The Growth of Preantral Follicles and the Impact of Different Supplementations and Circumstances: A Review Study with Focus on Bovine and Human Preantral Follicles

Abstract

One of the most important concerns cancer survivors face is fertility. Current treatment modalities often result in damage to the reproductive system. Different options have been proposed to preserve the fertility of affected women, and many attempts have been made to improve their chance of childbearing after therapy. Cryopreservation of ovarian tissue and follicles before the onset of cancer treatment and then either transplantation of ovarian tissue or culture of ovarian tissue and individual follicles in vitro is a commonly cited approach. Extensive research is being done to design an optimal condition for the culture of ovarian follicles. Improving follicle culture systems by understanding their actual growth needs might be a crucial step toward fertility preservation in cancer patients. This review article will try to provide a summary of the role of different factors and conditions on growth of human and bovine preantral follicles in vitro.

Introduction

Oogenesis is one of the most mysterious processes in nature and is more complicated than it might appear. The oocyte is not only the largest human cell, but it also has the ability to transfer genomic material to next generation. To have this ability, oocyte must have some particular characteristics (i.e., the capacity to transmit genomic information to the next generation without dying and having the capacity to go through several cell divisions after fertilization without the need for, but definitely capable of, transcription).

In mammals, before birth, most of follicles are in the primordial stage which one layer of follicular cells surrounds oocytes (Larsen, 2001). Then, after birth and puberty, a small cohort of follicles is recruited for further development monthly. In preantral stage (Secondary follicles), oocytes are covered by more than one layer of cuboidal granulosa cells (GCs), and oocytes have located centrally within preantral follicles.

At this stage, the oocyte grows, synthesizes, and stores mRNA for further development of the embryo following fertilization (Larsen, 2001). There are multiple studies which focused on later phases of follicle development (antral and preovulatory follicles), but on the contrary, very little is known about preantral follicles development and culture conditions can support further growth of both follicles and oocytes beyond the early preantral follicles stages and their exact maintenance requirements during in vitro culture (IVC) (Telfer and Zelinski, 2013).

Over the past two decades, there has been increased interest in studies regarding the application ovarian follicles as a great potential source for improved reproductive efficiency of domestic animals and protection of endangered species from extinction as well as fertility recovery in women who suffer from malignancy after radiation or chemotherapy procedures. In addition, advances in cryopreservation of ovarian tissue and follicles methodologies and Advances in anticancer treatments have increased the survival rates in children and adolescents with cancer and hopes in the area of reproductive science and infertility treatment (Feigin et al., 2008). Nevertheless, insufficient knowledge about follicle development and their standard requirements, especially in larger mammals, has indeed limited further progresses in this area.

Previous attempts on culture of primordial follicles taught us that isolated primordial follicles won't survive, grow, or produce mature, meiotically competent oocytes under standard in vitro conditions (Abir et al., 1997; Gosden et al., 2002; Smitz et al., 2010). Based on these results, two-step culture method was developed so that in the first step, immature primordial and primary follicles are activated and grown to the early antral stage within their native environment in the ovary and then in the second step their cumulus-oocyte complexes are retrieved for in vitro maturation (IVM) (Eppig and O'Brien, 1996; O'Brien et al., 2003). Apart from this strategy, individual preantral follicles also can be isolated from ovary and cultured in in vitro condition (Abir et al., 1997; Jewgenow and Paris, 2006; Mochida et al., 2013).

Different independent labs all over the world are trying to successfully culture preantral follicles and define appropriate IVC conditions that allow the preantral follicles to survive and grow. However, previous results indicate that the success rate of preantral follicles in culture varies depending on the particular animal being harvested. By examining relevant data, it is quite apparent that the success rate is lower in cattle in compared to other species such as goats (Magalhães et al., 2011a; Saraiva et al., 2010), sheep (Arunakumari et al., 2010; Luz et al., 2012), and mice, which live birth has been reported only in the later species from culture of primordial follicles in situ of ovarian tissue in fresh (Eppig and O'Brien, 1996; O'Brien et al., 2003) and frozen-thawed mouse ovaries (Mochida et al., 2013).

Abir et al. (2006, 2017) believe that to evaluate the effects of different factors on improvement of follicles and oocytes development, the best-optimized method is culture of ovarian strips, even freshly or in cryopreserved-thawed samples, and then isolation and culture of preantral follicles derived from those samples following in vitro fertilization (. Alongside these sterategies, there is another possibility to examine effects of differenet supplementations on growth and development of preantral follicles which is preantral follicles isolation and culutre ex vivo (Araújo et al., 2014a).

