BIOLOGY OF REPRODUCTION (2014) 90(4):85, 1–11 Published online before print 5 March 2014. DOI 10.1095/biolreprod.113.117077

Minireview The Ovarian Reserve of Primordial Follicles and the Dynamic Reserve of Antral Growing Follicles: What Is the Link?1 Danielle Monniaux,2,3,4,5,6 Fre´de´rique Cle´ment,7 Rozenn Dalbie`s-Tran,3,4,5,6 Anthony Estienne,3,4,5,6 Ste´phane Fabre,3,4,5,6 Camille Mansanet,3,4,5,6 and Philippe Monget3,4,5,6 3

in our knowledge of signaling pathways and their environmental and hormonal control during adult and fetal life opens new perspectives to improve the management of the ovarian reserves.

ABSTRACT The growing follicles develop from a reserve of primordial follicles constituted early in life. From this pre-established reserve, a second ovarian reserve is formed, which consists of gonadotropin-responsive small antral growing follicles and is a dynamic reserve for ovulation. Its size, evaluated by direct antral follicular count or endocrine markers, determines the success of assisted reproductive technologies in humans and embryo production biotechnologies in animals. Strong evidence indicates that these two reserves are functionally related. The size of both reserves appears to be highly variable between individuals of similar age, but the equilibrium size of the dynamic reserve in adults seems to be specific to each individual. The dynamics of both follicular reserves appears to result from the fine tuning of regulations involving two main pathways, the phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3 kinase (PI3K)/3phosphoinositide-dependent protein kinase-1 (PDPK1)/v-akt murine thymoma viral oncogene homolog 1 (AKT1) and the bone morphogenetic protein (BMP)/anti-Mu¨llerian hormone (AMH)/SMAD signaling pathways. Mutations in genes encoding the ligands, receptors, or signaling effectors of these pathways can accelerate or modulate the exhaustion rate of the ovarian reserves, causing premature ovarian insufficiency (POI) or increase in reproductive longevity, respectively. With female aging, the decline in primordial follicle numbers parallels the decrease in the size of the dynamic reserve of small antral follicles and the deterioration of oocyte quality. Recent progress

aging, anti-Mu¨llerian hormone, follicular development, ovary, premature ovarian failure

INTRODUCTION Antral follicle count (AFC) has been the subject of increasing interest during the last decade in humans and large mammals. From the improvement of ovarian ultrasonography and the validation of new endocrine markers, it is now possible to evaluate the number of antral follicles larger than 1 mm in diameter present in the ovaries of women and large domestic or wild species [1, 2]. Presently, this evaluation is a routine practice of primary importance to estimating the ovarian activity of individual females for clinical or breeding applications. AFC helps the clinicians to establish a diagnosis for female infertility, and it participates in predicting the reproductive capacity of both human and animal species [3, 4]. AFC can also predict the ovarian response of an individual to gonadotropin-based stimulatory treatments, hence the success of assisted reproductive technologies in humans and embryo production biotechnologies in farm and wild animals [5, 6]. In all species, the antrum cavity is formed when the growing follicle reaches a diameter between 200 and 300 lm. The antrum grows by accumulating fluid derived from blood flowing through the thecal capillaries and secretion products of follicular cells; some of them, such as hyaluronan and proteoglycans, generate an osmotic gradient that participates in antrum growth [7]. In humans and large mammals, the follicles grow slowly after antrum formation up to the stage when they become gonadotropin dependent and enter a phase of rapid terminal development, occurring in a wave-like pattern [8–10]. Gonadotropin dependence is acquired at a given follicular diameter, characteristic of each species (e.g., 200 lm in rodents, 1 mm in pig, 2 mm in sheep, 3–5 mm in human and cow, and about 10 mm in horse [11]). Below this diameter, the small antral follicles constitute a pool of gonadotropinresponsive follicles, which is the reserve for ovulation and ovarian biotechnologies. This is a dynamic reserve, since it is

