1 Gebelik öngörüsünde AMH Prof.Dr.Sezai ŞAHMAYİ.Ü.Cerrahpaşa Tıp Fakültesi Kadın hastalıkları ve Doğum ABD Üreme Endokrinolojisi ve İnfertilite Bilim Dalı
2 Primer ve küçük antral foliküllerden salgılanır. Granülosa hücreleri salgılar.FSH ile etkileşimi yok veya çok azdır.Overin foliküler yapısının tek markörüdür.Anti-Müllerian hormone: an ovarian reserve marker in primary ovarian insufficiencyJenny A. Visser, Izaäk Schipper, Joop S. E. Laven and Axel P. N. ThemmenVisser, J. A. et al. Nat. Rev. Endocrinol. advance online publication 10 January 2012; doi: /nrendoNat Rev Endocrinol Jan 10;8(6):Folliculogenesis—the process of follicle maturation from the primordial follicle to the ovulatory follicle. Follicles are continuously recruited from the dormant primordial follicle pool, the so-called initial recruitment, into the growing follicle pool and start to express AMH and inhibin B. After puberty, at every new cycle, a limited number of follicles is selected from this pool of small, growing follicles under the influence of FSH, the so-called cyclic recruitment. From this smaller cohort of growing follicles, ultimately one follicle is selected for dominance and ovulates under the influence of LH.52 The majority of growing follicles is removed through atresia, a hormonally controlled apoptotic process.143 To rescue follicles from atresia, FSH levels need to rise to a critical threshold concentration to allow FSH-dependent selection of a limited number of follicles. As a consequence of the continuous decline in primordial follicles throughout reproductive life, the number of growing follicles also decreases. Subsequently, serum inhibin B and estradiol levels decline, releasing the negative feedback on the hypothalamus and pituitary, which results in the characteristic menopausal monotropic rise in FSH and to a lesser extent in LH levels.64 Abbreviations: AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.Visser, J. A. et al. Nat. Rev. Endocrinol 10:331, 2012
3 Anti Müllerien Hormon (AMH) The positive correlation between serum AMH levelsand number of antral follicles is also observed in womenwith PCOS. The elevated levels of AMH in these womenstrongly suggest that serum AMH levels may also be usedin the diagnosis of PCOS. The difference in serum levelsof AMH between subgroups of PCOS women suggeststhat AMH might also be used to establish a subclassificationof this heterogeneous syndrome. However, morestudies, preferably prospective, with thoroughly analyzedpatient cohorts are necessary to define cutoff values. Inaddition, studies are necessary to determine whetherserum AMH levels are also indicative of improved ovarianfunction upon treatment of PCOS women.1.Foliküler recruitmenti inhibe eder.2.Preantral ve antral folikül gelişimini inhibe eder.Visser JA et al.:Reproduction. 131; 1, 2006La Marca A. et al.:Human Reproduction Update, 16:113, 2010.
