Theca: the forgotten cell of the ovarian follicle

in Reproduction
Authors: J M Young and A S McNeilly
View More View Less
  • Human Reproductive Sciences Unit, Medical Research Council, Edinburgh EH16 4TJ, UK

Theca cells function in a diverse range of necessary roles during folliculogenesis; to synthesize androgens, provide crosstalk with granulosa cells and oocytes during development, and provide structural support of the growing follicle as it progresses through the developmental stages to produce a mature and fertilizable oocyte. Thecal cells are thought to be recruited from surrounding stromal tissue by factors secreted from an activated primary follicle. The precise origin and identity of these recruiting factors are currently not clear, but it appears that thecal recruitment and/or differentiation involves not just one signal, but a complex and tightly controlled combination of multiple factors. It is clear that thecal cells are fundamental for follicular growth, providing all the androgens required by the developing follicle(s) for conversion into estrogens by the granulosa cells. Their function is enabled through the establishment of a vascular system providing communication with the pituitary axis throughout the reproductive cycle, and delivering essential nutrients to these highly active cells. During development, the majority of follicles undergo atresia, and the theca cells are often the final follicular cell type to die. For those follicles that do ovulate, the theca cells then undergo hormone-dependent differentiation into luteinized thecal cells of the corpus luteum. While the theca is an essential component of follicle development and ovulation, we do not yet fully understand the control of recruitment and function of theca cells, an important consideration since their function appears to be altered in certain causes of infertility.

Abstract

Theca cells function in a diverse range of necessary roles during folliculogenesis; to synthesize androgens, provide crosstalk with granulosa cells and oocytes during development, and provide structural support of the growing follicle as it progresses through the developmental stages to produce a mature and fertilizable oocyte. Thecal cells are thought to be recruited from surrounding stromal tissue by factors secreted from an activated primary follicle. The precise origin and identity of these recruiting factors are currently not clear, but it appears that thecal recruitment and/or differentiation involves not just one signal, but a complex and tightly controlled combination of multiple factors. It is clear that thecal cells are fundamental for follicular growth, providing all the androgens required by the developing follicle(s) for conversion into estrogens by the granulosa cells. Their function is enabled through the establishment of a vascular system providing communication with the pituitary axis throughout the reproductive cycle, and delivering essential nutrients to these highly active cells. During development, the majority of follicles undergo atresia, and the theca cells are often the final follicular cell type to die. For those follicles that do ovulate, the theca cells then undergo hormone-dependent differentiation into luteinized thecal cells of the corpus luteum. While the theca is an essential component of follicle development and ovulation, we do not yet fully understand the control of recruitment and function of theca cells, an important consideration since their function appears to be altered in certain causes of infertility.

What are theca cells?

Reproduction is the result of a coordinated signaling network between the gonads, pituitary, and hypothalamus. The ovary is responsible for nurturing growing oocytes until an estradiol signal from primed preovulatory follicles induces GNRH, and a consequent luteinising hormone (LH) surge, to release a mature oocyte, which is then capable of being fertilized to produce an embryo. Within the ovary, there are a number of cell types that support the growth and development of oocytes until ovulation. The oocyte is surrounded by a layer of granulosa cells, which change morphology and proliferate when an oocyte begins the process of folliculogenesis. Activated follicles are thought to recruit precursor thecal cells from the stromal layer surrounding the granulosa cells and oocyte. Together, these form the follicle structure that synthesizes steroid hormones (Hillier et al. 1994). Thecal cells are not capable of producing estrogen but do produce androgens in response to LH, which are then converted into estrogen by follicle stimulating hormone (FSH)-induced aromatase in the neighboring granulosa cells of selected growing follicles. Over the past decade, research has focused on granulosa cells and their interaction with the oocyte, and the theca has been somewhat forgotten as a necessary and vital part of the developmental process.

The classification system for folliculogenesis has been well defined in numerous publications (McNatty et al. 1999, 2007, Montgomery et al. 2001, Barnett et al. 2006, Edson et al. 2009). Briefly (see Fig. 1), primordial follicles (type 1) are in the resting stage before being activated to start development and the oocyte is surrounded by one layer of flattened granulosa cells; type 1a are the follicles transitioning through to the primary (type 2) stage when the granulosa cells become cuboidal. Primary follicles have one layer of cuboidal granulosa cells, secondary follicles (type 3) have two to four layers of granulosa cells, large preantral (type 4) follicles have four to six layers of granulosa cells, and antral follicles (type 5) have more than five layers of granulosa cells. It is after secondary follicle formation that the thecal cells begin to emerge and form a layer around the granulosa–oocyte structure. Throughout folliculogenesis, the rates of atresia increase, and the early stages of folliculogenesis proceed very slowly (Gougeon 1986, Hirshfield 1994); therefore, most follicles are observed at early stages of development. At the antral stage, follicles become gonadotropin dependent and form large antral follicles (type 5+), most of which undergo atresia, and few are selected for ovulation (reviewed by Scaramuzzi et al. (1993) and Edson et al. (2009)).

Figure 1
Figure 1

Thecal cell development and function during folliculogenesis. Thecal cells are vital for successful folliculogenesis. A primordial follicle consists of an oocyte and surrounding granulosa cells (GCs), and thecal layers are not formed until the follicle is activated and reaches the secondary stage of development. Thecal cells are required for the production of androgens to provide a structural scaffold, and they form the network of cells that support the vascular system, and after ovulation, thecal cells luteinize and form cells of the corpus luteum.

Citation: REPRODUCTION 140, 4; 10.1530/REP-10-0094

Origin of theca cells

Theca cells are first observed once a follicle has two or more layers of granulosa cells, which is around the time when thecal cells become LH responsive and steroidogenic enzymes are activated (Magoffin & Weitsman 1994). These specialized cells have long been thought to originate from fibroblast-like precursor cells within the ovarian stroma (Erickson et al. 1985, Orisaka et al. 2006, Honda et al. 2007). The putative undifferentiated progenitor theca cells do not express LH receptors (LHRs) or steroidogenic enzymes and are therefore not LH responsive, showing that initiation of theca cell differentiation is gonadotropin independent (Magoffin & Weitsman 1994). As theca cells are only associated with growing follicles, one would assume that the follicle itself produces factors that signal to the stroma to recruit cells that form the theca. Very few studies have investigated the factors that recruit thecal cells to the activated primary and secondary follicles. It is not currently clear whether cells surrounding the activated follicle differentiate into the theca layer, or whether they are in fact recruited from the stroma to form the theca layers. However, results from mature thecal cells cultured in vitro do provide clues about the origin of some recruiting factors and, more importantly, the complexity of this system and provide evidence of steroidogenic regulators with potential differentiative roles. Selected factors are discussed later in the review.

Structure of theca cells

Electron microscopic analysis of normal thecal development in ovine follicles throughout folliculogenesis showed that thecal layers from small follicles (<3 mm diameter) were composed of flattened theca cells together with capillaries and bundles of collagen lying next to the basal lamina (O'Shea et al. 1978). The thecal cells were either fibroblast-like cells or presumed steroidogenic cells with large amounts of smooth endoplasmic reticulum. As the follicles grew, the thecal cells hypertrophied, became less flattened and richer in endoplasmic reticulum, eventually producing pseudopodia, and contained many droplets of lipid but showed no signs of degradation.

