make extra eggs, higher hormone levels at the least. Ovaries with diminished reserve still have eggs that can turn into a pregnancy; unfortunately those ovaries respond to the most aggressive stimulations we know of by responding at a baseline level only. One of my colleagues compares the situation to a car that runs perfectly well at 30 miles per hour, and when you push the gas pedal all the way down, it goes…… 30 miles per hour.

Further, the eggs produced by ovaries with diminished reserve seem quite fragile. The tools we use, particularly HMG and IVF are often too much of a stress on these fragile eggs. Many fail to mature at all, many quickly move from immaturity to postmaturity (a sort of over cooking) and the few that withstand fertilization outside of the body rapidly dissolve away into numerous fragments since the ability of the resulting embryo to foster even cell division is compromised. The body, when left on its own, can still gently nurture some of these fragile eggs towards maturity in an effective way, and pregnancy is still feasible (although not nearly as common as we would like). When we bombard these same eggs with FSH or FSH and Lupron, or try to develop them in the in vitro environment, they do very poorly.

In these circumstances we are left with two polar extreme choices to offer patients: either to try on your own and hope that one of the infrequent natural pregnancies occur, or do IVF using a donor’s eggs. In the unfortunate cases where there are blocked tubes or a severe male factor, where a natural pregnancy is extremely unlikely even if a perfect egg were matured and released, the only real option, as of early 1998 anyway, is oocyte donation.

The Clomiphene Citrate Challenge Test

Returning to the subject of testing, I mentioned earlier that the FSH bounces in and out of the abnormal range during the diminished reserve period and that waiting for a “good month” is not helpful — that once the level starts appearing in the high range the ovaries as a whole can be considered unresponsive and the eggs more fragile. This leaves open the possibility of being misled by a normal value when the FSH is on the downswing of its variability. Are there ways to avoid this? Actually there are two. Recall that a finely tuned communication between the ovary and the brain will result in a low FSH value on days 2, 3, or 4 of the cycle. We have noted that the same fine tuning results in a low estradiol (estrogen) level at the same time. Further, an abnormally high estradiol level can artificially decrease the FSH and lull us into a false sense of security about the ovarian reserve. For these reasons we usually look at the estradiol (a.k.a. E2) level when testing FSH. And while there is no specific E2 level that precludes successful infertility treatment the way FSH levels can, E2 levels that are high (above 100 is a good benchmark) are good indications to look beyond just one FSH level for reassurance that the ovarian reserve is ok.

How do we look beyond the one FSH level? One way is just to repeat the day 3 tests several months in a row, but this is obviously inconvenient and wastes a lot of time. A quicker way is by using the second method of extended ovarian reserve testing, called the clomiphene citrate challenge test (a.k.a. CCCT).

Clomiphene Citrate Challenge Test:

• Day 3: FSH and E2 level
• Days 5–9: clomiphene citrate 100 mg (2 tablets)
• Day 10: FSH and E2 level

The basis for this test is that the FSH level should be lower on day 10 than on day 3. Using clomiphene citrate (a.k.a. Clomid or Serophene) on days 5 to 9, the FSH will actually rise on day 10 in women whose ovaries lack the ability to properly signal the brain. A high FSH level on day 10 is as bad as a high level on day 3, and can keep us from mistaking the bottom part of a bouncing FSH curve for false reassurance on the state of the ovaries.

[INCIID Editor’s Note, 2026: The clomiphene citrate challenge test (CCCT) is rarely used in clinical practice today. AMH testing and antral follicle count (AFC) via transvaginal ultrasound have largely replaced it as more reliable, less burdensome methods of assessing ovarian reserve. If your clinic recommends a CCCT, it is worth asking whether AMH and AFC have been evaluated first.]

Dr. Sable’s Closing Thoughts

I hate all of these tests. They are nothing but bad news. A bad level is always bad, good levels might still be bad and I can’t fix the underlying problem. And while oocyte donation offers many couples an excellent and fulfilling way to bypass the problem of diminished ovarian reserve, FSH testing is a constant reminder that we are still unable to help one of the largest groups of people who seek us out to help them conceive. Hopefully, advances in our ability to either rejuvenate the eggs in these women or to better separate the genetic from the growth components of eggs — and then use donor eggs with a woman’s own chromosomes — will change this scenario. Cytoplasm transfer is an important step in this direction; others are coming. I look forward to using FSH testing to help choose the right tools, rather than having them tell me I have none.

2026 Update: What Has Changed Since Dr. Sable Wrote This Essay

Editorial update by INCIID, 2026. All updates reflect current peer-reviewed literature and ASRM guidance.

Dr. Sable’s essay remains one of the most honest and patient-centered explanations of ovarian reserve ever written. His core insight — that egg quantity and egg quality are two different things, and that we are better at measuring one than the other — is as true in 2026 as it was in 1998. But the tools available to clinicians and patients have changed significantly. Here is what is new.