The successful production of healthy offspring after the culture of primordial follicles only has been reported in mice (O'Brien et al., 2003). However, there are some limited achievements within farm animals, from culture of preantral follicles, for instance, the production of embryos in goats (Magalhães et al., 2011b; Saraiva et al., 2010), sheep (Arunakumari et al., 2010) and buffaloes (Gupta et al., 2008). Meanwhile, only growth and antral cavity formation were achieved in the culture of preantral follicles in cattle (McLaughlin et al., 2010a).

In human, the most remarkable achievement is production of meiotically competent human oocytes in alginate encapsulation which is obtained through two-step IVC of mechanically isolated human preantral follicles (Xiao et al., 2015). Therefore, the development and optimization of IVC and non-invasive routine preantral follicle quantity and quality assessment methods might be one of the next possible steps in fertility preservation and restoration strategies in women.

Ovarian tissue cryopreservation using a large quanity of preantral follicles followed by IVC of follicles and IVM of oocytes is one the furure promising methods for preservation of fertility in young patients before abdominal surgery or aggressive chemo- and/or radiotherapy procedures which partially or entirely destroy their follicular reserve. Although, the progress in this area is very slow with tiny steps causing attentions turn into artifial ovary (Amorim et al., 2008; Dolmans et al., 2005; Soares et al., 2015), however this strategy could bypass the risk of reseeding cancer through re-implantation of ovarian tissue (Donnez et al., 2006, 2013; Jensen et al., 2017). Therefore, development of an optimal IVC system can improve the efficiency of fertility restoration, as well as minimize the risk of the reintroduction of cancer cells through ovarian tissue autotransplantation.

As we have stated earlier, IVC can be used as a tool which allow investigators to evaluate the effects of different factors (secreted by stromal cells or other follicles or even other organs) on growth and maturation of follicles and oocytes. In this review study, we have focused largely on the effects of the various supplementations and conditions on the growth of human and bovine preantral follicles, along with their possible mechanism of actions. Some factors such as gonadotropins and growth hormone (GH) will be considered earlier, because of their important roles in early follicular development. Then hormones and growth factors will be discussed subsequently.

In Table 1, we have summarized the effects of other factors that may have impacts on preantral follicles growth, however, we know very little about their explicit roles. To identify relevant papers to our review study, a computerized literature search was performed from 1998 until 2017, on PubMed and MEDLINE using single or combination of the following keywords: preantral follicle, in vitro growth requirements, fertility preservation, follicle in vitro growth and culture, ovarian tissue cryopreservation, oocyte maturation and bovine and human ovarian physiology.

Table 1.

A Summary of the Effect of Some Important Factors on the Growth of Ovarian Preantral Follicle and Their Presumptive Mechanism of Action