Theca cells are highly differentiated with structural features characteristic of steroid-secreting cells including abundant mitochondria with vesicular cristae, agranular endoplasmic reticulum, and lipid vesicles (reviewed by Magoffin (2005)). The mitochondria contain the first enzyme in the steroidogenic pathway, cholesterol side-chain cleavage cytochrome P450 (CYP11A), and the endoplasmic reticulum contains the remaining enzymes necessary to produce androgens. The lipid vesicles store the precursors for steroid hormone synthesis as cholesterol esters which are transported into the mitochondria by steroidogenic acute regulatory protein (STAR; reviewed by Manna et al. (2009)). Thecal cells are vital components of the follicle, providing both structural support and being the exclusive producer of ovarian androgens, which are necessary as substrates for estradiol production in the neighboring granulosa cells.

Steroidogenesis

Androgens synthesized in thecal cells are transported to the granulosa cells where P450 aromatase converts these androgens to estrone and 17β-estradiol. The steroidogenic enzymes are produced in a cell-specific manner (Wood & Strauss 2002), and in addition to the large amount of androgen receptor expressed in thecal and granulosa cells (but not in oocytes; Li et al. 2009a), studies indicate that a complete oocyte-independent system for androgen production exists within the growing follicle. Indeed, androgen and subsequent estradiol production can occur in mouse ovaries devoid of oocytes (McNeilly et al. 2000). Silencing 17α-hydroxylase (CYP17) in the rat ovary caused a decline in androstenedione, 17α-hydroxyprogesterone, and testosterone production, and also reduced progesterone levels (Li et al. 2009b); showing ovarian androgen biosynthesis can be inhibited by silencing CYP17 expression alone, and indicating a potential target for therapeutic development.

Androgen production from thecal cells in the gonadotropin-dependent stage is largely under the control of LH from the pituitary (Baird et al. 1981, Palermo 2007). LH is released in a pulsatile manner, and the frequency and amplitude of these pulses vary across the reproductive cycle in response to ovarian steroidogenic feedback. The pulse frequency of LH dictates the amounts of steroid hormones produced, where each pulse of LH is followed by an increase in androstenedione and estradiol secreted from the ovary in many species (Baird et al. 1976, 1981, Peluso et al. 1984, Schallenberger et al. 1984, Walters & Schallenberger 1984). When theca cells were cultured in vitro, low levels of LH also stimulated androgen production (Campbell et al. 1998, Ryan et al. 2008), whereas, at high doses, LH inhibited androstenedione production and stimulated progesterone secretion as well as changing cell morphology indicating that the high LH levels induced luteinization in these cells (Campbell et al. 1998). LH has been shown to increase levels of STAR and steroidogenic enzymes (CYP11A1, CYP17, and 3-β-hydroxysteroid dehydrogenase (HSD3B)) and LHR gene expression (Magoffin & Weitsman 1993a, 1993b, 1993c, 1994, Lavoie & King 2009; see Fig. 2).

Figure 2
Figure 2

Modulation of steroidogenic enzymes. Expression levels of genes encoding steroidogenic enzymes are regulated by many different factors within the ovary. The process of androgen production requires the following enzymes: cholesterol side-chain cleavage cytochrome P450 (CYP11A1), 17α-hydroxylase (CYP17) and 3-β-hydroxysteroid dehydrogenase (HSD3B), as well as steroidogenic acute regulatory protein (STAR). Theca cells from sheep, humans, and primates principally produce androstenedione, whereas rodents produce testosterone as precursors for estradiol production in the neighboring granulosa cells. The modulating factors are depicted here, where in green circles the stimulatory factors are shown, and the inhibitory factors are listed in red boxes. BMP, bone morphogenetic protein; GDF9, growth differentiation factor 9; HGF, hepatocyte growth factor; hCG, human chorionic gonadotropin; IGF, insulin-like growth factor; SCF, stem cell factor/kit ligand; TGFB, transforming growth factor β.

Citation: REPRODUCTION 140, 4; 10.1530/REP-10-0094

Insulin also plays an important role in thecal cell function. In vitro studies using thecal cells from porcine, bovine, and ovine ovaries have shown that insulin induced dose-dependent cell proliferation, increased steroid production, and increased the expression of genes encoding STAR, CYP11A1, and CYP17, thus promoting steroidogenesis (Morley et al. 1989, Campbell et al. 1995, 1998, Wrathall & Knight 1995, Mamluk et al. 1999, Smith et al. 2005; see Fig. 2).

The onset of thecal steroidogenic enzyme gene expression is similar in those mammalian species studied in depth (Pollack et al. 1997, Kerban et al. 1999, Lundy et al. 1999, Watson et al. 2000, Logan et al. 2002). Theca cells are first able to produce steroids just prior to antrum formation, as shown by the onset of expression of STAR, CYP11A1, CYP17, HSD3B, and LHR in thecal cells of preantral (large type 4) follicles, and the mRNA and protein localization at specific stages mirrored one another (Logan et al. 2002) and does not require gonadotropins (Scaramuzzi et al. 1993). mRNA encoding steroidogenic enzymes were also observed in the theca of bovine preantral follicles, although, unlike sheep, STAR expression was limited to thecal cells (Bao & Garverick 1998). Steroidogenic factor 1, a well-studied transcription factor regulating P450 enzymes and STAR, was expressed by granulosa cells, and protein was observed in both thecal and granulosa cells (Logan et al. 2002). Overall, the expression patterns found in the sheep ovary are similar to those observed in other mammalian species.

Angiogenesis

Small primordial follicles are located in the avascular region of the ovarian cortex, especially in larger species, and do not have their own vascular system. Once follicle growth is activated and a thecal layer has been recruited, a follicle develops its own vascular network within the surrounding thecal layer (see Fig. 1). Thecal cell proliferation begins early in the secondary stage of follicle development, although endothelial cell staining is still absent at this point showing that the theca forms before vascularization begins (Fraser & Duncan 2009). There are many potential factors involved in controlling angiogenesis in the developing follicle but vascular endothelial growth factor (VEGF) has a central role and has been studied extensively. VEGF, a potent mitogen for endothelial cells (Ferrara & Davis-Smyth 1997), stimulates vascular permeability (Connolly 1991, Senger et al. 1993), and is highly expressed in granulosa cells and at lower levels in the thecal layer of follicles from the secondary stage onwards in primate ovaries (Taylor et al. 2004). In rodents, cows, and pigs, VEGF expression is weak in early follicle development but increases as the follicle progresses to ovulation (Maisonpierre et al. 1997, Barboni et al. 2000, Greenaway et al. 2005), although levels of VEGF decrease in granulosa cells in sheep and marmoset follicles just prior to ovulation (Ravindranath et al. 1992, Redmer et al. 2001, Taylor et al. 2004). In primates, mRNA encoding VEGF has been observed at the secondary stage in both the theca and granulosa cells (Taylor et al. 2004). VEGF was upregulated in rat ovaries during the primordial to primary transition thus preceding vascularization (Kezele et al. 2005). Certainly at early stages of follicle development, inhibition of VEGF prevents endothelial cell proliferation, and decreases thecal cell proliferation therefore hindering follicle development (Wulff et al. 2002, Fraser et al. 2005, Fraser & Duncan 2009). Suppression of gonadotropins using a GNRH antagonist results in reduced thecal and endothelial cell proliferation, and lower vascular density in antral follicles (Taylor et al. 2004), an effect probably due to reduced production of VEGF (Fraser & Duncan 2009).

While VEGF is critically involved in regulating follicle development in many species (Barboni et al. 2000, Mattioli et al. 2001, Wulff et al. 2001a, 2001b, 2002, Hunter et al. 2004, Martelli et al. 2008), many other factors also contribute and modulate angiogenesis and vasculogenesis in mammals, such as transforming growth factor β (TGFB) superfamily members and their antagonists, angiopoietins, fibroblast growth factor (FGF), and gonadotropins, but whether they directly affect theca cell function remains to be explored.

