Is There a Need to Alter the Timing of Anti-Müllerian Hormone Measurement During the Menstrual Cycle?

Abstract

Introduction There are numerous conflicting studies which have addressed the question whether the measurement of anti-Müllerian hormone (AMH) concentrations should be done at a certain time during the menstrual cycle. We aimed to investigate AMH fluctuations during the follicular and luteal phases of the menstrual cycle and to determine whether AMH variations, if present, might influence the clinical utility of ovarian reserve markers.

Materials and Methods A total of 257 infertile women eligible for inclusion were categorized into three groups based on their total antral follicle count: 1. hypo-response group (< 7 follicles, n = 66), 2. normo-response group (7 – 19 follicles, n = 98), and 3. hyper-response group (> 19 follicles, n = 93).

Results Mean follicular AMH levels were elevated compared to levels in the luteal phase in all response groups (p < 0.001). There were significant and strong positive correlations between follicular and luteal AMH levels in all response groups (Spearmanʼs r = 0.822, r = 0.836, and r = 0.899, respectively; p < 0.001 for all groups). Fisherʼs Z-test comparisons of these correlations in all response groups demonstrated that there was no statistically significant difference (Z = 0.277, Z = − 1.001, and Z = − 1.425, respectively; p < 0.001).

Conclusion We found that serum AMH levels in the follicular phase were higher than those in the luteal phase in all three response groups. In current practice, fluctuations in serum AMH concentrations are not large enough to alter the timing of AMH measurements during the menstrual cycle. The issue is important for the assessment of ovarian reserve in infertile women with AMH levels near to the cut-off value.

Zusammenfassung

Einleitung Es gibt zahlreiche widersprüchliche Studien, die sich der Frage widmen, ob die Messung des Anti-Müller-Hormon-(AMH-)Spiegels an einem bestimmten Zeitpunkt im Menstruationszyklus durchgeführt werden sollte. Ziel dieser Studie war es, Fluktuationen des Anti-Müller-Hormon-Spiegels während der Follikelphase und der Lutealphase des Menstruationszykluses zu messen, auch um zu bestimmen, ob Fluktuationen des AMH-Spiegels, falls es sie gibt, den klinischen Nutzen als Marker der ovariellen Reserve beeinflussen könnten.

Material und Methoden Insgesamt 257 unfruchtbare Frauen, welche die Einschlusskriterien erfüllten, wurden in die Studien eingeschlossen und in 3 Reaktionsgruppen eingeteilt. Die Einteilung beruhte auf der jeweiligen Gesamtzahl antraler Follikel, wie folgt: 1. Hypo-Gruppe (< 7 Follikel, n = 66), 2. Normalgruppe (7 – 19 Follikel, n = 98), und 3. Hyper-Gruppe (> 19 Follikel, n = 93).

Ergebnisse Verglichen mit der Lutealphase war der durchschnittliche AMH-Spiegel während der Follikelphase in allen 3 Gruppen erhöht (p < 0,001). Es gab eine signifikante und starke positive Korrelation zwischen dem AMH-Spiegel in der Follikelphase und dem AMH-Spiegel in der Lutealphase bei allen Gruppen (Korrelationskoeffizient nach Spearman r = 0,822, r = 0,836 bzw. r = 0,899; p < 0,001 für alle Gruppen). Der Vergleich dieser Korrelationen mithilfe des Fisher-z-Tests zeigte, dass es in keiner der Gruppen einen statistisch signifikanten Unterschied gab (z = 0,277, z = − 1,001 bzw. z = − 1,425; p < 0,001).

Schlussfolgerung Es stellte sich heraus, dass in allen 3 Gruppen der AMH-Spiegel in der Follikelphase höher war als der AMH-Spiegel in der Lutealphase. Die Flukutationen des AMH-Spiegels sind jedoch nicht hoch genug, um den Zeitpunkt der AMH-Messung während des Menstruationszyklus in der aktuellen klinischen Praxis zu ändern. Dieses Thema ist aber für die Evaluierung der ovariellen Reserve von unfruchtbaren Frauen mit AMH-Spiegeln, die nahe beim Cut-off-Wert sind, von Bedeutung.

Key words

Anti-Müllerian hormone - AMH - fluctuation - ovarian reserve - variation - measurement

