Interpreting human follicular recruitment and antimüllerian hormone concentrations throughout life
2012; Elsevier BV; Volume: 98; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2012.07.1114
ISSN1556-5653
AutoresRichard Fleming, Tom Kelsey, Richard A. Anderson, William H. Wallace, Scott M. Nelson,
Tópico(s)Sexual Differentiation and Disorders
ResumoThe changes in the relationships between circulating antimüllerian hormone, the size of the primordial follicle pool, and follicular recruitment before and through the reproductive years have now been clarified, and show dynamic changes through sexual development. The constant relationship between the number of follicles and circulating antimüllerian hormone exists only after the age of 25 years, implying that the association between follicular recruitment and follicular survival to the later stages of development is not constant across the reproductive life course. This commentary assesses the factors that may underlie these relationships and their clinical implications for reproductive health. The changes in the relationships between circulating antimüllerian hormone, the size of the primordial follicle pool, and follicular recruitment before and through the reproductive years have now been clarified, and show dynamic changes through sexual development. The constant relationship between the number of follicles and circulating antimüllerian hormone exists only after the age of 25 years, implying that the association between follicular recruitment and follicular survival to the later stages of development is not constant across the reproductive life course. This commentary assesses the factors that may underlie these relationships and their clinical implications for reproductive health. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/flemingr-human-follicular-recruitment-anti-mullerian-hormone/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/flemingr-human-follicular-recruitment-anti-mullerian-hormone/ Human folliculogenesis is a protracted process involving multiple developmental stages, and our understanding of its control is largely based on cross-sectional observations of follicle numbers, and aspects of the final stages of maturation, including the development of antral follicles leading to ovulation. These latter stages involve the "classic" ovarian hormones, the sex steroids, inhibins A and B, and the gonadotropins, which have little apparent relevance to earlier stages of development. Knowledge of preantral and early antral follicle development is scant, as these stages have until recently been endocrinologically "silent" and too small for imaging in vivo. The recognition that antimüllerian hormone (AMH) is produced by preantral and small antral follicles with serum concentrations reflecting both the number of these small growing follicles and the primordial pool (1Weenen C. Laven J.S. von Bergh A.R. Cranfield M. Groome N.P. Visser J.A. et al.Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment.Mol Hum Reprod. 2004; 10: 77-83Crossref PubMed Scopus (979) Google Scholar, 2Visser J.A. Durlinger A.L.L. Peters I.J.J. van den Heuvel E.R. Rose U.M. Kramer P. et al.Increased oocyte degeneration and follicular atresia during the estrous cycle in anti-müllerian hormone null mice.Endocrinology. 2007; 148: 2301-2308Crossref PubMed Scopus (115) Google Scholar, 3Hansen K.R. Hodnett G.M. Knowlton N. Craig L.B. Correlation of ovarian reserve tests with histologically determined primordial follicle number.Fertil Steril. 2011; 95: 170-175Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar) now allows the opportunity for the study of aspects of these earlier stages and factors influencing development, as well as the inves-tigation of their relationship with fertility. Recent observations regarding the dynamics of follicular development provide us with important observations that should be put into context to improve our understanding of human ovarian function. In combination with established evidence, this new infor-mation may mark a critical point in how we think about ovarian function and fertility—for current clinical understanding and future research. The evidence moves us beyond simply describing the age-related decline in the primordial follicle pool or "ovarian reserve" (4Faddy M.J. Gosden R.G. Ovary and ovulation: a model confirming the decline in follicle numbers to the age of menopause in women.Hum Reprod. 