Life span of theca cells

Folliculogenesis is a process that spans many weeks where the majority of follicles undergo atresia and only a few become dominant and go on to ovulate successfully (reviewed by Scaramuzzi et al. (1993)). During atresia, cell death is not confined to a specific cell type, but the entire follicle is degraded during this process. There are various ways that ovarian cells have been reported to die including apoptosis, autophagy, necrosis, and cornification (Jolly et al. 1994, Van Wezel et al. 1999, D'Haeseleer et al. 2006). In bovine follicles, oocytes of preantral follicles are the first component to die, whereas in later stages of development, the granulosa cells die first, although in particular types of atresia, thecal cells also die very early (Rodgers & Irving-Rodgers 2009; see Fig. 3). In the cow, atretic antral follicles have been classified into two types; antral atresia and basal atresia. Basal atresia occurred only in small antral follicles (<5 mm in bovine ovaries) where the theca cell layer becomes disrupted, having high levels of collagen, early death of endothelial and thecal cells, reduced insulin-like factor 3 expression, and reduced androgen production associated with higher levels of progesterone in the follicular fluid in these follicles (Irving-Rodgers et al. 2003, Clark et al. 2004). These observations suggest that the theca is more susceptible to cell death early in follicular development compared to at later stages (Irving-Rodgers et al. 2001). In contrast, in atretic antral follicles where pyknotic nuclei were first observed in antral granulosa cells, thecal cells were the last to be disrupted (see Fig. 3). Thus, thecal cells from follicles undergoing atresia appear to respond differently depending on the stage of follicle development.

Figure 3
Figure 3

Theca cell fate. Atresia during follicle development is a more common fate of thecal cells than progression through to luteinization. In preantral follicles, the oocytes die first, and as follicles progress through development, follicles undergo basal or antral atresia. Thecal cells appear to be more susceptible to cell death early in follicular development, whereas in basally atretic follicles, the thecal layers are disrupted and are less vascular. Throughout all stages of development, antral granulosa cells are commonly the first cells to become atretic; hence, thecal cells are often the last to die during follicle atresia and the entire follicle is degraded during this process. FF, follicular fluid.

Citation: REPRODUCTION 140, 4; 10.1530/REP-10-0094

Since the blood supply is vital for follicle survival and transport of endocrine factors, vascularization is important in determining the fate of the follicle, and maintaining the blood supply is necessary for follicular health. The effect of atresia in the vasculature depends on the stage of follicle development when atresia is occurring. Small atretic follicles have reduced the numbers of capillaries in the thecal layers; the endothelium begins to degrade, and thecal capillaries become blocked by degrading material (O'Shea et al. 1977). Extensive hypertrophy of theca cells is observed during the early stages of atresia in human, rat, and rabbit, but not in sheep or bovine follicles (Himelstein-Braw et al. 1976, O'Shea et al. 1978, Erickson et al. 1985, Clark et al. 2004), which, together with the loss of granulosa cell function as they undergo apoptosis, results in androgens being the predominant steroids secreted by atretic antral follicles (Moor et al. 1978). In larger bovine antral follicles, the vasculature is well established in non-atretic follicles (Shimizu et al. 2003), while the thecal layers of atretic follicles show signs of apoptosis from the outer layers progressing internally, and throughout the vascular network (Jiang et al. 2003). Whether the changes in the vasculature observed during follicle atresia are the cause or the effect of the atretic process itself is yet to be established.

Follicle fate is regulated by apoptotic factors such as nodal, which is produced by the thecal cells and acts to promote apoptosis in the neighboring granulosa cells (Wang et al. 2006, Craig et al. 2007). The oncogene Skil (also known as SnoN), involved in regulating TGFB superfamily signal transduction, has been mapped in the mouse ovary recently and is expressed in the theca throughout development and during atresia (Xu et al. 2009). This factor can modulate differentiation, proliferation, and apoptosis of several cell types (reviewed by Deheuninck & Luo (2009)), and was shown to have a specific manner of expression relating to follicle atresia and luteinization, suggesting that SKIL may play roles in these processes (Xu et al. 2009). VEGF (Redmer et al. 2001, Fraser et al. 2005), FGF (Shimizu et al. 2002, 2003), and TGFB superfamily members (Tomic et al. 2002) have also been linked to follicle atresia.

Major factors influencing theca cell differentiation

The current evidence suggests that an activated follicle produces factors that induce thecal cell differentiation from stroma, but the exact identity and combination of the proteins remain unknown. Not unexpectedly, it appears that no single factor appears to be responsible, but complex networks of signals function synergistically to result in a fully functional steroidogenic thecal layer surrounding a developing follicle.

A recent in vitro study using bovine ovarian tissue showed that ovarian stromal cells cultured in the presence of granulosa cells from small antral follicles transformed into putative thecal cells with increased lipid droplets and androstenedione production (Orisaka et al. 2006). Studies suggest that granulosa cells, but not activated oocytes, are involved in the functional differentiation and acquisition of LH responsiveness in stromal cells, and the cellular origin of the stroma determines whether or not granulosa cells influence thecal cell differentiation and functionality such as expression of necessary steroidogenic enzymes and LHRs (Orisaka et al. 2006). It appears that stromal cells from the cortical region may be preprogrammed differently to medullary stromal cells, and able to respond to granulosa cell communication in a manner that medullary stromal cells are not.

Using neonatal mouse ovaries, putative thecal stem cells were purified and induced to differentiate in vitro (Honda et al. 2007). When these cells were treated with LH, insulin-like growth factor 1 (IGF1), stem cell factor (SCF, also known as kit ligand), or granulosa cell-conditioned media, the cells differentiated into thecal cells, and showed signs of lipid droplet accumulation, formation of smooth endoplasmic reticulum, mitochondria with tubular cristae, and produced androstenedione at later stages of culture. When these putative thecal cells were injected into ovaries of live mice, they were found to surround growing follicles akin to natural thecal cells in vivo.

Various factors have been studied in vitro for their effects on promoting thecal steroidogenesis. Selected molecules are discussed in the following sections.

Insulin-like growth factor

The ovary has a complete repertoire of IGF system components. IGF receptors are found on human thecal cells (Poretsky et al. 1985), and IGF1, the synthesis of which is regulated by FSH in the granulosa cells (Adashi et al. 1985, Hammond et al. 1985, Hernandez et al. 1989, Oliver et al. 1989), increases thecal cell proliferation in vitro (Hillier et al. 1991a, Stewart et al. 1995, Spicer & Chamberlain 1998, Huang et al. 2001, Mazerbourg & Hsueh 2003, Campbell et al. 2006, Kwintkiewicz & Giudice 2009). IGF1 alone stimulated the expression of LHRs (Magoffin & Weitsman 1994) and steroidogenic enzymes, CYP11A1 and HSD3B but not CYP17, and acts synergistically with LH to increase expression of these enzymes (Magoffin & Weitsman 1993a, 1993b, 1993c), and hence androgen synthesis in thecal cells in vitro (Hillier et al. 1991b; see Fig. 2). Interestingly, human stromal tissue cultured in vitro synthesized androgens when stimulated by insulin and IGF (Barbieri et al. 1983, 1984) giving additional evidence of IGF involvement in promoting thecal differentiation (see Fig. 4). IGF2 can stimulate bovine thecal steroidogenesis and acts through the type 1 IGF receptors (Spicer et al. 2004), so it may also play important roles in theca functionality.

