lbt lab tests t Conrolled Ovarian Hyperstimulation Dr Soheila Ansaripour

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1 lbt lab tests t and Conrolled Ovarian Hyperstimulation Dr Soheila Ansaripour Research Instituteof Avicenna 4/23/2012

2 Why good prediction of poor response good prediction i of OHSS application appropriate stimulation protocols good prediction of successful pregnancy

3 Cilinical Prediction Markers of Ovarian Response and Pregnancy Prediction of no response Age Menstrual cycle length (MCL) Previous no or low response Prediction of high response Age BMI PCO Previous high response

4 Female Age is very important in consideration of probability for conception because it is very much related to egg quality. A 45 year old can have good quality eggs (for her age) and still be fertile, although this is quite uncommon. At the other extreme, a 25 year old can have very poor quality eggs and be infertile unless she uses donor eggs. These are extreme examples, but the point is that egg quantity and quality tends to decline significantly in the 30s and faster in the early 40s, but egg quantity and quality in an individual woman can be average for her age, better than average, or worse than average.

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7 Menstrual Pattern Menstrual cycle length (MCL) a gradual shortening in cycle length may initiate in the late 30s, in parallel with higher serum (FSH) and lower serum levels of inhibins correlation between MCL and the antral follicle count (AFC) during ultrasonographic evaluation MCL had significant association with ovarian response to gonadotropinstimulus ti and embryoquality in IVF/ICSIcycles even if the interference of age is excluded, pregnancy rates are almost twice as high among womenwithcycles>34 days when compared with those with cycles<26 days

8 Lab Prediction Markers of Ovarian Response and Prgnancy Lab tests before starting COH Lab tests after starting 1. To determine ovarian reserve COH STATIC tests 1. To determine ovarian 3 day FSH,Estradiol,AMH, response 5 day Inhibin B Inhibin B 5 day AMH AFC,ovarian vol,ovarianovarian flow Estradiol DYNAMIC tests CCCT,EFFORT,GAST,AMH,, 5 2. To determine OHSS 2. To determine ovarian suppression Estradiol E2, Progestrone, US

9 Endocrine Static ti Tests ORTs

10 Estimated ROC curve and sensitivity specificity points for all studies reporting on the performance of basal FSH in the prediction of poor response. Broekmans F et al. Hum. Reprod. Update 2006;12: The Author 2niversity Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org006. Published by Oxford U

11 Estimated ROC curve and sensitivity specificity points for all studies reporting on the performance of basal FSH in the prediction of non-pregnancy. Broekmans F et al. Hum. Reprod. Update 2006;12: The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

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14 Broekmans FJ systematic review of tests predicting ovarian reserve andivfoutcome outcome. Human Reproduction Update Accuracy in the prediction of poor response and nonpregnancy is adequate only at very high threshold levels, but because of the very low numbers of abnormal tests has hardly any clinical value. Thetestwillnotbesuitableasadiagnostictestto exclude patients, but only as screening test for counselling purposes

15 de Carvalho et al Ovarian Reserve Assessment for Infertility Investigation ISRN Obstet Gynecol FSH continues to be an interesting ti testt on ovarian reserve investigation, since it is an easily accessible and low cost marker could be useful in pretreatment evaluation of specific groups of infertile women with anovulatory cycles, endometriosis or in patients over 35years of age. high FSH levels should not be used to exclude women from proceeding with ART

16 AMH a glycoprotein hormone of the TGF β superfamily expressed by granulosa cells as soon as the primordial follicles l are recruited The biological activity of AMH in women is not completely understood, but data along the last years suggest thatt it may act as a modulator of follicle l recruitment and a regulator of ovarian steroidogenesis

17 AMH AMH is considered to be a marker that can estimate the quantity and activity of retrievable follicles in early stages of maturation, thus being more reliable for the prediction of ovarianresponseresponse and reproductive e potential Compared to FSH, inhibin B, and E2, AMH has the advantage of reduced variability of its serum concentrations along the menstrual cycle

18 AMH

19 Estimated ROC curve and sensitivity specificity points for all studies reporting on the performance of AMH in the prediction of non-pregnancy. Broekmans F et al. Hum. Reprod. Update 2006;12: The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