1996; 11: 1484-1486Crossref PubMed Scopus (340) Google Scholar, 5Faddy M.J. Follicle dynamics during ovarian ageing.Mol Cell Endocrinol. 2000; 163: 43-48Crossref PubMed Scopus (215) Google Scholar, 6Hansen K.R. Knowlton N.S. Thyer A.C. Charleston J.S. Soules M.R. Klein N.A. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause.Hum Reprod. 2008; 23: 699-708Crossref PubMed Scopus (335) Google Scholar), to model the changes in rates of active follicular recruitment that underlies this attrition (7Wallace W.H. Kelsey T.W. Human ovarian reserve from conception to the menopause.PLoS One. 2010; 5: e8772Crossref PubMed Scopus (458) Google Scholar). Furthermore, models for the marker of functional ovarian reserve (i.e., AMH) (8Kelsey T.W. Wright P. Nelson S.M. Anderson R.A. Wallace W.H. A validated model of serum anti-mullerian hormone from conception to menopause.PLoS One. 2011; 6: e22024Crossref PubMed Scopus (315) Google Scholar) encompass previous population studies during childhood, adolescence, and adult life (9Nelson S.M. Messow M.C. Wallace A.M. Fleming R. McConnachie A. Nomogram for the decline in serum antimullerian hormone: a population study of 9,601 infertility patients.Fertil Steril. 2011; 95: 736-741Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 10Nelson S.M. Messow M.C. McConnachie A. Wallace H. Kelsey T. Fleming R. et al.External validation of nomogram for the decline in serum anti-Mullerian hormone in women: a population study of 15,834 infertility patients.Reprod Biomed Online. 2011; 23: 204-206Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 11Hagen C.P. Aksglaede L. Sorensen K. Main K.M. Boas M. Cleemann L. et al.Serum levels of anti-Mullerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 Turner syndrome patients.J Clin Endocrinol Metab. 2010; 95: 5003-5010Crossref PubMed Scopus (268) Google Scholar). It is the combination of these studies (7Wallace W.H. Kelsey T.W. Human ovarian reserve from conception to the menopause.PLoS One. 2010; 5: e8772Crossref PubMed Scopus (458) Google Scholar, 8Kelsey T.W. Wright P. Nelson S.M. Anderson R.A. Wallace W.H. A validated model of serum anti-mullerian hormone from conception to menopause.PLoS One. 2011; 6: e22024Crossref PubMed Scopus (315) Google Scholar, 12Kelsey T. Wright P. Nelson S.M. Anderson R.A. Wallace W.H.B. Data aggregation and analysis for assessment of ovarian reserve.Mol Cell Endocrinol. 2012; 18: 79-87Google Scholar), when examined in the context of human fertility, that provides a new perspective on follicular behavior, and may challenge some of our previous hypotheses of follicular development. A critical new observation was the distinguishing of the rate of change of the primordial follicle pool reserve (i.e., initial "recruitment") from the simple decline in its size (7Wallace W.H. Kelsey T.W. Human ovarian reserve from conception to the menopause.PLoS One. 2010; 5: e8772Crossref PubMed Scopus (458) Google Scholar). The critical and novel feature of the dynamic shape of the curve reveals that the rate of follicular recruitment is not a constant relationship with the size of the primordial follicular pool versus age. In fact, it shows a steady increase during childhood and adolescence to a maximum during the late teen years coincident with postpubertal establishment of adult ovarian function. It is followed immediately by an inexorable decline. Notably, the observation that follicular recruitment rates change in an age-dependent manner is entirely consistent with previous nonlinear regression and power models that described the decline in actual primordial follicle number with aging (4Faddy M.J. Gosden R.G. Ovary and ovulation: a model confirming the decline in follicle numbers to the age of menopause in women.Hum Reprod. 1996; 11: 1484-1486Crossref PubMed Scopus (340) Google Scholar, 6Hansen K.R. Knowlton N.S. Thyer A.C. Charleston J.S. Soules M.R. Klein N.A. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause.Hum Reprod. 2008; 23: 699-708Crossref PubMed Scopus (335) Google Scholar, 13Faddy M.J. Gosden R.G. Gougeon A. Richardson S.J. Nelson J.F. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause.Hum Reprod. 