Predicting Reproductive Age with Biomarkers of Ovarian Reserve—How (and What) Are We Measuring?

Abstract

Predicting the reproductive lifespan of an individual woman remains an elusive, yet clinically important, goal. The development of models and staging systems that accurately determine the end of natural fertility and the anticipated age of menopause will represent a significant advance in our ability to counsel women regarding family planning issues and in the individualization of risk assessment. Recent histological and longitudinal investigations have demonstrated a significant relationship between commonly used clinical markers of ovarian reserve and the true ovarian reserve, as assessed by the ovarian nongrowing follicle count and the age of menopause, respectively. Models and staging systems that have been developed based on these findings represent important advances in the field of women's health and promise to provide additional insights into the process of reproductive aging in general. Although the models developed to date appear to improve the prediction of the age of menopause as compared with chronological age alone, wide confidence intervals in the predicted age of menopause and less accurate predictions at ages remote from menopause limit their clinical utility for the individual woman. Future longitudinal and histological investigations are necessary to improve the accuracy of models of reproductive aging.

Keywords

ovarian reserve - nongrowing follicles - primordial follicles - anti-Müllerian hormone - antral follicle count

• References

• 1 te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002; 8 (2) 141-154
• 2 Leridon H. Demographic effects of the introduction of steroid contraception in developed countries. Hum Reprod Update 2006; 12 (5) 603-616
• 3 Matthews TJ, Hamilton BE. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief 2009; 21 (21) 1-8
• 4 Soules MR ; American Society for Reproductive Medicine. The story behind the American Society for Reproductive Medicine's prevention of infertility campaign. Fertil Steril 2003; 80 (2) 295-299
• 5 van Wayenburg CA, van der Schouw YT, van Noord PA, Peeters PH. Age at menopause, body mass index, and the risk of colorectal cancer mortality in the Dutch Diagnostisch Onderzoek Mammacarcinoom (DOM) cohort. Epidemiology 2000; 11 (3) 304-308
• 6 van Der Voort DJ, van Der Weijer PH, Barentsen R. Early menopause: increased fracture risk at older age. Osteoporos Int 2003; 14 (6) 525-530
• 7 van der Schouw YT, van der Graaf Y, Steyerberg EW, Eijkemans JC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996; 347 (9003) 714-718
• 8 Mondul AM, Rodriguez C, Jacobs EJ, Calle EE. Age at natural menopause and cause-specific mortality. Am J Epidemiol 2005; 162 (11) 1089-1097
• 9 Ossewaarde ME, Bots ML, Verbeek AL , et al. Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 2005; 16 (4) 556-562
• 10 Monninkhof EM, van der Schouw YT, Peeters PH. Early age at menopause and breast cancer: are leaner women more protected? A prospective analysis of the Dutch DOM cohort. Breast Cancer Res Treat 1999; 55 (3) 285-291
• 11 Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med 1980; 303 (3) 130-135
• 12 Treloar AE. Menstrual cyclicity and the pre-menopause. Maturitas 1981; 3 (3–4) 249-264
• 13 Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev 2009; 30 (5) 465-493
• 14 Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 1996; 81 (4) 1495-1501
• 15 Lambalk CB, van Disseldorp J, de Koning CH, Broekmans FJ. Testing ovarian reserve to predict age at menopause. Maturitas 2009; 63 (4) 280-291
• 16 Weiss G, Skurnick JH, Goldsmith LT, Santoro NF, Park SJ. Menopause and hypothalamic-pituitary sensitivity to estrogen. JAMA 2004; 292 (24) 2991-2996
• 17 Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev 1996; 17 (2) 121-155
• 18 Gougeon A. The early stages of follicular growth. In: Trounson AO, Gosden RG, , eds. Biology and Pathology of the Oocyte: Role in Fertility and Reproductive Medicine. Cambridge: Cambridge University Press; 2003: 29-41
• 19 Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod 1996; 11 (10) 2217-2222
• 20 Munné S, Chen S, Colls P , et al. Maternal age, morphology, development and chromosome abnormalities in over 6000 cleavage-stage embryos. Reprod Biomed Online 2007; 14 (5) 628-634
• 21 Block E. Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat (Basel) 1952; 14 (1–2, Suppl 16): 108-123