Figure 4
Figure 4

Thecal cell recruitment and differentiation. Evidence suggests that thecal stem cells reside in the ovarian stroma and are recruited by factors released from follicles after they are activated. Individual factors may be responsible for the recruitment of these cells, whereas others may promote differentiation and proliferation. The origin of these factors is not currently clear, but it appears that a complex and tightly controlled set of signals from multiple factors is required for thecal recruitment and differentiation. AMH, anti-Müllerian hormone; bFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; GDF9, growth differentiation factor 9; IGF, insulin-like growth factor; KGF, keratinocyte growth factor; LIF, leukemia inhibitory factor; SCF, stem cell factor (kit ligand).

Citation: REPRODUCTION 140, 4; 10.1530/REP-10-0094

Stem cell factor (SCF/kit ligand)

SCF, also known as kit ligand, is a growth factor that acts through the c-kit tyrosine kinase receptor (Zsebo et al. 1990, Besmer 1991), is synthesized by granulosa cells, and acts on differentiated thecal cells as well as undifferentiated stromal cells and oocytes where the receptor c-kit is located (Manova et al. 1990, 1993, Motro et al. 1991, Horie & Broxmeyer 1993, Motro & Bernstein 1993, Parrott & Skinner 1997). The addition of neutralizing antibodies to SCF and IGF1 together to follicle-conditioned media reduced the stimulatory effects on theca cell differentiation by more than 90% in vitro (Huang et al. 2001). In rat theca, neither SCF nor IGF1 alone stimulated androstenedione production, whereas, in combination, these factors dose dependently induced androgen production, but to a lesser extent than that induced by LH. The effects of adding these factors together with LH showed that IGF1 acted synergistically with LH to increase androgen production, whereas SCF had no added effect when in combination with LH. SCF alone decreased CYP17 and had no effect on the expression of CYP11A, HSD3B, or LHR expression (see Fig. 2). IGF1 alone had no effect on the expression of STAR and CYP17, but increased mRNA levels of LHR, CYP11A, and HSD3B. However, the combination of IGF1 and SCF increased the expression of STAR, CYP11A, CYP17, HSD3B, and LHR, giving strong evidence that these factors may act synergistically to regulate thecal cell differentiation into steroid-producing cells, at least in the rat.

SCF stimulated the growth of bovine primary cell cultures of theca and stromal cells under sub-confluent conditions in vitro, but when the cells were grown to confluence, SCF stimulated androstenedione production (Parrott & Skinner 1997). In contrast, SCF did not affect human chorionic gonadotropin-induced androgen production by bovine stromal cells (Parrott & Skinner 2000) suggesting that, in contrast to the rat, SCF alone affects bovine thecal cells once they have been differentiated.

The expression of SCF can also be modulated by leukemia inhibitory factor (LIF), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF; Parrott et al. 1994, Parrott & Skinner 1998, Nilsson et al. 2002). Thecal cells produce KGF and HGF (Parrott et al. 1994), which act on granulosa cells to produce SCF, which then signals back to the theca to produce KGF and HGF in a positive feedback mechanism (Parrott & Skinner 1998; see Fig. 5). Therefore, SCF may potentially act as a final common factor involved in thecal cell differentiation and activation.

Figure 5
Figure 5

Androgen production from theca cells. Factors released by cells comprising the follicle (granulosa cells, thecal cells, and oocytes) can modulate androgen production in thecal cells in addition to external influences such as gonadotropins and insulin. These molecules can stimulate (green) or inhibit (red) thecal androgen production both directly and/or indirectly. Specific molecules have been observed to act in opposing manners, indicating species-specific differences. bFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; GDF9, growth differentiation factor 9; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IGFBP, IGF-binding protein; IL1, interleukin-1; KGF, keratinocyte growth factor; LIF, leukemia inhibitory factor; SCF, stem cell factor/kit ligand; TGFB, transforming growth factor β; TNF, tumor necrosis factor α.

Citation: REPRODUCTION 140, 4; 10.1530/REP-10-0094

Basic bFGF

Basic FGF (bFGF) has been shown to affect somatic cell mitosis, steroid synthesis, differentiation, and apoptosis (Tilly et al. 1992, Lavranos et al. 1994, Vernon & Spicer 1994). bFGF is expressed by primordial and primary oocytes, and granulosa cells of larger preantral follicles, and in the theca of rodent, bovine, and human follicles (van Wezel et al. 1995, Yamamoto et al. 1997, Berisha et al. 2000, Nilsson et al. 2001). The receptors for bFGF have been found in granulosa and theca cells (Shikone et al. 1992, Wandji et al. 1992, Shimizu et al. 2002, Schams et al. 2009). In rat follicle cultures, bFGF activated primordial follicle development to the same extent as SCF (Nilsson et al. 2001) and also promoted cell growth in bovine thecal and stromal cells, and is therefore thought to act in a similar fashion to SCF by regulating somatic cell growth and development (Nilsson et al. 2001). While bFGF may also influence thecal development indirectly through stimulating SCF expression (Nilsson & Skinner 2004), bFGF, at least in the mouse, is not essential for folliculogenesis since the bFGF null mouse is fertile (Ortega et al. 1998).

TGFB superfamily members

TGFB superfamily members are now well established as having vital roles in controlling follicular growth and development (Shimasaki et al. 2004, Knight & Glister 2006, Xia & Schneyer 2009). The superfamily consists of a large group of proteins that include the bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), anti-Müllerian hormone (AMH; also known as Müllerian inhibiting substance (MIS)), activins, and inhibin, all of which are expressed in the ovary. These molecules bind to the BMP/TGFB/activin receptors to initiate phosphorylation cascades to influence gene expression in the cell nucleus. BMPs act through the SMAD1/5/8 pathway, whereas TGFB/activin/GDFs act through SMAD2/3. Evidence shows that specific members are involved in thecal cell recruitment, proliferation, and differentiation, which may or may not interact with the gonadotropins. Specific proteins will be discussed in this section, outlining the relevant research in this area and how each factor may contribute to theca growth and function.

Activin and inhibin

Activin and inhibin influence follicle activation, hormone synthesis, and luteolysis within the ovary (reviewed by Knight & Glister (2001)). Activin promoted the development of preantral follicles in sheep (Thomas et al. 2003) and human (Telfer et al. 2008) ovarian strips in culture, and this was also observed in rat studies (Li et al. 1995, Zhao et al. 2001), while in the mouse, activin from secondary follicles inhibited activation of small follicles (Mizunuma et al. 1999).

Studies on isolated human thecal cells cultured in vitro showed that activin suppressed androgen and progesterone production (Hillier et al. 1991a, Shukovski et al. 1993), while the activin antagonist inhibin enhanced LH-mediated androgen production (Hillier et al. 1991b). It has been suggested that granulosa cells secrete inhibin to control the amount of androgen synthesized by theca cells as substrates for estrogen synthesis in granulosa cells (Hillier et al. 1991b). Thus, activins have direct effects on thecal cell function, and are regulated by the extracellular antagonists inhibin and follistatin (Findlay 1993, Welt et al. 2002).

In some species, an indirect effect of activins may occur through stimulation of granulosa cell proliferation or preantral follicle development (Li et al. 1995, Choi et al. 2008), which may be enhanced by additional IGF1 (Li et al. 1998). Activin can act by upregulating FSH receptors and aromatase gene expression in granulosa cells, and is involved in promoting estradiol production (Nakamura et al. 1993, El-Hefnawy & Zeleznik 2001, Ogawa et al. 2003, Park et al. 2005). Furthermore, since estradiol may suppress activin expression, this forms a possible interaction between activin and estrogen signaling during folliculogenesis (Kipp et al. 2007). Increased estradiol and inhibin production by the putative preovulatory follicle(s) would act to suppress activin production through estradiol, and block activin action at the theca through inhibin, thus enhancing thecal androgen production.