1992; 7: 1342-1346Crossref PubMed Scopus (1022) Google Scholar). Similar to follicular recruitment, the substantiated evidence shows that circulating AMH also changes across the lifespan, with initial increases during childhood, then a distinct fluctuation around the time of puberty, followed by a secondary increase during the next decade to a maximum at around age 25 years (8Kelsey T.W. Wright P. Nelson S.M. Anderson R.A. Wallace W.H. A validated model of serum anti-mullerian hormone from conception to menopause.PLoS One. 2011; 6: e22024Crossref PubMed Scopus (315) Google Scholar). This pubertal inflection and individual consistency of AMH in the early pubertal years have now been confirmed in longitudinal studies (14Hagen C.P. Aksglaede L. Sørensen K. Mouritsen A. Andersson A.-M. Petersen J.H. et al.Individual serum levels of anti-Müllerian hormone in healthy girls persist through childhood and adolescence: a longitudinal cohort study.Hum Reprod. 2012; 27: 861-866Crossref PubMed Scopus (96) Google Scholar). There then follows a secondary increase in circulating AMH attaining maximal values around age 25 years. Subsequent to this peak AMH undergoes a relentless decline to values below the levels of assay sensitivity between ages 40 and 45 years. This consistent decline in AMH from age 25 years is now firmly established (9Nelson S.M. Messow M.C. Wallace A.M. Fleming R. McConnachie A. Nomogram for the decline in serum antimullerian hormone: a population study of 9,601 infertility patients.Fertil Steril. 2011; 95: 736-741Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 10Nelson S.M. Messow M.C. McConnachie A. Wallace H. Kelsey T. Fleming R. et al.External validation of nomogram for the decline in serum anti-Mullerian hormone in women: a population study of 15,834 infertility patients.Reprod Biomed Online. 2011; 23: 204-206Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 15Almog B. Shehata F. Suissa S. Holzer H. Shalom-Paz E. La Marca A. et al.Age-related normograms of serum antimullerian hormone levels in a population of infertile women: a multicenter study.Fertil Steril. 2011; 95: 2359-2363Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 16Seifer D.B. Baker V.L. Leader B. Age-specific serum anti-Mullerian hormone values for 17,120 women presenting to fertility centers within the United States.Fertil Steril. 2011; 95: 747-750Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar) and the mathematical expression of the decline closely mirrors the decline in the size of the primordial follicle pool. At this stage of life, it appears that the relationship between the decline in the size of the pool, the number of follicles undergoing recruitment, and AMH concentrations closely parallel each other (12Kelsey T. Wright P. Nelson S.M. Anderson R.A. Wallace W.H.B. Data aggregation and analysis for assessment of ovarian reserve.Mol Cell Endocrinol. 2012; 18: 79-87Google Scholar), and AMH has become established as a marker of the number of follicles achieving FSH sensitivity and being theoretically able to undergo the final stages of maturation—which, of course, can be exploited in the IVF setting (17Nelson S.M. Yates R.W. Fleming R. Serum anti-Mullerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles implications for individualization of therapy.Hum Reprod. 2007; 22: 2414-2421Crossref PubMed Scopus (314) Google Scholar, 18La Marca A. Sighinolfi G. Radi D. Argento C. Baraldi E. Artenisio A.C. et al.Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART).Hum Reprod Update. 2010; 16: 113-130Crossref PubMed Scopus (644) Google Scholar, 19Nelson S.M. Yates R.W. Lyall H. Jamieson M. Traynor I. Gaudoin M. et al.Anti-Mullerian hormone-based approach to controlled ovarian stimulation for assisted conception.Hum Reprod. 2009; 24: 867-875Crossref PubMed Scopus (278) Google Scholar). Possibly the most important observation is that this secondary increase in AMH takes place in the face of declining follicular recruitment. Figure 1 shows the profiles of initial follicular recruitment and AMH from birth to the menopause. It also shows the periods of maximal, and declining, human fertility (20te Velde E.R. Pearson P.L. The variability of female reproductive ageing.Hum Reprod Update. 