11 AMH – Oosit kalitesin.209In conclusion, our results demonstrated that serum AMH levels were highly correlated with the number of antralfollicles, and the oocyte quality and embryo development. It appears that AMH serum levels are associated withovarian response in ART cycles and can be served as a novel marker for ovarian reserve. Furthermore, withrespect to significant difference in clinical pregnancy outcome, serum levels of AMH may be used as a marker forpredicting the clinical pregnancy rate. However, further studies are needed to determine whether AMH can accuratelypredict the ART outcomes.Indeed several authors have found a significant positive correlation between AMH levels, oocyte quality (Hazout et al., 2004; Ebner et al., 2006; Silberstein et al., 2006; Cupisti et al., 2007; Fanchin et al., 2007, Lekamge et al., 2007) and embryo morphology (Silberstein et al., 2006). However, this relationship has not been confirmed by others (Smeenk et al., 2007; Lie Fong et al., 2008). La Marca 2010Different AMH levels may predict the qualityof oocytes, presence of postmaturity and nucleoli Z score,early cleavage and ICSI outcomes.Irez T, Ocal P, Guralp O, Cetin M, Aydogan B, Sahmay S.Arch Gynecol Obstet 284:1295, 2011
12 PKOS’nda serum AMH düzeyi PKOS’nda artmış serumAMH düzeyi folikül sayısıartışının yanında folikülerüretimin de artışındandır.PCOS (n.419)Control7,44Kontrol(n.482)2,24Serum AMH levels have been found to be significantly increased in PCOS compared with healthy women. Figure 2 Box-and-whisker plots showing the values of serum AMH (1.8 ng/ml _ 10.8 ng/l) (n=164) and in controls (n =74). Horizontal small barsrepresent the 10–90th percentile range, and the boxes indicate the25th-75th percentile range. The horizontal line in each box correspondsto the median. Average AMH .... in PCOS, and in control.Sahmay S, Atakul N et al.:in press
13 PCOS’lu hastalarda AMH düzeyi ile IVF sonuçları ilişkisi AbstractObjective: The purpose of this study is to investigate the role of serum anti-Mu¨ llerian hormone(AMH), follicle-stimulating hormone (FSH) and antral follicle count (AFC) for the predictionof clinical pregnancy rates (CPR) in women with polycystic ovary syndrome (PCOS) undergoingIVF treatment.Design: Prospective cohort study.Setting: University hospital.Patients: One hundred and fifty consecutive women with PCOS.Interventions: All women underwent controlled ovarian stimulation with long agonist protocolfollowed by IVF procedure. Outcomes of pregnant and non-pregnant groups were compared.Main outcome measure: CPR; AMH, FSH and AFC means and percentiles.Results: Fifty-one (34%) clinical pregnancies were observed in 150 women. Mean AMH wasand ng/mL in pregnant and non-pregnant women, respectively (p¼0.594).The CPR were 27.8%, 35.0% and 37.8% in 525%, 25%–75% and 475% AMH percentiles,respectively (p¼0.656). There were also no significant difference in mean FSH and AFCbetween pregnant and non-pregnant women (p¼0.484 and p¼0.165, respectively).Conclusion: AMH, FSH and AFC are not predictive for CPR in women with PCOS undergoingIVF treatment. Mean AMH values were not significantly different between pregnant andnon-pregnant women. Although CRP increased in parallel with the raise in AMH percentiles,this remained insignificant.Sahmay S, Guralp O, Aydogan B, Cepni I, Oral E, Irez T:Gynecol Endocrinol Online, 2013
14 PCOS’lu hastalarda AMH düzeyi ile IVF sonuçları ilişkisi Sahmay S, Guralp O, Aydogan B, Cepni I, Oral E, Irez T:Gynecol Endocrinol Online, 2013
15 AMH – AFS – Oosit sayısı PCOS ve nPCOS`da gebelik oranları PCOS grupta gebe olmayanlardagelişen oosit sayısıGebe olanlardan daha fazlaAMH (ng/ml) AFS ve Oosit sayısıŞahmay S, Aydogan B, Metehan I ve ark. Baskıda
16 Persantillere göre PCOS ve nonPCOS’da gebelik oranları Pregnancy%AMHng/mlPregnancy ratesÜstteki çizgiler persantillere göre gebelik oranlarını, alttaki sütunlar ise persantil AMH değerlerini gösteriyor.Her 2 grupta da gebelik oranları AMH düzeyi ile paralel artış gösteriyor, fakat anlamlı değil.Bu bizim 2 çalışmanın toplu sonucu.Şahmay S, Aydogan B, Metehan I ve ark. Baskıda