1

Supported by the INRA Prediction of Ovulation (PREDICTOV) project, by the Regulation of the Gonadotrope Axis (REGATE) INRIA/INRA Large Scale Initiative Action, by the Agence Nationale pour la Recherche (ANR-2010-BLAN-1608-01) and by French fellowships from the Re´gion Centre and INRA to A.E. and C.M. 2 Correspondence: Danielle Monniaux, Physiologie de la Reproduction et des Comportements, Centre INRA Val-de-Loire, 37380 Nouzilly, France. E-mail: [email protected] Received: 20 December 2013. First decision: 30 January 2014. Accepted: 19 February 2014. Ó 2014 by the Society for the Study of Reproduction, Inc. eISSN: 1529-7268 http://www.biolreprod.org ISSN: 0006-3363

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Institut National de la Recherche Agronomique (INRA), UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France 4 Centre National de la Recherche Scientifique (CNRS), UMR7247, Nouzilly, France 5 Universite´ Franc¸ois Rabelais de Tours, Tours, France 6 Institut Franc¸ais du Cheval et de l’Equitation (IFCE), Nouzilly, France 7 Institut National de Recherche en Informatique et en Automatique (INRIA), Paris-Rocquencourt Research Centre, Le Chesnay, France

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Downloaded from www.biolreprod.org. FIG. 1. Compared oogenesis and folliculogenesis: Temporal sequence of events in the life of different mammals. For each species, the developmental phases corresponding to 1) meiosis initiation and formation of the reserve of primordial follicles, 2) folliculogenesis before puberty, and 3) folliculogenesis and occurrence of ovulation after puberty are mapped as blue, green, and orange bars, respectively. Ages are indicated under the bars. Before birth, ages are indicated as days postconception (dpc). After birth, ages are indicated as days, months, or years. The boundary between the blue and green bars corresponds to the stage at which most primordial follicles have been formed. Follicles can enter growth before the complete setting up of this reserve (as illustrated in Fig. 2). The boundary between the green and orange bars corresponds to the first occurrence of complete follicular development culminating in ovulation. In most species, the reserve of primordial follicles is formed before birth or in the early postnatal period; however, meiosis is initiated only after birth in rabbit. The complete exhaustion of the reserve occurs only in humans and some primates, likely associated with their long life span. Adapted from Monniaux et al. 1997 [11] and Maule´on 1969 [13] with permission.

emptied by the cyclic follicle-stimulating hormone (FSH)orchestrated entry of follicles in the follicular waves of terminal development, and renewed by the continuous growth of smaller follicles [12]. When clinicians and zootechnicians talk about ovarian reserve, they usually refer to this dynamic reserve of small antral follicles. However, the wording ‘‘ovarian reserve’’ can be confusing, since the growing follicles themselves develop from a first reserve of primordial follicles, which is constituted early in life. In this review, we consider these two different ovarian reserves: the former, the pre-established reserve of primordial follicles, and the latter, the dynamic reserve of small antral follicles. The subject of this review concerns the general features of these reserves, the tools available for evaluating

them quantitatively and qualitatively, their interrelationships, and the regulation of the transitions between reserves throughout life in physiological, pathological, and experimental situations. THE PRE-ESTABLISHED RESERVE OF PRIMORDIAL FOLLICLES The setting up of the reserve of primordial follicles occurs during fetal or neonatal life in all mammals, but the timing of the processes underlying the formation and the exhaustion of the reserve is clearly species specific [13] (Fig. 1). In all species, the formation of the germ cell reserve, called oogenesis, begins with the migration of primordial germ cells 2

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FIG. 3. Numerical changes in the ovarian reserve of germ cells throughout life in humans. Data were obtained by histological analyses. Months p.c., months postconception. Adapted from Baker 1963 [25] with permission.

