Clinical Review

How ovarian reserve testing can (and cannot) address your patients’ fertility concerns

OBG Manag. 2018 November;30(11):46-50,55-56

References

Forman MR, Mangini LD, Thelus-Jean R, Hayward MD. Life-course origins of the ages at menarche and menopause. Adolesc Health Med Ther. 2013;4:1-21.
Reichman DE, Goldschlag D, Rosenwaks Z. Value of antimüllerian hormone as a prognostic indicator of in vitro fertilization outcome. Fertil Steril. 2014;101(4):1012-1018.e1.
Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, et al. Association between biomarkers of ovarian reserve and infertility among older women of reproductive age. JAMA. 2017;318(14):1367-1376.
Farr SL, Schieve LA, Jamieson DJ. Pregnancy loss among pregnancies conceived through assisted reproductive technology, United States, 1999-2002. Am J Epidemiol. 2007;165(12):1380-1388.
Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al. The nature of aneuploidy with increasing age of the female partner: a review of 1,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril. 2014;101(3):656-663.e1.
Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril. 2015;103(3):e9-e17.
Kwee J, Schats R, McDonnell J, Lambalk CB, Schoemaker J. Intercycle variability of ovarian reserve tests: results of a prospective randomized study. Hum Reprod. 2004;19(3):590-595.
Thum MY, Abdalla HI, Taylor D. Relationship between women’s age and basal follicle-stimulating hormone levels with aneuploidy risk in in vitro fertilization treatment. Fertil Steril. 2008;90(2):315-321.
Roberts JE, Spandorfer S, Fasouliotis SJ, Kashyap S, Rosenwaks Z. Taking a basal follicle-stimulating hormone history is essential before initiating in vitro fertilization. Fertil Steril. 2005;83(1):37-41.
Bishop LA, Richter KS, Patounakis G, Andriani L, Moon K, Devine K. Diminished ovarian reserve as measured by means of baseline follicle-stimulating hormone and antral follicle count is not associated with pregnancy loss in younger in vitro fertilization patients. Fertil Steril. 2017;108(6):980-987.
Tal R, Seifer DB. Ovarian reserve testing: a user’s guide. Am J Obstet Gynecol. 2017;217(2):129-140.
Ferraretti AP, La Marca L, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616-1624.
Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103(6):e44-e50.
Hvidman HW, Bentzen JG, Thuesen LL, Lauritsen MP, Forman JL, Loft A, et al. Infertile women below the age of 40 have similar anti-Müllerian hormone levels and antral follicle count compared with women of the same age with no history of infertility. Hum Reprod. 2016;31(5):1034-1045.
Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006;12(6):685-718.
Iliodromiti S, Anderson RA, Nelson SM. Technical and performance characteristics of anti-Mullerian hormone and antral follicle count as biomarkers of ovarian response. Hum Reprod Update. 2015;21(6):698-710.
Bentzen JG, Forman JL, Pinborg A, Lidegaard Ø, Larsen EC, Friis-Hansen L, et al. Ovarian reserve parameters: a comparison between users and non-users of hormonal contraception. Reprod Biomed Online. 2012;25(6):612-619.
Broer SL, Broekmans FJ, Laven JS, Fauser BC. Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update. 2014;20(5):688-701.
Lie Fong S, Visser JA, Welt CK, de Rijke YB, Eijkemans MJ, Broekmans FJ, et al. Serum anti-müllerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood. J Clin Endocrinol Metab. 2012;97(12):4650-4655.
Hamdine O, Eijkemans MJ, Lentjes EW, Torrance HL, Macklon NS, Fauser BC, et al. Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Müllerian hormone. Hum Reprod. 2015;30(1):170-178.
Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective, comparative analysis of anti-Mullerian hormone, inhibin-B, and three-dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation. Fertil Steril. 2010;93(3):855-864.
Silberstein T, MacLaughlin DT, Shai I, Trimarchi JR, Lambert-Messerlian G, Seifer DB, et al. Mullerian inhibiting substance levels at the time of HCG administration in IVF cycles predict both ovarian reserve and embryo morphology. Hum Reprod. 2006;21(1):159-163.
Korsholm AS, Petersen KB, Bentzen JG, Hilsted LM, Andersen AN, Hvidman HW. Investigation of anti-Müllerian hormone concentrations in relation to natural conception rate and time to pregnancy. Reprod Biomed Online. 2018;36(5):568-575.
Quinn MM, Kao CN, Ahmad AK, Haisenleder DJ, Santoro N, Eisenberg E, et al. Age-stratified thresholds of anti-Müllerian hormone improve prediction of polycystic ovary syndrome over a population-based threshold. Clin Endocrinol (Oxf).
Dewailly D, Gronier H, Poncelet E, Robin G, Leroy M, Pigny P, et al. Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries. Hum Reprod. 2011;26(11):3123-129.
Schiffner J, Roos J, Broomhead D, Helden JV, Godehardt E, Fehr D, et al. Relationship between anti-Müllerian hormone and antral follicle count across the menstrual cycle using the Beckman Coulter Access assay in comparison with Gen II manual assay. Clin Chem Lab Med. 2017;55(7):1025-1033.
Gracia CR, Shin SS, Prewitt M, Chamberlin JS, Lofaro LR, Jones KL, et al. Multi-center clinical evaluation of the Access AMH assay to determine AMH levels in reproductive age women during normal menstrual cycles. J Assist Reprod Genet. 2018;35(5):777-783.
Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update. 2014;20(3):370-385.
Kissell KA, Danaher MR, Schisterman EF, Wactawski-Wende J, Ahrens KA, Schliep K, et al. Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women. Hum Reprod. 2014;29(8):1764-1772.
Dólleman M, Verschuren WM, Eijkemans MJ, Dollé ME, Jansen EH, Broekmans FJ, et al. Reproductive and lifestyle determinants of anti-Müllerian hormone in a large population-based study. J Clin Endocrinol Metab. 2013;98(5):2106-2115.
Kallio S, Puurunen J, Ruokonen A, Vaskivuo T, Piltonen T, Tapanainen JS. Antimüllerian hormone levels decrease in women using combined contraception independently of administration route. Fertil Steril. 2013;99(5):1305-1310.
Kim CW, Shim HS, Jang H, Song YG. The effects of uterine artery embolization on ovarian reserve. Eur J Obstet Gynecol Reprod Biol. 2016 ;206:172-176.
Lin W, Titus S, Moy F, Ginsburg ES, Oktay K. Ovarian aging in women with BRCA germline mutations. J Clin Endocrinol Metab. 2017;102(10):3839-3847.
Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606-614.
American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee. Female age-related fertility decline. Committee Opinion No. 589. Fertil Steril. 2014;101(3):633-634.
National Collaborating Centre for Women’s and Children’s Health (UK). Menopause: Full Guideline. London: National Institute for Health and Care Excellence (UK); 2015 Nov 12. (NICE Guideline, No. 23). Premature ovarian insufficiency. Available from: www.ncbi.nlm.nih.gov/books/NBK343476/.
Freeman EW, Sammel MD, Lin H, Gracia CR. Anti-mullerian hormone as a predictor of time to menopause in late reproductive age women. J Clin Endocrinol Metab. 2012;97(5):1673-1680.
van Rooij IA, den Tonkelaar I, Broekmans FJ, Looman CW, Scheffer GJ, de Jong FH, et al. Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause. 2004;11(6 Pt 1):601-606.
European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926-937.
Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014;124(1):193-197.