• 22 Gougeon A, Chainy GB. Morphometric studies of small follicles in ovaries of women at different ages. J Reprod Fertil 1987; 81 (2) 433-442
• 23 Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7 (10) 1342-1346
• 24 Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod 2008; 23 (3) 699-708
• 25 Gundersen HJ, Bagger P, Bendtsen TF , et al. The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 1988; 96 (10) 857-881
• 26 West MJ. New stereological methods for counting neurons. Neurobiol Aging 1993; 14 (4) 275-285
• 27 Wallace WHB, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS ONE 2010; 5 (1) e8772
• 28 Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989; 51 (4) 651-654
• 29 Toner JP, Philput CB, Jones GS, Muasher SJ. Basal follicle-stimulating hormone level is a better predictor of in vitro fertilization performance than age. Fertil Steril 1991; 55 (4) 784-791
• 30 Smotrich DB, Widra EA, Gindoff PR, Levy MJ, Hall JL, Stillman RJ. Prognostic value of day 3 estradiol on in vitro fertilization outcome. Fertil Steril 1995; 64 (6) 1136-1140
• 31 Frattarelli JL, Bergh PA, Drews MR, Sharara FI, Scott RT. Evaluation of basal estradiol levels in assisted reproductive technology cycles. Fertil Steril 2000; 74 (3) 518-524
• 32 Seifer DB, Lambert-Messerlian G, Hogan JW, Gardiner AC, Blazar AS, Berk CA. Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome. Fertil Steril 1997; 67 (1) 110-114
• 33 Hall JE, Welt CK, Cramer DW. Inhibin A and inhibin B reflect ovarian function in assisted reproduction but are less useful at predicting outcome. Hum Reprod 1999; 14 (2) 409-415
• 34 Tomas C, Nuojua-Huttunen S, Martikainen H. Pretreatment transvaginal ultrasound examination predicts ovarian responsiveness to gonadotrophins in in-vitro fertilization. Hum Reprod 1997; 12 (2) 220-223
• 35 Chang M-Y, Chiang C-H, Hsieh T-T, Soong Y-K, Hsu K-H. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998; 69 (3) 505-510
• 36 Frattarelli JL, Lauria-Costab DF, Miller BT, Bergh PA, Scott RT. Basal antral follicle number and mean ovarian diameter predict cycle cancellation and ovarian responsiveness in assisted reproductive technology cycles. Fertil Steril 2000; 74 (3) 512-517
• 37 Bancsi LFJMM, Broekmans FJM, Eijkemans MJC, de Jong FH, Habbema JDF, te Velde ER. Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve. Fertil Steril 2002; 77 (2) 328-336
• 38 Hansen KR, Morris JL, Thyer AC, Soules MR. Reproductive aging and variability in the ovarian antral follicle count: application in the clinical setting. Fertil Steril 2003; 80 (3) 577-583
• 39 van Rooij IAJ, Broekmans FJ, te Velde ER , et al. Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17 (12) 3065-3071
• 40 Seifer DB, MacLaughlin DT, Christian BP, Feng B, Shelden RM. Early follicular serum müllerian-inhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril 2002; 77 (3) 468-471
• 41 Broer SL, Mol BW, Hendriks D, Broekmans FJ. The role of antimullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count. Fertil Steril 2009; 91 (3) 705-714
• 42 Loumaye E, Billion JM, Mine JM, Psalti I, Pensis M, Thomas K. Prediction of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test. Fertil Steril 1990; 53 (2) 295-301
• 43 Tanbo T, Dale PO, Lunde O, Norman N, Abyholm T. Prediction of response to controlled ovarian hyperstimulation: a comparison of basal and clomiphene citrate-stimulated follicle-stimulating hormone levels. Fertil Steril 1992; 57 (4) 819-824
• 44 Padilla SL, Bayati J, Garcia JE. Prognostic value of the early serum estradiol response to leuprolide acetate in in vitro fertilization. Fertil Steril 1990; 53 (2) 288-294
• 45 Winslow KL, Toner JP, Brzyski RG, Oehninger SC, Acosta AA, Muasher SJ. The gonadotropin-releasing hormone agonist stimulation test—a sensitive predictor of performance in the flare-up in vitro fertilization cycle. Fertil Steril 1991; 56 (4) 711-717
• 46 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
• 47 Verhagen TE, Hendriks DJ, Bancsi LF, Mol BW, Broekmans FJ. The accuracy of multivariate models predicting ovarian reserve and pregnancy after in vitro fertilization: a meta-analysis. Hum Reprod Update 2008; 14 (2) 95-100
• 48 Sun W, Stegmann BJ, Henne M, Catherino WH, Segars JH. A new approach to ovarian reserve testing. Fertil Steril 2008; 90 (6) 2196-2202
• 49 Scott Jr RT, Elkind-Hirsch KE, Styne-Gross A, Miller KA, Frattarelli JL. The predictive value for in vitro fertility delivery rates is greatly impacted by the method used to select the threshold between normal and elevated basal follicle-stimulating hormone. Fertil Steril 2008; 89 (4) 868-878