17 PKOS’da Reprodüktif yaşam süresi PKOS:n.85nPKOS:n.892010-Is polycystic ovary syndrome an exception for reproductive aging?Fahimeh Ramezani Tehrani1,*, Masoud Solaymani-Dodaran2,3,Mehdi Hedayati 4, and Fereidoun Azizi5Human Reproduction, Vol.25, No.7 pp. 1775–1781, 2010conclusions: The reproductive lifespan of PCOS women extends on average 2 years beyond that of normo-ovulatory women.Figure 2 The left panel shows the scatter plot depicting the change in the AMH levels (value visit 2–value visit 1) in relation to time intervalsbetween visit 1 and visit 2 (multiplication sign and dotted line), and the scatter plot depicting the change in AMH levels (value visit 3–value visit2) in relation to time intervals between visit 2 and visit 3 (black diamonds and solid line) in PCOS cases. The right panel shows the scatter plot depictingthe change in AMH levels (value visit 2–value visit 1) in relation to time intervals between visit 1 and visit 2 (multiplication sign and dotted line), andthe scatter plot depicting the change in AMH levels (value visit 3–value visit 2) in relation to time intervals between visit 2 and visit 3 (black diamondsand solid line) in normo-ovulatory controls.background: Anti-Mullerian hormone (AMH) is increased in women with polycystic ovary syndrome (PCOS), suggesting a delay inovarian aging. We examined AMH levels in PCOS and normo-ovulatory women in a population-based cohort over a period of 10 yearsand used this information to estimate their menopausal age.methods: Of a subset of 1002 non-menopausal women randomly selected from the Tehran Lipid and Glucose Study, 85 cases of PCOSwere diagnosed.We frequency-matched our control subjects with PCOS cases based on age and BMI. AMH levels were assessed at the timeof recruitment (T1) and twice after that (T2 and T3). AMH levels were then plotted against age of the individual at the time of the measurementand the most appropriate model was selected. Menopause was calculated based on AMH levels below 0.2 ng/ml.results: AMH levels were significantly higher in PCOS cases compared with controls at the beginning of the study ( versusng/ml, P ¼ 0.03), but the difference diminished considerably in subsequent assessments. The rate of AMH decline in PCOScases decreased in the second compared with the first interval; however, no apparent change in the rate of decline was observed in controls.Estimated ages at menopause were 51 [95% confidence interval (CI), 34–81] and 49 (95% CI, 38–63) years in PCOS cases and controls,respectively.Tehrani FR et al.:Human Reprod 25: 1775–1781, 2010
18 AMH >1ng/ml - Gebelik oranları (n.226) pYaş31,32±4,032,27±4,4NSİnfertilite Süresi (yıl)6,46±4,16,67±4,0VKİ25,02±4,725,13±4,1AMH3,23±2,92,70±1,9NS(0,132)E241,04±22,046,22±23,1LH4,17±2,83,87±2,0FSH5,67±2,06,16±2,2TSH1,70±0,71,91±1,1PRL17,7±11,916,27±6,0Stimulasyon Süresi9,49±1,89,14±1,9Total Ünite2333±8872498±1085Antral follikül sayısı8,71±4,37,65±3,6Total oosit8,50±4,27,6±4,3HCG günü Follikül sayısı12,33±4,910,78±5,2Sahmay S, Aydogan B , Gezer A et al (baskıda)
19 AMH <1ng/ml - Gebelik oranları (n.100) pYaş31,31±4,034,09±4,350,013İnfertilite Süresi (yıl)6,05±3,46,16±4,7NSVKİ25,38±3,025,9±4,7AMH0,77±0,190,63±0,31NS(0.57)E287,82±61,770,78±65,3LH4,2±2,54,01±2,8FSH6,52±2,67,2±3,0TSH2,09±1,41,7±0,9PRL15,88±4,916,99±7,2Stimulasyon Süresi9,15±1,39,23±2,0Total Ünite2713±8413179±1059Antral follikül sayısı6,66±4,35,18±2,7Total oosit5,78±4,64,01±3,10,046HCG günü Follikül sayısı6,11±3,75,64±3,7Sahmay S, Aydogan B , Gezer A et al (baskıda)
20 AMH düzeyi - Gebelik oranları AMH > 1ng/ml% 24,7AMH < 1ng/ml% 19Soldaki tabloda AMH<1 olanlarda demografik data var. Sadece yaş ve Total oosit sayısında anlamlı fark var. Bu da bize yaş faktörünün önemini vurgulamaktadır.Sağdaki grafikte ise AMH<1 olanlarda gebe olan ve olmayanlarda ortalam AMH değerleri görülmekte. Diğer bulgularımızda olduğu gibi Low-AMH hastalarda da AMH değerleri arasında fark yok.p=0,159Gebelik+Gebelik-ToplamAMH>156 %24.8170 %75.2%100AMH≤119 %1981 % 81%10075 % 23251 % 77326 %100Sahmay S, Aydogan B , Gezer A et al (baskıda)