2002; 8: 141-154Crossref PubMed Scopus (856) Google Scholar). The symmetry of the peak of the AMH curve within the limits of the period of maximal human fertility is a compelling coincidence. Another notable observation is that the start of the decline in human fertility (in the early 30s), begins when AMH concentrations are significantly higher than those seen during puberty. There are, however, important differences in the profiles of follicle recruitment and AMH during these years that deserve further attention. The first direct conclusion to draw from these combined observations is that the relationship between follicular recruitment and follicular survival to the later stages of development is not a constant. If we assume that circulating AMH is a marker of the total number of maturing granulosa cells (GC) (2Visser J.A. Durlinger A.L.L. Peters I.J.J. van den Heuvel E.R. Rose U.M. Kramer P. et al.Increased oocyte degeneration and follicular atresia during the estrous cycle in anti-müllerian hormone null mice.Endocrinology. 2007; 148: 2301-2308Crossref PubMed Scopus (115) Google Scholar, 21Laven J.S. Mulders A.G. Visser J.A. Themmen A.P. De Jong F.H. Fauser B.C. Anti-Mullerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age.J Clin Endocrinol Metab. 2004; 89: 318-323Crossref PubMed Scopus (414) Google Scholar), then because this product achieves a maximum concentration a full decade after the peak of recruitment is an indication that throughout that decade more follicles, and therefore an increasing proportion of the follicles, are achieving later stages of maturation with associated numbers of maturing GCs (this in the absence of changes in gonadotropins during that period of early adulthood). Figure 1 identifies the two maxima of follicular recruitment and follicular survival, and demonstrates how peak AMH appears to correlate with fertility. The evolving change in AMH before age 25 years (in the face of declining initial recruitment) indicates that this stage of increasing follicular survival is critically important for optimal human fertility. As the full hierarchy of follicles within the ovary becomes established after puberty, local autocrine and paracrine effects, reflecting the different stages of follicular development, may further influence ongoing follicular development. The mechanisms of interfollicular regulation are poorly understood (22Durlinger A.L. Visser J.A. Themmen A.P. Regulation of ovarian function: the role of anti-Mullerian hormone.Reproduction. 2002; 124: 601-609Crossref PubMed Scopus (588) Google Scholar, 23Da Silva-Buttkus P. Marcelli G. Franks S. Stark J. Hardy K. Inferring biological mechanisms from spatial analysis: prediction of a local inhibitor in the ovary.Proc Natl Acad Sci U S A. 2009; 106: 456-461Crossref PubMed Scopus (70) Google Scholar), but the sequences of development of maturing follicles profoundly influence the survival of other follicles. Furthermore, although it is recognized that follicles enter their endocrine (pituitary controlled) stages only at the end of development, it is feasible that products of this relationship may promote the survival of follicles at earlier stages of development. The increase in circulating AMH is only discontinued when, around age 25 years, the increase in the proportion of follicles attaining the later stages of development is overwhelmed by the decline in the number of follicles undergoing recruitment, a decline that started a decade earlier. Before the onset of puberty, from birth to age 9 years there is a strong positive correlation (r = 0.92) between circulating AMH and follicular recruitment (Fig. 1). Follicular recruitment is increasing in association with a rise in AMH concentration at a time when the pituitary-ovarian axis is generally regarded as being quiescent and circulating sex steroids are minimal. As the correlation of AMH and recruitment is so strong at this stage we should not overlook the possibility that AMH may play a permissive or even stimulatory role in follicular recruitment, for which there is some direct human evidence (24Schmidt K.L. Kryger-Baggesen N. Byskov A.G. Andersen C.Y. Anti-Mullerian hormone initiates growth of human primordial follicles in vitro.Mol Cell Endocrinol. 