Supplement	Species and Reference	Main function (s)	Presumptive mechanism of action
Somatotropin	Cattle (Gong et al., 1991, 1994; Herrier et al., 1994)	Increase the number of small follicles and peripheral insulin concentrations as well as enhance the recruitment of small follicles.	Somatotropin maybe affects the recruitment of small follicles by increasing peripheral concentrations of IGF-I, or of insulin or both concentrations.
Steroids
Estrogen	Bovine (Hulshof et al., 1995)	Augment of preantral follicle growth caused by an increase in GC size.	The stimulatory effects of steroids on the growth of preantral follicles are mostly due to increase in GC size, not GCs proliferations.
Estrogen	Bovine (Hulshof et al., 1995)	Estradiol (10⁻⁸ M) enhances small preantral follicles (30–70 μm) diameter during a culture period of 7 days.
Androgens	Bovine (Yang and Fortune, 2006)	Testosterone can promote the primary to secondary follicle transition in the culture of cortical fragments.	Acting through the AR, promote the growth of primate preantral follicles by amplifying the effects of FSH.
Androgens	Monkey (Vendola et al., 1998)	During 3 or 10 days of ovarian culture, testosterone increases total numbers of non-resting follicles, and numbers of primary, preantral, preantral, and small antral (but not preovulatory) follicles as well as granulosa and theca cell proliferation.
Kit and KL	Bovine (Wandji et al., 1996; Parrott and Skinner, 2000)	Activation of almost all of primordial follicles in pieces of ovary spontaneously.	Maybe due to anti-apoptotic actions of KL.
Kit and KL	Bovine (Wandji et al., 1996; Parrott and Skinner, 2000)	The addition of KL to the culture medium of strips of bovine ovarian cortex recruits theca cells to surround primary follicles and increase [³H] thymidine incorporation by bovine stromal cells in monolayer culture in a dose-dependent manner.	Maybe due to anti-apoptotic actions of KL.
FBS	Bovine (Hulshof, et al., 1995)	The addition of 10% FBS into media will increase follicle diameter and percentage of BrdU-labeled cells as well as the number of cells per area granulosa. Elimination of serum from the culture medium will not affect the percentage of labeled cells, but the diameter increase is lower, and the cells are smaller.	Apparently, serum affects the size of the GCs from small preantral follicles rather than the stimulation of cell proliferation.
bFGF	Bovine (Neufeld et al., 1987; Wandji et al., 1996)	bFGF (50 ng/mL) enhances thymidine incorporation by GCs in bovine preantral follicles. bFGF is also able to slightly maintains survival rate in bovine preantral follicles. Meanwhile, bFGF strongly inhibits the effect of FSH on progesterone secretion.	Due to proliferation effects of bFGF on GCs.
	Bovine (Neufeld et al., 1987; Wandji et al., 1996)		Keratinocyte growth factor may play a role in the growth of follicles by promoting GC proliferation, suppressing apoptosis in preantral follicles, and enhancing early follicle cell differentiation.
	Human (Garor et al., 2009; Wang et al., 2014)
	Bovine (Parrott and Skinner, 1998)
		Also, bFGF maintains follicular survival, promotes in vitro growth of GCs, and increases the diameter of bovine preantral follicles.
		200 ng bFGF/mL would increase the diameter, viability and survival rate of the follicles as well as the percentage of follicles in the pre-antral stage during 8 days of culture.
		bFGF plays a critical role in the E2 secretion by early follicles. Higher doses of bFGF enhance follicular development in serum-free media.
		Keratinocyte growth factor, as a number of the heparin-binding fibroblast growth factor family (FGF-7), directly stimulates GC proliferation and indirectly inhibits GC differentiated functions.
cAMP	Human (Zhang et al., 2004)	During 14 days of ovarian cortical slices culture, cAMP is able to increase the proportion of secondary follicles to primordial follicles and follicle viability as well on the day of 21.	cAMP is one of the important elements of an intracellular cascade of FSH and therefore cAMP might replace at least some FSH action of early follicular development.
Fresh vs. Cryopreserved	Bovine and human (Kagawa et al., 2009; Paynter et al., 1999; Silva et al., 2009)	Different studies have shown that there is no significant difference for follicular damage, oocyte viability following freezing-thawing of ovarian fragments with those freshly cultured. These data indicate that it is possible to freeze/thaw bovine ovarian tissue while retaining a reasonable yield of morphologically intact follicles.	It seems that detrimental effects of freezing-thawing cycle are not as destructive as it can reduce the survival and growth rate significantly in cultured isolated follicles or ovarian tissues, however, there are some reports showing that ultrastructureally, cheeling would affect follicles during vitrification (Salehnia et al., 2002).
AA	Bovine (Thomas et al., 2001)	it was observed that AA increases follicular survival rate, follicular integrity, and regulation of MMPs and metalloproteinases (TIMPs), essential enzymes which are involved in basement membrane remodeling, both in gene and protein level.	Due to contribution of AA in folliculogenesis, AA acts as an antioxidant or actively contributes to collagen biosynthesis, steroidogenesis, and apoptosis (Murad et al., 1981).
ITS	Human (Abedelahi et al., 2008)	Those follicles which were cultured in presence of ITS with accompany by human serum albumin for 10 days, were significantly larger, more developed and showed significantly less atresia than those cultured with serum alone.	This has been supposed that ITS can improve follicular growth through increasing antioxidant capacity of oocyte and GCs via reducing ROS and inhibits lipid peroxidation (Raghu et al., 2002).
			Transferrin acts as a detoxifying protein via removing toxic metals from the medium (Barnes and Sato, 1980).
			Selenium fights with oxidative stress via regulating the activity of glutathione peroxidase (Stadtman, 1974).

AA, ascorbic acid; AR, androgen receptor; bFGF, basic Fibroblastic Growth Factor; cAMP, cyclic Adenosine Monophosphate; FBS, fetal bovine serum; FSH, follicle stimulating hormone; GC, granulosa cell; IGF, insulin-like growth factor; ITS, insulin, transferrin, and selenium; KL, kit ligand; MMP, matrix metalloproteinase; ROS, reactive oxygen species.

Gonadotropins

Expression of the follicle stimulating hormone receptor (FSHR) has been reported in GCs of bovine preantral follicles (El-Hefnawy and Zeleznik, 2001) as well as multilayer human follicles (Oktay et al., 1997). Regarding luteinizing hormone receptor (LHR), its protein was not detected in primordial and primary follicles, whereas, in preovulatory follicles maximum expression was detected (Yung et al., 2014). The first appearance of a clear signal of LHR protein was observed in GCs and theca cells of small human antral follicle (Yung et al., 2014). For a period of 18 days, FSH (as a follicular growth primary regulator) can stimulate the follicle growth. One explanation for this FSH action might be through stimulation of hyaluronan synthase-2 (HAS2) expression. Subsequently, after HAS and the generation of an osmotic gradient, follicular fluid begins to accumulate into preantral follicles leading to follicular growth (Araújo et al., 2014b; Vasconcelos et al., 2013).