20 Broekmans FJ systematic review of tests predictingovarian reserve and IVF outcome. Human Reproduction Update sensitivity of 75% and specificity of 85% would imply that test performs only moderately For non pregnancy prediction, sensitivity of 40% and specificity of 95% would imply that the test has hardly any value, unless very low threshold levels would be used, which will certainly lead to only very small percentages of abnormal tests. Additional studies

21 Anti Mullerian hormone as a predictive marker in ART. Hum Rep Update 2010 AMH better marker than age, FSH, estradiol and inhibin B. similar performance for AMH andafc In clinical practice, AMH measurement may be useful in the prediction of poor response and alsoof hyper response

22 Circulating basal anti Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization.fertility Sterility 2009 Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC

23 A prospective, comparative analysis of anti Müllerian hormone, inhibin B, and three dimensional ultrasound determinants of ovarian reserve in the prediction i of poor response to controlled ovarian stimulation. Fertility and Sterility 2010 The AFC and AMH are the most significant predictors of poor response but are not predictive of non conception, which is dependent on the woman's age.

24 AMH The lack of a consensual cutoff combining satisfactory sensitivity and specificity considerable drawback levels<1ng/ml poor response levels from 1 to 4ng/mL normal response levels>4ng/ml high response

25 Inhibin B glycoproteinhormones ofthe (TGF β) secreted by granulosa and theca cells. Inhibin B inhibits pituitary FSH secretion and paracrine action on developing follicles

26 Seifer DB Day 3 serum inhibin B is predictive of assisted itdreproductive technologies outcome. Fertility and Sterility 1997 demonstrated diminished basal serum concentrations of inhibin B, in spite of non elevated dday 3 FSH levels. l In poor responders inhibin B levels 45pg/mL greater estrogen responses and higher amounts of oocytes lower levelsl cancellations were three times more

27 Peñarrubia J Day 5 inhibin B serum concentrations and antral follicle count as predictors of ovarian response and live birth in assisted reproduction cycles stimulated with gonadotropin after pituitary suppression. Fertility and Sterility 2010 day 5 inhibin B was associated with live birth rates after IVF with 68.71% sensitivity and 88.51% specificity, which was statistically significant and stronger than any other variable investigated

28 Broekmans FJ systematic review of tests predicting ovarian reserve and IVF outcome. Human Reproduction Update high rate of false positives in routine determination of basal inhibin B and cautiously exclusion of patients from IVF programs with base on its levels. even using very low inhibin B levels, accuracy of the test in predicting poor response was only modest when compared with the other available markers, even though it can be used as a tool for counseling infertile couples

29 Estradiol rising FSH levels in older women advanced follicular development and early selection of a dominant follicle early elevations in serum E2 Measurement of both FSH and E2 on cycle day 3 help to diminish the incidence of false negative tests based on measurement of FSH alone when both markers are precociously elevated, poor ovarian response is likely to occur

30 Estradiol E2 may be used to guide the clinician as to whether the stimulation with gonadotropins can be started, Considering the low predictive accuracy and the lack of high sensitivity and specificity cutoff levels,itsroleasa determinant for couples inclusion in ART programs should be evaded

31 Endocrine Dynamic Tests

32 CCCT 100mg clomiphene citrate was administered to women aged 35yearsfromdays5 9of the menstrual cycle. FSH, LH, and E2 levels were primarily determined on cycle days 2 3, and response was determined on cycle days Diminished ovarian reserve was determined by day 3 FSH >14.9mIU/mL or day 10 FSH> day 3 FSH

33 CCCT values of likelihood ratios of positive and negative CCCT did not provide sufficient evidence for prediction of non pregnancy or ART cycle cancellation in 20 eligible studies. the absence of standardized abnormal test definitions prevented strong conclusions and authors could not support its use as a prognostic tool

34 Gonadotropin Analogue Stimulation Test (GAST) measurement of FSH, LH, inhibin B B, and E2 levels flare up within 24 hours of administration of gonadotropin analogue wide variety of (GnRH) analogue doses and administration timing, hormones tested in initial and final samples, and their thresholds were not standardized.just like the CCCT, GAST should not be an eligible ovarian reserve test in clinical routine, with the present bodyof evidence.

35 Exogenous FSH Ovarian Reserve Test (EFORT) is based on the increase of E2 and inhibin B 24 hours after the administration of 300IU of (rfsh) on cycle day 3 as with CCCT and GAST, methodology for EFORT is far from uniform parameters should be avoided in determining ovarian reserve for infertile patients.

36 Thank you for your attention