21 Canlı doğumu öngören parametreler Anti-Mu¨llerian hormone-based prediction model for a live birth in assisted reproductionA La Marca a,*, SM Nelson c, G Sighinolfi a, M Manno d, E Baraldi a, L Roli a, S Xella a, T Marsella a, D Tagliasacchi a, R D’Amico b, A Volpe aReproductive BioMedicine Online (2011) 22, 341– 349Abstract Prediction of assisted reproduction treatment outcome has been the focus of clinical research for many years, with a varietyof prognostic models describing the probability of an ongoing pregnancy or a live birth. This study assessed whether serumanti-Mu¨llerian hormone (AMH) concentrations may be incorporated into a model to enhance the prediction of a live birth in womenundergoing their first IVF cycle, by analysing a database containing clinical and laboratory information on IVF cycles carried outbetween 2005 and 2008 at the Mother–Infant Department of University Hospital, Modena. Logistic regression was used to examinethe association of live birth with baseline patient characteristics. Only AMH and age were demonstrated in regression analysis topredict live birth, so a model solely based on these two criteria was generated. The model permitted the identification of live birthwith a sensitivity of 79.2% and a specificity of only 44.2%. In the prediction of a live birth following IVF, a distinction, however moderate,can be made between couples with a good and a poor prognosis. The success of IVF was found to mainly depend on maternalage and serum AMH concentrations, one of the most relevant and valuable markers of ovarian reserve.La Marca A et al.:Rep Biomed Online 22:341, 2011
23 Serum AMH ve IVF gebelik oranları Serum Anti-Mullerian Hormone Levels Affect the Rate of Ongoing Pregnancy After In Vitro FertilizationHiroyuki Honnma, MD, PhD1, Tsuyoshi Baba, MD, PhD2,Masahiro Sasaki, MD, PhD1, Yoshiki Hashiba, MD, PhD1,Hisanori Oguri, MD, PhD1, Takanori Fukunaga, PhD1,Toshiaki Endo, MD, PhD2, and Yoshimasa Asada, MD, PhD1Reprod Sci Jan;20(1):51-9.Figure 1. Adjusted and nonadjusted ongoing pregnancy rates in 4serum AMH groups. Patients were divided into the 4 indicated groupsbased on cutoff values for the rates of ongoing pregnancy. Theadjusted ongoing pregnancy rate was referenced to the <12.4pmol/L group and was adjusted for serum AMH group, basal FSH,age, peak serum E2, total dose of gonadotropin, total number ofoocytes, and selection of the protocol and F-TET/FET cycles. Linearapproximations are also shown for the adjusted and nonadjustedpregnancy rates. FET indicates fresh embryo transfer; F-TET,frozen-thawed embryo transfer; FSH, follicle-stimulating hormone;AMH, anti-Mullerian hormoneAbstractWe used logistic regression analysis to investigate the relationship between serum anti-Mullerian hormone (AMH) levels and therate of ongoing pregnancy. Retrospective data were collected from 1043 women who had undergone their first cycle of in vitrofertilization (IVF), including 540 cycles of fresh embryo transfer and 503 cycles of frozen-thawed embryo transfer. The patients weredivided into 4 groups based on the cutoff values from a receiver–operating characteristic curve: 0.0 to 12.4, 12.5 to 25.5, 25.6 to 44.1,and >44.2 pmol/L. After adjustment for multiple confounders, the serum AMH group was found to be significantly related to the rateof ongoing pregnancy in total cycles ( vs pmol/L; P ¼ .0088, odds ratio, 1.909: vs pmol/L; P ¼ .0281, oddsratio, 2.109: vs >44.2 pmol/L; P ¼ .0008, odds ratio, 2.840). In conclusion, there appears to be a significant relationship betweenserum AMH levels and the ongoing pregnancy rate in first IVF treatment cycles after adjustment for multiple confounders.Honnma H et al.: Reprod Sci Jan;20(1):51-9.