Inhibin is a critical factor in the control of steroid production and for control of gonadotropin secretion (McNeilly 2001, Padmanabhan & McNeilly 2001, McNeilly et al. 2003), but the effects of inhibin on thecal cell recruitment and differentiation are not known. Inhibin alone increased androgen production from human thecal cells in culture and also blocked the inhibitory effect of added activins (Hillier et al. 1991b). Inhibin is thought to modulate hormone production through antagonizing activin and BMPs, rather than through a signal cascade of its own (Wiater & Vale 2003, Farnworth et al. 2006).

Bone morphogenetic proteins

During folliculogenesis, BMPs are released at specific time points and act in either an autocrine or paracrine manner to modulate growth, differentiation, and function of follicular cells. BMP expression patterns have been investigated in rodents, ruminants, and primates, and observations suggest that species-specific differences occur for some molecules (reviewed by Shimasaki et al. (2004)).

BMP4 is expressed in the stromal cells surrounding primordial follicles, and BMP4/7 are expressed in the theca layer of antral follicles (Shimasaki et al. 1999, Nilsson & Skinner 2003, Lee et al. 2004). In neonatal rat ovaries, BMP4/7 increased the formation of primary follicles (Nilsson & Skinner 2003) and the percentage of growing follicles in the adult rat ovary (Nilsson & Skinner 2003, Lee et al. 2004).

BMP6 is produced by oocytes, but its function appears to differ between rodents and ruminants (Otsuka et al. 2001, Glister et al. 2004, Shi et al. 2009b). In sheep (Souza et al. 2002) and bovine (Kayani et al. 2009) ovaries, full complements of BMP/activin receptors were observed in granulosa, theca, and luteal tissues.

Human theca-derived tumor cells show reduced androstenedione production in vitro when treated with BMP4, and this effect is enhanced in the presence of cAMP agonists (Dooley et al. 2000). BMPs 2/4/6/7 all significantly decreased androstenedione secretion from ovine and bovine thecal cells in vitro while moderately increasing progesterone production and cell numbers (Glister et al. 2005, Campbell et al. 2006), and reducing CYP17 gene expression, and to a lesser effect for STAR, CYP11A1, and HSD3B (Glister et al. 2005; see Fig. 2). The BMP antagonist, chordin, reversed the inhibitory effects of BMP7 on androgen production in bovine theca cells (Glister et al. 2005), while gremlin selectively reversed the effects of BMP4 but not BMP6 or 7. The BMP antagonist follistatin did not affect BMP-inhibited androgen production (Glister et al. 2005). Taken together, observations indicate that BMPs may act directly on theca to inhibit androgen production and also function to regulate the expression of factors from granulosa cells that act in a paracrine manner on thecal steroidogenesis. There are many BMP mutations that lead to aberrant fertility (McNatty et al. 2005), and these proteins may play roles in theca recruitment.

Growth differentiation factor 9

GDF9 is primarily produced specifically by the oocyte (McNatty et al. 2004), although it may also be produced in human (Shi et al. 2009a) and porcine (Paradis et al. 2009) granulosa and porcine theca cells (Paradis et al. 2009). Mutations of the GDF9 gene lead to arrested folliculogenesis at the primary stage in mice, sheep, and humans (Shimasaki et al. 2004, Laissue et al. 2006, Kovanci et al. 2007, Nicol et al. 2009), suggesting that GDF9 is not vital for follicle activation but it is vital for onward primary growth. Follicles from GDF9 null mice and sheep (Thoka) lack supporting thecal cells indicating a role for GDF9 in the regulation of thecal recruitment, differentiation, and proliferation, but this appears to be dependent on the stage of follicle development (Dong et al. 1996, Elvin et al. 1999a, 1999b, Nicol et al. 2009). GDF9 alone, and in combination with IGF1, stimulated bovine thecal cell proliferation, but was found to inhibit IGF1- and LH-induced progesterone and androgen production, as well as decreasing LHR, LH-induced cAMP, and CYP11A1 expression levels without altering IGF1 receptor, STAR, or CYP17 levels (Spicer et al. 2008; see Fig. 2). The level of proliferation appeared higher in theca cells from small follicles compared to those from large follicles, and this may be related to higher levels of the putative GDF9 receptor, ALK5, in theca cells from small follicles. Thus, in small follicles, GDF9 could enhance proliferation, yet have no effect on promoting differentiation of thecal cells. GDF9 increased androgen production in rat thecal cells (Solovyeva et al. 2000), but reduced androgen production from human thecal cells indicating some important species-specific differences (Yamamoto et al. 2002). Alternatively, the difference may be due to luteinization of the cells in culture.

GDF9 may also act in an indirect manner to modulate theca cell function, perhaps through regulating SCF expression (Dong et al. 1996, Joyce et al. 2000, Nilsson & Skinner 2002, Wang & Roy 2004). GDF9 also stimulated inhibin production (Hayashi et al. 1999, Kaivo-Oja et al. 2003, Roh et al. 2003), and the GDF9–inhibin-α double knockout mouse model is observed to have morphological thecal cells surrounding preantral follicles (Wu et al. 2004). However, these cells do not appear to have been differentiated into thecal cells since the expression of theca cell markers such as CYP17A1, LHR, or KIT are absent. These findings indicate that recruitment of putative theca-like cells can occur in the absence of GDF9, but differentiation of these cells does not appear to occur. GDF9 appears to have an indirect function on thecal cells, perhaps by promoting granulosa cell proliferation.

Transforming growth factor β

Both TGFB1 and TGFB2 are present in theca cells from follicles at the small preantral stage of development onwards and in stromal tissue and vascular systems in sheep ovaries, but not in granulosa cells or oocytes (Juengel et al. 2004). The receptors, TGFBR1 and TGFBR2, had variable expression, and R1 was found in stromal and vascular cells, whereas R2 mRNA was found in thecal cells from the preantral stage onwards through development, as well as in the surface epithelium and some stromal cells. Furthermore, latent TGFB-binding proteins, which affect the bioavailability of TGFBs in tissues, are localized to the ovarian cortical stroma and theca externa of bovine antral follicles (Prodoehl et al. 2009). TGFB1 has been reported to suppress androgen synthesis from human and rat thecal cells (Fournet et al. 1996, Attia et al. 2000; see Fig. 5), while in the mouse, TGFB1 increased Cyp11a, Cyp17, and Hsd3b gene expression at various times during the culture period (Fournet et al. 1996), but inhibited STAR expression in a human thecal-like tumor cell line (Attia et al. 2000; see Fig. 2). A study using whole rat ovarian dispersed cell cultures suggested that TGFB1 blocks steroidogenesis at the level of CYP17 (Hernandez et al. 1990). These results are not clear-cut, but it appears that in the human at least, TGFB has a similar role to activin and BMPs in suppressing androgen production.

Hedgehog proteins

The hedgehog pathway has recently been shown to intersect with pathways involved with FGF receptor 2, BMPs, and other regulatory networks (Katoh 2009). Theca cells appear to be modulated by hedgehog signaling with the expression of hedgehog target genes Ptch1, Ptch2, Hip1, and Gli1 all present within theca cells (Wijgerde et al. 2005). Hedgehog proteins are expressed in the granulosa cells, but oocytes are unable to respond since they do not contain the necessary receptors. Hedgehog target genes are expressed in the pre-thecal cell compartment, and are therefore possible markers of pre-thecal cells and potentially involved in inducing theca cell differentiation. In cultured bovine thecal cells, sonic hedgehog-induced cell proliferation and androstenedione production (see Fig. 4), and hedgehog genes were shown to activate Gli1 transcription factor in thecal cells (Spicer et al. 2009). In a transgenic mouse model, the hedgehog pathway was dominantly activated, and these mice displayed defective thecal development with reduced or absent smooth muscle actin normally seen in the thecal layer of growing follicles (Ren et al. 2009). The dominant activation of the hedgehog pathway therefore appears to block the differentiation of precursor cells into muscle cells that are normally located in the outer thecal layers, and are perhaps required for ovulation.

