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 hysterosalpingogram 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

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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

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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)

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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 cycle; measuring FSH on day 3 off ers a glimpse Hypothalamus of the functioning of the hypothalamic–pituitary–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 hormone (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. ity of testing (FIGURE 2, page 34). Premature elevations of estradiol early in the follicular phase are driven by rising FSH levels in the smaller follicular cohorts in women with women with declining ovarian reserve. Ab- diminished ovarian reserve produce less normally elevated estrogen levels then feed inhibin-B and estradiol and, therefore, less back negatively on pituitary production of negative feedback on clomiphene-induced FSH and mask an elevation that might oth- pituitary FSH release.6,7 Th e result: persistent erwise reveal diminished ovarian reserve. elevation of the day 10 FSH value and a posi- Measurement of both FSH and estradiol on tive screen for diminished ovarian reserve. cycle day 3 may therefore help decrease the In some women, day 10 FSH is elevated Commonly cited incidence of false-negative testing. even after a normal day 3 value. Th is makes criteria for normal Commonly cited criteria for normal the CCCT more sensitive than basal FSH ovarian reserve are: ovarian reserve are: testing; it can identify women who might go • early follicular • early follicular phase FSH <10 mIU/mL unrecognized if evaluated by day 3 FSH and phase FSH, • estradiol <80 pg/mL.1 estradiol levels alone. It is extremely important to note, how- <10 mIU/mL ever, that these are general guidelines and More expensive and labor-intensive • estradiol, that cutoff s are both laboratory- and prac- than the alternatives <80 pg/mL tice-specifi c. Interpretation of the CCCT requires that FSH and estradiol both be assessed on days 3 and 10. An elevated FSH (≥10 mIU/mL) on either 2 | Clomiphene citrate—more day indicates diminished ovarian reserve. sensitive than FSH testing As with basal FSH testing, elevated estradiol Like basal FSH testing, the CCCT is an indi- (≥80 pg/mL) on day 3 is considered abnor- rect assessment of ovarian reserve. Unlike mal. Th e day 10 estradiol value of the CCCT FSH testing, the CCCT is provocative. It in- refl ects whether or not clomiphene citrate volves administration of 100 mg of clomi- was administered appropriately, and should phene citrate (Clomid) on days 5 through 9 be elevated. However, the signifi cance of the of the menstrual cycle, with FSH and estra- day 10 estradiol level has been debated with diol measured on days 3 and 10. Once clo- respect to its predictive value for pregnancy miphene citrate is administered, FSH and in infertile populations.8 LH levels rise, followed by an increase in es- Th e addition of day 10 FSH assessment tradiol and inhibin. Evidence suggests that improves the sensitivity of the CCCT over

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6 tests to assess ovarian reserve in the ofﬁ ce FIGURE 2 Monthly and lifetime variations (pregnancy and response to superovulation in estradiol and FSH drugs) in all but a narrow group of patients undergoing IVF. Performance is particularly FSH limited in: Estradiol 60 • young women 250 Menses • women in the general infertility popula- 50 tion who are not utilizing IVF.9–13 200 40 Additional drawbacks of basal FSH test- (pg/ml) 150 30 ing and the CCCT include:

(mlU/ml • signifi cant variability of test results from 100 20

FSH cycle to cycle (intercycle variability) 50 10 • limited time frame within which the tests 17ß-Estradiol can be performed (intracycle variability). 0 0 Th e basal FSH test and CCCT have high 0 7 14 21 28 Menstrual cycle days specifi city (98% to 99% for each) as an assessment of reproductive performance in infer- 120 250 menopause tile women and generate few false-positive results.5,6 However, the high screen cutoff s 150 100 that allow for such specifi city come at a price:

(pg/ml) Few women will screen positive, and sensi- 50 80 tivity of the tests is low (between 7% and 8% (mlU/ml 40 60 for basal FSH and between 25% and 40% for FSH the CCCT). Such low sensitivity means that 30 40