• 50 Hansen KR, Hodnett GM, Knowlton N, Craig LB. Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril 2011; 95 (1) 170-175
• 51 Sherman BM, West JH, Korenman SG. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab 1976; 42 (4) 629-636
• 52 Reyes FI, Winter JS, Faiman C. Pituitary-ovarian relationships preceding the menopause. I. A cross-sectional study of serum follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone levels. Am J Obstet Gynecol 1977; 129 (5) 557-564
• 53 Klein NA, Houmard BS, Hansen KR , et al. Age-related analysis of inhibin A, inhibin B, and activin a relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. J Clin Endocrinol Metab 2004; 89 (6) 2977-2981
• 54 Randolph Jr JF, Crawford S, Dennerstein L , et al. The value of follicle-stimulating hormone concentration and clinical findings as markers of the late menopausal transition. J Clin Endocrinol Metab 2006; 91 (8) 3034-3040
• 55 Harlow SD, Gass M, Hall JE , et al; STRAW+10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop +10: addressing the unfinished agenda of staging reproductive aging. Climacteric 2012; 15 (2) 105-114
• 56 Harlow SD, Gass M, Hall JE , et al; STRAW + 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Fertil Steril 2012; 97 (4) 843-851
• 57 Harlow SD, Gass M, Hall JE , et al; STRAW + 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab 2012; 97 (4) 1159-1168
• 58 Harlow SD, Gass M, Hall JE , et al; STRAW 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause 2012; 19 (4) 387-395
• 59 Sowers MR, Eyvazzadeh AD, McConnell D , et al. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab 2008; 93 (9) 3478-3483
• 60 Welt C, Sidis Y, Keutmann H, Schneyer A. Activins, inhibins, and follistatins: from endocrinology to signaling. A paradigm for the new millennium. Exp Biol Med (Maywood) 2002; 227 (9) 724-752
• 61 Vale W, Rivier C, Hsueh A , et al. Chemical and biological characterization of the inhibin family of protein hormones. Recent Prog Horm Res 1988; 44: 1-34
• 62 Weiss J, Crowley Jr WFJ, Halvorson LM, Jameson JL. Perifusion of rat pituitary cells with gonadotropin-releasing hormone, activin, and inhibin reveals distinct effects on gonadotropin gene expression and secretion. Endocrinology 1993; 132 (6) 2307-2311
• 63 Groome NP, Illingworth PJ, O'Brien M , et al. Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab 1996; 81 (4) 1401-1405
• 64 Corson SL, Gutmann J, Batzer FR, Wallace H, Klein N, Soules MR. Inhibin-B as a test of ovarian reserve for infertile women. Hum Reprod 1999; 14 (11) 2818-2821
• 65 Creus M, Peñarrubia J, Fábregues F , et al. Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome. Hum Reprod 2000; 15 (11) 2341-2346
• 66 Gracia CR, Sammel MD, Freeman EW , et al. Defining menopause status: creation of a new definition to identify the early changes of the menopausal transition. Menopause 2005; 12 (2) 128-135
• 67 Burger HG, Hale GE, Robertson DM, Dennerstein L. A review of hormonal changes during the menopausal transition: focus on findings from the Melbourne Women's Midlife Health Project. Hum Reprod Update 2007; 13 (6) 559-565
• 68 Scheffer GJ, Broekmans FJ, Dorland M, Habbema JD, Looman CW, te Velde ER. Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility. Fertil Steril 1999; 72 (5) 845-851
• 69 Rosen MP, Sternfeld B, Schuh-Huerta SM, Reijo Pera RA, McCulloch CE, Cedars MI. Antral follicle count: absence of significant midlife decline. Fertil Steril 2010; 94 (6) 2182-2185
• 70 Yang YS, Hur MH, Kim SY, Young K. Correlation between sonographic and endocrine markers of ovarian aging as predictors for late menopausal transition. Menopause 2011; 18 (2) 138-145
• 71 Hansen KR, Craig LB, Zavy MT, Klein NA, Soules MR. Ovarian primordial and nongrowing follicle counts according to the Stages of Reproductive Aging Workshop (STRAW) staging system. Menopause 2012; 19 (2) 164-171
• 72 Hehenkamp WJ, Looman CW, Themmen AP, de Jong FH, Te Velde ER, Broekmans FJ. Anti-Müllerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab 2006; 91 (10) 4057-4063
• 73 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 (2) 77-83
• 74 Fanchin R, Schonäuer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-Müllerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003; 18 (2) 323-327