AMH: The Test That Changed the Conversation

The most important development since Dr. Sable wrote this essay is the widespread adoption of Anti-Müllerian Hormone (AMH) testing. AMH is a hormone produced directly by the small follicles in the ovaries — the same follicles that contain developing eggs. Because AMH reflects the current pool of those follicles, it serves as a more direct and stable measure of ovarian reserve than FSH.

Unlike FSH, AMH does not require testing on a specific day of the menstrual cycle and does not fluctuate as dramatically from month to month. A single AMH result gives a reasonably reliable snapshot of how many eggs a woman is likely to have available. Higher AMH generally means more follicles; lower AMH suggests fewer. AMH has also proven useful in predicting how a woman’s ovaries will respond to stimulation medications during an IVF cycle — something clinics now use to plan medication protocols before retrieval.

However — and this is the point Dr. Sable would most want patients to understand — AMH tells you about quantity, not quality. A good AMH result does not mean your eggs are chromosomally normal. It does not predict whether your eggs will fertilize successfully, develop into healthy embryos, or result in a live birth. AMH is a screening tool, not a guarantee. Current research from ASRM confirms that diminished ovarian reserve, as measured by AMH, does not appear to significantly impact embryo quality or live birth rates on a per-embryo basis. A woman with low AMH may have fewer eggs retrieved, but the eggs she does produce may be just as likely to be chromosomally normal as those of a woman with higher AMH — particularly when age is accounted for.

What AMH cannot tell you:

• Whether your eggs are chromosomally normal
• Whether fertilization will succeed
• Whether an embryo will implant
• Whether a pregnancy will result in a live birth

Antral Follicle Count (AFC): Seeing the Reserve Directly

Alongside AMH, the antral follicle count (AFC) has become a standard part of ovarian reserve assessment. Performed via transvaginal ultrasound early in the menstrual cycle, AFC involves counting the small visible follicles in both ovaries. Each follicle contains a developing egg. The count correlates strongly with AMH levels and gives clinicians a direct visual confirmation of reserve. When AMH and AFC results agree, clinicians can have more confidence in the picture. When they diverge — for example, a normal AMH but low AFC, or vice versa — the clinical picture becomes more nuanced and response to stimulation may fall somewhere between the two readings.

PGT-A: The Closest We Have Come to Assessing Egg Quality

Dr. Sable closed his essay hoping for advances that would allow clinicians to separate the genetic from the growth components of eggs. Preimplantation Genetic Testing for Aneuploidy (PGT-A) is the most significant step in that direction.

After eggs are retrieved and fertilized during an IVF cycle, the resulting embryos develop for five to six days to the blastocyst stage. At that point, a small number of cells can be biopsied and the chromosomes analyzed. Embryos with the correct number of chromosomes — called euploid embryos — are more likely to implant and result in a live birth. Embryos with chromosomal abnormalities — called aneuploid — are less likely to succeed and more likely to result in miscarriage.

PGT-A is important because it gives patients and clinicians actual information about specific embryos, rather than inferences drawn from hormone levels. A woman with a good AMH result who produces ten eggs may find that only two or three of those embryos are euploid — which is entirely normal, particularly as age increases. Conversely, a woman with a low AMH who produces only three eggs may find that one or two are euploid and viable for transfer.

It is important to note that PGT-A is not without controversy. ASRM’s 2024 Committee Opinion notes that its value as a routine screening tool in all IVF cycles remains a subject of ongoing clinical debate, and results should be interpreted in the context of a patient’s full clinical picture. PGT-A for polygenic disorders (PGT-P) — screening embryos for risk of complex conditions like heart disease — was specifically concluded by ASRM in December 2025 to not be ready for clinical use.

AI and Time-Lapse Imaging: Emerging Tools

Fertility laboratories are increasingly using artificial intelligence and time-lapse imaging systems to monitor embryo development continuously from fertilization through the blastocyst stage. These systems record how embryos divide and develop, and AI models trained on thousands of embryo images can identify developmental patterns associated with higher or lower implantation potential. These tools are still evolving and are not universally available, but they represent exactly the kind of advance Dr. Sable anticipated — ways of learning more about individual eggs and embryos without disrupting them.

The Bottom Line for Patients in 2026

Nearly three decades after Dr. Sable wrote this essay, his fundamental frustration remains valid: we are still far better at counting eggs than assessing their quality, and we still cannot fix the underlying biology of diminished reserve. What has changed is that we now have better tools for understanding what we are working with before and after retrieval, and better ways of selecting the most viable embryos for transfer.

If you are beginning a fertility evaluation, a complete ovarian reserve assessment in 2026 typically includes:

• AMH blood test (can be done any day of the cycle)
• Day 3 FSH and estradiol (still used alongside AMH for a more complete picture)
• Antral follicle count (AFC) via transvaginal ultrasound

If you are proceeding to IVF and want information about the chromosomal status of your embryos, ask your clinic about PGT-A and whether it is appropriate for your situation.

No test will tell you with certainty whether you will conceive. But the combination of AMH, AFC, and — when appropriate — PGT-A gives patients and clinicians a much more complete picture than FSH alone ever could.

Dr. Sable’s essay was Originally published 1998. Editorial notes and updates added by INCIID in 2026.

References

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