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Testing and Interpreting Measures of Ovarian Reserve: a Committee Opinion

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Testing and Interpreting Measures of Ovarian Reserve: a Committee Opinion ASRM PAGES Testing and interpreting measures of ovarian reserve: a committee opinion Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama Ovarian reserve is defined as the number of oocytes remaining in the ovary, or oocyte quantity (oocyte number). Markers of ovarian reserve include hormone levels and sonographically measured features of the ovaries. These markers can be useful as predictors of oocyte yield following controlled ovarian stimulation and oocyte retrieval. However, they are poor predictors of reproductive potential independently from age. This document replaces the document of the same name last published in 2012 (Fertil Steril 2012;98:1407–15). (Fertil SterilÒ 2020;114:1151–7. Ó2020 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/31403 he process of reproductive aging oocyte quality, which relates to the Inhibin B and AMH are glycopro- has traditionally centered on the potential of a fertilized oocyte to result tein hormones produced by small T principle that human oocytes in a live-born infant. Female infants are ovarian follicles and are therefore peak in number during fetal life, un- born with 500,000 to 1 million oo- direct measures of the follicular pool. dergo ovulation or atresia thereafter, cytes, follicular atresia and ovulation Whereas AMH is primarily secreted by and do not regenerate. Reproductive result in a slow depletion of oocyte primary, preantral, and early antral fol- and ovarian senescence occurs with number over time, and menopause sub- licles, inhibin B is secreted primarily by depletion of the number of oocytes, or sequently ensues. Ovarian reserve cor- preantral follicles. As the number of ovarian reserve. Women in later stages relates inversely with age, but there is ovarian follicles declines with age, of reproductive aging (perimenopause considerable variation in ovarian both AMH and early-follicular-phase and menopause), when menses become reserve among women of the same inhibin B concentrations decline. irregular, have lower ovarian reserve chronologic age (2). Decreased inhibin B secretion lowers than women in earlier reproductive the level of central negative feedback, stages, when menstrual cycles are nor- resulting in increased pituitary FSH mally regular (1). Ovarian reserve can secretion and in higher late-luteal and be indirectly measured with the use of WHAT ARE MEASURES OF early-follicular FSH concentrations hormone levels or ultrasound imaging OVARIAN RESERVE? (an indirect measure). In turn, the of the ovaries. This document reviews Ovarian reserve tests include both earlier increase in FSH levels stimulates the evidence relating to the clinical biochemical tests and ultrasound imag- an earlier onset of new follicular utility and predictive value of ovarian ing of the ovaries. Biochemical tests of growth and an increase in E2 concen- reserve testing as predictors of repro- ovarian reserve can be divided further trations, ultimately decreasing the ductive potential. into early-follicular-phase measure- length of the follicular phase and the ments of FSH, E2, or inhibin B; mea- overall cycle. These hormone tests are surement of cycle-day-independent therefore used as markers of ovarian WHAT IS OVARIAN antimullerian€ hormone (AMH); and reserve. RESERVE? provocative tests, such as the clomi- fi Ovarian reserve is de ned as the num- phene citrate challenge test (CCCT). Basal Serum FSH and E ber of oocytes remaining in the ovary, Biochemical measures of ovarian 2 or oocyte quantity (oocyte number). reserve are intended to directly or indi- Basal serum FSH concentrations are Ovarian reserve, or oocyte quantity rectly measure the oocyte or follicular elevated on day 2, 3, or 4 of the men- (oocyte number), is different from pool. strual cycle in women with diminished ovarian reserve (DOR). Elevated basal Received September 10, 2020; accepted September 11, 2020. serum FSH is a specific, but not sensi- Reprint requests: American Society for Reproductive Medicine, 1209 Montgomery Highway, Birming- ham, AL 35216-2809 (E-mail: [email protected]). tive, test for DOR (3). However, FSH levels have significant inter- and intra- Fertility and Sterility® Vol. 114, No. 6, December 2020 0015-0282/$36.00 Copyright ©2020 American Society for Reproductive Medicine, Published by Elsevier Inc. cycle variability that limits the reli- https://doi.org/10.1016/j.fertnstert.2020.09.134 ability of a single measurement. High VOL. 114 NO. 6 / DECEMBER 2020 1151 ASRM PAGES intercycle variability suggests more advanced DOR (4, 5). The antral follicles as those measuring 