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In reproductive medicine, there are few, if any, more pressing concerns from our patients than the biological clock, i.e., ovarian aging. While addressing this issue with women can be challenging, particularly for those who are anxious regarding their advanced maternal age, gynecologists must possess a thorough understanding of available diagnostic testing. This article will review the various methods to assess ovarian age and appropriate clinical management.
Ovarian reserve tests
Ovarian reserve represents the quality and quantity of oocytes. The former is defined by the woman’s chronologic age, which is the greatest predictor of fertility. From a peak monthly fecundity rate at age 30 of approximately 20%, the slow and steady decline of fertility ensues. Quantity represents the number of oocytes remaining from the original cohort.
Ovarian reserve is most provocatively gauged by the follicle response to gonadotropin stimulation, typically during an in vitro fertilization (IVF) cycle.
Several biomarkers have been used to assess ovarian age. These include FSH, estradiol, and inhibin B. In general, these tests are more specific than sensitive, i.e., “normal” results do not necessarily exclude decreased ovarian reserve. But as a screening tool for decreased ovarian reserve, the most important factor is the positive predictive value (PPV). Statistically, in a population of women at low risk for decreased ovarian reserve, the PPV will be low despite sensitivity and specificity.
While inhibin B is a more direct and earlier reflection of ovarian function produced by granulose cells, assays lacked consistent results and a standardized cut-off value. FSH is the last biomarker to be affected by decreased ovarian reserve so elevations reflect more “end-stage” ovarian aging.
Additional tests for decreased ovarian reserve include antral follicle count (AFC) and the clomiphene citrate challenge test (CCCT). AFC is determined by using transvaginal ultrasound to count the number of follicular cysts in the 2- to 9-mm range. While AFC can be performed on any day of the cycle, the ovary is most optimally measured on menses because of less cystic activity. A combined AFC of 3-6 is considered severe decreased ovarian reserve. The CCCT involves prescribing clomiphene citrate 100 mg daily from cycle day 5-9 to measure FSH on cycle days 3 and 10. An FSH level greater than 10 IU/L or any elevation in FSH following CCCT is considered decreased ovarian reserve.
FSH had been the standard but levels may dramatically change monthly, making testing only valuable if it is elevated. Consequently, antimüllerian hormone (AMH) and AFC are considered the most useful tools to determine decreased ovarian reserve because of less variability. The other distinct advantage is the ability to obtain AMH any day in the menstrual cycle. Recently, in women undergoing IVF, AMH was superior to FSH in predicting live birth, particularly when their values were discordant (J Ovarian Res. 2018;11:60). While there is no established consensus, the ideal interval for repeating AMH appears to be approximately 3 months (Obstet Gynecol 2016;127:65S-6S).
AMH
AMH is expressed in the embryo at 8 weeks by the Sertoli cells of the testis causing the female reproductive internal system (müllerian) to regress. Without AMH expression, the müllerian system remains and the male (woffian duct system) regresses. The discovery of AMH production by the granulosa cells of the ovary launched a new era in the evaluation and management of infertile women. First reported in Fertility & Sterility in 2002 as a much earlier potential marker of ovarian aging, low levels of AMH predict a lower number of eggs in IVF.
AMH levels are produced in the embryo at 36 weeks’ gestation and increase up to the age of 24.5 years, decreasing thereafter. AMH reflects primordial (early) follicles that are FSH independent. The median AMH level decreases per year according to age groups are: 0.25 ng/mL in ages 26-30; 0.2 ng/mL in ages 31-36 years; and 0.1 ng/mL above age 36. (PLOS ONE 2015 doi: 10.1371/journal.pone.0125216).
AMH has also been studied as a potential biomarker to diagnose PCOS. While many women with PCOS have elevated AMH levels (typically greater than 3 ng/mL), there is no consensus on an AMH value that would be a criterion.
Many women, particularly those electing to defer fertility, express interest in obtaining their AMH level to consider planned oocyte cryopreservation, AKA, social egg freezing. While it is possible the results of AMH screening may compel women to electively freeze their eggs, extensive counseling on the implications and pitfalls of AMH levels is essential. Further, AMH cannot be used to accurately predict menopause.
