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• W1972509745 abstract "The use of a letrozole challenge test to predict ovarian response is described. The authors show that a ratio of cycle day 7 to cycle day 3 post-letrozole FSH level >1.5 is associated with poor ovarian response. The use of a letrozole challenge test to predict ovarian response is described. The authors show that a ratio of cycle day 7 to cycle day 3 post-letrozole FSH level >1.5 is associated with poor ovarian response. The prediction of the ovarian response to exogenous ovarian stimulation is one of the most important tasks in the planning of a controlled ovarian hyperstimulation treatment cycle. The predictive factors often used for this purpose are patient age, history of previous response to stimulation, early follicular-phase FSH and E2 levels, anti-müllerian hormone (AMH) level, early follicular-phase antral follicle count, and various dynamic tests.Early follicular FSH level is the main factor currently being used to predict ovarian response. Cycle day 2–4 FSH has to be measured together with E2 and is known to have significant intra- and intercycle variability (1Maheshwari A. Gibreel A. Bhattacharya S. Johnson N.P. Dynamic tests of ovarian reserve: a systematic review of diagnostic accuracy.Reprod Biomed Online. 2009; 18: 717-734Abstract Full Text PDF PubMed Scopus (40) Google Scholar). Furthermore, FSH levels are affected by luteal-phase priming. A recent meta-analysis has come to the conclusion that the test achieves reasonable accuracy only with a high threshold and as a result has poor sensitivity (2Broekmans F.J. Kwee J. Hendriks D.J. Mol B.W. Lambalk C.B. A systematic review of tests predicting ovarian reserve and IVF outcome.Hum Reprod Update. 2006; 12: 685-718Crossref PubMed Scopus (927) Google Scholar).Anti-müllerian hormone is the product of granulosa cells of ovarian follicles at the early developmental stage, and its level was shown to correlate with ovarian reserve. Sowers et al. (3Sowers M. McConnell D. Gast K. Zheng H. Nan B. McCarthy J.D. et al.Anti-Mullerian hormone and inhibin B variability during normal menstrual cycles.Fertil Steril. 2010; 94: 1482-1486Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) have recently shown that AMH also changes during the cycle and therefore should be measured at the early follicular phase. Many recent studies have tried to interpret the frequent contradiction between AMH and FSH results, with no clear conclusions (3Sowers M. McConnell D. Gast K. Zheng H. Nan B. McCarthy J.D. et al.Anti-Mullerian hormone and inhibin B variability during normal menstrual cycles.Fertil Steril. 2010; 94: 1482-1486Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 4Gleicher N. Weghofer A. Barad D.H. Discordances between follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH) in female infertility.Reprod Biol Endocrinol. 2010; 8: 64Crossref PubMed Scopus (46) Google Scholar, 5Harris I.D. Wang S. Roth L. Alvero R. McShane P. Schlaff W.D. When antimullerian and follicle stimulating hormone offer a discrepant prognosis of ovarian reserve, in vitro fertilization outcomes are worse than when both values predict poor ovarian reserve.Fertil Steril. 2010; : S26Abstract Full Text Full Text PDF Google Scholar, 6Leader B. Baca Q. Seifer D. Baker L. Discordance between antimullerian hormone (AMH) and day 3 follicle stimulating (FSH) levels in the assessment of ovarian reserve.Fertil Steril. 2010; : S23Abstract Full Text Full Text PDF PubMed Google Scholar).Dynamic tests include the clomiphene citrate challenge test, the exogenous FSH ovarian response test, and the GnRH agonist stimulation test. These dynamic tests examine the changes in serum levels of FSH or E2 before and after the ovarian challenge. These tests are performed in a cycle before the actual treatment cycle and are therefore expensive and time consuming and, because of their poor predictive value, are not frequently used.Letrozole is an aromatase inhibitor that is used for ovarian stimulation, on the basis of its ability to block estrogen (E) synthesis, resulting in decreased negative feedback of E on pituitary FSH secretion. We hypothesized that an elevated ratio of FSH on cycle day 7 (CD7) after letrozole stimulation, compared with cycle day 3 (CD3), may predict poor response to gonadotropin stimulation in the same cycle of treatment.The aim of this study was to analyze the usefulness of the ratio of CD7 FSH after letrozole to CD3 FSH in predicting poor ovarian response. The study was a retrospective analysis of all the IUI and timed intercourse cycles in which letrozole stimulation (2.5 mg once per day on CD3 to CD7) was followed by gonadotropin injections conducted at the Toronto