#5 My patient is not ready to be pregnant. If her results are abnormal, should she freeze eggs?

For patients who might be interested in seeking fertility preservation and ART, earlier referral to a reproductive specialist to discuss risks and benefits of oocyte or embryo cryopreservation is always preferable. The younger a woman is when she undergoes fertility preservation, the better. Among patients planning to delay conception, each one’s decision is driven by her personal calculations of the cost, risk, and benefit of egg or embryo freezing—a picture of which ovarian reserve testing is only one piece.

#6 Can these tests predict menopause?

Menopause is a clinical diagnosis, defined as 12 months without menses (without hormone use or other causes of amenorrhea). In such women, FSH levels are elevated, but biochemical tests are not part of the menopause diagnosis.³⁶ In the years leading to menopause, FSH levels are highly variable and unreliable in predicting time to menopause.

AMH has been shown to correlate with time to menopause. (Once the AMH level becomes undetectable, menopause occurs in a mean of 6 years.^37,38) Patients do not typically have serial AMH measurements, however, so it is not usually known when the hormone became undetectable. Therefore, AMH is not a useful test for predicting time to menopause.

Premature ovarian insufficiency (loss of ovarian function in women younger than age 40), should be considered in women with secondary amenorrhea of 4 months or longer. The diagnosis requires confirmatory laboratory assessment,³⁶ and findings include an FSH level greater than 25 mIU/mL on 2 tests performed at least 1 month apart.^39,40

Ovarian reserve tests: A partial view of reproductive potential

The answers we have provided highlight several key concepts and conclusions that should guide clinical practice and decisions made by patients:

Ovarian reserve tests best serve to predict ovarian response during IVF; to a far lesser extent, they might predict birth outcomes from IVF. These tests have not, however, been shown to predict spontaneous pregnancy.
Ovarian reserve tests should be administered purposefully, with counseling beforehand regarding their limitations.
Abnormal ovarian reserve test results do not necessitate ART; however, they may prompt a patient to accelerate her reproductive timeline and consult with a reproductive endocrinologist to consider her age and health-related risks of infertility or pregnancy loss.
Patients should be counseled that, regardless of the results of ovarian reserve testing, attempting conception or pursuing fertility preservation at a younger age (in particular, at <35 years of age) is associated with better outcomes.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

