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6 Office Tests to Assess Ovarian Reserve, and What They Tell 6 offi ce 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. CASE Samantha F. Butts, MD, Borderline® Dowden test result prompts Health referral Media MSCE A 36-year-old nulliparous woman is seen in your offi ce Dr. Butts is Assistant Professor for evaluation after 6 months of infertility. She is ovula- of Obstetrics and Gynecology, Copyrighttory, and has been using an ovulation-prediction kit to time Division of Infertility and For personal use only intercourse. You learn that she had Chlamydia trachomatis IN THIS Reproductive Endocrinology, ARTICLE at University of Pennsylvania infection in the distant past, but elicit no other signifi cant Medical School in Philadelphia. medical or surgical history. She reports that she smoked How six markers approximately one pack of cigarettes a day for 15 years of ovarian reserve David B. Seifer, MD but gave up smoking 5 years ago. stack up You order a hysterosalpingogram, followed by day 3 Dr. Seifer is Co-Director of page 32 Genesis Fertility and Repro- testing of follicle-stimulating hormone (FSH). The hystero- salpingogram is normal; the FSH level is 7.5 mIU/mL and ductive Medicine at Maimonides Monthly and Medical Center in Brooklyn, NY, the estradiol level is 30 pg/mL—both in the normal range. lifetime variations and Professor of Obstetrics, The patient asks for testing of anti-Müllerian hor- Gynecology and Reproductive mone (AMH; also known as Müllerian-inhibiting substance) in estradiol and Sciences at Mount Sinai School because she has read that it is a new marker of fertility. FSH of Medicine in New York City. The result is 0.5 ng/mL, a borderline value. After reviewing page 34 these results, you refer her to a reproductive endocrinolo- The University of Medicine and Dentistry of New Jersey (UMDNJ) owns a patent gist for further management. Advantages of relating to the use of anti-Müllerian Was the test for AMH indicated? And is this referral the anti-Müllerian hormone/Müllerian inhibiting substance for predicting ovarian response in women appropriate? hormone assay with infertility. The patent is based in part page 37 on work that Dr. Seifer carried out while employed at UMDNJ. In accordance he referral is entirely appropriate, even though the with UMDNJ policy, Dr. Seifer, a named patient has not been trying to conceive for a full inventor on this patent, assigned his interest in the invention to UMDNJ. year. Why? Th e AMH value suggests that her ovarian UMDNJ has a licensing agreement with T Diagnostic Systems Laboratory for the reserve is in early decline. She would benefi t from evalua- use of the claimed invention. Dr. Seifer tion by a subspecialist who can review the entire spectrum receives a portion of the royalties, as determined by UMDNJ policy, that UMDNJ of treatments, including aggressive options such as ovula- gains from this licensing agreement. tion induction and in vitro fertilization (IVF), to optimize her reproductive success. CONTINUED ON PAGE 30 obgmanagement.com Vol. 20 No. 11 | November 2008 | OBG Management 29 For mass reproduction, content licensing and permissions contact Dowden Health Media. 29_r1_OBGM1108 29 10/23/08 12:07:20 PM Ovarian reserve 6 tests to assess ovarian reserveTh is inarticle the reviewsoffi ce the various biomark- their counterparts did 20 years ago: ers available to assess ovarian reserve in • In 1980, 40% of women having their fi rst women who experience infertility: baby were younger than 25 years, and only • day 3 (basal) FSH 5% were older than 35 • clomiphene citrate challenge • In 2000, 25% of women were younger than • gonadotropin-releasing hormone (GnRH) 25 when their fi rst child was born, and 15% agonist stimulation were older than 35. • inhibin-B • antral follicle count (AFC) Who should be tested? • AMH. Ovarian reserve is a complex clinical phe- Th e AFC and AMH tend to detect the nomenon that is infl uenced by age, genetics, earliest changes in ovarian reserve, followed, and environmental variables. Th e decline in sequentially, by inhibin-B, the clomiphene a woman’s ovarian reserve over time is irre- citrate challenge test (CCCT), and basal versible; the trajectory of this decline is fun- FSH. damental to the odds of fertility with age and Th e tests we describe are used primar- the timing of the menopausal transition. At ily to assess treatment prognosis in infertile present, the markers used most often in clin- women. In time, however, appropriate popu- ical practice have some utility but also suff er lation screening of ovarian reserve may be from several drawbacks (TABLE, page 32). feasible to provide many more women with For the general practitioner performing information about their reproductive poten- an infertility evaluation, we recommend fo- tial and help them shape their life plan. cusing on the following groups of women for ovarian reserve testing: What makes a test valuable? • women over 30 years of age Ovarian reserve describes a woman’s repro- • women with a history of exposure to a con- ductive potential—specifi cally, the number fi rmed