2005; 234: 87-93Crossref PubMed Scopus (84) Google Scholar). This contrasts with evidence indicating inhibitory roles at postpubertal stages. Therefore, the most likely explanation of this correlation is that circulating AMH in the prepubertal period simply reflects the slow increase in follicular activity (recruitment and development) that is required through these years. However, in the period after the onset of puberty there is a breakdown in the association between AMH and follicular recruitment (r = −0.55). There is a temporary decline or plateau in circulating AMH concentrations, whereas follicular recruitment continues to increase to peak around ages 14–15 years. Following the peak of follicular recruitment at ages 14–15 years through to the period of maximal fertility peaking at age 25 years, there is a strong negative correlation (r = −0.83) between circulating AMH and follicular recruitment, with AMH increasing to a peak around age 25 years in association with a clear slow down in follicular recruitment. We may postulate that AMH is exerting a negative effect on follicular recruitment during this time, in line with other experimental evidence (2Visser J.A. Durlinger A.L.L. Peters I.J.J. van den Heuvel E.R. Rose U.M. Kramer P. et al.Increased oocyte degeneration and follicular atresia during the estrous cycle in anti-müllerian hormone null mice.Endocrinology. 2007; 148: 2301-2308Crossref PubMed Scopus (115) Google Scholar). However, more importantly, we propose that this secondary increase in AMH is a consequence of an increasing proportion of the follicles achieving later stages of development, when more GCs can contribute to the circulating total mass of AMH (maximized follicular survival). If this latter process relies on maturation of the pituitary-ovary axis, and also requires more follicles to produce the survival and growth factors, there will be intrinsic organizational delays. Therefore, the postpubertal decade of increasing AMH, which is of similar magnitude to that before puberty, must reflect an increase in the rate of survival of follicles, as the ovary matures. Presumably, this is due to an increasing expression and influence of growth and survival factors between the ages of 15 and 25 years. After 25 years there is an uninterrupted and strong positive correlation (r = 0.96) between AMH and decreasing follicular recruitment as the pool of nongrowing follicles declines and eventually becomes exhausted at the menopause. It is this decline in follicular recruitment, albeit associated with a maximal proportion of the available follicles achieving maturation, that results in a smaller number of follicles achieving the later stages of follicular development, which underlies the decline in AMH and explains the close relationship between AMH and egg yields seen in the IVF setting. It is clearly imperative to determine the roles of the specific growth and survival factors, including potentially AMH itself, on follicular development, and also the additional elements and circumstances that may influence their activity. Preantral follicle development is associated with the expression of many members of the transforming growth factor β (TGF-β) family and their regulators (25Fenwick M.A. Mansour Y.T. Franks S. Hardy K. Identification and regulation of bone morphogenetic protein antagonists associated with preantral follicle development in the ovary.Endocrinology. 2011; 152: 3515-3526Crossref PubMed Scopus (28) Google Scholar), illustrating the potential complexity of local regulation. There are several circumstances where modification of AMH by a pharmacologic or physiological condition may contribute to understanding of these events and factors involved. Prospective longitudinal cohorts have shown that GnRH analogue therapy reduces AMH concentrations, although this takes many months to be fully elaborated (26Anderson R.A. Themmen A.P.N. Al Qahtani A. Groome N.P. Cameron D.A. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer.Hum Reprod. 2006; 21: 2583-2592Crossref PubMed Scopus (284) Google Scholar). It is possible that the intraovarian changes after this withdrawal of FSH reflect a reversal of the slow postpubertal changes. Antimüllerian hormone is markedly suppressed during pregnancy (a condition of profound FSH suppression) with recovery in the postpartum period (27Nelson S.M. Stewart F. Fleming R. Freeman D.J. Longitudinal assessment of antimullerian hormone during pregnancy—relationship with maternal adiposity, insulin, and adiponectin.Fertil Steril. 2010; 93: 1356-1358Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Careful analysis of the effect of long-term oral contraception (OC) use indicates some partial AMH suppression, despite incomplete gonadotropin suppression (28van den Berg M.H. van Dulmen-den Broeder E. Overbeek A. Twisk J.W. Schats R. van Leeuwen F.E. et al.Comparison of ovarian function markers in users of hormonal contraceptives during the hormone-free interval and subsequent natural early follicular phases.Hum Reprod. 