However, multiple studies have confirmed that the effects of FSH on follicular growth directly depend on the follicular size and developmental stage (Nagashima et al., 2017; Oktay et al., 1997; Weil et al., 1999). In a study by Oktay et al. (1997) it was shown that human isolated primordial follicles don't express FSHR; but some of the primary follicles and all multilayer follicles express FSHR. This means, the role of FSH in earlier stages of follicular growth, if any, is obscure.

FSH plays an important role as a survival factor through inhibition of apoptosis proteins and maintains morphology (Silva et al., 2014). Some investigations have indicated that FSH increases not only the expression of FSHR mRNA in GCs but also ultrastructural analysis has revealed that the antral follicles grown in FSH containing media have an intact morphology and higher viability as well as higher GCs mitochondria and endoplasmic reticulum intact structure, though fluorescence analysis did not reveal these results (Markstrom et al., 2002; Silva et al., 2014).

FSH leads to follicular growth through different pathways including induction of GC's proliferation and differentiation and induction of theca cells to synthesize androgen substrate which is converted to estrogen (Gougeon, 1982). FSH and estrogen act together to induce antral formation in cultured preantral follicles. In a study this was shown that addition of human recombinant FSH and/or 17β-estradiol to serum-free medium lead to a larger diameter increase during culture of small bovine preantral follicles compared with that of the control.

About FSH, this was due to an increase in cell proliferation, while with estradiol this was caused by an increase in GC size (Hulshof et al., 1995). Some studies have also shown that FSH has some interactions with other factors (such as Activins, bone morphogenetic protein 15 [BMP15] and 2, Fetuin, oxygen tension, insulin-like growth factor I [IGF-I], and growth differentiation factor 9 [GDF9] and so on) for regulation of follicular development and growth (Cossigny et al., 2012). We will discuss more about the synergetic interaction of FSH with other factors in other sections.

In a study by Abir et al. (1997) they demonstrated that addition of low concentration of LH (2.5 ng/mL) lead to follicular growth and antral development. Abir et al. (1997) believed that addition of LH alone, without FSH, won't increase the follicular growth, whereas, the addition of both FSH and LH into human follicles culture medium will increase the size of follicles, especially for those follicles were cultured for 3 weeks. One explanation for such observation is that human FSHR expresses in GCs even in primary follicles, but human LHR appears only on theta cells from preantral stages. Human LHR appears on GCs only at the preovulatory phase (Gougeon, 1996; Kobayashi et al., 1990; Shima et al., 1987).

Growth Hormone

Based on previous reports, the GH is a well-known factor in the ovary which promotes steroidogenesis, ovarian puberty initiation, gonadotropin responsiveness, and ovulation (Hull and Harvey, 2000, 2001). Also, expression of GH receptor (GHR) has been detected in oocyte (Heap et al., 1996; Kölle et al., 1998; Lobie et al., 1990) and GC (Kölle et al., 1998) as well as preantral follicles from rats (Lobie et al., 1990). Transcripts of GHR have been detected in primordial, primary, secondary follicles and oocytes of the bovine ovary, as well as corpus luteum (Kölle et al., 1998). In human, the expression of the GHR protein and mRNA was detectable in oocytes, GC, and stroma cells from both sources (fetuses and women/girls) (Abir et al., 2008b). Apart from these observations, gene deficiencies in the GHR lead to a decrease in primordial follicle development and an increase in follicular atresia in mice (Slot et al., 2006).

GH increases GCs and theca cells proliferation and estradiol production in the culture system of cattle GCs, especially in 3D culture systems (Araújo et al., 2014a; Kobayashi et al., 2000; Langhout et al., 1991). In addition, this was observed that during early stages of folliculogenesis, there is a positive interaction between GH and estradiol, so that the addition of GH to the culture medium of bovine preantral follicle enhances estradiol synthesis (Shimizu et al., 2008), but this interaction changes in late stages of folliculogenesis so that, GH prevents preovulatory follicles development.

Insulin, IGF-I and IGF-II

Several instances confirm the evidence that IGF-I serves an essential role, either alone or in combination with other factors (Louhio et al., 2000; Schams et al., 1999), in normal steroidogenesis function and development of mammalian ovary (Baker et al., 1996). Some studies have indicated that IGF-I in combination with FSH promotes proliferation and differentiation of GCs in vitro, as well as steroid production (Campbell et al., 1996; Spicer and Echternkamp, 1995). Rawan et al. (2015) demonstrated that IGF-I (1 and 100 ng/mL) increases the expression of LHR mRNA in bovine GCs from small (<6 mm) and large (≥9 mm) follicles. Moreover, they indicate that IGF-I increases androstenedione and E2 production in GCs from both small and large follicles, but increases progesterone only in large follicles.