gonadotoxin, i.e., tobacco smoke, Ovarian reserve and quality of oocytes she possesses.1 Bio- chemotherapy, radiation therapy is infl uenced by chemical tests of ovarian reserve emerged • women with a strong family history of early age, genetics, and during the rise of assisted reproductive tech- menopause or premature ovarian failure environmental nologies (ART) in the late 1980s to predict • women who have had extensive ovarian variables both responsiveness to superovulation drugs surgery, i.e., cystectomy and unilateral oo- and the odds of pregnancy with treatment. phorectomy. Ideally, a test that assesses ovarian re- Testing tends to have the highest yield serve should be aff ordable, straightforward, in these groups. Women who have abnormal rapidly interpretable, and minimally inva- results should be referred to a reproductive sive. It also should be able to detect changes endocrinologist for further evaluation and that begin early in reproductive life. To be treatment. applicable to large populations of reproduc- Th e six tests are described below. tive-age women, it should be of use anytime in the menstrual cycle, and should provide reproducible and highly accurate assessment 1 | Basal FSH—widely used but of the reproductive aging process. only moderately informative Our ability to off er tests that accurately Day 3 FSH and the CCCT are the most wide- measure ovarian reserve has a signifi cant im- ly used measures of ovarian reserve in ART pact on women at risk of infertility and early practice. Th e use of early follicular-phase FSH menopause and on those who choose to de- as a marker of ovarian reserve and fertility was lay childbearing for personal (nonmedical) proposed 20 years ago with the emergence reasons. Th ese tests have become increas- of IVF.2–4 Th e test is an indirect assessment of ingly relevant because women are choosing ovarian reserve in that it measures pituitary to have their fi rst child at a later age than production of FSH in response to feedback 30 OBG Management | November 2008 | Vol. 20 No. 11 30_r1_OBGM1108 30 10/23/08 12:07:24 PM Ovarian reserve TABLE How six markers of ovarian reserve stack up Refl ects Intracycle changes Out-of- Test (year and intercycle Sensitivity in ovarian pocket described) Timing variability (specifi city) reserve Normal levels Confounders cost Basal Day 3 of Clinically 7%–8% Late • Early follicular • High estradiol level $125– follicle- menstrual signifi cant (98%–99%) phase FSH level (decreases) $150 stimulating cycle <10 mIU/mL • Oral contraceptive hormone • Estradiol level use (decreases) (FSH) (1988) <80 pg/mL • Pregnancy (decreases) Clomiphene Days 3 Clinically 25%–40% Late • Day 3 FSH level • High day 3 $550– citrate and 10 of signifi cant (98%–99%) <10 mIU/mL; estradiol level $600 challenge menstrual day 3 estradiol (decreases day test (1989) cycle level <80 pg/mL 3 FSH) • Day 10 FSH level • Low day 10 <10 mIU/mL estradiol (increases day 10 FSH) • Oral contraceptive use (decreases) • Pregnancy (decreases) GnRH agonist Early Clinically 32%–89% Late Variable • Oral contracep- $300– (1988) follicular signifi cant (79%–97%) tives (decrease $350 phase of estradiol levels) menstrual • Pregnancy cycle (increases estro- gens) Inhibin-B Early fol- Clinically 33%–81% Early Variable in the • Obesity $150– (1997) licular phase signifi cant (29%–95%) literature; normal (decreases) $200 of menstrual cutoffs range from • PCOS (increases) cycle ≥45–80 pg/mL • Exogenous FSH administration (increases) • Oral contraceptive use (decreases) Antral Early fol- Clinically 8%–60% Earliest ≥5–10 total antral • Oral contraceptive $300– follicle count licular phase signifi cant (33%–96%) follicles use (decreases) $500 (1997) of menstrual (includes • Polycystic ovary cycle interobserver syndrome (PCOS) variability) (increases) Anti-Müllerian At any time; Minimal 49%–76% Earliest >0.7 ng/mL • PCOS (increases) $150– hormone/ not cycle- (89%–94%) • Obesity $400 Müllerian- dependent (decreases) inhibiting • Exogenous FSH substance administration (2002) (decreases) 32 OBG Management | November 2008 | Vol. 20 No. 11 32_r1_OBGM1108 32 10/23/08 12:07:28 PM from ovarian hormones. Estradiol and inhib- FIGURE 1 The HPO axis in-B reach a nadir early in the menstrual cy- cle; measuring FSH on day 3 off ers a glimpse Hypothalamus of the functioning of the hypothalamic–pitu- itary–ovarian axis before ovarian hormone GnRH levels rise later in the cycle (FIGURE 1).5,6 Women who have normal ovarian reserve Pituitary have suffi cient ovarian hormone production LH, FSH early in the menstrual cycle to maintain FSH levels within the normal range. Conversely, a Ovary “monotropic” elevation in FSH—one that is unaccompanied by a rise in luteinizing hor- mone (LH)—refl ects poor hormone produc- Estradiol, Inhibin-B tion from an aging pool of ovarian follicles and disinhibition of FSH production.5,6 The FSH level opens a window onto the function of FSH measurements are typically com- the hypothalamic–pituitary–ovarian axis before ovarian bined with estradiol to enhance the sensitiv- hormone levels rise in the cycle.
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