Predicting outcomes
No biomarker is necessarily predictive of pregnancy but more a gauge of gonadotropin dosage to induce multifollicular development. AMH is a great predictor of oocyte yield with IVF (J Assist Reprod Genet. 2009;26[7]:383-9). However, in women older than 35 undergoing IVF, low AMH levels have been shown to reduce pregnancy rates (J Hum Reprod Sci. 2017;10:24–30). During IVF cycle attempts, an ultra-low AMH (≤0.4) resulted in high cancellation rates, reduced the number of oocytes retrieved and embryos developed, and lowered pregnancy rates in women of advanced reproductive age.
Alternatively, a study of 750 women who were not infertile and were actively trying to conceive demonstrated no difference in natural pregnancy rates in women aged 30-44 irrespective of AMH levels (JAMA. 2017;318[14]:1367-76).
A special consideration is for cancer patients who are status postgonadotoxic chemotherapy. Their oocyte attrition can be accelerated and AMH levels can become profoundly low. In those patients, current data suggest there is a modest recovery of postchemotherapy AMH levels up to 1 year. Further, oocyte yield following stimulation may be higher than expected despite a poor AMH level.
Conclusion
Ovarian aging is currently best measured by combining chronologic age, AFC, and AMH. There is no current evidence that AMH levels should be used to exclude patients from undergoing IVF or to recommend egg donation. Random screening of AMH levels in a low-risk population for decreased ovarian reserve may result in unnecessary alarm.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.
In reproductive medicine, there are few, if any, more pressing concerns from our patients than the biological clock, i.e., ovarian aging. While addressing this issue with women can be challenging, particularly for those who are anxious regarding their advanced maternal age, gynecologists must possess a thorough understanding of available diagnostic testing. This article will review the various methods to assess ovarian age and appropriate clinical management.
Ovarian reserve tests
Ovarian reserve represents the quality and quantity of oocytes. The former is defined by the woman’s chronologic age, which is the greatest predictor of fertility. From a peak monthly fecundity rate at age 30 of approximately 20%, the slow and steady decline of fertility ensues. Quantity represents the number of oocytes remaining from the original cohort.
Ovarian reserve is most provocatively gauged by the follicle response to gonadotropin stimulation, typically during an in vitro fertilization (IVF) cycle.
Several biomarkers have been used to assess ovarian age. These include FSH, estradiol, and inhibin B. In general, these tests are more specific than sensitive, i.e., “normal” results do not necessarily exclude decreased ovarian reserve. But as a screening tool for decreased ovarian reserve, the most important factor is the positive predictive value (PPV). Statistically, in a population of women at low risk for decreased ovarian reserve, the PPV will be low despite sensitivity and specificity.
While inhibin B is a more direct and earlier reflection of ovarian function produced by granulose cells, assays lacked consistent results and a standardized cut-off value. FSH is the last biomarker to be affected by decreased ovarian reserve so elevations reflect more “end-stage” ovarian aging.
Additional tests for decreased ovarian reserve include antral follicle count (AFC) and the clomiphene citrate challenge test (CCCT). AFC is determined by using transvaginal ultrasound to count the number of follicular cysts in the 2- to 9-mm range. While AFC can be performed on any day of the cycle, the ovary is most optimally measured on menses because of less cystic activity. A combined AFC of 3-6 is considered severe decreased ovarian reserve. The CCCT involves prescribing clomiphene citrate 100 mg daily from cycle day 5-9 to measure FSH on cycle days 3 and 10. An FSH level greater than 10 IU/L or any elevation in FSH following CCCT is considered decreased ovarian reserve.
FSH had been the standard but levels may dramatically change monthly, making testing only valuable if it is elevated. Consequently, antimüllerian hormone (AMH) and AFC are considered the most useful tools to determine decreased ovarian reserve because of less variability. The other distinct advantage is the ability to obtain AMH any day in the menstrual cycle. Recently, in women undergoing IVF, AMH was superior to FSH in predicting live birth, particularly when their values were discordant (J Ovarian Res. 2018;11:60). While there is no established consensus, the ideal interval for repeating AMH appears to be approximately 3 months (Obstet Gynecol 2016;127:65S-6S).