Synergism

A common trend appears to be emerging where the TGFB superfamily members are involved in fine tuning the modulation of androgen biosynthesis and steroidogenic enzyme gene expression. TGFBs, activin, and GDF9 all signal through SMAD2/3, whereas BMPs signal through the SMAD1/5/8 signaling pathway (Shimasaki et al. 2004). It makes sense that these two independent pathways influence the expression of completely separate groups of genes; otherwise, they would simply utilize the same pathway for the same effects. If the two pathways do in fact activate separate sets of genes, then these genes appear to be having similar effects on steroidogenesis. BMP4/6/7 suppress STAR, CYP11A1, CYP17, and HSD3B (Glister et al. 2005), and TGFB acts similarly by suppressing CYP17. GDF9 conversely appears to function in a more complicated manner, where it increases CYP17 expression while suppressing CYP11A1 levels. These contrasting results in different species coincide with the observed effects on androgen production, where in rat theca cells, GDF9 enhanced androgen synthesis (Solovyeva et al. 2000), but in bovine theca cells, GDF9 acted in an inhibitory manner (Spicer et al. 2008). There may be important species-specific differences in the function of GDF9 in particular, and this may also be the case with other TGFB superfamily members and therefore requires closer investigation.

There are also important species differences between rodents and humans with regard to stem cells. Mouse ES cells require LIF (Smith et al. 1992) and BMPs (Ying et al. 2003) to maintain pluripotency, whereas human counterparts rely on activin/nodal (Vallier et al. 2004, 2005, James et al. 2005) and FGFs (Xu et al. 2005). However, studies have shown that the same genes; POU5F1 (OCT4), SOX2, and NANOG, are required for pluripotency in both species. Activin/nodal signaling controls expression of the key pluripotency factor NANOG. NANOG prevents differentiation induced by FGF signaling and limits transcriptional activity of SMAD2/3 (Vallier et al. 2009). By studying each factor in isolation, one is able to infer a specific function and role in ovarian folliculogenesis. However, we know that in vivo this is clearly not the case, and many different factors at varying, tightly controlled, concentrations all work synergistically to control the very delicate balance between the life and death of an ovarian follicle. The level and pattern of gene expression are vital factors; moreover, crosstalk between pathways and the presence of antagonists are additional levels of control for folliculogenesis and are yet to be fully elucidated.

Concluding remarks

Classically, it was thought that the oocyte was passively carried along the developmental process, and its maturation was controlled entirely by the production of endocrine hormones and surrounding somatic cell factors influencing the follicle as a whole. The latest concept in reproductive biology is that the oocyte itself is actively involved in regulating the surrounding somatic cells in order to provide an environment suitable for its own maturation. With this new and exciting theory in mind, it is possible that the oocyte itself is responsible for sending the signal for primordial follicle activation and thecal cell recruitment. However, since oocytes produce only limited factors, it is most likely that the interaction and communication between the oocyte and its somatic cells control the follicle development as a whole, and when one component fails, the entire process is halted. Nevertheless, thecal cells are vital for folliculogenesis in the ovary. They are specialized cells that are recruited to surround an activated follicle and provide structural support at first, and then by proliferating and differentiating, and acquiring a capillary network, they have become essential components of developing follicles. Their primary function is to synthesize androgens which act as substrates for estrogen production in granulosa cells, which is crucial for the pituitary–gonadal axis and endocrine control of reproduction. Androgen production is largely under the control of LH produced by the pituitary and transported to thecal cells via the blood stream. However, it is now clear that many other factors play an essential and important role in the modulation of theca function, including IGFs, insulin, FGF, SCF, TGFB superfamily members, and their related pathways and regulators. Theca cells have been somewhat forgotten more recently, where topical research has focused on granulosa cells and oocytes, but these specialized cells have a highly significant role in follicular function and are crucial for normal follicular development.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was funded by MRC (G7.002.0007.01) to A S McNeilly, which supports J M Young.

Acknowledgements

We would like to thank Ted Pinner for preparation of the figures, and Bruce Campbell for useful discussions.

References

  • Adashi EY, Resnick CE, D'Ercole AJ, Svoboda ME & Van Wyk JJ 1985 Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocrine Reviews 6 400420 doi:10.1210/edrv-6-3-400.

    • Search Google Scholar
    • Export Citation
  • Attia GR, Dooley CA, Rainey WE & Carr BR 2000 Transforming growth factor beta inhibits steroidogenic acute regulatory (StAR) protein expression in human ovarian thecal cells. Molecular and Cellular Endocrinology 170 123129 doi:10.1016/S0303-7207(00)00335-X.

    • Search Google Scholar
    • Export Citation
  • Baird DT, Swanston I & Scaramuzzi RJ 1976 Pulsatile release of LH and secretion of ovarian steroids in sheep during the luteal phase of the estrous cycle. Endocrinology 98 14901496 doi:10.1210/endo-98-6-1490.

    • Search Google Scholar
    • Export Citation
  • Baird DT, Swanston IA & McNeilly AS 1981 Relationship between LH, FSH, and prolactin concentration and the secretion of androgens and estrogens by the preovulatory follicle in the ewe. Biology of Reproduction 24 10131025 doi:10.1095/biolreprod24.5.1013.

    • Search Google Scholar
    • Export Citation
  • Bao B & Garverick HA 1998 Expression of steroidogenic enzyme and gonadotropin receptor genes in bovine follicles during ovarian follicular waves: a review. Journal of Animal Science 76 19031921.

    • Search Google Scholar
    • Export Citation
  • Barbieri RL, Makris A & Ryan KJ 1983 Effects of insulin on steroidogenesis in cultured porcine ovarian theca. Fertility and Sterility 40 237241.

  • Barbieri RL, Makris A & Ryan KJ 1984 Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca. Obstetrics and Gynecology 64 73S80S.

    • Search Google Scholar
    • Export Citation
  • Barboni B, Turriani M, Galeati G, Spinaci M, Bacci ML, Forni M & Mattioli M 2000 Vascular endothelial growth factor production in growing pig antral follicles. Biology of Reproduction 63 858864 doi:10.1095/biolreprod63.3.858.

    • Search Google Scholar
    • Export Citation
  • Barnett KR, Schilling C, Greenfeld CR, Tomic D & Flaws JA 2006 Ovarian follicle development and transgenic mouse models. Human Reproduction Update 12 537555 doi:10.1093/humupd/dml022.

    • Search Google Scholar
    • Export Citation
  • Berisha B, Schams D, Kosmann M, Amselgruber W & Einspanier R 2000 Expression and tissue concentration of vascular endothelial growth factor, its receptors, and localization in the bovine corpus luteum during estrous cycle and pregnancy. Biology of Reproduction 63 11061114 doi:10.1095/biolreprod63.4.1106.

    • Search Google Scholar
    • Export Citation
  • Besmer P 1991 The kit ligand encoded at the murine Steel locus: a pleiotropic growth and differentiation factor. Current Opinion in Cell Biology 3 939946 doi:10.1016/0955-0674(91)90111-B.

    • Search Google Scholar
    • Export Citation
  • Campbell BK, Scaramuzzi RJ & Webb R 1995 Control of antral follicle development and selection in sheep and cattle. Journal of Reproduction and Fertility. Supplement 49 335350.