In bovine, Insulin (30 ng/mL) acts in synergy with FSH (200 ng/mL) to stimulate steroidogenesis via GCs proliferation (Gong et al., 1994) and in another study this was reported which insulin (at doses >500 ng/mL) is necessary for follicular activation and subsequent survival of bovine follicles in vitro (Yang and Fortune, 2002). One possible explanation for such action of insulin might be through activation of the P450 AROM enzyme and increased levels of E2 (Gong et al., 1991; Yang and Fortune, 2002).

In human, this was reported that the proportion of primary follilces increase significantly when human ovarian cortical tissue slides treated with insulin, IGF-II and IGF-II compared with control group after 2 weeks in vitro (Louhio et al., 2000). In addition, IGF-I also was shown to induce expression of proliferating cell nuclear antigen (PCNA) in the GCs of primary follicles. This observations suggest that insulin, IGF-II and IGF-II may act as a survival factor for early stages human follicles. In a study by Wright et al. (1999) they demonestred which Human follicles in tissue cultured for 10 days with human serum albumin and ITS (insulin/transferrin/selenium mix) were larger, more developed and showed significantly less atresia than those cultured with serum alone.

In contrast with the observations above, some other controversial reports indicate that human recombinant IGF-I does not change the relative proportions of primary versus secondary follicles in bovine cortical pieces after 8 days of culture (Derrar et al., 2000). Meanwhile, some others believe that IGF-I negatively affects follicular health, activation, and growth of follicles in bovine cortical pieces (Yang and Fortune, 2002).

Bone Morphogenetic Proteins

The presence of BMP15 for accurate follicular development in full period of growth and various mammalian species, is crucial (Juengel et al., 2002; Otsuka et al., 2011). There is a study demonstrating that the expression of BMP15 gene differs among species, being higher in poly-ovulatory (pig) than in mono-ovulatory (cow) species (Crawford and McNatty, 2012). BMP15 is expressed in oocytes (Hosoe et al., 2011), and FSH is a crucial factor for accurate regulation of BMP15 gene expression. The combination of FSH and BMP15 has conflicting results in the regulation of follicular development. For instance, BMP15 increases expression of FSHR in cultured bovine preantral follicles leading to increased antrum formation and GC proliferation (Thomas et al., 2005).

There is an entirely different response to BMP15 in murine; that BMP15 blocks FSHR gene expression in GCs and subsequently blocking FSH-induced synthesis of progesterone and inhibiting the expression of proteins (STAR and P450scc) involved in steroidogenesis (Otsuka et al., 2001; Passos et al., 2013). In human, addiction of BMP15 promoted activation of human primordial follicles, in a dose dependent manner, via intracellular signal-mediated pathways Smad1, Smad5 and Smad8 (Margulis et al., 2009; Shimasaki et al., 2004), and when both BMP15 and GDF9 were added the impacts were further (Kedem et al., 2010). Meanwhile, it has been shown that deletion in bmp15 gene is associated with initial stages of human folliculogenesis (Di Pasquale et al., 2004).

In a study by Abir et al. (2008a) it was shown that BMP4 and BMP7 are two other factors from TGFβ super family which their transcripts and proteins are detectable in oogonia or oocytes and stroma cells from women and girls in along with their receptors and this suggests a possible role for them during follicular development, especially in primordial follicle activation. In a recent study by Cunha et al. this was shown that the presence of 100 ng/mL BMP4 in culture medium of bovine preantral follicles enclosed in fragments ovarian tissue increases oocyte and follicular diameters of primary and secondary follicles (da Cunha et al., 2017).

The presence of BMP2 receptor has been confirmed in GCs from primary, secondary and antral follicles (Erickson and Shimasaki, 2003), as well as in theca cells and oocytes from antral follicles (Fatehi et al., 2005). BMP2 also has a synergetic effect with FSH in increasing diameter of bovine follicles, GCs steroid production and expression of estrogen receptor in bovine oocytes. This also has been determined that 10 ng/mL BMP2 promotes the growth of primordial follicles in vitro and keeps the morphology and ultrastructure of secondary follicles during 18 days culture (Burkhart et al., 2010; Rossi et al., 2015). Meanwhile, some believe that BMP2 has an important role during the early development of ovarian function especially in the formation of primordial germ cells (Ying and Zhao, 2001).