17ß-Estradiol many women will not conceive after infertil- 20 20 ity treatment despite a normal test result.5,11 Overall, the tests are not highly informative 0 0 for many women who get tested. 10 20 30 40 50 60 70 Years of age Once abnormal, normal results How 17ß-estradiol and follicle-stimulating hormone levels vary over are meaningless the menstrual cycle (top) and a woman’s lifetime (bottom). Once an FSH level or the CCCT has ever been abnormal, the patient has diminished ovarian reserve; normal values in subsequent menstrual cycles do not improve the odds of basal FSH measurement, but makes it a more pregnancy with treatment.14 Th is fact can be expensive and labor-intensive test (TABLE, a signifi cant source of confusion and frustra- page 32).5,6 Th e CCCT involves administration tion for patients. of clomiphene citrate, a safe drug (though it can have side eff ects), and two blood draws instead of one. Nevertheless, both tests are 3 | GnRH agonist stimulation relatively noninvasive, rapid measures of —no better than FSH testing ovarian reserve. Th is test was developed in the search for a very sensitive assessment of ovarian reserve. Drawbacks of the tests It was designed to uncover subtle abnor- Both basal FSH testing and the CCCT are malities in pituitary and ovarian dynamics. widely used, although support for their abil- It involves administering a gonadotropin- ity to predict ovarian reserve in the infertile releasing hormone (GnRH) agonist such as population has been challenged recently. leuprolide acetate (Lupron) on day 2 or 3 of Newer data demonstrate that these tests are the menstrual cycle and measuring pituitary limited in their ability to predict outcome and ovarian hormone responses.5,15

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One group of investigators demonstrated cles present in the ovary and, therefore, ovar- a correlation between stimulated estradiol ian reserve. Total AFCs of less than 5 to 10 are levels and responsiveness during IVF,16 but suggestive of diminished ovarian reserve. 24,25 other studies have shown that the test does In IVF cycles, AFC has proven to be an not perform signifi cantly better than day 3 accurate predictor of number of oocytes re- FSH in predicting ovarian reserve.17,18 trieved, risk of cycle cancellation, and odds of Th e sensitivity of GnRH agonist test- conception.24,25 Some investigators have even ing for pregnancy is moderate (32% to 89%); suggested that, compared with other markers specifi city ranges from 79% to 97%.19 of ovarian reserve, AFC is the best independent predictor of outcome in IVF cycles.7,26–27 In a group of normally cycling women 4 | Inhibin-B—not helpful with proven fertility, AFC also showed a when used alone strong correlation with age, declining slowly Th is glycoprotein hormone produced by gran- until age 37 and more rapidly thereafter.28,29 ulosa cells of developing follicles is a direct AFC sensitivity for pregnancy is moder- measure of ovarian reserve when assessed in ate and varies widely in published reports the early follicular phase of the menstrual cy- (8% to 60%), whereas specifi city tends to be cle.20 Women treated with IVF who have a low higher (33% to 96%).19 inhibin-B level—particularly when using cutoff s below the range of 45–80 pg/mL—have Drawbacks of AFC been shown to respond poorly to superovu- • Because of the need to perform transvagi- lation and have a lower pregnancy rate than nal ultrasonography, AFC is a more inva- women with high inhibin-B.21,22 One group sive and often more expensive test than of investigators demonstrated that women hormonal biomarkers with clinical evidence of diminished ovarian • Accurate assessment of AFC requires an reserve but a normal FSH level also had low experienced sonographer and can be lim- inhibin-B production, suggesting that it may ited in patients who have had pelvic sur- An accurate 22 be a more sensitive marker than FSH. gery or uterine fi broids and in those who antral follicle Inhibin-B testing involves a simple blood are obese count requires draw. However, the test has been incorporat- • Moderate interobserver and intercycle an experienced ed into clinical assessment of ovarian reserve variability of AFC determinations limits its sonographer and only to a limited degree, due to the lack of re- reproducibility29,30 can be limited liable assays and controversy concerning its • As with basal FSH measurement, the inter- by ﬁ broids or prognostic value.23 cycle variability of AFC does not correlate obesity Because of these limitations, routine well with IVF outcome in individual pa- testing of serum inhibin-B in isolation of tients.30 other markers of ovarian reserve is not rec- ommended. 6 | Anti-Müllerian hormone— many advantages 5 | Antral follicle count—good Th e drawbacks of the tests just described— predictor of IVF outcome e.g., intercycle variability, lack of uniform Transvaginal ultrasonographic determina- cutoff s, and limited ability to predict IVF tion of the number of ovarian follicles that outcomes—make the development of more measure between 2 mm and 10 mm in diam- reliable measures of ovarian reserve a prior- eter in the early follicular phase of the cycle ity in reproductive medicine. AMH is a highly yields the AFC. As a direct marker of the co- promising marker that appears to have many hort of growing follicles in the early men- advantages over other tests and may have strual cycle, the AFC is believed to correlate the greatest power to predict ovarian aging in strongly with the number of primordial folli- women of reproductive age. CONTINUED ON PAGE 38