2010; 25: 1520-1527Crossref PubMed Scopus (85) Google Scholar). Antimüllerian hormone is produced by growing follicles up to approximately 8 mm in diameter (1Weenen C. Laven J.S. von Bergh A.R. Cranfield M. Groome N.P. Visser J.A. et al.Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment.Mol Hum Reprod. 2004; 10: 77-83Crossref PubMed Scopus (979) Google Scholar); the larger of these are undoubtedly gonadotropin sensitive and there is evidence that even earlier stages of follicular development may be partially gonadotropin regulated (29McGee E.A. Hsueh A.J. Initial and cyclic recruitment of ovarian follicles.Endocrinol Rev. 2000; 21: 200-214Crossref PubMed Scopus (1149) Google Scholar). It is therefore unclear whether these suppressions of circulating AMH are due to gonadotropin-dependent changes in recruitment or follicular survival. However, the apparently rapid recovery implies that modified metabolism of growth and survival factors may be involved. Due to the close relationship between AMH and the functional ovarian reserve in mature women, most clearly demonstrated in the IVF setting, and indications that it is of value in predicting time to and age at the menopause (30van Rooij I.A. Tonkelaar I. Broekmans F.J. Looman C.W. Scheffer G.J. de Jong F.H. et al.Anti-mullerian hormone is a promising predictor for the occurrence of the menopausal transition.Menopause. 2004; 11: 601-606Crossref PubMed Scopus (243) Google Scholar, 31van Disseldorp J. Faddy M.J. Themmen A.P. de Jong F.H. Peeters P.H. van der Schouw Y.T. et al.Relationship of serum antimullerian hormone concentration to age at menopause.J Clin Endocrinol Metab. 2008; 93: 2129-2134Crossref PubMed Scopus (218) Google Scholar, 32Tehrani F.R. Solaymani-Dodaran M. Azizi F. A single test of antimullerian hormone in late reproductive-aged women is a good predictor of menopause.Menopause. 2009; 16: 797-802Crossref PubMed Scopus (90) Google Scholar, 33Broer S.L. Eijkemans M.J. Scheffer G.J. van Rooij I.A. de Vet A. Themmen A.P. et al.Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women.J Clin Endocrinol Metab. 2011; 96: 2532-2539Crossref PubMed Scopus (273) Google Scholar), it can be speculated that AMH may be used in young adult women to identify their likely reproductive lifespan. This may be of particular application in determining appropriate courses of action for fertility preservation in young women, particularly those undergoing potentially damaging treatment in the form of radiotherapy/chemotherapy (34Anderson R.A. Cameron D.A. Pretreatment serum anti-mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer.J Clin Endocrinol Metab. 2011; 96: 1336-1343Crossref PubMed Scopus (185) Google Scholar, 35Anderson R.A. Nelson S.M. Wallace W.H. Measuring anti-Mullerian hormone for the assessment of ovarian reserve: when and for whom is it indicated?.Maturitas. 2012; 71: 28-33Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). However, the magnitude of the postpubertal increase in AMH concentration indicates that this should be taken into consideration during clinical decision making in teenage girls. The profound changes in the relationship between AMH and the primordial follicle pool and follicular recruitment during the first three decades of life indicate that we should be aware of making simple clinical assumptions. In the absence of long-term studies relating prepubertal AMH to later reproductive function, the simple quantitative relationship in the younger female cannot be assumed to be representative for clinical evaluation as it is in adults. It is likely that circulating AMH in the early years represents a different circumstance (i.e., follicle pool) from that in the mature years, and therefore, there may also be important qualitative and quantitative relationships. It is clear that follicles of young girls in late prepubertal and peripubertal life develop in an environment of growth factors, gonadotropins, and steroids that differ markedly from that of postpubertal women. Therefore, does the follicle of the young woman contain eggs and GCs under the same control mechanisms and relationships as in the older woman? There is now evidence from analyses of ovarian tissue from adolescent girls suggesting that the prepubertal ovary contains significant numbers of "abnormal" follicles that are lost during adolescence, and that the growth potential of immature follicles is markedly reduced at that time (36Anderson RA, McLaughlin