Growth Differentiation Factor 9

There are multiple reports indicating that GDF9 alone or in combination with its closest homolog BMP15, may be involved in initiating primordial follicle growth (Juengel et al., 2002; Oron et al., 2010; Otsuka et al., 2011; Paulini and Melo, 2011). In human, the expression of GDF9 receptors have been identified in unilaminar follicles (Aaltonen et al., 1999; Oron et al., 2010; Teixeira Filho et al., 2002) and this was proposed that GDF9 acts through activation of intracellular cascade of Smad 2 and Smad 3 (Oron et al., 2010; Paulini and Melo, 2011).

Addition of GDF9 to culture medium of human primordial follicles could promote the survival and follicle development (Hreinsson et al., 2002) and in another study in accompany with BMP15 this was shown that the number of developing follicles was greater with GDF9 or BMP15 alone than with no BMP15 or GDF9 (Kedem et al., 2011). Although, it seems that both GDF9 and BMP15 promote activation of human primordial follicles from girls/women ovarian tissues as well as 17β-estradiol secretion, however, in a dose dependent manner, this is obvious that GDF9 seems more beneficial (Kedem et al., 2011).

It is supposed that GDF9 can up-regulate the expression of kit ligand (KL) in bovine GCs (Nilsson and Skinner, 2002) following increasing recruitment of theca cell from the surrounding stromal cells under influence of KL expression which ultimately lead to promote follicle progression (Parrott and Skinner, 2000).

In bovine, the addition of GDF9 in combination with FSH could increase follicular growth and antrum formation in cultured secondary follicles. This was also shown that GDF9 stimulates expression of versican and perlecan and coordinates positively with FSH to increase HAS2 expression (Vasconcelos et al., 2013). There is no evidence for effect of GDF9 on preantral follicle development in vitro in human, however, there are some studies in rats and goats which have shown that the addition of GDF9 to cultured preantral and primordial follicles increases follicular growth (Martins et al., 2008; Orisaka et al., 2006; Vitt et al., 2000).

Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a cellular mitogenic factor, along with its receptor, are expressed in preantral follicles of various species including, bovine (Geva and Jaffe, 2000; Yang and Fortune, 2007), caprine (Bruno et al., 2009; Sharma and Sudan, 2010), and human (Cui et al., 2004). The presence of VEGF in the culture medium of bovine preantral follicles promotes the percentage of antrum cavity formation and follicular growth rate (Araújo et al., 2014a; Yang and Fortune, 2007). Three different mechanisms have been proposed for VEGF for its role in follicular growth:

(1) VEGF induces proliferation in theca and GCs and eventually, resulting in the development of larger follicles and accumulation of intrafollicular fluid (Araújo et al., 2014a).

(2) Another potential role and mechanism has been proposed for VEGF through phosphatidylinositol-3-kinase (PI3K)/AKT intracellular pathway as angiogenic action (Abramovich et al., 2010). VEGF as an angiogenic factor improves follicle growth by increasing the permeabilization of the ovarian cell (Danforth et al., 2003; Quintana et al., 2004) and accessibility of growth factors, gonadotropins, steroids, and oxygen as well (Araújo et al., 2013).

(3) VEGF also increases the expression of HAS1 (Vasconcelos et al., 2013) and HAS2 gene (Schoenfelder and Einspanier, 2003) as two essential enzymes which are involved in follicular cavity formation and growth.

In human, the expression of VEGF-A and its two receptors (VEGFR1, VEGFR2) have been studied in human preantral follicles (Abir et al., 2010), and this was shown that mRNA transcripts and proteins for VEGFR1 and VEGFR2 are detectable in oocytes, GCs, and stroma cells from fetuses and girls/women as well as the protein for VEGF-A.

In bovine, the protein for VEGF-A was strongly expressed in GCs and theca cells from secondary stages onward (Yang and Fortune, 2007) and in in vitro condition, in lower doses of (0.1–10 ng/mL) VEGF-A could increase the number of secondary follicles in a dose-dependent manner.

Recently, Asadi et al. showed that VEGF₁₆₅ improves the activation of resting follicles and increases the percentage of secondary growing follicles after 6 days of human ovarian tissue culture system. They also demonstrated that addition of VEGF₁₆₅ alone or in combination with Fetuin into the culture medium of human ovarian tissue increase 17β-estradiol at day 6 and progesterone from the fourth day of the culture period. In this study, after 6 days of culture, increased levels of BMP15, GDF9 and Inhibin B mRNAs, high levels of total antioxidant capacity and expression of superoxide dismutase 1 and CAT genes was observed as well as low levels of reactive oxygen species (ROS) and lipid peroxidation (Asadi et al., 2016).