Center for Advanced Reproductive Technology between January 2007 and December 2009. The study protocol was approved by the institutional review board. To be included, the cycle was required to have the values of FSH, LH, and E2 on CD3 and CD7, as well as number and size of follicles on transvaginal ultrasound at each visit. We defined a CD7:CD3 FSH ratio of ≥1.5 as a positive result of the letrozole challenge test. For the definition of poor ovarian response we chose to use the total number of units of FSH needed to achieve each mature follicle (≥1.6 cm). This allowed us to include cycles with a different target number of mature follicles and any value of CD3 FSH. We chose two cutoff values to define poor response: ≥150 IU and ≥225 IU of FSH per mature follicle. For each of the cutoff values, we calculated the sensitivity, specificity, positive predictive value, positive and negative likelihood ratios, and diagnostic odds ratio (2Broekmans F.J. Kwee J. Hendriks D.J. Mol B.W. Lambalk C.B. A systematic review of tests predicting ovarian reserve and IVF outcome.Hum Reprod Update. 2006; 12: 685-718Crossref PubMed Scopus (927) Google Scholar).A total of 303 cycles of the 360 consecutive cycles included a complete set of data. On the basis of the response to gonadotropin injections, patients were divided into four groups: patients that needed [1] <75 U of FSH per mature follicle (n = 47), [2] 75–150 U per mature follicle (n = 109), [3] >150–225 U per mature follicle (n = 65), and [4] >225 units of FSH per mature follicle (n = 82). Neither the average patient age nor CD3 FSH level in each group was statistically different. The average age was 34.8, 35.3, 34.9, and 36.3 years, and the average CD3 FSH level in these groups was 7.13 IU, 6.71 IU, 7.32 IU, and 7.41 IU respectively. We compared the prevalence of ratios ≥1.5 for CD7:CD3 FSH, LH, and E2 (Fig. 1). The only test that had more positive results in the poor-response groups was the CD7:CD3 FSH. Analysis of the CD7:CD3 FSH test characteristics for 150 U and 225 U per mature follicle gave a sensitivity of 50% and 84.2% and a specificity of 0 and 76.8%, respectively. The positive likelihood ratios were 0.69 and 14.37, respectively, the negative likelihood ratios were 0.0 and 0.82, respectively, and the diagnostic odds ratios were 0.0 and 17.62, respectively.Tests for ovarian reserve were designed to assist physicians in predicting ovarian response to fertility treatments. Decisions that need to be made are the type of stimulation protocol, dose of ovarian stimulation, and chance for success. Analysis of the predictive value of the tests that are currently available shows that although some of the tests are accurate in predicting success, they involve high thresholds, thus resulting in a very low sensitivity (2Broekmans F.J. Kwee J. Hendriks D.J. Mol B.W. Lambalk C.B. A systematic review of tests predicting ovarian reserve and IVF outcome.Hum Reprod Update. 2006; 12: 685-718Crossref PubMed Scopus (927) Google Scholar). Letrozole administration in the early follicular phase inhibits E production by the granulosa cells. As a result, feedback inhibition by the rising levels of E on pituitary FSH secretion is postponed, allowing the development of more follicles. As shown in Figure 1, aromatase enzyme activity quite frequently escapes the inhibition of letrozole, probably by the induction of more enzyme units by increasing concentration of FSH. As a result, E levels rise and reduce levels of serum FSH. This is seen more frequently in good responders (Fig. 1). However, in poor responders with fewer follicles and fewer FSH receptors per follicle, the increase in E2 is not so significant and the negative feedback on FSH is lower, resulting in higher circulating levels of FSH. Furthermore, a major mechanism of FSH clearance from the circulation involves receptor binding (7Fletcher P.W. Reichert Jr., L.E. Cellular processing of follicle-stimulating hormone by Sertoli cells in serum-free culture.Mol Cell Endocrinol. 1984; 34: 39-49Crossref PubMed Scopus (48) Google Scholar), and hence poor responders with fewer follicles will have a slower rate of FSH clearance and a persistently higher serum concentration of FSH.The results of the present study suggest that the letrozole CD7:CD3 FSH ratio may identify patients who will be poor responders requiring a higher-dose ovarian stimulation regimen. The use of the FSH ratio of ≥1.5 to predict poor response, defined as ≥225 IU of FSH per mature follicle, resulted in acceptable predictive capabilities, as expressed by the high sensitivity and specificity and a good positive likelihood ratio, which is independent of prevalence (8Peirce J.C. Gerkin R.D. The likelihood ratio as one of—if not