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6 tests to assess ovarian reserve in the ofﬁ ce Ovarian reserve declines with age, but not uniformly

A normal female is born with 1 mil- The effect of age on fertility is be- aggressive fertility treatment. lion to 2 million oocytes, a number lieved to arise from changes in both The biologic basis for differences that declines continuously, primar- oocyte number and quality. Multiple in ovarian reserve among similar ily through the process of follicular investigators have found a greater groups of women is not completely atresia. By the onset of puberty, the frequency of cellular abnormalities in understood, but is probably rooted in number of oocytes has declined to oocytes from older women.1,2,5,15,57 genetic, lifestyle, and environmental approximately 300,000. As a woman Although ovarian reserve declines factors that affect granulosa cell and enters her late 30s, when the total with age in all women, women of oocyte function. Identifying sensitive number of oocytes is approximately similar ages can have very different biomarkers that can determine ovar- 25,000, the pace of oocyte depletion degrees of ovarian reserve, and some ian reserve independent of age is begins to increase, as does the rate of women who have very poor ovarian critical to predict fertility and age at spontaneous miscarriage.1,55,56 reserve may never conceive, despite menopause.5

How it works Does it predict oocyte quality? AMH is a glycoprotein growth factor and a AMH has performed well as a biomarker, member of the transforming growth factor- comparable in most series to AFC and su- ß superfamily.31 It is primarily produced by perior to FSH. AMH levels are strongly cor- the pool of early-growing follicles, which are related with the number of oocytes retrieved believed to serve as a proxy for the number during IVF and the odds of cycle cancellation of primordial follicles in the ovary. Th e num- due to poor response35–41—but does it accu- ber of primordial follicles at a given point in rately characterize oocyte quality, the other The age-related time represents the ovarian reserve. AMH element of ovarian reserve? decline in AMH levels above 0.7 ng/mL are considered nor- Some reports have shown a strong asso- is gradual but mal; values between 0.3 ng/mL and 0.7 ng/ ciation between AMH levels and surrogates measurable even mL are consistent with borderline ovarian of oocyte quality, including fertilization, oo- in young women reserve, according to 2007 data from Repro- cyte morphology, embryo quality, and preg- source Corp. nancy and miscarriage rates,36–41 but others AMH has been studied as a marker of have not.42 Some reports demonstrate a rela- ovarian reserve for 6 years, with multiple re- tionship between AMH and some but not all ports describing declines in levels with age surrogate markers of oocyte quality.40 and with diminishing oocyte numbers. It is undetectable at menopause.32 Advantages of AMH Th e age-related decline in AMH is grad- • It demonstrates minimal intracycle vari- ual but measurable even in young women, ability.32,43–45 Compared with other mark- consistently preceding changes in other ers of ovarian reserve, which must be markers of ovarian reserve such as FSH and measured early in the follicular phase of inhibin-B.32–35 Th e longitudinal changes in the menstrual cycle, AMH can be assessed AMH have been demonstrated in ovulatory at random times, making it a more conve- premenopausal women and healthy volun- nient method for patients and physicians teers with proven fertility.33,34 In one series • It demonstrates minimal intercycle vari- of women followed over a mean of 4 years ability32,34 (ages 25 to 46), AMH testing was superior to • AMH levels are not signifi cantly aff ected by day 3 FSH, inhibin-B, and AFC in its ability to the hormonal changes of pregnancy, oral predict the onset of cycle irregularity and the contraceptive use, or GnRH treatment, and menopausal transition.33 can be measured in these settings.46,47

