Rafael A. Cabrera, M.D.
Medical Director, Houston IVF
920 Frostwood Ste 720
Houston, TX 77024
1120 Medical Plaza Dr, Ste 335
The Woodlands, TX 77380
It is known that the decline in fecundity with female age occurs long before menopause despite continued ovulatory cycles. Fertility peaks when a woman is in her late teens and early twenties and begins to decline at age thirty, dropping even more rapidly after age 35 years. Fertility plummets after age 40 and pregnancy after age 45 is rare.
The age-related decrease in fertility is due to decreases in both oocyte quality and quantity rather than to poor endometrial receptivity, as demonstrated by the observation of high success rates in oocyte donation programs. Women are born with a limited number of eggs. Since no new ones are formed throughout a woman’s life, the number of eggs steadily declines over time. As women age, the quality of their eggs declines as well due to an increasing prevalence of aneuploidy in aging oocytes.
This decline in fertility has been observed in population-based studies, ovulation induction and assisted reproduction. At any age, ART may improve the chances of becoming pregnant with the transfer of multiple embryos, but cannot make up for the loss of fertility due to the effects of aging on the number and quality of oocytes.
The fact that the age-related decrease in fertility is primarily due to defective oocyte quality also explains the association between advancing age and increased risk of chromosomal abnormality in newborns as well as the association between advancing age and the increased risk of spontaneous miscarriage.
The term “ovarian reserve” refers to a woman’s current supply of eggs, and is closely associated with reproductive potential. Age is the most important predictor of a woman’s reproductive potential, but age alone has limited predictive value. Although we expect the ovary to age in a certain way, biological aging of the ovaries can occur independently of chronological age. That is why screening for ovarian reserve is a fundamental part of the initial infertility evaluation.
The simplest and most commonly used test to assess the ovarian reserve is the early follicular (cycle day 3) serum FSH concentration. Generally, normal FSH levels are below 10 mIU/mL and values between 10-14 are considered borderline. A single elevated FSH level connotes a poor prognosis even for IVF success, regardless of age, even when values in subsequent cycles are normal. In a study of 1,034 patients with an FSH≥ 14.2mIU/mL the overall pregnancy rate was 2.7% with a 71.4% rate of early pregnancy loss among those who conceived (Levi et al., 2001). Cycle day 3 is chosen because at this time the estrogen level is expected to be low, a critical feature, as FSH levels are subject to a negative feedback by estrogen and inhibin. Thus, any determination of FSH needs to include the corresponding estradiol level to indicate that the FSH level was drawn, when the estrogen level was low. Early elevations in serum estradiol usually reflect the early follicular development observed in older cycling women driven by rising FSH levels. A high cycle day 3 estradiol (greater than 80 pg/mL), in the absence of an estradiol-producing cyst, is predictive of low fecundability.
In a patient with infrequent menstruation, an FSH level and estrogen level could be measured at random and are valid if the estrogen level is low In amenorrheic women, an FSH level will help identify patients with ovarian failure (candidates for donor oocytes) and those with hypothalamic dysfunction (candidates for ovarian stimulation).
The clomiphene citrate challenge test (CCCT) is a more sensitive test of ovarian reserve that is based on the assumption that adequate ovarian reserve is associated with a healthy group of developing follicles. When stimulated with clomiphene this group of follicles should be capable of producing enough estrogen and inhibin to suppress FSH production. This test involves the measurement of basal cycle day 3 FSH and estradiol and stimulated cycle day 10 FSH after treatment with clomiphene citrate (100mg/day, cycle days 5-9). An elevated cycle day 10 FSH has the same poor prognosis as an elevated day 3.
Screening for ovarian reserve with day 3 FSH and estradiol or the CCCT is fundamental in the initial evaluation of infertility women of any age. In our practice we use the more sensitive CCCT to to screen women older than 35 and use the day 3 FSH and estradiol for all other patients. Women with diminished ovarian reserve have uniformly poor prognosis, regardless of age, other identified causes of infertility or type of treatment. When ovarian reserve testing is normal age still remains an important prognostic factor.
Based on this, two admirable goals of all women’s health providers should be 1) to
increase the awareness of the link between fertility and aging, and 2) to promptly identify patients with advanced age (greater than 35) or other signs of early diminished ovarian reserve and refer them to an infertility specialist.
When the ovarian reserve is abnormal, the best course of action is compassionate honest counseling. Ovarian reserve tests are generally reliable but certainly not infallible. An abnormal test does not preclude the possibility of pregnancy. Test results should not be used to deny treatment, except perhaps when grossly abnormal. They are best utilized to obtain prognostic information that can help guide the choice of treatment and best use of available resources.