    • Search Google Scholar
    • Export Citation
  • Campbell BK, Baird DT & Webb R 1998 Effects of dose of LH on androgen production and luteinization of ovine theca cells cultured in a serum-free system. Journal of Reproduction and Fertility 112 6977 doi:10.1530/jrf.0.1120069.

    • Search Google Scholar
    • Export Citation
  • Campbell BK, Souza CJ, Skinner AJ, Webb R & Baird DT 2006 Enhanced response of granulosa and theca cells from sheep carriers of the FecB mutation in vitro to gonadotropins and bone morphogenic protein-2, -4, and -6. Endocrinology 147 16081620 doi:10.1210/en.2005-0604.

    • Search Google Scholar
    • Export Citation
  • Choi J, Lee B, Lee E, Yoon BK & Choi D 2008 Effect of activin A and insulin-like growth factor-I on in vitro development of preantral follicles isolated from cryopreserved ovarian tissues in the mouse. Cryobiology 57 209215 doi:10.1016/j.cryobiol.2008.08.004.

    • Search Google Scholar
    • Export Citation
  • Clark LJ, Irving-Rodgers HF, Dharmarajan AM & Rodgers RJ 2004 Theca interna: the other side of bovine follicular atresia. Biology of Reproduction 71 10711078 doi:10.1095/biolreprod.104.029652.

    • Search Google Scholar
    • Export Citation
  • Connolly DT 1991 Vascular permeability factor: a unique regulator of blood vessel function. Journal of Cellular Biochemistry 47 219223 doi:10.1002/jcb.240470306.

    • Search Google Scholar
    • Export Citation
  • Craig J, Orisaka M, Wang H, Orisaka S, Thompson W, Zhu C, Kotsuji F & Tsang BK 2007 Gonadotropin and intra-ovarian signals regulating follicle development and atresia: the delicate balance between life and death. Frontiers in Bioscience 12 36283639 doi:10.2741/2339.

    • Search Google Scholar
    • Export Citation
  • Deheuninck J & Luo K 2009 Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Research 19 4757 doi:10.1038/cr.2008.324.

  • D'Haeseleer M, Cocquyt G, Van Cruchten S, Simoens P & Van den Broeck W 2006 Cell-specific localisation of apoptosis in the bovine ovary at different stages of the oestrous cycle. Theriogenology 65 757772 doi:10.1016/j.theriogenology.2005.07.008.

    • Search Google Scholar
    • Export Citation
  • Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N & Matzuk MM 1996 Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383 531535 doi:10.1038/383531a0.

    • Search Google Scholar
    • Export Citation
  • Dooley CA, Attia GR, Rainey WE, Moore DR & Carr BR 2000 Bone morphogenetic protein inhibits ovarian androgen production. Journal of Clinical Endocrinology and Metabolism 85 33313337 doi:10.1210/jc.85.9.3331.

    • Search Google Scholar
    • Export Citation
  • Edson MA, Nagaraja AK & Matzuk MM 2009 The mammalian ovary from genesis to revelation. Endocrine Reviews 30 624712 doi:10.1210/er.2009-0012.

  • El-Hefnawy T & Zeleznik AJ 2001 Synergism between FSH and activin in the regulation of proliferating cell nuclear antigen (PCNA) and cyclin D2 expression in rat granulosa cells. Endocrinology 142 43574362 doi:10.1210/en.142.10.4357.

    • Search Google Scholar
    • Export Citation
  • Elvin JA, Clark AT, Wang P, Wolfman NM & Matzuk MM 1999a Paracrine actions of growth differentiation factor-9 in the mammalian ovary. Molecular Endocrinology 13 10351048 doi:10.1210/me.13.6.1035.

    • Search Google Scholar
    • Export Citation
  • Elvin JA, Yan C, Wang P, Nishimori K & Matzuk MM 1999b Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary. Molecular Endocrinology 13 10181034 doi:10.1210/me.13.6.1018.

    • Search Google Scholar
    • Export Citation
  • Erickson GF, Magoffin DA, Dyer CA & Hofeditz C 1985 The ovarian androgen producing cells: a review of structure/function relationships. Endocrine Reviews 6 371399 doi:10.1210/edrv-6-3-371.

    • Search Google Scholar
    • Export Citation
  • Farnworth PG, Stanton PG, Wang Y, Escalona R, Findlay JK & Ooi GT 2006 Inhibins differentially antagonize activin and bone morphogenetic protein action in a mouse adrenocortical cell line. Endocrinology 147 34623471 doi:10.1210/en.2006-0023.

    • Search Google Scholar
    • Export Citation
  • Ferrara N & Davis-Smyth T 1997 The biology of vascular endothelial growth factor. Endocrine Reviews 18 425 doi:10.1210/er.18.1.4.

  • Findlay JK 1993 An update on the roles of inhibin, activin, and follistatin as local regulators of folliculogenesis. Biology of Reproduction 48 1523 doi:10.1095/biolreprod48.1.15.

    • Search Google Scholar
    • Export Citation
  • Fournet N, Weitsman SR, Zachow RJ & Magoffin DA 1996 Transforming growth factor-beta inhibits ovarian 17 alpha-hydroxylase activity by a direct noncompetitive mechanism. Endocrinology 137 166174 doi:10.1210/en.137.1.166.

    • Search Google Scholar
    • Export Citation
  • Fraser HM & Duncan WC 2009 SRB Reproduction, Fertility and Development Award Lecture 2008. Regulation and manipulation of angiogenesis in the ovary and endometrium. Reproduction, Fertility, and Development 21 377392 doi:10.1071/RD08272.

    • Search Google Scholar
    • Export Citation
  • Fraser HM, Wilson H, Morris KD, Swanston I & Wiegand SJ 2005 Vascular endothelial growth factor Trap suppresses ovarian function at all stages of the luteal phase in the macaque. Journal of Clinical Endocrinology and Metabolism 90 58115818 doi:10.1210/jc.2005-1199.

    • Search Google Scholar
    • Export Citation
  • Glister C, Kemp CF & Knight PG 2004 Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4, -6 and -7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin. Reproduction 127 239254 doi:10.1530/rep.1.00090.

    • Search Google Scholar
    • Export Citation
  • Glister C, Richards SL & Knight PG 2005 Bone morphogenetic proteins (BMP) -4, -6, and -7 potently suppress basal and luteinizing hormone-induced androgen production by bovine theca interna cells in primary culture: could ovarian hyperandrogenic dysfunction be caused by a defect in thecal BMP signaling? Endocrinology 146 18831892 doi:10.1210/en.2004-1303.

    • Search Google Scholar
    • Export Citation
  • Gougeon A 1986 Dynamics of follicular growth in the human: a model from preliminary results. Human Reproduction 1 8187.

  • Greenaway J, Gentry PA, Feige JJ, LaMarre J & Petrik JJ 2005 Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development. Biology of Reproduction 72 10711078 doi:10.1095/biolreprod.104.031120.

    • Search Google Scholar
    • Export Citation
  • Hammond JM, Baranao JL, Skaleris D, Knight AB, Romanus JA & Rechler MM 1985 Production of insulin-like growth factors by ovarian granulosa cells. Endocrinology 117 25532555 doi:10.1210/endo-117-6-2553.

    • Search Google Scholar
    • Export Citation
  • Hayashi M, McGee EA, Min G, Klein C, Rose UM, van Duin M & Hsueh AJ 1999 Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles. Endocrinology 140 12361244 doi:10.1210/en.140.3.1236.