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38_r1_OBGM1108 38 10/23/08 12:07:45 PM Utility of AMH is limited in tive years were shown to have an AMH level PCOS and obesity 70% lower than those in women who were not Th e ability to use AMH as a marker of ovar- obese.54 Th ese diff erences have not been well ian aging in women who have polycystic studied in younger obese women. ovary syndrome (PCOS) and in women who are obese may be limited by the ovulatory Which test is best? dysfunction in these populations. Circulat- AMH may be preferable to the other tests ing levels of AMH are higher in women with to assess ovarian reserve because it can be PCOS than in unaff ected women, a fi nding measured any time during the menstrual thought to be indicative of oligo-ovulation cycle or between cycles. AMH measurement and poor follicular development in polycys- is also useful if a woman is taking oral contra- tic ovaries.48–53 ceptives or leuprolide acetate because these In a recent series investigating AMH medications may confound the results of the levels in women with PCOS, AMH and the other test methods. In addition, AMH may degree of insulin resistance were positively be the earliest indicator of decline in ovar- correlated, and the AMH level was negatively ian reproductive function. As such, it may correlated with the number of menses in a highlight cases that merit a search for other year.49 Th e consistently positive correlation causes of infertility and make it possible to between AMH and PCOS may suggest a fu- treat them in a timely manner. ture role for this marker as a diagnostic tool. Elevated AMH may reveal occult PCOS In obese women who do not have PCOS, and warn of signifi cant risk of ovarian hyper- AMH production may be lower than in women stimulation prior to ovulation induction with of normal weight. In a recent series, normally gonadotrophins, so that the clinician can cycling obese women in the later reproduc- plan smaller doses.