• 75 Hale GE, Zhao X, Hughes CL, Burger HG, Robertson DM, Fraser IS. Endocrine features of menstrual cycles in middle and late reproductive age and the menopausal transition classified according to the Staging of Reproductive Aging Workshop (STRAW) staging system. J Clin Endocrinol Metab 2007; 92 (8) 3060-3067
• 76 van Rooij IA, Broekmans FJ, Scheffer GJ , et al. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 2005; 83 (4) 979-987
• 77 Seifer DB, Baker VL, Leader B. Age-specific serum anti-Müllerian hormone values for 17,120 women presenting to fertility centers within the United States. Fertil Steril 2011; 95 (2) 747-750
• 78 van Disseldorp J, Faddy MJ, Themmen APN , et al. Relationship of serum antimüllerian hormone concentration to age at menopause. J Clin Endocrinol Metab 2008; 93 (6) 2129-2134
• 79 Kelsey TW, Wright P, Nelson SM, Anderson RA, Wallace WH. A validated model of serum anti-müllerian hormone from conception to menopause. PLoS ONE 2011; 6 (7) e22024
• 80 de Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Antimüllerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril 2002; 77 (2) 357-362
• 81 Tran ND, Cedars MI, Rosen MP. The role of anti-müllerian hormone (AMH) in assessing ovarian reserve. J Clin Endocrinol Metab 2011; 96 (12) 3609-3614
• 82 de Boer EJ, den Tonkelaar I, te Velde ER, Burger CW, van Leeuwen FE ; OMEGA-project group. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003; 18 (7) 1544-1552
• 83 Lawson R, El-Toukhy T, Kassab A , et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod 2003; 18 (3) 527-533
• 84 Nikolaou D, Lavery S, Turner C, Margara R, Trew G. Is there a link between an extremely poor response to ovarian hyperstimulation and early ovarian failure?. Hum Reprod 2002; 17 (4) 1106-1111
• 85 Gülekli B, Bulbul Y, Onvural A , et al. Accuracy of ovarian reserve tests. Hum Reprod 1999; 14 (11) 2822-2826
• 86 Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life. Int J Fertil 1967; 12 (1, Pt 2) 77-126
• 87 Taffe JR, Dennerstein L. Menstrual patterns leading to the final menstrual period. Menopause 2002; 9 (1) 32-40
• 88 Mitchell ES, Woods NF, Mariella A. Three stages of the menopausal transition from the Seattle Midlife Women's Health Study: toward a more precise definition. Menopause 2000; 7 (5) 334-349
• 89 Harlow SD, Mitchell ES, Crawford S, Nan B, Little R, Taffe J ; ReSTAGE Collaboration. The ReSTAGE Collaboration: defining optimal bleeding criteria for onset of early menopausal transition. Fertil Steril 2008; 89 (1) 129-140
• 90 Taffe JR, Cain KC, Mitchell ES, Woods NF, Crawford SL, Harlow SD. “Persistence” improves the 60-day amenorrhea marker of entry to late-stage menopausal transition for women aged 40 to 44 years. Menopause 2010; 17 (1) 191-193
• 91 Klein NA, Harper AJ, Houmard BS, Sluss PM, Soules MR. Is the short follicular phase in older women secondary to advanced or accelerated dominant follicle development?. J Clin Endocrinol Metab 2002; 87 (12) 5746-5750
• 92 Soules MR, Sherman S, Parrott E , et al. Executive Summary: Stages of reproductive aging workshop (STRAW). Fertil Steril 2001; 76 (5) 874-878
• 93 Lass A. Assessment of ovarian reserve: is there still a role for ovarian biopsy in the light of new data?. Hum Reprod 2004; 19 (3) 467-469
• 94 Broekmans FJ, Faddy MJ, Scheffer G, te Velde ER. Antral follicle counts are related to age at natural fertility loss and age at menopause. Menopause 2004; 11 (6, Pt 1) 607-614
• 95 van Rooij IA, Tonkelaar Id, Broekmans FJ , et al. Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause 2004; 11 (6, Pt 1) 601-606
• 96 Broer SL, Eijkemans MJC, Scheffer GJ , et al. Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women. J Clin Endocrinol Metab 2011; 96 (8) 2532-2539
• 97 Tehrani FR, Shakeri N, Solaymani-Dodaran M, Azizi F. Predicting age at menopause from serum antimüllerian hormone concentration. Menopause 2011; 18 (7) 766-770
• 98 Tehrani FR, Solaymani-Dodaran M, Tohidi M, Gohari MR, Azizi F. Modeling age at menopause using serum concentration of anti-mullerian hormone. J Clin Endocrinol Metab 2013; 98 (2) 729-735
• 99 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
• 100 Freeman EW, Sammel MD, Lin H, Boorman DW, Gracia CR. Contribution of the rate of change of antimüllerian hormone in estimating time to menopause for late reproductive-age women. Fertil Steril 2012; 98 (5) 1254-1259 , e1–e2
• 101 Gougeon A, Ecochard R, Thalabard JC. Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod 1994; 50 (3) 653-663