Neural Growth Factors

The neural growth factors (NGFs) are mostly recognized for their role in the nervous system, but their expression in the ovarian cells has been detected (Abir et al., 2005; Anderson et al., 2002; Dissen et al., 2001; Salas et al., 2006). NGFs mediate their intracellular function through two types receptors; the low-affinity universal NT receptor, p75, and the specific high-affinity tyrosine kinase (Trk) receptors (Chao and Hempstead, 1995; Raffioni et al., 1993). In the culture medium of bovine antral follicles, NGFs could enhance the secretion of androstenedione and progesterone as well as prostaglandin E2 in cultured theca cells (Dissen et al., 2000).

The same results were observed in human samples when GCs from antral follicle were treated with NGF which led to an increased E2 secretion (Salas et al., 2006) as well as an increase in the FSH expression and increased FSH sensitivity following higher E2 concentrations in response to FSH (Salas et al., 2006; Streiter et al., 2015).

Various studies have shown that in antral follicles NGFs may have a role in ovulation stimulation, promotion of the follicular cells proliferation, inhibition of GC apoptosis, or Presumptively in oocyte maturation and pre implantation embryonic development as well as stimulation of steroidogenesis and prostaglandin production (Streiter et al., 2015).

Activin A

The expression of activin and its receptor has been reported in theca and GCs and oocytes of bovine preantral follicles (Hulshof et al., 1997). There are different opinions regarding the role of Activins in follicular development (Silva et al., 2014). Some believe that activins are important factors for initial phases of preantral follicular growth in mammals and are vital for the maintenance of bovine preantral follicle morphology and integrity of oocytes during first 8 days as well (McLaughlin et al., 2010a). Moreover, there are some other reports showing that Activins contribute in primordial follicles growth in vitro (Fortune et al., 2000; Telfer et al., 2008), as well as GCs proliferation and antral cavity formation (McLaughlin et al., 2010a).

In bovine, the studies have shown that a significant preantral follicle and oocyte growth were observed in activin-exposed follicles, with or without FSH (McLaughlin et al., 2010b). In human, culture of ovarian strips in presence of activin showed a higher percentage of normal follicle, antrum formation and follicular size compared with control group (Telfer et al., 2008). But, some others demonstrated that combination of activins and FSH does not stimulate bovine preantral follicle growth after 12 days of culture and inhibits the positive effects of FSH after 18 days. One explanation might be due to the decline in HAS1, HAS2, FSHR, and PCNA gene expression levels (Silva et al., 2014).

Oxygen Tension

There are various opinions regarding the role of oxygen tension during in vitro follicular growth and development, and these differences might be due to the animal variation derived from different reproductive seasons (Xu et al., 2011). Some researchers believe that oxygen tension should be low for better in vitro follicle growth and health in bovine (Gigli et al., 2006) and sheep (Cecconi et al., 1999), because of a higher probability of ROS production during high oxygen tension condition and its possible cytotoxic activity (Evans et al., 2004; Silva et al., 2010). However, there are some other studies that show there is no significant difference between low or high oxygen tension (Silva et al., 2010).

Xu et al. (2011) demonstrated that follicle survival and growth and antrum formation rate increase in the presence of low oxygen tension (5%), high FSH concentration and Fetuin. In addition, in another study, it was stated that there is an increased percentage of antrum formation in low oxygen tension (5%) condition relative to high oxygen tension (20%) in caprine preantral follicles (Xu et al., 2011). Cecconi et al. (1999) also showed that low O₂ concentration (5%) promote follicle growth, antrum formation and production of healthy cumulus–oocyte complex in ovine preantral follicle culture. Moreover, during canine cumulus–oocyte complexes results have shown that low O₂ tension (5%) in compared with 20%, lead to a lower percentage of cumulus cell apoptosis (Silva et al., 2009).

Finally, in encapsulated 3D culture of macaques follicles, the results showed that physiological level of O₂ (5%) is more efficient for macaque follicle survival, growth, function, and oocyte quality, as well as for promoting anti-mullerian hormone production (Salmon et al., 2004; Thomas et al., 2007; Weenen et al., 2004). It has also been proposed that in low oxygen tension condition, follicles increases antrum cavity formation to avoid hypoxia in the follicle wall (Redding et al., 2007).

Fetuin

Fetuin is an acidic glycoprotein which is originally isolated from fetal bovine serum and can be detected in several species (Nie, 1992). The human homolog of fetuin is called α2 HS-glycoprotein, which is the major glycoprotein component of fetal blood and body fluids. It is produced by hepatocytes of the liver (Arnaud and Kalabay, 2002). There are different reports showing that GCs secrete a significant amount of fetuin into follicular fluid (Høyer et al., 2001; Kalab et al., 1993). Fetuin acts as a protease inhibitor and prevents from zona pellucida (ZP) hardening and maintains ZP solubility (Dell'Aquila et al., 1999; Ducibella et al., 1988).