the most important—operating characteristic of a diagnostic test.J Gen Intern Med. 2003; 18: 75Crossref PubMed Google Scholar). The prediction of the ovarian response to exogenous ovarian stimulation is one of the most important tasks in the planning of a controlled ovarian hyperstimulation treatment cycle. The predictive factors often used for this purpose are patient age, history of previous response to stimulation, early follicular-phase FSH and E2 levels, anti-müllerian hormone (AMH) level, early follicular-phase antral follicle count, and various dynamic tests. Early follicular FSH level is the main factor currently being used to predict ovarian response. Cycle day 2–4 FSH has to be measured together with E2 and is known to have significant intra- and intercycle variability (1Maheshwari A. Gibreel A. Bhattacharya S. Johnson N.P. Dynamic tests of ovarian reserve: a systematic review of diagnostic accuracy.Reprod Biomed Online. 2009; 18: 717-734Abstract Full Text PDF PubMed Scopus (40) Google Scholar). Furthermore, FSH levels are affected by luteal-phase priming. A recent meta-analysis has come to the conclusion that the test achieves reasonable accuracy only with a high threshold and as a result has poor sensitivity (2Broekmans F.J. Kwee J. Hendriks D.J. Mol B.W. Lambalk C.B. A systematic review of tests predicting ovarian reserve and IVF outcome.Hum Reprod Update. 2006; 12: 685-718Crossref PubMed Scopus (927) Google Scholar). Anti-müllerian hormone is the product of granulosa cells of ovarian follicles at the early developmental stage, and its level was shown to correlate with ovarian reserve. Sowers et al. (3Sowers M. McConnell D. Gast K. Zheng H. Nan B. McCarthy J.D. et al.Anti-Mullerian hormone and inhibin B variability during normal menstrual cycles.Fertil Steril. 2010; 94: 1482-1486Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) have recently shown that AMH also changes during the cycle and therefore should be measured at the early follicular phase. Many recent studies have tried to interpret the frequent contradiction between AMH and FSH results, with no clear conclusions (3Sowers M. McConnell D. Gast K. Zheng H. Nan B. McCarthy J.D. et al.Anti-Mullerian hormone and inhibin B variability during normal menstrual cycles.Fertil Steril. 2010; 94: 1482-1486Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 4Gleicher N. Weghofer A. Barad D.H. Discordances between follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH) in female infertility.Reprod Biol Endocrinol. 2010; 8: 64Crossref PubMed Scopus (46) Google Scholar, 5Harris I.D. Wang S. Roth L. Alvero R. McShane P. Schlaff W.D. When antimullerian and follicle stimulating hormone offer a discrepant prognosis of ovarian reserve, in vitro fertilization outcomes are worse than when both values predict poor ovarian reserve.Fertil Steril. 2010; : S26Abstract Full Text Full Text PDF Google Scholar, 6Leader B. Baca Q. Seifer D. Baker L. Discordance between antimullerian hormone (AMH) and day 3 follicle stimulating (FSH) levels in the assessment of ovarian reserve.Fertil Steril. 2010; : S23Abstract Full Text Full Text PDF PubMed Google Scholar). Dynamic tests include the clomiphene citrate challenge test, the exogenous FSH ovarian response test, and the GnRH agonist stimulation test. These dynamic tests examine the changes in serum levels of FSH or E2 before and after the ovarian challenge. These tests are performed in a cycle before the actual treatment cycle and are therefore expensive and time consuming and, because of their poor predictive value, are not frequently used. Letrozole is an aromatase inhibitor that is used for ovarian stimulation, on the basis of its ability to block estrogen (E) synthesis, resulting in decreased negative feedback of E on pituitary FSH secretion. We hypothesized that an elevated ratio of FSH on cycle day 7 (CD7) after letrozole stimulation, compared with cycle day 3 (CD3), may predict poor response to gonadotropin stimulation in the same cycle of treatment. The aim of this study was to analyze the usefulness of the ratio of CD7 FSH after letrozole to CD3 FSH in predicting poor ovarian response. The study was a retrospective analysis of all the IUI and timed intercourse cycles in which letrozole stimulation (2.5 mg once per day on CD3 to CD7) was followed by gonadotropin injections conducted at the Toronto Center for Advanced Reproductive Technology between January 2007 and December 2009. The study protocol was approved by the institutional review board. To be included, the cycle was required to have the values of FSH, LH, and E2 on CD3 and CD7, as well as number and size of follicles on transvaginal ultrasound at each visit. We defined a CD7:CD3 FSH ratio of ≥1.5 as