References

Forman MR, Mangini LD, Thelus-Jean R, Hayward MD. Life-course origins of the ages at menarche and menopause. Adolesc Health Med Ther. 2013;4:1-21.
Reichman DE, Goldschlag D, Rosenwaks Z. Value of antimüllerian hormone as a prognostic indicator of in vitro fertilization outcome. Fertil Steril. 2014;101(4):1012-1018.e1.
Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, et al. Association between biomarkers of ovarian reserve and infertility among older women of reproductive age. JAMA. 2017;318(14):1367-1376.
Farr SL, Schieve LA, Jamieson DJ. Pregnancy loss among pregnancies conceived through assisted reproductive technology, United States, 1999-2002. Am J Epidemiol. 2007;165(12):1380-1388.
Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al. The nature of aneuploidy with increasing age of the female partner: a review of 1,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril. 2014;101(3):656-663.e1.
Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril. 2015;103(3):e9-e17.
Kwee J, Schats R, McDonnell J, Lambalk CB, Schoemaker J. Intercycle variability of ovarian reserve tests: results of a prospective randomized study. Hum Reprod. 2004;19(3):590-595.
Thum MY, Abdalla HI, Taylor D. Relationship between women’s age and basal follicle-stimulating hormone levels with aneuploidy risk in in vitro fertilization treatment. Fertil Steril. 2008;90(2):315-321.
Roberts JE, Spandorfer S, Fasouliotis SJ, Kashyap S, Rosenwaks Z. Taking a basal follicle-stimulating hormone history is essential before initiating in vitro fertilization. Fertil Steril. 2005;83(1):37-41.
Bishop LA, Richter KS, Patounakis G, Andriani L, Moon K, Devine K. Diminished ovarian reserve as measured by means of baseline follicle-stimulating hormone and antral follicle count is not associated with pregnancy loss in younger in vitro fertilization patients. Fertil Steril. 2017;108(6):980-987.
Tal R, Seifer DB. Ovarian reserve testing: a user’s guide. Am J Obstet Gynecol. 2017;217(2):129-140.
Ferraretti AP, La Marca L, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616-1624.
Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103(6):e44-e50.
Hvidman HW, Bentzen JG, Thuesen LL, Lauritsen MP, Forman JL, Loft A, et al. Infertile women below the age of 40 have similar anti-Müllerian hormone levels and antral follicle count compared with women of the same age with no history of infertility. Hum Reprod. 2016;31(5):1034-1045.
Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006;12(6):685-718.
Iliodromiti S, Anderson RA, Nelson SM. Technical and performance characteristics of anti-Mullerian hormone and antral follicle count as biomarkers of ovarian response. Hum Reprod Update. 2015;21(6):698-710.
Bentzen JG, Forman JL, Pinborg A, Lidegaard Ø, Larsen EC, Friis-Hansen L, et al. Ovarian reserve parameters: a comparison between users and non-users of hormonal contraception. Reprod Biomed Online. 2012;25(6):612-619.
Broer SL, Broekmans FJ, Laven JS, Fauser BC. Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update. 2014;20(5):688-701.
Lie Fong S, Visser JA, Welt CK, de Rijke YB, Eijkemans MJ, Broekmans FJ, et al. Serum anti-müllerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood. J Clin Endocrinol Metab. 2012;97(12):4650-4655.
Hamdine O, Eijkemans MJ, Lentjes EW, Torrance HL, Macklon NS, Fauser BC, et al. Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Müllerian hormone. Hum Reprod. 2015;30(1):170-178.
Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective, comparative analysis of anti-Mullerian hormone, inhibin-B, and three-dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation. Fertil Steril. 2010;93(3):855-864.