2–10 mm in mean diameter overall correlation among different FSH assays is high, but in the greatest two-dimensional plane across the ovary. AFC absolute values can differ from one another (6). Basal E2 alone has low intercycle variability and high interobserver reli- should not be used to screen for DOR. The test has value only ability in experienced centers (18–22). as an aid to the correct interpretation of a normal basal serum FSH value, as follows. An early rise in serum E2 concentra- SELECTING A MARKER OF OVARIAN RESERVE tions is a classic characteristic of reproductive aging and AMH levels appear to be a more sensitive marker of ovarian can lower an otherwise elevated basal FSH level into the reserve compared with early-follicular-phase hormone levels. normal range, thereby causing a misinterpretation of the AMH tends to decline before FSH rises (17); thus, high FSH is a test. When the basal FSH concentration is normal but the E 2 specific marker for DOR but fails to detect a more subtle level is elevated (>60–80 pg/mL), this may indicate ovarian decline in ovarian reserve. AMH testing is simpler to admin- dysfunction attributable to DOR (7). ister. AFC and AMH have been shown in multiple studies to be equivalent (23). When performed in an experienced center, Clomiphene Citrate Challenge Test AFC is a reasonable alternative to AMH. The CCCT involves measurements of serum FSH before (cycle day 3) and after (cycle day 10) treatment with clomiphene cit- DO OVARIAN RESERVE TESTS PREDICT rate (100 mg daily, cycle days 5–9). Whereas rising inhibin B REPRODUCTIVE POTENTIAL AMONG WOMEN and E2 levels derived from a growing cohort of ovarian folli- WITH UNPROVEN FERTILITY? cles will suppress FSH in women with responsive ovaries, the Ovarian reserve declines with age, as do fertility rates. This smaller follicular cohorts that can be recruited in women with has led to the presumption that ovarian reserve should predict DOR will generate less inhibin B and E , resulting in decreased 2 reproductive potential; however, this has not been borne out negative feedback inhibition of FSH secretion and higher in studies so far. A number of studies have been conducted to stimulated FSH concentrations. An elevated FSH concentra- assess the value of markers of ovarian reserve as markers of tion after clomiphene stimulation therefore suggests DOR. current reproductive potential. In prospective cohort studies, Provocative testing with the use of the CCCT may increase markers of ovarian reserve were poor predictors of reproduc- sensitivity for DOR (8). However, compared with basal FSH tive potential as measured by fecundability (the probability of and ultrasonographically determined antral follicle count conceiving in a given menstrual cycle), cumulative probabil- (AFC), the clomiphene-stimulated day-10 FSH level is not su- ity of pregnancy, or incidence of infertility. perior to nondynamic tests for predicting poor ovarian The EAGER (Effects of Aspirin in Gestation and Repro- response or pregnancy after in vitro fertilization (IVF) duction) trial enrolled women aged 18–40 years with a history (8–10) or unassisted conception in women with infertility of one or more pregnancy losses (N ¼ 1,202). Women with (11). For this reason, this test should be abandoned. low AMH levels (<1 ng/mL) had similar cumulative preg- nancy rates as women with normal values (1.0–3.5 ng/mL) € Antimullerian Hormone (24). The Time to Conceive study, including a prospective Serum concentrations of AMH, produced by granulosa cells of cohort of 750 women aged 30–44 years without known his- early follicles, are gonadotropin independent and, therefore, tory of or risk factors for infertility, found that women with remain relatively consistent within and between menstrual low AMH levels (<0.7 ng/mL) or high FSH values (>10 IU/ cycles in both normal, young, ovulating women and women L) had similar cumulative pregnancy rates after 6 and 12 cy- with infertility (12–15). AMH levels may be decreased in cles of attempting pregnancy compared with women with women currently using hormonal contraceptives and, normal levels (25). Similarly, markers of ovarian reserve do therefore, should be interpreted with caution in those not predict the probability of conceiving after unmedicated patients (16). AMH is a more sensitive measure of ovarian donor-sperm insemination cycles (26). reserve than FSH and tends to decline before FSH rises (17). For this reason, AMH has largely replaced basal FSH and E2 DO OVARIAN RESERVE TESTS PREDICT level testing as a biomarker of ovarian reserve. Basal FSH REPRODUCTIVE POTENTIAL AMONG WOMEN and E2 levels may provide additional information in women WITH INFERTILITY? with very low AMH levels. Based on the limited data available,
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