In spite of dramatic advances in infertility treatment, age related infertility remains as one of the most difficult challenges. Reproductive endocrinologists have known for years that the pregnancy rate is inversely related to the female partner’s age. This is based on decreasing Oocyte quantity and quality which combines to create a diminished ovarian reserve with advancing age. Ovarian Reserve describes a woman’s capacity to respond to Ovulation Inductionby producing a reasonable number of good quality eggs. Coupling this issue of age with our current societal trend of increased numbers of women who delay childbearing for educational and career goals, we now have a dramatic increase in age related infertility. For those providing primary care to women, it is now much more important to carefully counsel patients regarding family planning issues, especially with regards to advancing age and diminished successful pregnancy rates. Patients who are in their early to mid thirties or beyond who are considering pregnancy or have been trying for any length of time without success warrant an early referral for evaluation.
Diminished Ovarian Reserve:
As with any distribution in medicine, there is a bell curve and the same is true for the period of diminished ovarian reserve. As a consequence we are now identifying patients in their teens, twenties, and early thirties whose ovarian function is the equivalent of the average 44 year old. Therefore we have now begun to think in terms of “ovarian age” as opposed to chronologic age; the two are often not synonymous. Diminished ovarian reserve refers to a group of patients at any age that are cycling regularly but whose ovaries, and the oocytes contained within, have a markedly decreased ability to produce pregnancies. Risk factors for this entity include age > 35, previous ovarian surgery, single ovary, unexplained infertility, and history of poor Stimulation with injectable Ovulation drugs. The patients exhibiting diminished ovarian reserve often have identifiable clinical characteristics. The patients Cycle intervals become subtly but progressively shorter with 21 to 27 day cycle intervals common. This is due primarily to a shortened follicular phase and correlates with patient histories of positive ovulation predictor kits on cycle day 9 or 10. Progesterone levels may rise prematurely. Premenstrual syndrome symptoms seem to be more common in this group especially those of emotional swings and anger. The rate of Spontaneous Abortion is higher as well. Based on the above, several diagnostic categories in reproductive medicine, such as Luteal Phase defect, which have been formerly of questionable significance, and hard to study or characterize, may have at least part of their basis in diminished ovarian reserve.
Ovarian Reserve Testing:
The methods for assessing ovarian reserve are classified into two groups: passive testing and dynamic testing. The goal of both approaches is to provide information regarding oocyte quality and quantity. Passive methods include Day 3 FSH & Estradiol, Inhibin B, Antimullerian Hormone as well as baseline Ultrasound for Antral Follicle Count and ovarian volume. The most commonly used dynamic test is the Clomiphene Citrate Challenge Test (CCCT).
FSH & E s tradiol:
The earliest tests of ovarian response were the cycle day 3 FSH and later the addition of cycle day 3 estradiol tests. If the FSH or the estradiol level is high on day 3, patients are more likely to respond poorly to stimulation with gonadotropins and have greatly reduced pregnancy rates both with IVF and ovulation induction with IUI. This is due to the aging follicle’s failure to produce adequate amounts of inhibin, a hormone that feeds back to the pituitary to suppress FSH production. The estradiol is elevated due to the elevation of FSH earlier in the cycle. An earlier and more marked rise in FSH, results in earlier follicular recruitment and a shortened follicular phase of the cycle. As a rule we would like to see FSH< 8mIU/ml and estradiol
Levels of Inhibin B in cycle day 3 serum offers a newer measure for ovarian reserve and is secreted by the granulosa cells of the ovarian follicle, in response to gonadotropins. Inhibins have been defined based on their activity of suppressing pituitary secretion. Thus, the serum concentrations of Inhibin B and FSH are inversely related, and at low serum levels of Inhibin B, FSH concentration goes up. During a normal menstrual cycle, Inhibin B serum concentration increases gradually in the follicular phase to a broad peak at 7 days prior to the LH Surge , and may constitute the limiting factor for the duration of the inter-cycle FSH rise. It has been establish that FSH secretion is controlled by Inhibin B and thus, Inhibin B measurement is a more direct way of assessing follicular functions rather than FSH alone. Whereas FSH is a response to ovarian function, Inhibin B is expressed as an ovarian function of the granulosa cells of the ovary. Normal Inhibin B is > 45ng/ml.