AMH
AMH is expressed in the embryo at 8 weeks by the Sertoli cells of the testis causing the female reproductive internal system (müllerian) to regress. Without AMH expression, the müllerian system remains and the male (woffian duct system) regresses. The discovery of AMH production by the granulosa cells of the ovary launched a new era in the evaluation and management of infertile women. First reported in Fertility & Sterility in 2002 as a much earlier potential marker of ovarian aging, low levels of AMH predict a lower number of eggs in IVF.
AMH levels are produced in the embryo at 36 weeks’ gestation and increase up to the age of 24.5 years, decreasing thereafter. AMH reflects primordial (early) follicles that are FSH independent. The median AMH level decreases per year according to age groups are: 0.25 ng/mL in ages 26-30; 0.2 ng/mL in ages 31-36 years; and 0.1 ng/mL above age 36. (PLOS ONE 2015 doi: 10.1371/journal.pone.0125216).
AMH has also been studied as a potential biomarker to diagnose PCOS. While many women with PCOS have elevated AMH levels (typically greater than 3 ng/mL), there is no consensus on an AMH value that would be a criterion.
Many women, particularly those electing to defer fertility, express interest in obtaining their AMH level to consider planned oocyte cryopreservation, AKA, social egg freezing. While it is possible the results of AMH screening may compel women to electively freeze their eggs, extensive counseling on the implications and pitfalls of AMH levels is essential. Further, AMH cannot be used to accurately predict menopause.
Predicting outcomes
No biomarker is necessarily predictive of pregnancy but more a gauge of gonadotropin dosage to induce multifollicular development. AMH is a great predictor of oocyte yield with IVF (J Assist Reprod Genet. 2009;26[7]:383-9). However, in women older than 35 undergoing IVF, low AMH levels have been shown to reduce pregnancy rates (J Hum Reprod Sci. 2017;10:24–30). During IVF cycle attempts, an ultra-low AMH (≤0.4) resulted in high cancellation rates, reduced the number of oocytes retrieved and embryos developed, and lowered pregnancy rates in women of advanced reproductive age.
Alternatively, a study of 750 women who were not infertile and were actively trying to conceive demonstrated no difference in natural pregnancy rates in women aged 30-44 irrespective of AMH levels (JAMA. 2017;318[14]:1367-76).
A special consideration is for cancer patients who are status postgonadotoxic chemotherapy. Their oocyte attrition can be accelerated and AMH levels can become profoundly low. In those patients, current data suggest there is a modest recovery of postchemotherapy AMH levels up to 1 year. Further, oocyte yield following stimulation may be higher than expected despite a poor AMH level.
Conclusion
Ovarian aging is currently best measured by combining chronologic age, AFC, and AMH. There is no current evidence that AMH levels should be used to exclude patients from undergoing IVF or to recommend egg donation. Random screening of AMH levels in a low-risk population for decreased ovarian reserve may result in unnecessary alarm.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.
In reproductive medicine, there are few, if any, more pressing concerns from our patients than the biological clock, i.e., ovarian aging. While addressing this issue with women can be challenging, particularly for those who are anxious regarding their advanced maternal age, gynecologists must possess a thorough understanding of available diagnostic testing. This article will review the various methods to assess ovarian age and appropriate clinical management.
Ovarian reserve tests
Ovarian reserve represents the quality and quantity of oocytes. The former is defined by the woman’s chronologic age, which is the greatest predictor of fertility. From a peak monthly fecundity rate at age 30 of approximately 20%, the slow and steady decline of fertility ensues. Quantity represents the number of oocytes remaining from the original cohort.
Ovarian reserve is most provocatively gauged by the follicle response to gonadotropin stimulation, typically during an in vitro fertilization (IVF) cycle.
Several biomarkers have been used to assess ovarian age. These include FSH, estradiol, and inhibin B. In general, these tests are more specific than sensitive, i.e., “normal” results do not necessarily exclude decreased ovarian reserve. But as a screening tool for decreased ovarian reserve, the most important factor is the positive predictive value (PPV). Statistically, in a population of women at low risk for decreased ovarian reserve, the PPV will be low despite sensitivity and specificity.
While inhibin B is a more direct and earlier reflection of ovarian function produced by granulose cells, assays lacked consistent results and a standardized cut-off value. FSH is the last biomarker to be affected by decreased ovarian reserve so elevations reflect more “end-stage” ovarian aging.