FIG. 2. Histological appearance of pig ovarian cortex during oogenesis and after puberty. A) Formation of primordial follicles and follicle growth activation in the ovarian cortex of a 21-day-old immature piglet. At this stage, oogenesis and folliculogenesis coexist within the ovarian cortex. Proliferating oogonia, oocytes in meiotic prophase, primordial follicles, and early growing follicles are located according to a centripetal gradient of development and growth activation. B) Ovarian cortex of a 6-mo-old (young adult) gilt. At this stage, oogenesis has been completed, and the ovarian cortex has enlarged and contains a lower density of primordial follicles in the vicinity of growing follicles. a, antrum of a small antral follicle; bv, blood vessels; g, granulosa; gf, growing follicles; mp, oocytes in meiotic prophase; o, oogonia; oe, ovarian epithelium; pf, primordial follicles; t, theca. Bar ¼ 100 lm. (Estienne and Monniaux, unpublished pictures.)

into the gonadal ridges and their proliferation as oogonia within ovarian nests or cysts. Then oogonia enlarge and develop into primary oocytes, which initiate meiotic prophase. The breakdown of the cysts leads to the formation of 30-lmdiameter primordial follicles, each one consisting of a primary oocyte arrested at the diplotene stage of prophase I of meiosis, surrounded by one layer of somatic cells, the pregranulosa, the cellular origin (ovarian or mesonephric surface epithelial cells) of which remains the subject of controversy [14, 15]. Abnormal follicle formation is associated with a massive loss of oocytes at this stage. After forming, the primordial follicles may begin to grow either immediately or after a gap, depending on the species [16]. Alternatively, they become quiescent. In this latter case, they will either degenerate or resume their growth several months or years later. The molecular mechanisms underlying 3

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oogenesis and follicle growth activation have been the subject of recent reviews [17–20]. Each stage of oogenesis overlaps in time with the preceding and the following ones. Oogonia, oocytes in meiotic prophase, primordial follicles, and growing follicles can coexist in the ovarian cortex during oogenesis. Interestingly, they are located according to a centripetal gradient of development and growth activation (as in the rat [21] and mouse [22, 23]). For instance, in the ovarian cortex of piglets, the first growing follicles (which were the first to be formed) are found in the deepest part of the cortex, near the medulla, whereas proliferating oogonia are located close to the ovarian epithelium (Fig. 2A). By comparison, the ovarian cortex of young adults has clearly enlarged and lost its previous spatial organization (Fig. 2B). It contains a lower density of quiescent primordial follicles, often grouped in nests [24], in the vicinity of growing or degenerating preantral and antral follicles. Oogenesis and folliculogenesis are directly responsible for the changes in germ cell numbers observed in ovaries during fetal and postnatal life (e.g., human [25] and cow [26]) (Fig. 3). After a huge peak of germ cells early in life, the reserve decreases sharply with time, falling to 300 000 at puberty and being nearly exhausted at menopause in humans and some primates [27]. Germ cell renewal by neo-oogenesis has been proposed as a possible mechanism to replenish the pool [28, 29]; however, the importance of this process remains disputed [18, 20, 30]. Considering the low number of follicles that will actually undergo development until ovulation (approximately 500 ovulations in a woman’s life), the follicular reserve at puberty appears greatly oversized. Whether the exhaustion of the reserve is complete or incomplete depends on the loss rate and growing speed of the follicles on the one hand, and the lifetime of the species on the other. The size of the reserve of primordial follicles seems to be quite variable between individuals of the same species. From the few available histological analyses, more than 20-fold individual variations in follicle numbers have been reported at birth as well as at puberty (e.g., human [31] and cow [3]). In humans, without considering the pathological situations of POI, the large numerical differences existing between individuals at a young age may have important functional consequences on the length of the reproductive lifespan [31, 32].

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FIG. 4. Relationship between the numbers of small antral follicles and plasma AMH concentrations in three ruminant species. A) In Holstein cows (n ¼ 18), follicles were counted by ovarian ultrasonography. B) In Saanen goats (n ¼ 15) and (C) in Merinos d’Arles ewes (n ¼ 12), follicles were counted after dissection from ovaries recovered from animals at slaughter. AMH concentrations were determined in plasma samples recovered at the time of follicular counting. Each square represents data from one animal. The correlation coefficients in cows, goats, and sheep were 0.79 (P , 0.001), 0.89 (P , 0.001), and 0.62 (P , 0.05), respectively (Estienne and Fabre, unpublished results in C, and data in A and B adapted from Monniaux et al. 2013 [50] with permission).