M, Wallace WH, Telfer EE. Follicle health and early growth in vitro: implications for fertility preservation in the adolescent girl. Hum Reprod 2012;27(Suppl 2):O–296.Google Scholar). These observations indicate the need for specific understanding of the adolescent ovary, and that concepts derived from later-life ovarian function should not be directly extrapolated. Gynecologists and pediatricians are frequently presented with girls and young women with apparently delayed ovarian function, and it has been proposed that circulating AMH may help guide advice and practice (37Hagen C.P. Aksglaede L. Sorensen K. Mouritsen A. Juul A. Clinical use of anti-Mullerian hormone (AMH) determinations in patients with disorders of sex development: importance of sex- and age-specific reference ranges.Pediatr Endocrinol Rev. 2011; 9: 525-528PubMed Google Scholar). This may indeed be the case, but it is important to recognize that under normal circumstances much of the increase in circulating AMH arises after puberty. Consequently, it is imperative that the profiles of AMH through the early fertile years in the many different clinical circumstances are ascertained with clarity. Considering that the condition of polycystic ovary syndrome (PCOS) is associated with elevated concentrations of circulating AMH and numbers of small antral follicles in the mature woman (38Dewailly 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: 3123-3129Crossref PubMed Scopus (326) Google Scholar), it becomes imperative to ascertain the profiles of AMH in these women as they proceed from puberty to maturity. The aim would be to determine the contributions of increased follicular survival in the peripubertal and postpubertal years, and/or increased size of the primordial follicle pool from birth, as both, either independently or in combination, should result in increased AMH concentration and antral follicle cohort size. As the relationship between AMH and follicle numbers is stage specific, their differing relations through the stages need to be determined, and specific phenotypes explored. In the healthy girl, by the time of the pubertal plateau in AMH level the size of the primordial follicle pool has declined by approximately 75% and the number of follicles initiating growth and development is at its maximum. The means by which the AMH profile, during the next decade or so, can attain values associated with PCOS can include a number of possibilities and combinations. The primary suggestion would be a larger starting cohort (39Webber L.J. Stubbs S. Stark J. Trew G.H. Margara R. Hardy K. et al.Formation and early development of follicles in the polycystic ovary.Lancet. 2003; 362: 1017-1021Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 40Maciel G.A.R. Baracat E.C. Benda J.A. Markham S.M. Hensinger K. Chang R.J. et al.Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2004; 89: 5321-5327Crossref PubMed Scopus (170) Google Scholar). An alternative explanation would be an exaggerated secondary increase due to increased activity or sensitivity to the "survival-promoting factors," perhaps stimulated by androgenic action (41Abbott D.H. Tarantal A.F. Dumesic D.A. Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys.Am J Primatol. 2009; 71: 776-784Crossref PubMed Scopus (132) Google Scholar). Increased GC secretion of AMH in PCOS may compound this factor (42Pellatt L. Hanna L. Brincat M. Galea R. Brain H. Whitehead S. et al.Granulosa cell production of anti-Mullerian hormone is increased in polycystic ovaries.J Clin Endocrinol Metab. 2007; 92: 240-245Crossref PubMed Scopus (362) Google Scholar). However, a new potential hypothesis presents itself from these observations. If puberty, and thus the secondary pubertal increase in AMH, is delayed, the primordial follicle pool will be significantly smaller at the start of the secondary increase, and it would be expected that the early adult AMH peak would be lower. Conversely, girls entering puberty earlier will have a larger follicle pool and a greater secondary AMH "potential." Thus, the subsequent AMH peak will be dictated by the timing of the pubertal plateau (i.e., the age at which the secondary increase begins). In the median circumstances shown in Figure 1, the pool will decline by 10%–20% across the age range shown. Variations and combinations of these models will exist leading to different phenotypes. Thus, the hyperandrogenic individual with