References 1. Practice Committee of the American Society for 9. Esposito MA, Coutifaris C, Barnhart KT. A mod- WJ, Soules MR. Th e anterior pituitary response to a Reproductive Medicine. Age and infertility in women. erately elevated day 3 FSH concentration has limited gonadotropin-releasing hormone challenge test in Fertil Steril. 2006;86:S248–S252. predictive value, especially in younger women. Hum normal older reproductive age women. Fertil Steril. 2. Muasher SJ, Oehninger S, Simonetti S, Matta J, El- Reprod. 2002;17:118–123. 1996;65:539–544. lis LM, Liu H-C. Th e value of basal and/or stimulated 10. Bancsi L, Broekmans FJM, Wol BWJ, Habbema DK, 18. Galtier-Dereure F, De Bouard V, Picto MC, et al. serum gonadotropin levels in prediction of stimula- te Velde ER. Performance of basal follicle-stimulating Ovarian reserve test with the gonadotrophin-releasing tion response and in vitro fertilization outcome. Fertil hormone in the prediction of poor ovarian response hormone agonist buserelin: correlation with in-vitro fer- Steril. 1988;50:298–307. and failure to become pregnant after in vitro fertiliza- tilization outcome. Hum Reprod. 1996;11:1393–1398. 3. Scott RT, Toner JP, Muasher SJ, Oehninger S, Rob- tion: a meta-analysis. Fertil Steril. 2003;79:1091–1100. 19. Broekmans FJ, Fwee J, Hendricks DJ, Mol BW, inson S, Rosenwaks Z. Follicle stimulating hormone 11. Jain T, Soules MR, Collins JA. Comparison of basal Lambalk CB. A systematic review of tests predicting levels on cycle day 3 are predictive of in vitro fertiliza- follicle-stimulating hormone versus the clomiphene ovarian reserve and IVF outcome. Hum Reprod Up- tion outcome. Fertil Steril. 1989;51:651–654. citrate challenge test for ovarian reserve screening. date. 2006;12:685–718. 4. Toner JP, Philiput CB, Jones GS, Muasher SJ. Basal Fertil Steril. 2004;82:180–185. 20. Klein NA, Illingworth PJ, Groome NP, NcNeilly follicle stimulating hormone level is a better predictor 12. Toner JP. Modest follicle-stimulating hormone AS, Battaglia DE, Soules MR. Decreased inhibin B of in vitro fertilization outcome than age. Fertil Steril. elevations in younger women: warn but don’t dis- secretion is associated with the monotropic FSH rise 1991;55:784–791. qualify. Fertil Steril. 2004;81:1493–1495. in older, ovulatory women: a study of serum and fol- 5. Barnhart K, Osheroff J. Follicle stimulating hor- 13. Van Rooij IAJ, de Jong E, Broekmans FJM, Looman licular fl uid levels of dimeric inhibin A and B in spon- mone as a predictor of fertility. Curr Opin Obstet Gy- CWN, Habbeman DK, te Velde ER. High follicle-stim- taneous menstrual cycles. J Clin Endocrinol Metab. necol. 1998;10:227–232. ulating hormone levels should not necessarily lead to 1996;81:2742–2745. 6. Hofmann GE, Danforth DR, Seifer DB. Inhibin-B: the exclusion of subfertile patients from treatment. 21. Seifer DB, Lambert-Messerlian G, Hogan JW, the physiologic basis of the clomiphene citrate chal- Fertil Steril. 2004;81:1478–1485. et al. Day 3 serum inhibin-B is predictive of assisted lenge test for ovarian reserve screening. Fertil Steril. 14. Scott RT, Hofmann GE, Oehninger S, Muasher SJ. reproductive technologies outcome. Fertil Steril. 1998;69:474–477. Intercycle variability of day 3 follicle-stimulating hor- 1997;67:110–114. 7. Yong PY, Baird DT, Th ong KJ, McNeilly AS, An- mone levels and its eff ect on stimulation quality in in 22. Seifer DB, Scott RT Jr, Bergh PA, et al. Women with derson RA. Prospective analysis of the relationships vitro fertilization. Fertil Steril. 1990;54:297–302. declining ovarian reserve may demonstrate a decrease between the ovarian follicle cohort and basal FSH 15. Bulkulmez O, Arici A. Assessment of ovarian re- in day 3 serum inhibin B before a rise in day 3 follicle- concentration, the inhibin response to exogenous serve. Curr Opin Obstet Gynecol. 2004;16:231–237. stimulating hormone. Fertil Steril. 1999;72:63–65. FSH and ovarian follicle number at diff erent stages of 16. Ranieri DM, Quinn F, Makhlouf A, et al. Simul- 23. Corson SL, Gutmann J, Batzer FR, Wallace H, Klein the normal menstrual cycle and after pituitary down- taneous evaluation of basal follicle-stimulating hor- N, Soules MR. Inhibin-B as a test of ovarian reserve for regulation. Hum Reprod. 2003;18:35–44. mone and 17-beta-estradiol response to gonado- infertile women. Hum Reprod. 1999;14:2818–2821. 8. Scott RT Jr, Illions EH, Kost ER, Dellinger C, Hof- tropin-releasing hormone analogue stimulation: an 24. Tomas C, Nuojua-Huttunen S, Martikainen H. mann GE, Navot D. Evaluation of the signifi cance of improved predictor of ovarian reserve. Fertil Steril. Pretreatment transvaginal ultrasound examination the estradiol response during the clomiphene citrate 1998;70:227–233. predicts ovarian responsiveness to gonadotrophins in challenge test. Fertil Steril. 1993;60:242–246. 17. Fujimoto VY, Klein NA, Battaglia DE, Bremmer in-vitro fertilization. Hum Reprod. 1997;12:220–223.

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39_r1_OBGM1108 39 10/23/08 12:07:49 PM IN THE Ovarian reserve UNITED STATES, THE PRESS