THE DYNAMIC RESERVE OF SMALL ANTRAL FOLLICLES The size of this reserve, estimated by AFC, appears to be highly variable between individuals of similar age (e.g., human [34] and cow [35–37]). As the small antral follicles are the direct targets of gonadotropin treatments, the large betweenindividual variability in their numbers constitutes the most limiting factor in the success of assisted reproductive technologies in humans [38–40] and embryo production biotechnologies in other animals [36, 41–45]. Presently, AFC can be performed by two different methods: ovarian ultrasonography, which provides accurate estimations of follicle numbers, and the measurement of endocrine markers, giving an indirect estimate of the reserve size. Concerning the latter approach, the measurement of FSH and inhibin in serum can help to make a diagnosis, since the combination of high FSH and low inhibin concentrations are indicative of low numbers of growing follicles, yet they are not the most accurate markers. It is now well established that AMH is the best endocrine marker of the population of small antral follicles in humans [46, 47] as well as in ruminants [37, 48, 49] (Fig. 4). The close relationship existing between AFC and AMH is explained by the facts that 1) AMH expression in female mammals is strictly restricted to granulosa cells of growing follicles and 2) the granulosa cells of the largest preantral and the small antral healthy growing follicles express the highest amounts of AMH in ovaries [50]. In the ovaries of young adults, both direct (AFC) and indirect (AMH concentrations) estimations of the size of the reserve of small antral follicles have highlighted little numerical change with time. For example, in cows, a high individual repeatability of both AFC [35] and AMH plasma concentrations [37, 51, 52] has been observed over several months and up to 1 yr. Moreover in the goat, a species that 4

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presents a seasonal breeding activity, plasma AMH concentrations show little change with season [49]. Therefore, it can be assumed that the population of small antral follicles remains in a dynamic balance, with exits numerically compensated by entries, and that the equilibrium size of this dynamic reserve is specific to each individual. The mechanisms regulating the size of the dynamic reserve are not fully understood. Interestingly, in young adult heifers, animals with low numbers of primordial follicles also have highly reproducible low AFC [53]. Moreover, when considering populations of individuals with different ages, highly significant correlations have been found between the numbers of primordial follicles and AFC in mice [54] and humans [55]. Altogether, these observations strongly indicate that the preestablished and dynamic reserves are functionally related. It is amazing that the size of the reserve of primordial follicles formed early in life can be related to, and even seems to determine, the ovarian activity of the adult. In fact, this relationship likely implies that finely tuned regulation of germ and somatic cell survival, proliferation, and/or differentiation involves the same factors and the same molecular mechanisms from the formation of the primordial follicles up to the stage when the follicles become gonadotropin dependent and enter terminal development. From the available data, two main signaling pathways play major roles in all these processes. The first one is the PTEN/PI3K/PDPK1 (previously known as PDK1)/AKT1 (previously known as AKT or PKB) signaling pathway, which regulates germ cell survival, as well as follicular growth activation [56–59] and follicle growth [60]. This pathway is activated by various hormones, growth factors, and cytokines. Among them, insulin, insulin-like growth factors (IGF), and KIT ligand are known to be key regulating factors of the survival and differentiation of germ and somatic ovarian cells [18, 61, 62]. The second important signaling pathway involves SMAD (vertebrate homolog of Mothers Against Decapentaplegic [MAD]) transcription factors, which are activated by factors of the transforming growth factor-b (TGFB) super family (i.e., BMP and AMH for the SMAD1/5/8 pathway), and the TGFB and activins for the SMAD2/3 pathway. It orchestrates the formation and development of follicles under the control of oocyte- (BMP15, GDF9) and somatic cell (BMP2, BMP4, AMH, activins) -derived factors, which have been the subject of many recent investigations [63– 67], including a multiscale modeling approach focused on the coupling between somatic cell kinetics and oocyte growth [68]. The main endocrine and paracrine mechanisms regulating the

Despite its indisputable interest, an accurate estimation of the size of the reserve of primordial follicles of an individual remains difficult, due to the lack of molecular markers. From the results of a recent study combining laser capture microdissection with transcriptome analysis in sheep ovary, oocyte-specific factors, such as DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 (DDX4) (previously known as VASA), which was found to be highly expressed in primordial follicles, might be proposed as possible molecular markers [33]; however, their validation as accurate markers of the reserve in a fragment of ovarian cortex remains to be assessed.

