6 office tests to assess ovarian reserve, and what they tell you
Several tests of ovarian reserve are at your disposal. The help is welcome—but they’re not equally informative or reliable.
IN THIS ARTICLE
For the general practitioner performing an infertility evaluation, we recommend focusing on the following groups of women for ovarian reserve testing:
- women over 30 years of age
- women with a history of exposure to a confirmed gonadotoxin, i.e., tobacco smoke, chemotherapy, radiation therapy
- women with a strong family history of early menopause or premature ovarian failure
- women who have had extensive ovarian surgery, i.e., cystectomy and unilateral oophorectomy.
Testing tends to have the highest yield in these groups. Women who have abnormal results should be referred to a reproductive endocrinologist for further evaluation and treatment.
The six tests are described below.
TABLE
How six markers of ovarian reserve stack up
| Test (year described) | Timing | Intracycle and intercycle variability | Sensitivity (specificity) | Reflects changes in ovarian reserve | Normal levels | Confounders | Out-of-pocket cost |
|---|---|---|---|---|---|---|---|
| Basal follicle-stimulating hormone (FSH) (1988) | Day 3 of menstrual cycle | Clinically significant | 7%–8% (98%–99%) | Late | • Early follicular phase FSH level <10 mIU/mL • Estradiol level <80 pg/mL | • High estradiol level (decreases) • Oral contraceptive use (decreases) • Pregnancy (decreases) | $125–$150 |
| Clomiphene challenge test (1989) | Days 3 and 10 of menstrual cycle | Clinically significant | 25%–40% (98%–99%) | Late | • Day 3 FSH level <10 mIU/mL; day 3 estradiol level <80 pg/mL • Day 10 FSH level <10 mIU/mL | • High day 3 estradiol level (decreases day 3 FSH) • Low day 10 estradiol (increases day 10 FSH) • Oral contraceptive use (decreases) • Pregnancy (decreases) | $550–$600 |
| GnRH agonist (1988) | Early follicular phase of menstrual cycle | Clinically significant | 32%–89% (79%–97%) | Late | Variable | • Oral contraceptives (decrease estradiol levels) • Pregnancy (increases estrogens) | $300–$350 |
| Inhibin-B (1997) | Early follicular phase of menstrual cycle | Clinically significant | 33%–81% (29%–95%) | Early | Variable in the literature; normal cutoffs range from ≥45–80 pg/mL | • Obesity (decreases) • PCOS (increases) • Exogenous FSH administration (increases) • Oral contraceptive use (decreases) | $150–$200 |
| Antral follicle count (1997) | Early follicular phase of menstrual cycle | Clinically significant (includes interobserver variability) | 8%–60% (33%–96%) | Earliest | ≥5–10 total antral follicles | • Oral contraceptive use (decreases) • Polycystic ovary syndrome (PCOS) (increases) | $300–$500 |
| Anti–Müllerian hormone/Müllerian-inhibiting substance (2002) | At any time; not cycle-dependent | Minimal | 49%–76% (89%–94%) | Earliest | >0.7 ng/mL | • PCOS (increases) • Obesity (decreases) • Exogenous FSH administration (decreases) | $150–$400 |
1 | Basal FSH—widely used but only moderately informative
Day 3 FSH and the CCCT are the most widely used measures of ovarian reserve in ART practice. The use of early follicular-phase FSH as a marker of ovarian reserve and fertility was proposed 20 years ago with the emergence of IVF.2-4 The test is an indirect assessment of ovarian reserve in that it measures pituitary production of FSH in response to feedback from ovarian hormones. Estradiol and inhibin-B reach a nadir early in the menstrual cycle; measuring FSH on day 3 offers a glimpse of the functioning of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise later in the cycle ( FIGURE 1 ).5,6
FIGURE 1 The HPO axis
The FSH level opens a window onto the function of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise in the cycle. Women who have normal ovarian reserve have sufficient ovarian hormone production early in the menstrual cycle to maintain FSH levels within the normal range. Conversely, a “monotropic” elevation in FSH—one that is unaccompanied by a rise in luteinizing hormone (LH)—reflects poor hormone production from an aging pool of ovarian follicles and disinhibition of FSH production.5,6
FSH measurements are typically combined with estradiol to enhance the sensitivity of testing ( FIGURE 2, ). Premature elevations of estradiol early in the follicular phase are driven by rising FSH levels in women with declining ovarian reserve. Abnormally elevated estrogen levels then feed back negatively on pituitary production of FSH and mask an elevation that might otherwise reveal diminished ovarian reserve. Measurement of both FSH and estradiol on cycle day 3 may therefore help decrease the incidence of false-negative testing.
Commonly cited criteria for normal ovarian reserve are:
- early follicular phase FSH, <10 mIU/mL
- estradiol, <80 pg/mL1
It is extremely important to note, however, that these are general guidelines and that cutoffs are both laboratory- and practice-specific.
FIGURE 2 Monthly and lifetime variations in estradiol and FSH
How 17ß-estradiol and follicle-stimulating hormone levels vary over the menstrual cycle (top) and a woman’s lifetime (bottom).
2 | Clomiphene citrate—more sensitive than FSH testing
Like basal FSH testing, the CCCT is an indirect assessment of ovarian reserve. Unlike FSH testing, the CCCT is provocative. It involves administration of 100 mg of clomiphene citrate (Clomid) on days 5 through 9 of the menstrual cycle, with FSH and estradiol measured on days 3 and 10. Once clomiphene citrate is administered, FSH and LH levels rise, followed by an increase in estradiol and inhibin. Evidence suggests that the smaller follicular cohorts in women with diminished ovarian reserve produce less inhibin-B and estradiol and, therefore, less negative feedback on clomiphene-induced pituitary FSH release.6,7 The result: persistent elevation of the day 10 FSH value and a positive screen for diminished ovarian reserve.