Antimullerian Hormone (A M H):
AMH is a protein hormone structurally related to inhibin. It too is expressed by the granulosa cells of the follicle in the reproductive age and controls the formation of primary follicles by inhibiting excessive follicular recruitment by FSH. It therefore has a role in folliculogenesis. Substantial evidence exists that AMH levels correlate better with ovarian reserve then either FSH or Inhibin and research on AMH continues. At present, if used clinically, the interpretation of AMH levels should be performed in the context of other clinical measures. The normal range for AMH is .41 ng/ml – 6 ng/ml.
Antral Follicle Count & Ovarian Volume:
Another reliable method for ovarian reserve testing uses transvaginal ultrasound. At the beginning of a menstrual cycle, using ultrasound we can visualize and measure small follicles available to respond to stimulation in the ovary. A normal follicle will be less than 9 or 10 mm in diameter. Studies have demonstrated that as a woman ages, the number of these follicles that are visible at the beginning of the menstrual cycle decreases significantly. It likely represents a decrease in the number of viable eggs that remain in the ovary. This is demonstrated by the fact that women with a diminished antral follicle count respond poorly to fertility medications have a greater likelihood of having IVF cycles cancelled for poor response, and when they do complete IVF cycles, their pregnancy rates are lower. Studies differ on the exact number of follicles that would be considered decreased but most would be in agreement that a total number of less then 10 should be considered a decreased AFC. As the oocytes are being “lost”, the ovaries become smaller and as a consequence decreased ovarian volume also correlates with decrease ovarian reserve. Using transvaginal ultrasound, the volume of each ovary can be calculated by measuring the length, width and depth. Normal dimensions are generally considered to be 1.5cm x 2 cm x 3.5 cm.
Clomiphene Citrate Challenge Test:
In short, clomiphene citrate is given at a dose of 100 mg on days 5 through 9 of the cycle and FSH levels are determined on days 3 and 10. An estradiol level can be done on cycle day 3 as well to add supportive diagnosis. Various “cut off” values have been reported in the literature which is confusing due to various lab techniques (and the evolution of international standards for FSH since the time the test was introduced Our feeling is that an FSH value of greater than 10 mIU/ml for either cycle day 3 or 10 indicates in an abnormal test. The rationale for the test is simple. The cycle day 3 value is unstimulated and represents the same basal value used in the cycle day 3 FSH screening as described above. Clomiphene stimulates an increased release of FSH early in the follicular phase which improves follicular function and when normal the follicle would produce enough inhibin and estradiol to negatively feed back to the pituitary and suppress FSH production by cycle day 10. Clomiphene adds a provocative element which uncovers patients who might otherwise not be detected with basal FSH screening.
How to Manage Test Results:
There are several caveats about the test results. First, if the test is normal, say in a 35 year old, it does not mean that the ovaries are normal for age. The only conclusion that can be drawn is that the ovaries are functioning similarly to a female less than 43 years of age. That patient could be destined to enter diminished reserve in one or ten years. Secondly, studies that have evaluated the test carefully, have not found a stratification of normals and abnormals; the test is either positive or negative. In women over 40 years of age, there are few reported cases of an abnormal test associated with a successful pregnancy. These patients then can be definitively counseled that alternative treatments to “own-egg IVF” such as donor egg or adoption must be considered. Decreased ovarian reserve at any age portends a poor prognosis to treatment including the use of IVF, the most efficacious infertility treatment available today. Alternative stimulation protocols have been proposed but significant improvements in the pregnancy rate are lacking in patients with diminished ovarian reserve. It has been proposed that even prior to a clinically detectable abnormal test; ovarian reserve is declining. Thus a significant portion of the unexplained infertility population who would have a frankly positive test and then an undisclosed number who are nearing the period of frank diminished ovarian reserve, have abnormal ovarian function
In summary age and infertility is an increasing problem due to general societal trends for women to delay childbearing until later ages. Patients with diminished ovarian reserve demonstrate a clinical picture which can be detected with thorough evaluation. Day 3 FSH and Estradiol and the CCCT may be the best screening tests for diminished ovarian reserve. They can be administered quickly, safely and easily to any infertility patient. Abnormal testing suggests a poor future pregnancy outcome for the individual patient and the older the patient the poorer the prognosis. The results however, should in no way restrict or exclude patients from care rather they should indicate the need for aggressive evaluation and treatment.