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dynamic reserve of small antral follicles are summarized in Figure 5. For each individual, the size of the dynamic reserve could result from the fine tuning of these regulations. Even if a longer interval from calving to conception has been reported in cows with low AFC [69], it can be noted that female fertility is generally compatible with a large range of AFC values in each species. Moreover, the number of ovulations (or natural ovulation rate) that is characteristic of each species, breed, or strain does not depend on the size of the dynamic reserve.

Rather, it results from mechanisms of follicular selection that have been described elsewhere [12, 70] and are outside the scope of this review. The existence of a large betweenindividual variability in the number of small antral follicles is generally masked in normal conditions, but is revealed when individuals are subjected to assisted reproductive technologies. For instance, in ruminants, animals with low AFC are poor embryo donors in the protocols of embryo production [42, 44, 49, 52, 71]. 5

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FIG. 5. Regulations of the transitions between the follicular reserves. A) Endocrine and paracrine regulations of the dynamic reserve of small antral follicles: main current hypotheses. The dynamic reserve is filled by growing follicles originating from the pre-established reserve of primordial follicles, which is gradually emptied by both follicle growth activation and follicle degeneration. The transition between the reserves is regulated by various growth factors, acting in a paracrine or/and endocrine way. Among them, activins and BMP are mitogenic and antiapoptotic factors for granulosa cells, whereas AMH produced by the granulosa cells of the large preantral and the small antral follicles restricts primordial follicle activation and modulates follicle development. During the transition between the reserves, the development of each growing follicle also depends, importantly, on the molecular dialog established between the oocyte that produces the bone morphogenetic factors GDF9 and BMP15 and its surrounding granulosa cells that secrete the oocyte growth promoting factor Kit ligand (KITLG). Insulin and IGF, acting mostly in an endocrine way, can support the development of the growing follicles by sensitizing their granulosa and theca cells to FSH and luteinizing hormone (LH), respectively. The dynamic reserve is emptied by the cyclic FSH-orchestrated entry of follicles in the follicular waves of terminal development. At this stage, a variety of intrafollicular regulation, involving particularly BMP, the inhibin/activin system, and the IGF system (IGFs and their binding proteins) can, importantly, modulate the gonadotropin-dependent differentiation of granulosa and theca cells, thus determining the fate of each antral follicle (i.e., atresia or development towards ovulation). B) Betweenindividual variations in the reserve sizes and transition rate between the reserves in a mono-ovulating species. One ovary per individual is schematized. Ovaries with a high reserve of primordial follicles display a high AFC. They waste their follicles as a result of the high recruitment and atresia rates of the primordial and growing follicles, respectively. In contrast, both processes are markedly slowed down in ovaries with a small-sized reserve, while intermediate situations with medium-sized reserves and moderate rates can also be encountered. The size of the dynamic reserve results from the fine tuning of the regulations described in A. The number of ovulations (one in this example) is independent of the size of the reserve.