Silberstein T, MacLaughlin DT, Shai I, Trimarchi JR, Lambert-Messerlian G, Seifer DB, et al. Mullerian inhibiting substance levels at the time of HCG administration in IVF cycles predict both ovarian reserve and embryo morphology. Hum Reprod. 2006;21(1):159-163.
Korsholm AS, Petersen KB, Bentzen JG, Hilsted LM, Andersen AN, Hvidman HW. Investigation of anti-Müllerian hormone concentrations in relation to natural conception rate and time to pregnancy. Reprod Biomed Online. 2018;36(5):568-575.
Quinn MM, Kao CN, Ahmad AK, Haisenleder DJ, Santoro N, Eisenberg E, et al. Age-stratified thresholds of anti-Müllerian hormone improve prediction of polycystic ovary syndrome over a population-based threshold. Clin Endocrinol (Oxf).
Dewailly D, Gronier H, Poncelet E, Robin G, Leroy M, Pigny P, et al. Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries. Hum Reprod. 2011;26(11):3123-129.
Schiffner J, Roos J, Broomhead D, Helden JV, Godehardt E, Fehr D, et al. Relationship between anti-Müllerian hormone and antral follicle count across the menstrual cycle using the Beckman Coulter Access assay in comparison with Gen II manual assay. Clin Chem Lab Med. 2017;55(7):1025-1033.
Gracia CR, Shin SS, Prewitt M, Chamberlin JS, Lofaro LR, Jones KL, et al. Multi-center clinical evaluation of the Access AMH assay to determine AMH levels in reproductive age women during normal menstrual cycles. J Assist Reprod Genet. 2018;35(5):777-783.
Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update. 2014;20(3):370-385.
Kissell KA, Danaher MR, Schisterman EF, Wactawski-Wende J, Ahrens KA, Schliep K, et al. Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women. Hum Reprod. 2014;29(8):1764-1772.
Dólleman M, Verschuren WM, Eijkemans MJ, Dollé ME, Jansen EH, Broekmans FJ, et al. Reproductive and lifestyle determinants of anti-Müllerian hormone in a large population-based study. J Clin Endocrinol Metab. 2013;98(5):2106-2115.
Kallio S, Puurunen J, Ruokonen A, Vaskivuo T, Piltonen T, Tapanainen JS. Antimüllerian hormone levels decrease in women using combined contraception independently of administration route. Fertil Steril. 2013;99(5):1305-1310.
Kim CW, Shim HS, Jang H, Song YG. The effects of uterine artery embolization on ovarian reserve. Eur J Obstet Gynecol Reprod Biol. 2016 ;206:172-176.
Lin W, Titus S, Moy F, Ginsburg ES, Oktay K. Ovarian aging in women with BRCA germline mutations. J Clin Endocrinol Metab. 2017;102(10):3839-3847.
Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606-614.
American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee. Female age-related fertility decline. Committee Opinion No. 589. Fertil Steril. 2014;101(3):633-634.
National Collaborating Centre for Women’s and Children’s Health (UK). Menopause: Full Guideline. London: National Institute for Health and Care Excellence (UK); 2015 Nov 12. (NICE Guideline, No. 23). Premature ovarian insufficiency. Available from: www.ncbi.nlm.nih.gov/books/NBK343476/.
Freeman EW, Sammel MD, Lin H, Gracia CR. Anti-mullerian hormone as a predictor of time to menopause in late reproductive age women. J Clin Endocrinol Metab. 2012;97(5):1673-1680.
van Rooij IA, den Tonkelaar I, Broekmans FJ, Looman CW, Scheffer GJ, de Jong FH, et al. Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause. 2004;11(6 Pt 1):601-606.
European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926-937.
Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014;124(1):193-197.

How ovarian reserve testing can (and cannot) address your patients’ fertility concerns

References

#5 My patient is not ready to be pregnant. If her results are abnormal, should she freeze eggs?

#6 Can these tests predict menopause?

Ovarian reserve tests: A partial view of reproductive potential

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