6 tests to assessCANNOT ovarian reserve in the25. ofﬁChang ce MY, Chiang CH, Hsieh TT, Soong YK, Hsu licular fl uid of the preovulatory follicle are predictive of KH. Use of the antral follicle count to predict the outcome the implantation potential of the ensuing embryo ob- BE CENSORED. of assisted reproductive technologies. Fertil Steril. 1998; tained by in vitro fertilization. J Clin Endocrinol Metab. 69:505–510. 2007;92:1796–1802. 26. Hung E, Tang OS, Ho PC. Th e signifi cance of the 42. Smeenk JM, Sweep FC, Zielhuis GA, Kremer JA, THE INTERNET number of antral follicles prior to stimulation in pre- Th omas CM, Braat DD. Anti-Müllerian hormone predicting ovarian responses in an IVF programme. Hum dicts ovarian responsiveness, but not embryo quality CANNOT Reprod. 2000;15:1937–1942. or pregnancy, after in vitro fertilization or intracyoplas- 27. Bancsi LFJMM, Broekmans FJM, Eijkemans MJC, mic sperm injection. Fertil Steril. 2007;87:223–226. BE CENSORED. de Jong FH, Habbema JDF, te Velde ER. Predictors of 43. Hehenkamp WJ, Looman CW, Th emmen AP, de poor ovarian response in in vitro fertilization: a pro- Jong FM, Te Velde ER, Broekmans FJ. Anti-Müllerian spective study comparing basal markers of ovarian hormone levels in the spontaneous menstrual cycle reserve. Fertil Steril. 2002;77:328–336. do not show substantial fl uctuation. J Clin Endocrinol POLITICAL 28. Ng EH, Yeung WS, Fong DY, Ho PC. Eff ects of Metab. 2006;91:4057–4063. age on hormonal and ultrasound markers of ovarian 44. La Marca A, Stabile G, Artenisio AC, Volpe A. Se- ADVERTISING reserve in Chinese women with proven fertility. Hum rum anti-Müllerian hormone throughout the men- Reprod. 2003;18:2169–2174. strual cycle. Hum Reprod. 2006;21:3103–3107. CANNOT 29. Scheff er GJ, Broekmans FJ, Dorland M, Habbema 45. Tsepelidis S, Devreker F, Demeestere F, Flahaut I, JD, Looman CW, te Velde ER. Antral follicle counts Gervy A, Englert C. Stable serum levels of anti-Mülle- BE CENSORED. by transvaginal ultrasonography are related to age rian hormone during the menstrual cycle: a prospec- in women with proven natural fertility. Fertil Steril. tive study in normo-ovulatory women. Hum Reprod. 1999;72:845–851. 2007;22:1837–1840. WHY ARE 30. Hansen KR, Morris JL, Th yer AC, Soules MR. Re- 46. La Marca A, Giulini, Orvieto R, De Leo V, Volpe A. productive aging and the variability in the ovarian Anti-Müllerian hormone concentrations in maternal SOME MEMBERS antral follicle count: application in the clinical setting. serum during pregnancy. Hum Reprod. 2005;20:1569– Fertil Steril. 2003;80:577–583. 1572. OF CONGRESS & 31. Cate RL, Mattaliano RJ, Hession C, et al. Isolation 47. Somunkiran A, Yavuz T, Yucel O, Ozdemir I. Anti- of the bovine and human genes for Müllerian inhib- Müllerian hormone levels during hormonal contra- ACADEMIA iting substance and expression of the human gene in ception in women with polycystic ovary syndrome. animal cells. Cell. 1986;45:685–698. Eur J Obstet Gynecol Reprod Biol. 2007;134:196–201. TRYING TO CENSOR 32. de Vet A, Laven JSE, de Jong FH, Th emmen APN, 48. Al-Qahtani A, Groome NP. Anti-Müllerian hor- Fauser BCJM. Anti-Müllerian hormone serum lev- mone: Cinderella fi nds new admirers. J Clin Endocri- MEDICAL els: a putative marker for ovarian aging. Fertil Steril. nol Metab. 2006;91:3760–3762. 2002;77:357–362. 49. La Marca A, Orvieto R, Giulini S, Jasonni VM, COMMUNICATIONS? 33. van Rooij IAJ, Broekmans FJM, Scheff er GJ, et al. Volpe A, De Leo V. Müllerian-inhibiting substance in Serum anti-Müllerian hormone levels best refl ect women with polycystic ovary syndrome: relationship the reproductive decline with age in normal women with hormonal and metabolic characteristics. Fertil with proven fertility: a longitudinal study. Fertil Steril. Steril. 2004;82:970–971. 2005;83:979–987. 