MONNIAUX ET AL. TABLE 1. Experimental and natural mutations in genes encoding factors of the TGFB super family and their effects on the size of the two follicular reserves, the transition rate between them, and the occurrence of a premature depletion. Animal species and genetic model /

First reserve*

Mouse, Amh

Normal

Mouse, Inha/ Mouse, Bmp15/

Normal Normal

Mouse, Bmp15 overexpression

Normal

Mouse, Gdf9/ Mouse, Gdf9þ/ Mouse, Inha /Gdf9/ Mouse, Bmp15/Gdf9þ/ Sheep, BMP15 homozygous loss-of-function mutations Sheep, GDF9 homozygous loss-of-function mutations Sheep, BMP15 heterozygous loss-of-function mutations Sheep, BMPR1BQ249R partial loss-of-function mutation

Normal Normal Normal Normal Normal Normal Normal Low

Transition rate

Premature depletion 

Second reserve$

References

Accelerated rate and increased atresia Accelerated Fairly normal

High

Yes

[73, 74]

High Normal to low

[76] [82]

Accelerated rate and increased atresia No transition Normal Accelerated Increased atresia No transition No or few transition Unknown Slow

Normal

ND Reported in some animals Yes

0 Normal Normal Low 0 0 to very low High High

/ No ND Yes / / No No

[79] [79] [75, 77] [82] [83–85] [80, 81] [91, 92] [84, 92, 93]

[78]

* The pre-established reserve of primordial follicles. The dynamic reserve of small antral follicles.   ND, not determined, due to the premature death of animals by tumor development. $

As shown in the mouse genetic models described above, it is unusual to have beneficial effects of mutations on AFC without adverse side effects on the ovarian reserves in the long term (Table 1). However, in sheep carrying either heterozygous lossof-function BMP15 mutations or the BMPR1BQ249R partial lossof-function mutation, high AFC is not accompanied by the premature depletion of the reserves [84, 91–93]. Rather, in the latter genetic model, despite the presence of a low reserve of primordial follicles at birth, the ovarian reserves at 5 yr of age are higher in ewes carrying the mutation, suggesting that attenuation of the intraovarian signaling pathway of BMPs may in fact be a successful means of limiting follicle consumption, hence preserving reproductive longevity and fertility [93]. Another promising way to increase the lifespan of the ovarian reserves was proposed from the dramatic prolongation of the ovarian lifespan observed after Bax deletion in mice, suggesting that the mitochondrial factors of the Bcl2 family or the death effector caspase cascade could modulate numerical changes in the ovarian reserve through their pro- or antiapoptotic actions [94, 95]. However, up to now, no mutations in apoptosis regulator genes have been found to be associated with the exhaustion rate of the ovarian reserves in humans, so their importance in POI syndrome remains hypothetical.

Both ovarian reserves are exhausted at menopause in humans and some primates, unlike in most mammals (Figs. 1 and 3). In some pathological situations, a premature depletion of follicles is observed, which affects approximately 1%–2% of women under the age of 40 yr and results in POI. Some genetic component has been evidenced among the possible causes of POI [72]. Various natural or experimentally induced mutations in genes encoding the ligands, receptors, or signaling effectors of the PTEN/PI3K/PDPK1/AKT1 or the SMAD signaling pathways can accelerate the exhaustion rate of the ovarian reserves and cause POI. The deletion of Pten, PDPK1, Ribosomal protein S6 (Rps6), or Forkhead box O3 (Foxo3, previously known as Foxo3A) in mouse oocytes induces a dramatic activation and/or premature loss of the primordial follicles, resulting in POI around the onset of sexual maturity [56–58]. In regard to the SMAD pathway, no data are available on the exhaustion rate of the reserve of primordial follicles in Smad mutant mice [66]. However, mutations in some factors of the TGFB super family have been shown to affect the transition of growing follicles between the two follicular reserves (Table 1). In mice, the deletions of Amh [73, 74] or Inha [75–77], as well as the overexpression of Bmp15 [78], accelerate this transition, resulting in a premature depletion of the reserve of primordial follicles. In contrast, the deletion of Gdf9 blocks the growth of primary follicles, causing primary sterility [79], and a similar phenotype is observed in sheep carrying homozygous GDF9 mutations responsible for a loss of function of the protein [80, 81]. Interestingly, the transition of follicles between the reserves is not impaired in mice when Bmp15 is deleted [82], whereas it is completely blocked in sheep carrying homozygous loss-of-function mutations in BMP15 [83–86], indicating that the involvement of BMP15 in the control of follicular development is species specific. In humans, various mutations in BMP15 and, to a lesser extent, in GDF9 and INHA, have been found to be associated with POI [72, 87, 88], and genetic variants of AMH and its receptor AMHR2 are associated with different ages at menopause [89, 90], confirming the importance of these factors in the lifespan of the ovarian reserves.