a positive result of the letrozole challenge test. For the definition of poor ovarian response we chose to use the total number of units of FSH needed to achieve each mature follicle (≥1.6 cm). This allowed us to include cycles with a different target number of mature follicles and any value of CD3 FSH. We chose two cutoff values to define poor response: ≥150 IU and ≥225 IU of FSH per mature follicle. For each of the cutoff values, we calculated the sensitivity, specificity, positive predictive value, positive and negative likelihood ratios, and diagnostic odds ratio (2Broekmans F.J. Kwee J. Hendriks D.J. Mol B.W. Lambalk C.B. A systematic review of tests predicting ovarian reserve and IVF outcome.Hum Reprod Update. 2006; 12: 685-718Crossref PubMed Scopus (927) Google Scholar). A total of 303 cycles of the 360 consecutive cycles included a complete set of data. On the basis of the response to gonadotropin injections, patients were divided into four groups: patients that needed [1] <75 U of FSH per mature follicle (n = 47), [2] 75–150 U per mature follicle (n = 109), [3] >150–225 U per mature follicle (n = 65), and [4] >225 units of FSH per mature follicle (n = 82). Neither the average patient age nor CD3 FSH level in each group was statistically different. The average age was 34.8, 35.3, 34.9, and 36.3 years, and the average CD3 FSH level in these groups was 7.13 IU, 6.71 IU, 7.32 IU, and 7.41 IU respectively. We compared the prevalence of ratios ≥1.5 for CD7:CD3 FSH, LH, and E2 (Fig. 1). The only test that had more positive results in the poor-response groups was the CD7:CD3 FSH. Analysis of the CD7:CD3 FSH test characteristics for 150 U and 225 U per mature follicle gave a sensitivity of 50% and 84.2% and a specificity of 0 and 76.8%, respectively. The positive likelihood ratios were 0.69 and 14.37, respectively, the negative likelihood ratios were 0.0 and 0.82, respectively, and the diagnostic odds ratios were 0.0 and 17.62, respectively. Tests for ovarian reserve were designed to assist physicians in predicting ovarian response to fertility treatments. Decisions that need to be made are the type of stimulation protocol, dose of ovarian stimulation, and chance for success. Analysis of the predictive value of the tests that are currently available shows that although some of the tests are accurate in predicting success, they involve high thresholds, thus resulting in a very low sensitivity (2Broekmans F.J. Kwee J. Hendriks D.J. Mol B.W. Lambalk C.B. A systematic review of tests predicting ovarian reserve and IVF outcome.Hum Reprod Update. 2006; 12: 685-718Crossref PubMed Scopus (927) Google Scholar). Letrozole administration in the early follicular phase inhibits E production by the granulosa cells. As a result, feedback inhibition by the rising levels of E on pituitary FSH secretion is postponed, allowing the development of more follicles. As shown in Figure 1, aromatase enzyme activity quite frequently escapes the inhibition of letrozole, probably by the induction of more enzyme units by increasing concentration of FSH. As a result, E levels rise and reduce levels of serum FSH. This is seen more frequently in good responders (Fig. 1). However, in poor responders with fewer follicles and fewer FSH receptors per follicle, the increase in E2 is not so significant and the negative feedback on FSH is lower, resulting in higher circulating levels of FSH. Furthermore, a major mechanism of FSH clearance from the circulation involves receptor binding (7Fletcher P.W. Reichert Jr., L.E. Cellular processing of follicle-stimulating hormone by Sertoli cells in serum-free culture.Mol Cell Endocrinol. 1984; 34: 39-49Crossref PubMed Scopus (48) Google Scholar), and hence poor responders with fewer follicles will have a slower rate of FSH clearance and a persistently higher serum concentration of FSH. The results of the present study suggest that the letrozole CD7:CD3 FSH ratio may identify patients who will be poor responders requiring a higher-dose ovarian stimulation regimen. The use of the FSH ratio of ≥1.5 to predict poor response, defined as ≥225 IU of FSH per mature follicle, resulted in acceptable predictive capabilities, as expressed by the high sensitivity and specificity and a good positive likelihood ratio, which is independent of prevalence (8Peirce J.C. Gerkin R.D. The likelihood ratio as one of—if not the most important—operating characteristic of a diagnostic test.J Gen Intern Med. 2003; 18: 75Crossref PubMed Google Scholar)." @default.
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• W1972509745 title "Use of letrozole challenge test to adjust gonadotropin dose in non–down-regulated cycles" @default.
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