50. Piltonen T, Morin-Papunen L, Koivunen R, Per- 34. van Rooij IAJ, Tonkelaar I, Broekmans FJ, et al. heentupa A, Ruokonen A, Tapanainen JS. Serum anti- Anti-Müllerian hormone is a promising predictor for Müllerian hormone levels remain high until late repro- Diabetes. Cancer. Obesity. Respiratory the occurrence of the menopausal transition. Meno- ductive age and decrease during metformin therapy in disease. America’s medical professionals pause. 2004;11:601–606. women with polycystic ovary syndrome. Hum Reprod. are busier than ever. How can they stay 35. Tremellen KP, Kolo M, Gilmore A, Lekamge DN. 2005;20:1820–1836. current with medical advances and still Anti-Müllerian hormone as a marker of ovarian re- 51. Pigny P, Merlen E, Robert Y, et al. Elevated serum serve. Aust N Z J Obstet Gynaecol. 2005;45:20–24. level of anti-Müllerian hormone in patients with poly- improve their patients’ well-being? 36. Silberstein T, MacLaughlin DT, Shai I, et al. Mülle- cystic ovary syndrome: relationship to the ovarian fol- rian-inhibiting substance levels at the time of HCG ad- licle excess and to the follicular arrest. J Clin Endocri- Information is part of quality care. Yet ministration in IVF cycles predict both ovarian reserve nol Metab. 2003;88:5957–5962. government controls threaten to keep and embryo morphology. Hum Reprod. 2006;21:159– 52. Cook CL, Siow Y, Brenner AG, Fallat ME. Relation- doctors in the dark about current 163. ship between serum anti-Müllerian substance and 37. Seifer DB, MacLaughlin DT, Christian BP, Feng other reproductive hormones in untreated women medical advances. B, Shelden RM. Early follicular serum Müllerian-in- with polycystic ovary syndrome and endometriosis. Restrictions on how much information hibiting substance levels are associated with ovar- Fertil Steril. 1997;67:962–965. ian response during assisted reproductive technology 53. Pellatt L, Hanna L, Brincat M, et al. Granulosa consumers and doctors can know about cycles. Fertil Steril. 2002;77:468–471. cell production of anti-Müllerian hormone is in- current and new treatments reduce 38. Ebner T, Sommergruber M, Moser M, Shebl O, creased in polycystic ovaries. J Clin Endocrinol Metab. their ability to advocate for care. Schreier-Lechner E, Tews G. Basal level anti-Müllerian 2007;92:240–245. hormone is associated with oocyte quality in stimu- 54. Freeman EW, Gracia CG, Sammel MD, Lin H, Using censorship as a policy tool to lated cycles. Hum Reprod. 2006;21:2022–2026. Lim LC, Strauss JF 3rd. Association of anti-Müllerian 39. Hazout A, Bouchard P, Seifer DB, Aussage P, Junca hormone levels with obesity in later reproductive-age control healthcare costs is a bad idea! AM, Cohen-Bacrie P. Serum anti-Müllerian hormone/ women. Fertil Steril. 2007;87:101–106. Yet that’s what vocal pockets of academic Müllerian-inhibiting substance appears to be a more 55. Scott RT, Opsahl MS, Leonardi MR, Neall GS, Il- medicine and Congress have in mind. discriminatory marker of ART outcome than follicu- lions EH, Navot D. Life table analysis of pregnancy rates lar stimulating hormone, inhibin B or estradiol. Fertil in a general infertility population relative to ovarian We are concerned that some members Steril. 2004;82:1323–1329. reserve and patient age. Hum Reprod. 1995;10:1706– of Congress and Academia are seeking 40. Nelson SM, Yates RW, Fleming R. Serum anti-Mül- 1710. lerian hormone and FSH: prediction of live birth and 56. Speroff L, Fritz M, eds. Clinical Gynecologic Endo- to restrict the content of CME and other extremes of response in stimulated cycles—implica- crinology and Infertility. 7th ed. Philadelphia: Lippin- industry-sponsored communications tions for individualization of therapy. Hum Reprod. cott Williams & Wilkins; 2004. without input from practicing physicians. 2007;22:2414–2421. 57. Lim AS, Tsakok MFH. Age-related decline in 41. Fanchin R, Mendez Lozano DH, Frydman N, et fertility: a link to degenerative oocytes? Fertil Steril. Information is the first step to care. al. Anti-Müllerian hormone concentrations in the fol- 1997;68:265–271. To learn more, visit cohealthcom.org.

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