DYNAMICS OF THE FOLLICULAR RESERVES DURING LIFE The reserve of primordial follicles is progressively depleted throughout life, but the activation rate of primordial follicles varies as the ovary ages. In the young ovaries, the follicles that were formed first during oogenesis in the deepest part of the cortex massively activate first (Fig. 2), and are then relayed by follicles located in outer parts of the cortex, and follicular activation rate is progressively reduced [21]. Based on a statistical study of the human ovarian reserve size from conception to menopause, the rate of follicular activation has been estimated to increase from birth until approximately age 14 yr, then to decrease toward menopause [31]. However, in another study, an accelerated decay rate of the reserve was found before menopausal transition, resulting from enhanced follicular activation rate in aging ovaries [96]. With aging, the decline in primordial follicle numbers parallels the decrease in 6

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OVARIAN RESERVE EXHAUSTION: GENETIC DETERMINISM

OVARIAN RESERVE AND ANTRAL FOLLICLES

size of the dynamic reserve of small antral follicles [97–99] and AMH blood concentrations [100, 101]. These numerical changes are accompanied by changes in the quality of the follicles of the dynamic reserve. In ruminants, oocytes recovered from small antral follicles before puberty display a suboptimal developmental competence in in vitro embryo production systems compared to oocytes from adults, and this poor oocyte quality is associated with differences in RNA stores [102]. Similarly, in humans, during childhood and adolescence there is a high proportion of morphologically abnormal follicles that show reduced capacity for in vitro growth [103]. In mice, the loss of follicles during the prepubertal period has been proposed to be an active process necessary to eliminate the follicles that are in excess, containing poor quality oocytes [104]. Compromised oocyte quality also occurs in aged ovaries [98, 105, 106], due to unfavorable microenvironment (vascularization defects, oxidative stress, influence of toxic compounds), leading to a high prevalence of aneuploidy [107]. During the premenopausal

period, the high FSH endocrine levels, resulting from the decline in the number of inhibin-secreting follicles, may also have deleterious effects upon follicle and oocyte quality [108, 109], while increasing multiple ovulations [110]. These qualitative and quantitative follicular changes contribute to female infertility and constitute an important limit to the success of assisted reproductive technologies in premenopausal women [111]. The dynamics of the follicular reserves and the associated endocrine changes throughout life are summarized in Figure 6. THE MANAGEMENT OF THE OVARIAN RESERVES: FUTURE DIRECTIONS As described above, the existence of a large, betweenindividual variability in AFC constitutes the most limiting factor in the success of assisted reproductive technologies [36, 38–45]. Moreover, between-individual variability in the transition rates between ovarian reserves and in the gonadotropin-regulated development of the antral follicles toward 7

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FIG. 6. Schematic representation of the ovarian reserves, including their exhaustion dynamics and associated endocrine changes in AMH, FSH, and inhibin throughout life. The reserves are represented by two tanks, the first containing the primordial follicles, which can either degenerate after activation and entry into growth or develop and enter the second tank, containing the small antral, gonadotropin-responsive follicles. The endocrine changes are represented by a balance between FSH and inhibin. The fulcrum of the balance is AMH, the endocrine levels of which are proportional to the number of healthy small antral follicles present in the second tank. Left panel: in early life, the first tank contains a high number of primordial follicles; most of the primordial follicles, which were formed first during oogenesis (red balls), are also the first to be activated and to enter the second tank. At that point, there is a burst of growing follicles, mirrored by high AMH endocrine levels and associated with high and low inhibin (INH) and FSH endocrine levels, respectively. These growing follicles enclose oocytes with suboptimal developmental competence after in vitro fertilization. In vivo, all growing follicles will degenerate by atresia before or after entering the second tank. Middle panel: in the adult age period, the number of primordial follicles has decreased and the first tank contains follicles formed later during oogenesis (green balls), which are able to give rise to growing follicles containing oocytes with optimal developmental competence. The second tank has reached an equilibrium size (with exits broadly compensated by entries), which is specific to each individual, correlated with the size of the first tank and mirrored by AMH endocrine levels. The antral follicles present in the second tank can enter terminal development, and some of them will be selected for ovulation. Right panel: in the presenescence period, the first tank contains a low number of aged primordial follicles (black balls), which are able to give rise to growing follicles containing low-quality oocytes. The second tank has a reduced size, associated with low to undetectable AMH endocrine levels that can, therefore, enhance follicular growth activation. The high FSH endocrine levels present at this stage could be responsible for the increased occurrence of multiple ovulations in mono-ovulating species during aging (period of premenopause in women).