Some studies show that fetuin in combination with high FSH and 5% O₂ increases the follicle survival, promotes the growth of follicles (Xu et al., 2011), and may stimulate the action of macrophages and healthy GCs such that they may behave in a macrophage-like manner during follicular atresia in different species (Høyer et al., 2001; Inoue et al., 2000; Kasuya, 1997; Van Wezel et al., 1999; Wang et al., 1998). Also, fetuin has a synergetic effect with VEGF, which can activate resting follicles and increase the number of growing follicles as well as 17β-estradiol and progesterone in vitro (Asadi et al., 2016).

PTEN Inhibitor and/or PI3K Activator

There are multiple factors which their important role for primordial follicle activation from the dormant state have been shown (Hsueh et al., 2015). Although, the exact mechanism of action is not very well known in these factors, however, the PIP3/Akt signal pathway is supposed to has an essential role among other intercellular pathways (Adhikari and Liu, 2009). It has been shown that in mutant mice with oocyte-specific phosphatase and tensin homolog deleted on chromosome (PTEN) deletion, all dormant primordial follicles were activated spontaneously at early neonatal stage and ovarian follicles were depleted during early life (Reddy et al., 2008).

The same phenotypes also were observed in forkhead box O3 deficient mice (Castrillon et al., 2003; Fan et al., 2008). Transient incubation of neonatal mouse ovaries in vitro with PTEN inhibitor or even with PI3K activating peptide leads to the activation of dormant primordial follicles (Abir et al., 2013; Kawamura et al., 2016; Li et al., 2010). Combining activated ovarian tissues with ovarian tissue autotransplantation in human premature ovarian failure (POF) patients was resulted in two healthy babies with two additional pregnancies (Kawamura et al., 2015; McLaughlin et al., 2014).

3D Versus 2D Culture System

It has been reported that isolated follicles could only grow and survive in a supporting matrix made by either collagen or sodium alginate (Abir et al., 1997, 1999; Araújo et al., 2014a). Using flat surfaces for culture of human follicles lead to disruption of oocyte and surrounding GCs interaction (Xiao et al., 2015; Xu et al., 2009). Xiao et al. demonstrated that the follicular size and the rate of antrum formation increase following culture of small human preantral follicles in 0.5% alginate hydrogels (Xut et al., 2009). This group also developed a novel strategy to produce mature metaphase II (MII) oocytes, wherein follicles were cultured using a two-steps strategy (Xu et al., 2009).

This method let to greater terminal diameters, higher hormone production as well as production of mature MII oocyte (Xu et al., 2009). Possibly, this support may acts through maintaining of intercellular interactions between GCs and oocyte in this 3D system (Abir et al., 1997, 1999; Wang et al., 2014; Yin et al., 2016).

However, the successful rate using 3D culture system in human and bovine and other larger mammalian is not satisfying and one hypothesis for this might be due to larger oocyte size and further required culture time (Araújo et al., 2014a; West et al., 2007).

Conclusion

Based on our knowledge, the closest animal species to human reproduction is the primate; however, it is quite costly and difficult to use them in our studies. In the context of reproductive physiology, after primates, bovine are the second closest animal species to human, meaning most of their reproductive characteristics are very similar to human reproduction such as ovulations per cycle and time until antrum formation and so on (Campbell et al., 2003). It is worth noting that rodent models are poor models for studying human ovarian physiology because of their polyovular nature and their small size. Meanwhile, bovine are cheap to handle and house, making them the best candidate for studying human reproduction.

Because of similar ovarian physiology between human and bovine ovarian physiology, same duration in ovulatory cycle, follicular phase, luteal phase and gestation and also same sizes in the time of antrum formation, diameter of follicles that become gonadotropin dependent and diameter of ovulatory follicles, investigations on bovine ovarian physiology and follicular growth and development can be an eventually carried over to human ovarian physiology (Campbell et al., 2003).

There has been huge progress in cryopreservation of ovarian tissues and follicles, which ultimately require a culture of individual follicles to use in ART procedures. Therefore, improving follicle culture systems and knowing their actual growth requirements might be a great step toward fertility preservation in cancer patients. Meanwhile, newly discovered ovarian stem cells in adult mammalian ovaries is also another alternative which potentially has this capacity to be used as a co-cultured system with preantral follicles to increase their growth and development (Parvari et al., 2016; Aliakbari et al, 2016a,b; Yazdekhasti et al., 2016).

At the end, IVC systems in the development of competent follicles and oocytes is at the its infant stage and further studies are needed to define optimal culture system conditions and standards to maintain follicular traits at higher quality [i.e., higher morphology, survival, proliferation, steroidogenesis, and gene expression (Araújo et al., 2014b)].

Footnotes

Author Disclosure Statement

The authors declare that no competing financial interests exist.

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