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Cardone & Associates Reproductive Medicine & Infertility, LLC

Low Ovarian Reserve

Ovarian reserve is the pool of eggs present in the ovaries at any given time. Low ovarian reserve is when there is a physiological decrease in the number of eggs, resulting in an insufficient number to ensure a reasonable chance of pregnancy. Generally, it is caused by aging ovaries. Patients can have diminished ovarian reserve but intact ovarian function.

Where Did All the Eggs Go?

Females begin life at one of the earliest stages of development with millions of eggs. Unfortunately, nature plays a cruel trick by letting the vast majority of them decay before they are ever needed for reproduction.

In utero, there is a rapid multiplication of germ cells starting at six to eight weeks. By the time the female fetus is at 16-20 weeks, she has a peak of six to seven million eggs. This number declines to one to two million eggs at birth, falling even further to 250,000 to 500,000 eggs at puberty.

At 37 years of age, a woman will only have 25,000 eggs and at menopause less than 1000.

There are three types of eggs in the ovary: a pool of immature eggs, eggs that are selected to mature and prepare for ovulation in a particular cycle, and a pool of atrophic or dead eggs. The eggs are encased in follicles that support and nourish them until they mature, though the vast majority never do so. Every month, a certain number or percentage of immature eggs are selected for maturation. One of these eggs will ovulate and the rest will regress, die and be reabsorbed into the ovary through atresia. The number of eggs selected is dependent on the number of immature eggs in the pool.

Causes of Low Ovarian Reserve

Low ovarian reserve is a premature decrease in the number of eggs and can be caused by chromosomal anomalies such as Turner Syndrome, where there the woman does not have two X chromosomes, or gene abnormalities such as Fragile X.

Also ovarian tissue can be destroyed through torsion, surgical removal of part or all of the ovary, ovarian cysts caused by endometriosis, benign or malignant ovarian tumors, radiation or chemotherapy, immunological conditions, pelvic adhesions, or a high body mass index.

Low Ovarian Reserve and IVF Success

Low ovarian reserve only becomes an issue when a woman has problems getting pregnant. Other women experience this condition in their 30’s and 40’s, but may have had their children earlier in life, so it does not negatively affect them.

IVF success for all age groups is extremely dependent on how many eggs the doctor can obtain at the egg retrieval. A poor responder by definition is a woman from whom three or fewer mature follicles are formed after ovarian stimulation. There is three times less chance of pregnancy if we obtain less than four eggs from poor responders.

Fewer eggs mean fewer embryos to choose for the embryo transfer. Many times poor responders are older so the quality of their eggs is poorer, which decreases the chance of pregnancy and increases the chance of miscarriages. The patient’s response to ovarian stimulation is usually proportionate to their ovarian reserve.

There are several baseline tests used to determine if a woman is a poor responder:

  • Follicle stimulating hormone (FSH)
  • Estradiol (E2)
  • Inhibin B
  • Anti-Mullerian hormone (AMH)
  • Antral follicle count (AFC)

There also are dynamic tests like the Clomiphene Citrate Challenge Test (CCCT), exogeneous follicle stimulating hormone reserve test (EFFORT), and GAST, the ovarian response to GnRH agonist (GnRHa) test.

The next step is for the doctor to determine the best stimulation protocol for a poor responder.

The basic principle is to get as many eggs as possible. There is no perfect protocol. There is a large variability of response among poor responders to the same protocol. No one hat fits all and many times it boils down to trying different protocols.

Examples of different stimulation protocols:

  • OCP/MicroFlare Lupron with high FSH dosing
  • High FSH/HMG dosing with GnRh antagonist
  • Combination MicroFlare and Antagonist with high FSH/HMG dosing
  • Letrozole or Clomiphene and FSH/HMG
  • Estrogen/progesterone in previous cycle day 2
  • Estrogen in luteal phase of previous cycle
  • Estrogen and Antagonist start in 2nd part of luteal phase
  • Low dose FSH/HMG stimulation
  • Natural or minimally sustained cycle

Growth hormone as an adjunct to stimulation seems to help, but GHRF (growth horomone releasing factor), Pyridostigmine, oral L-arginine, transdermal testosterone, baby aspirin, DHEA, and acupuncture don’t seem to do so.

How do we decide whom to treat and what stimulation protocol to use?

Age is one of the most important factors to consider. The implications are vastly different when a 35-year-old woman only produces one to two (1-2) eggs than if a 45-year-old woman produces the same number. Unfortunately age not only affects the number of eggs but more importantly affects the quality of the egg.

The doctor needs to lower the day 2 FSH level if it is higher than 15. In our experience if the FSH at the start of stimulation is greater than 15, the chances of having more than 1-2 eggs is very low.

This decrease with ovarian age is due to two important occurrences that happen with time:

  • Decrease in the numbers of eggs in the ovaries
  • Decrease in the quality of the eggs present in the ovaries

FSH Levels and Live Birth Rates

FSH Level

All ages

<38

>38

<10

25%

32%

12%

10-15

13%

21%

8%

16-20

14%

20%

10%

>20

3%

17%

0

We also look at the Antral Follicle Count on first day of planned stimulation. if it is one to two, chances are high that we will not have more than one to two follicles develop that cycle regardless of how much drugs the patient is given.

We perform an evaluation cycle to determine the AMH (anti-mullerian hormone) and AFC (antral follicle count) levels to see if it even makes sense to stimulate the ovaries. The AMH level indicates the number of eggs in the ovaries; the higher the number the greater the number of eggs. If the ovarian reserve is very low, you won’t get more than one to two follicles. Then the doctor might suggest a natural cycle or a low dose IVF cycle

It is very important to be realistic about the chances of success so that the couple/individual can make the appropriate treatment decision or to use alternative options like donor eggs or adoption.

Summary
Poor ovarian response is what is significantly less than expected to ovarian stimulation: less or equal to three eggs  It is important for the doctor to know this since success with IVF is very dependent on the number of eggs we obtain at egg retrieval.

If we know a patient is likely to be a poor responder, then we can adjust our ovarian stimulation protocol to try to increase the number of eggs

Also if we know by testing AMH and AFC levels that is unlikely that we will get more than one to two eggs with a hefty stimulation using a high quantity of medication, then we may want to go with either a natural cycle or low stimulation protocol. This avoids the high cost and effort and obtains the same results.

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