24 Yaş ve AMH değerine göre gebelik olasılığı Anti-Mu¨llerian hormone-based prediction model for a live birth in assisted reproductionA La Marca a,*, SM Nelson c, G Sighinolfi a, M Manno d, E Baraldi a, L Roli a, S Xella a, T Marsella a, D Tagliasacchi a, R D’Amico b, A Volpe aReproductive BioMedicine Online (2011) 22, 341– 349Abstract Prediction of assisted reproduction treatment outcome has been the focus of clinical research for many years, with a varietyof prognostic models describing the probability of an ongoing pregnancy or a live birth. This study assessed whether serumanti-Mu¨llerian hormone (AMH) concentrations may be incorporated into a model to enhance the prediction of a live birth in womenundergoing their first IVF cycle, by analysing a database containing clinical and laboratory information on IVF cycles carried outbetween 2005 and 2008 at the Mother–Infant Department of University Hospital, Modena. Logistic regression was used to examinethe association of live birth with baseline patient characteristics. Only AMH and age were demonstrated in regression analysis topredict live birth, so a model solely based on these two criteria was generated. The model permitted the identification of live birthwith a sensitivity of 79.2% and a specificity of only 44.2%. In the prediction of a live birth following IVF, a distinction, however moderate,can be made between couples with a good and a poor prognosis. The success of IVF was found to mainly depend on maternalage and serum AMH concentrations, one of the most relevant and valuable markers of ovarian reserve.La Marca A et al.:Rep Biomed Online 22:341, 2011
25 40 yaş üstünde AMH ve gebelik oranları The predictability of serum anti-Müllerian level in IVF/ICSI outcomes for patients of advanced reproductive ageRobert KK Lee1,2†, Frank SY Wu1†, Ming-Huei Lin1, Shyr-Yeu Lin1 and Yuh-Ming Hwu1,3*Reproductive Biology and Endocrinology 2011, 9:115AbstractBackground: The role of serum anti-Müllerian hormone (AMH) as predictor of in-vitro fertilization outcomes hasbeen much debated. The aim of the present study is to investigate the practicability of combining serum AMHlevel with biological age as a simple screening method for counseling IVF candidates of advanced reproductiveage with potential poor outcomes prior to treatment initiation.Methods: A total of 1,538 reference patients and 116 infertile patients aged greater than or equal to 40 yearsenrolled in IVF/ICSI cycles were recruited in this retrospective analysis. A reference chart of the age-relateddistribution of serum AMH level for Asian population was first created. IVF/ICSI patients aged greater than or equalto 40 years were then divided into three groups according to the low, middle and high tertiles the serum AMHtertiles derived from the reference population of matching age. The cycle outcomes were analyzed and comparedamong each individual group.Results: For reference subjects aged greater than or equal to 40 years, the serum AMH of the low, middle and hightertiles were equal or lesser than 0.48, and equal or greater than 1.23 ng/mL respectively. IVF/ICSI patientsaged greater than or equal to 40 years with AMH levels in the low tertile had the highest cycle cancellation rate(47.6%) with zero clinical pregnancy. The nadir AMH level that has achieved live birth was 0.56 ng/mL, which wasequivalent to the 36.4th percentile of AMH level from the age-matched reference group. The optimum cut-off levelsof AMH for the prediction of nonpregnancy and cycle cancellation were 1.05 and 0.68 ng/mL, respectively.Conclusions: Two criteria: (1) age greater than or equal to 40 years and (2) serum AMH level in the lowest tertile(equal or lesser than 33.3rd percentile) of the matching age group, may be used as markers of futility forcounseling IVF/ICSI candidates.Lee RKK, et al.: Reproductive Biology and Endocrinology 2011, 9:115
26 Kötü yanıt – AMHSahmay S, Cetin M, Ocal P, Kaleli S, Senol H, Birol F, Irez T.:Reprod Med Biol.10:9, 2011