consequent increased survival factor drive may have an increased AMH concentration relative to her primordial pool size, whereas the woman with high AMH level and high antral follicle count, but with normal ovulatory frequency and androgen profiles may derive simply from normal survival factor activity superimposed on a larger primordial follicle pool size. There will be a number of hypotheses worthy of investigation subsequent to these observations, which may help in our understanding of the range of phenotypes in PCOS. One potential outcome of these studies would be to ascertain whether AMH can be used to predict the possibility of PCOS in adolescents or even in children. Increased understanding of the local regulation of follicle development and interaction with AMH production will also shed light on the pathophysiology of PCOS. We have previously demonstrated a wide variation in the rates of follicular recruitment depending on the age of the menopause (7Wallace W.H. Kelsey T.W. Human ovarian reserve from conception to the menopause.PLoS One. 2010; 5: e8772Crossref PubMed Scopus (458) Google Scholar), and AMH has been shown to have strong predictive potential, depending on age (43Freeman E.W. Sammel M.D. Lin H. Gracia C.R. Anti-mullerian hormone as a predictor of time to menopause in late reproductive age women.J Clin Endocrinol Metab. 2012; 97: 1673-1680Crossref PubMed Scopus (195) Google Scholar). Consistent with this is the observation that women with a lower follicular recruitment (i.e., a reduced number of oocytes retrieved in the context of IVF) are at increased risk of an earlier menopause (44de Boer E.J. den Tonkelaar I. te Velde E.R. Burger C.W. Klip H. van Leeuwen F.E. A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause.Fertil Steril. 2002; 77: 978-985Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 45Lawson R. El-Toukhy T. Kassab A. Taylor A. Braude P. Parsons J. 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: 527-533Crossref PubMed Scopus (97) Google Scholar). Collectively, this suggests that either the woman with an early menopause began life with a smaller primordial follicle pool, or that she failed to undergo the postpubertal increase in follicular survival shown by the normal woman, or both. The fact that women who smoke show both a lower AMH level and an early menopause suggests that follicular survival at least plays a significant role in this phenomenon. The evidence supporting the use of AMH level to predict the age of the menopause is growing (30van Rooij I.A. Tonkelaar I. Broekmans F.J. Looman C.W. Scheffer G.J. de Jong F.H. et al.Anti-mullerian hormone is a promising predictor for the occurrence of the menopausal transition.Menopause. 2004; 11: 601-606Crossref PubMed Scopus (243) Google Scholar, 31van Disseldorp J. Faddy M.J. Themmen A.P. de Jong F.H. Peeters P.H. van der Schouw Y.T. et al.Relationship of serum antimullerian hormone concentration to age at menopause.J Clin Endocrinol Metab. 2008; 93: 2129-2134Crossref PubMed Scopus (218) Google Scholar, 46Sowers M.R. Eyvazzadeh A.D. McConnell D. Yosef M. Jannausch M.L. Zhang 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: 3478-3483Crossref PubMed Scopus (300) Google Scholar), with larger studies clearly demonstrating that it adds to rather than replaces age (43Freeman E.W. Sammel M.D. Lin H. Gracia C.R. Anti-mullerian hormone as a predictor of time to menopause in late reproductive age women.J Clin Endocrinol Metab. 2012; 97: 1673-1680Crossref PubMed Scopus (195) Google Scholar). Large cohort studies to explore this in more detail are required, and these should include evaluations in the peripubertal/immediate postpubertal years to establish clearly at what age and stage of sexual maturity we can use AMH level as a guide for reproductive lifespan advice. In conclusion, the changes in the relationships between circulating AMH levels, the size of the primordial follicle pool, and follicular recruitment before and through the reproductive years have now been clarified, and show dynamic changes through sexual development. The constant relationship between the number of follicles and circulating AMH levels exists only after the age of 25 years. The implications of the different relationships seen before this age require more research to answer a number of important questions with direct and indirect clinical implications.
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