Schlüsselwörter

Anti-Müller-Hormon - AMH - Fluktuation - ovarielle Reserve - Variation - Messung

• References

• 1 Dittrich R, Kliesch S, Schüring A. et al. Fertility Preservation for Patients with Malignant Disease. Guideline of the DGGG, DGU and DGRM (S2 k-Level, AWMF Registry No. 015/082, November 2017) – Recommendations and Statements for Girls and Women. Geburtsh Frauenheilk 2018; 78: 567-584
• 2 Guenther V, Alkatout I, Junkers W. et al. Fertility Preservation in Female Patients with Breast Cancer – a Current Overview. Geburtsh Frauenheilk 2017; 77: 1088-1094
• 3 Broer SL, Mol BW, Hendriks D. et al. The role of anti-Mullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count. Fertil Steril 2009; 91: 705-714
• 4 Broekmans FJ, de Ziegler D, Howles CM. et al. The antral follicle count: practical recommendations for better standardization. Fertil Steril 2010; 94: 1044-1051
• 5 Iliodromiti S, Anderson RA, Nelson SM. Technical and performance characteristics of anti-Müllerian hormone and antral follicle count as biomarkers of ovarian response. Hum Reprod Update 2015; 21: 698-710
• 6 Broer SL, Dólleman M, Opmeer BC. et al. AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis. Hum Reprod Update 2011; 17: 46-54
• 7 Broer SL, Dólleman M, van Disseldorp J. et al. IPD-EXPORT Study Group. Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis. Fertil Steril 2013; 100: 420-429.e7
• 8 La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update 2014; 20: 124-140
• 9 Fleming R, Seifer DB, Frattarelli JL. et al. Assessing ovarian response: antral follicle count versus anti-Mullerian hormone. Reprod Biomed Online 2015; 31: 486-496
• 10 Amanvermez R, Tosun M. An Update on ovarian aging and ovarian reserve tests. Int J Fertil Steril 2016; 9: 411-415
• 11 Ng EH, Tang OS, Ho PC. The significance of the number of antral follicles prior to stimulation in predicting ovarian responses in an IVF programme. Hum Reprod 2000; 15: 1937-1942
• 12 Ferraretti AP, La Marca A, Fauser BC. et al. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011; 26: 1616-1624
• 13 Coelho Neto MA, Martins WP, Lima ML. et al. Ovarian response is a better predictor of clinical pregnancy rate following embryo transfer than is thin endometrium or presence of an endometrioma. Ultrasound Obstet Gynecol 2015; 46: 501-505
• 14 Kollmann M, Martins WP, Raine-Fenning N. Examining the ovaries by ultrasound for diagnosing hyperandrogenic anovulation: updating the threshold for newer machines. Fertil Steril 2014; 101: e25
• 15 Jeppesen JV, Anderson RA, Kelsey TW. et al. Which follicles make the most anti-Mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol Hum Reprod 2013; 19: 519-527
• 16 La Marca A, Grisendi V, Griesinger G. How much does AMH really vary in normal women?. Int J Endocrinol 2013; 2013: 959487
• 17 La Marca A, Sighinolfi G, Radi D. et al. Anti-Müllerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update 2010; 16: 13-30
• 18 Hehenkamp WJ, Looman CW, Themmen AP. et al. Anti-Müllerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab 2006; 91: 4057-4063
• 19 Tsepelidis S, Devreker F, Demeestere I. et al. Stable serum levels of anti-Müllerian hormone during the menstrual cycle: a prospective study in normoovulatory women. Hum Reprod 2007; 22: 1837-1840
• 20 van Disseldorp J, Lambalk CB, Kwee J. et al. Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts. Hum Reprod 2010; 25: 221-227
• 21 La Marca A, Giulini S, Tirelli A. et al. Antimullerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology. Hum Reprod 2007; 22: 766-771
• 22 Hadlow N, Longhurst K, McClements A. et al. Variation in antimüllerian hormone concentration during the menstrual cycle may change the clinical classification of the ovarian response. Fertil Steril 2013; 99: 1791-1797
• 23 Sowers M, McConnell D, Gast K. et al. Anti-Müllerian hormone and inhibin B variability during normal menstrual cycles. Fertil Steril 2010; 94: 1482-1486
• 24 La Marca A, Spada E, Grisendi V. et al. Normal serum anti-Müllerian hormone levels in the general female population and the relationship with reproductive history. Eur J Obstet Gynecol Reprod Biol 2012; 163: 180-184
• 25 Wunder DM, Bersinger NA, Yared M. et al. Statistically significant changes of antimüllerian hormone and inhibin levels during the physiologic menstrual cycle in reproductive age women. Fertil Steril 2008; 89: 927-933
• 26 Weenen C, Laven JS, Von Bergh AR. et al. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 2004; 10: 77-83
• 27 Cook CL, Siow Y, Taylor S. et al. Serum müllerian-inhibiting substance levels during normal menstrual cycles. Fertil Steril 2000; 73: 859-861
• 28 Randolph JF, Harlow SD, Helmuth ME. et al. Updated assays for inhibin B and AMH provide evidence for regular episodic secretion of inhibin B but not AMH in the follicular phase of the normal menstrual cycle. Hum Reprod 2014; 29: 592-600
• 29 Kumar A, Kalra B, Patel A. et al. Development of a second generation anti-Mullerian hormone (AMH) ELISA. J Immunol Methods 2010; 362: 51-59
• 30 Rustamov O, Smith A, Roberts SA. et al. Anti-Mullerian hormone: poor assay reproducibility in a large cohort of subjects suggests sample instability. Hum Reprod 2012; 27: 3085-3091
• 31 Robertson DM, Kumar A, Kalra B. et al. Detection of serum antimüllerian hormone in women approaching menopause using sensitive antinüllerian hormone enzyme-linked immunosorbent assays. Menopause 2014; 12: 1277-1286
• 32 Hagen CP, Sørensen K, Anderson RA. et al. Serum levels of antimüllerian hormone in early maturing girls before, during, and after suppression with GnRH agonist. Fertil Steril 2012; 98: 1326-1330
• 33 Tran ND, Cedars MI, Rosen MP. The role of anti-mullerian hormone (AMH) in assessing ovarian reserve. J Clin Endocrinol Metab 2011; 96: 3609-3614
• 34 Depmann M, van Disseldorp J, Broer SL. et al. Fluctuations in anti-Müllerian hormone levels throughout the menstrual cycle parallel fluctuations in the antral follicle count: a cohort study. Acta Obstet Gynecol Scand 2016; 95: 820-828