Age and Fertility
by Dr Robert Gustofson, CCRM
The assessment of ovarian reserve
Ovarian reserve is the capacity of the ovary to provide eggs that are capable of fertilization resulting in a healthy and successful pregnancy. Though the definition seems simple enough, the assessment of ovarian reserve is much more complicated. It is also impossible to assess the absolute ability of a woman to conceive or not based on ovarian reserve. A woman with poor ovarian reserve may still conceive, however, the frequency of conception would be significantly reduced.
The assessment of ovarian reserve should be performed in women older than 35 years, a history of smoking, unexplained infertility, prior ovarian surgery, a family history of ovarian failure, prior chemotherapy or radiation therapy, symptoms of perimenopause, and women with recurrent pregnancy loss. The goal of ovarian reserve testing is to predict the probability of pregnancy. There is no one test that is 100% predictive and most have limited use outside the setting of assisted reproductive technology.
Several common methods to assess ovarian reserve exist; the easiest and quickest method of assessment is the age of the woman. Unfortunately, age is the rate limiting step for determination of ovarian reserve. Regardless of any other testing, it must always be interpreted in relation to this critical factor. Pregnancy rates for women decrease precipitously after age 35 and these women should, therefore, consider evaluation after attempting conception for no more 6 months.
Laboratory assessments of ovarian reserve are meant to stratify chances of pregnancy based on age. Normal lab testing simply means that the chance of pregnancy is equal to what age would predict but never better. Abnormal testing signifies that the chances of pregnancy are worse than what a woman’s age would predict. For example, a 35 year old woman with abnormal testing would have chances of pregnancy lower than her age would have suggested. Similarly, a woman who is 43 years old with “normal” testing still has low chances of pregnancy based on age.
The most common method to assess ovarian reserve is follicular menstrual cycle day 3 follicle stimulating hormone (FSH). With decreasing quality and/or quantity of eggs, the oocytes are more resistant to FSH and require more hormone from the pituitary to maintain regular menses. The higher the FSH value signifies worsening ovarian reserve. For most labs, an FSH value greater than 10 mIU/mL is considered abnormal and requires further evaluation.
Day 3 FSH can only be interpreted when evaluating estradiol at the same time. As FSH increases, the ovarian follicles begin producing estradiol. With increasing estradiol, the pituitary receives negative feedback and will decrease FSH values. Because of this relationship, an elevation in estradiol will falsely lower the FSH value, an aspect of ovarian reserve that would be missed unless estradiol was known. An elevation in estradiol level should be considered a poor prognositic indicator of ovarian reserve and as significant as an elevation in FSH. A follicular estradiol greater than 50 pg/ml is abnormal and should prompt further investigation.
In women older than 37 years old or with a history concerning for diminished ovarian reserve, the use of a clomiphene citrate challenge test should be considered. For this examination, clomiphene citrate 100 mg is administered orally menstrual cycle days 5-9 with assessment of FSH and estradiol on day 10. The day 10 FSH level may be lower than, equal to, or higher than the day 3 FSH without significance. Similar to day 3 FSH, a level greater than 10 mIU/mL shows a decrease in ovarian reserve. Studies have also shown that a woman’s ovarian reserve is only as good as their worst FSH value. For example, a woman with an FSH of 8 mIU/ml on day 3 and an FSH of 13 mIU/ml will only have chances of pregnancy equal to the FSH of 13 mIU/ml. Similarly, a woman who assesses her day 3 FSH multiple months with values of 5, 8, and 15 mIU/ml will have chances of pregnancy equal to 15 regardless of the lower values previously.
More recent studies have demonstrated the utility of anti-mullerian hormone (AMH) to help quantify the number of oocytes remaining. AMH is a glycoprotein secreted by preantral and antral follicle granulosa cells surrounding the oocytes. As the number of oocytes become depleted, the number of granulosa cells are depleted and the AMH level decreases accordingly. AMH is not cycle dependent and can be drawn at any time as well as while taking oral contraceptives. Due to variations in AMH assays, there is no level considered to be normal and, for most labs, is still considered experimental.
Ultrasonographic evaluation of the ovaries through resting follicle count is a simple, but very robust, adjunct to testing ovarian reserve. Performed during the follicular phase, a transvaginal ultrasound counts the number of follicles measuring 2-9 mm in combination between both ovaries. A resting follicle count less than 10 is indicative of decreased quality of oocytes. Pregnancy rates through IVF have been shown to be lowered by 50% when the resting follicle count is less than 5.
When evaluating all methods to assess ovarian reserve, the most important remains age, followed by resting follicle count, AMH, and, finally, FSH assessment. The exception to the rule is when FSH is significantly elevated. Even with normal AMH and resting follicle count, an elevated FSH is concerning and necessitates referral to an infertility specialist. Abnormalities in any of the measurements of ovarian reserve should prompt rapid referral as there may be a limited time for pregnancy.
This battery of tests can often be incorporated into most practitioners’ evaluation of infertility. As opposed to simple day 3 FSH alone, this testing offers a composite evaluation of ovarian reserve and may avoid ineffective treatment or prolonging a needed referral when there are diminished chances of pregnancy.