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regulating their dynamics, new perspectives have been opened to improve the management of the ovarian reserves in the near future.

ovulation can account for important differences between females in fertility and longevity of reproductive function. This variability likely has strong genetic components, but the crucial question to answer now is: how to optimize the dynamics of the follicular reserves? One strategy is to target the PTEN/PI3K/PDPK1/AKT1 pathway, particularly by acting upon metabolism through environmental and hormonal factors. This can apply to the improvement of embryo production in animals, since increases in insulin and IGF1 consecutive to a short-term feeding regimen with a high energy intake (flushing) have been shown to increase AFC and the follicular responses to gonadotropins in ruminants [112, 113]. This could also be applied to human clinics, particularly to restore the fertility of women with polycystic ovary syndrome (PCOS), a common hyperandrogenic disorder often associated with metabolic alterations, chiefly insulin resistance and obesity. The ovaries of PCOS women are characterized by a slow transition between follicular reserves, blocking of antral follicular development, and anovulation despite a high AFC [114, 115]; interestingly, improving insulin sensitivity by dietary therapy and exercise regimens, or by administrating insulin-sensitizing drugs [116– 118], can mobilize the growing follicles and restore ovulation. In a very interesting complementary perspective, new treatments for PCOS patients have been proposed recently to reinforce the activation of AKT1 signaling; they consist of the local disruption of the Hippo signaling pathway regulated by actin polymerization, as AKT1 and Hippo pathways can act in concert to regulate follicular growth [119]. An alternative strategy is to target the BMP/AMH/SMAD pathway. For example, in sheep, it has been recently shown that the knockdown of AMH bioactivity by active immunization leads to a decline in the numbers of small growing follicles, but an increase in AFC and ovulation numbers [120]. In contrast, the administration of AMH would lower follicle growth activation and preserve more follicles for development later in life, thereby causing a delay in the onset of menopause, as hypothesized in a lifelong model for the female reproductive cycle [121]. From these studies, AMH knockdown may have short-term therapeutic value in women who respond poorly to ovarian stimulation, whereas AMH treatment might preserve the follicular reserves in the long term. From the sheep genetic models described above [84, 91–93], targeting the signaling pathway of BMPs by immunization or specific antagonists may also be a promising way to increase both AFC in the short term and reproductive longevity in the long term. Moreover, the discovery of epigenetic regulation has highlighted the importance of developmental programming for ovarian function. In sheep, testosterone exposure during fetal life causes reproductive and metabolic disruptions, reproducing the human PCOS syndrome in adult animals [122]. This experimental situation might reflect, at least partly, some pathological cases, since endocrine disorders of PCOS occur in female infants born to mothers with PCOS [115]. As another example, maternal nutrition and health during gestation in cows have been shown to influence AFC in prepubertal and adult offspring [123, 124]. All these observations indicate that interactions between genes and the maternal-fetal hormonal environment at the time of the formation of the reserve of primordial follicles may program postnatal ovarian function. In conclusion, the pre-established reserve of primordial follicles and the dynamic reserve of small antral follicles are functionally related and under both genetic and environmental control. From the recent improvements in the methods available to estimate the reserve size, and our increased knowledge of the cellular processes and signaling pathways

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