Additional tests for decreased ovarian reserve include antral follicle count (AFC) and the clomiphene citrate challenge test (CCCT). AFC is determined by using transvaginal ultrasound to count the number of follicular cysts in the 2- to 9-mm range. While AFC can be performed on any day of the cycle, the ovary is most optimally measured on menses because of less cystic activity. A combined AFC of 3-6 is considered severe decreased ovarian reserve. The CCCT involves prescribing clomiphene citrate 100 mg daily from cycle day 5-9 to measure FSH on cycle days 3 and 10. An FSH level greater than 10 IU/L or any elevation in FSH following CCCT is considered decreased ovarian reserve.
FSH had been the standard but levels may dramatically change monthly, making testing only valuable if it is elevated. Consequently, antimüllerian hormone (AMH) and AFC are considered the most useful tools to determine decreased ovarian reserve because of less variability. The other distinct advantage is the ability to obtain AMH any day in the menstrual cycle. Recently, in women undergoing IVF, AMH was superior to FSH in predicting live birth, particularly when their values were discordant (J Ovarian Res. 2018;11:60). While there is no established consensus, the ideal interval for repeating AMH appears to be approximately 3 months (Obstet Gynecol 2016;127:65S-6S).
AMH
AMH is expressed in the embryo at 8 weeks by the Sertoli cells of the testis causing the female reproductive internal system (müllerian) to regress. Without AMH expression, the müllerian system remains and the male (woffian duct system) regresses. The discovery of AMH production by the granulosa cells of the ovary launched a new era in the evaluation and management of infertile women. First reported in Fertility & Sterility in 2002 as a much earlier potential marker of ovarian aging, low levels of AMH predict a lower number of eggs in IVF.
AMH levels are produced in the embryo at 36 weeks’ gestation and increase up to the age of 24.5 years, decreasing thereafter. AMH reflects primordial (early) follicles that are FSH independent. The median AMH level decreases per year according to age groups are: 0.25 ng/mL in ages 26-30; 0.2 ng/mL in ages 31-36 years; and 0.1 ng/mL above age 36. (PLOS ONE 2015 doi: 10.1371/journal.pone.0125216).
AMH has also been studied as a potential biomarker to diagnose PCOS. While many women with PCOS have elevated AMH levels (typically greater than 3 ng/mL), there is no consensus on an AMH value that would be a criterion.
Many women, particularly those electing to defer fertility, express interest in obtaining their AMH level to consider planned oocyte cryopreservation, AKA, social egg freezing. While it is possible the results of AMH screening may compel women to electively freeze their eggs, extensive counseling on the implications and pitfalls of AMH levels is essential. Further, AMH cannot be used to accurately predict menopause.
Predicting outcomes
No biomarker is necessarily predictive of pregnancy but more a gauge of gonadotropin dosage to induce multifollicular development. AMH is a great predictor of oocyte yield with IVF (J Assist Reprod Genet. 2009;26[7]:383-9). However, in women older than 35 undergoing IVF, low AMH levels have been shown to reduce pregnancy rates (J Hum Reprod Sci. 2017;10:24–30). During IVF cycle attempts, an ultra-low AMH (≤0.4) resulted in high cancellation rates, reduced the number of oocytes retrieved and embryos developed, and lowered pregnancy rates in women of advanced reproductive age.
Alternatively, a study of 750 women who were not infertile and were actively trying to conceive demonstrated no difference in natural pregnancy rates in women aged 30-44 irrespective of AMH levels (JAMA. 2017;318[14]:1367-76).
A special consideration is for cancer patients who are status postgonadotoxic chemotherapy. Their oocyte attrition can be accelerated and AMH levels can become profoundly low. In those patients, current data suggest there is a modest recovery of postchemotherapy AMH levels up to 1 year. Further, oocyte yield following stimulation may be higher than expected despite a poor AMH level.
Conclusion
Ovarian aging is currently best measured by combining chronologic age, AFC, and AMH. There is no current evidence that AMH levels should be used to exclude patients from undergoing IVF or to recommend egg donation. Random screening of AMH levels in a low-risk population for decreased ovarian reserve may result in unnecessary alarm.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.