27 OHSS öngörüsü-AMH sınır değeri 3,3 ng/mln.41/695Sensitivite %90Spesifite %71Ocal P, Sahmay S, Cetin M, Irez T et all. J Assist Reprod Genet. 28:1197, 2011
30 AMH düzeyi ile Gebelik Öngörüsü mümkün mü ? Sahmay S , Anckaert E ,Yılmaz N 2012, Lamazou 2012(IUI cycle), Aleyasin A. 2011,Zhang NF 2011 (male serum),Nakhuda GS 2011 (donor cycle),Kunt C 2011,Lamazou F 2011 (modified natural IVF cycle),Riggs R 2011(donor cycle), Broer SL 2010, Freiesleben NC 2010 (IUI), Tremellen K 2010 (IUI), Li HW 2010 (IUI),Guerif F 2009,Gnoth C 2008,Lee TH 2008,McIIveen M 2007,Smeenk JM 2007,Broekmans FJ 2006, Van Rooij IA 2006,Penarrubia J 2005La Marca 2011,Gleicher N 2010,Kini S 2010, Blazar AS 2011, Majumder K 2010,Li HW 2010(IUI),Kaya O 2010,Pabuccu R 2010(FF),Wu CH 2009, Elgindy EA 2008, Nelson SM 2007,Eldar-Geva T. et al. 2005,Hazout A 2004HAYIREVET
31 Over cevabında yararlı belirteçler 1716610La Marca A et al.: Human Reproduction Update, 16:113, 2010
32 Over cevabı-AFS ve AMH Nelson SM.:Fertil Steril, 2013 Biomarkers of ovarian response:current and future applicationsScott M. Nelson, Ph.D.Fertility and Sterility® Vol. -, No. -,Antim€ullerian hormone (AMH) stratified individualization oftreatment as used by the author. Ovarian response categoriesdictate risk, and treatment strategies are designed to minimize riskwhile maximizing oocyte yield within each response category.Negligible response means that the conventional criteria fortriggering (three follicles R17 mm) is unlikely to be achieved. Forall antagonist cycles with an excessive response, an agonist triggeris adopted. The AMH measurements are for the AMH Gen II assay,d the values are in pmol/L. The suggested antral follicle count(AFC) thresholds are based on the correlation of AMH and AFC andassociated response category literature (30, 65).With our increasing appreciation that simply maximizing oocyte yield for all patients is no longer an appropriate stimulation strategyand that age alone cannot accurately predict ovarian response, there has been an explosion in the literature regarding the utility ofbiomarkers to predict and individualize treatment strategies. Antral follicle count (AFC) and antim€ullerian hormone (AMH) have begunto dominate the clinical scene, and although frequently pitted against each other as alternatives, both may contribute and indeed besynergistic. Their underlying technologies are continuing to develop rapidly and overcome the standardization issues that have limitedtheir development to date. In the context of in vitro fertilization (IVF), their linear relationship with oocyte yield and thereby extremes ofovarian response has led to improved pretreatment patient counseling, individualization of stimulation strategies, increased cost effectiveness,and enhanced safety. This review highlights that although biomarkers of ovarian response started in the IVF clinic, their futureextends well beyond the boundaries of assisted reproduction. The automation of AMH and its introduction into the routine repertoire ofclinical biochemistry has tremendous potential. A future where primary care physicians, endocrinologists, and oncologists can rapidlyassess ovarian dysfunction and the ovarian reserve more accurately than with the current standard of follicle-stimulating hormone(FSH) is an exciting possibility. For women, the ability to know the duration of their own reproductivelife span will be empowering and allow them to redefine the meaning of family planning.(Fertil Steril 2013;-:-– by American Society for Reproductive Medicine.)Nelson SM.:Fertil Steril, 2013
33 Özet AMH gebelik öngörüsünde yararlı değildir. AMH düzeyi ile gebelik oranları arasında pozitif korelasyon vardır.AMH için tek ölçüm yeterlidir.Zayıf yanıt ve OHSS öngörülmesinde yararlıdır.Hastanın tedavi endikasyonda kesin ve tek bir belirleyici yoktur.Özellikle ek bir bulgu olmaksızın sadece çok düşük AMH değerlerinde de gebelik mümkündür.Klinik olarak düşük AMH değerlerinden ziyade yüksek değerler daha önem taşımaktadır.
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