    • Search Google Scholar
    • Export Citation
  • Hernandez ER, Roberts CT Jr, LeRoith D & Adashi EY 1989 Rat ovarian insulin-like growth factor I (IGF-I) gene expression is granulosa cell-selective: 5′-untranslated mRNA variant representation and hormonal regulation. Endocrinology 125 572574 doi:10.1210/endo-125-1-572.

    • Search Google Scholar
    • Export Citation
  • Hernandez ER, Hurwitz A, Payne DW, Dharmarajan AM, Purchio AF & Adashi EY 1990 Transforming growth factor-beta 1 inhibits ovarian androgen production: gene expression, cellular localization, mechanisms(s), and site(s) of action. Endocrinology 127 28042811 doi:10.1210/endo-127-6-2804.

    • Search Google Scholar
    • Export Citation
  • Hillier SG, Yong EL, Illingworth PJ, Baird DT, Schwall RH & Mason AJ 1991a Effect of recombinant activin on androgen synthesis in cultured human thecal cells. Journal of Clinical Endocrinology and Metabolism 72 12061211 doi:10.1210/jcem-72-6-1206.

    • Search Google Scholar
    • Export Citation
  • Hillier SG, Yong EL, Illingworth PJ, Baird DT, Schwall RH & Mason AJ 1991b Effect of recombinant inhibin on androgen synthesis in cultured human thecal cells. Molecular and Cellular Endocrinology 75 R1R6 doi:10.1016/0303-7207(91)90234-J.

    • Search Google Scholar
    • Export Citation
  • Hillier SG, Whitelaw PF & Smyth CD 1994 Follicular oestrogen synthesis: the ‘two-cell, two-gonadotrophin’ model revisited. Molecular and Cellular Endocrinology 100 5154 doi:10.1016/0303-7207(94)90278-X.

    • Search Google Scholar
    • Export Citation
  • Himelstein-Braw R, Byskov AG, Peters H & Faber M 1976 Follicular atresia in the infant human ovary. Journal of Reproduction and Fertility 46 5559 doi:10.1530/jrf.0.0460055.

    • Search Google Scholar
    • Export Citation
  • Hirshfield AN 1994 Relationship between the supply of primordial follicles and the onset of follicular growth in rats. Biology of Reproduction 50 421428 doi:10.1095/biolreprod50.2.421.

    • Search Google Scholar
    • Export Citation
  • Honda A, Hirose M, Hara K, Matoba S, Inoue K, Miki H, Hiura H, Kanatsu-Shinohara M, Kanai Y & Kono T 2007 Isolation, characterization, and in vitro and in vivo differentiation of putative thecal stem cells. PNAS 104 1238912394 doi:10.1073/pnas.0703787104.

    • Search Google Scholar
    • Export Citation
  • Horie M & Broxmeyer HE 1993 Involvement of immediate-early gene expression in the synergistic effects of steel factor in combination with granulocyte–macrophage colony-stimulating factor or interleukin-3 on proliferation of a human factor-dependent cell line. Journal of Biological Chemistry 268 968973.

    • Search Google Scholar
    • Export Citation
  • Huang CT, Weitsman SR, Dykes BN & Magoffin DA 2001 Stem cell factor and insulin-like growth factor-I stimulate luteinizing hormone-independent differentiation of rat ovarian theca cells. Biology of Reproduction 64 451456 doi:10.1095/biolreprod64.2.451.

    • Search Google Scholar
    • Export Citation
  • Hunter MG, Robinson RS, Mann GE & Webb R 2004 Endocrine and paracrine control of follicular development and ovulation rate in farm species. Animal Reproduction Science 82–83 461477 doi:10.1016/j.anireprosci.2004.05.013.

    • Search Google Scholar
    • Export Citation
  • Irving-Rodgers HF, van Wezel IL, Mussard ML, Kinder JE & Rodgers RJ 2001 Atresia revisited: two basic patterns of atresia of bovine antral follicles. Reproduction 122 761775 doi:10.1530/rep.0.1220761.

    • Search Google Scholar
    • Export Citation
  • Irving-Rodgers HF, Krupa M & Rodgers RJ 2003 Cholesterol side-chain cleavage cytochrome P450 and 3beta-hydroxysteroid dehydrogenase expression and the concentrations of steroid hormones in the follicular fluids of different phenotypes of healthy and atretic bovine ovarian follicles. Biology of Reproduction 69 20222028 doi:10.1095/biolreprod.103.017442.

    • Search Google Scholar
    • Export Citation
  • James D, Levine AJ, Besser D & Hemmati-Brivanlou A 2005 TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132 12731282 doi:10.1242/dev.01706.

    • Search Google Scholar
    • Export Citation
  • Jiang JY, Macchiarelli G, Tsang BK & Sato E 2003 Capillary angiogenesis and degeneration in bovine ovarian antral follicles. Reproduction 125 211223 doi:10.1530/rep.0.1250211.

    • Search Google Scholar
    • Export Citation
  • Jolly PD, Tisdall DJ, Heath DA, Lun S & McNatty KP 1994 Apoptosis in bovine granulosa cells in relation to steroid synthesis, cyclic adenosine 3′,5′-monophosphate response to follicle-stimulating hormone and luteinizing hormone, and follicular atresia. Biology of Reproduction 51 934944 doi:10.1095/biolreprod51.5.934.

    • Search Google Scholar
    • Export Citation
  • Joyce IM, Clark AT, Pendola FL & Eppig JJ 2000 Comparison of recombinant growth differentiation factor-9 and oocyte regulation of KIT ligand messenger ribonucleic acid expression in mouse ovarian follicles. Biology of Reproduction 63 16691675 doi:10.1095/biolreprod63.6.1669.

    • Search Google Scholar
    • Export Citation
  • Juengel JL, Bibby AH, Reader KL, Lun S, Quirke LD, Haydon LJ & McNatty KP 2004 The role of transforming growth factor-beta (TGF-beta) during ovarian follicular development in sheep. Reproductive Biology and Endocrinology 2 78 doi:10.1186/1477-7827-2-78.

    • Search Google Scholar
    • Export Citation
  • Kaivo-Oja N, Bondestam J, Kamarainen M, Koskimies J, Vitt U, Cranfield M, Vuojolainen K, Kallio JP, Olkkonen VM & Hayashi M 2003 Growth differentiation factor-9 induces Smad2 activation and inhibin B production in cultured human granulosa-luteal cells. Journal of Clinical Endocrinology and Metabolism 88 755762 doi:10.1210/jc.2002-021317.

    • Search Google Scholar
    • Export Citation
  • Katoh M 2009 FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. Journal of Investigative Dermatology 129 18611867 doi:10.1038/jid.2009.97.

    • Search Google Scholar
    • Export Citation
  • Kayani AR, Glister C & Knight PG 2009 Evidence for an inhibitory role of bone morphogenetic protein(s) in the follicular–luteal transition in cattle. Reproduction 137 6778 doi:10.1530/REP-08-0198.

    • Search Google Scholar
    • Export Citation
  • Kerban A, Boerboom D & Sirois J 1999 Human chorionic gonadotropin induces an inverse regulation of steroidogenic acute regulatory protein messenger ribonucleic acid in theca interna and granulosa cells of equine preovulatory follicles. Endocrinology 140 667674 doi:10.1210/en.140.2.667.

    • Search Google Scholar
    • Export Citation
  • Kezele PR, Ague JM, Nilsson E & Skinner MK 2005 Alterations in the ovarian transcriptome during primordial follicle assembly and development. Biology of Reproduction 72 241255 doi:10.1095/biolreprod.104.032060.

    • Search Google Scholar
    • Export Citation
  • Kipp JL, Kilen SM, Woodruff TK & Mayo KE 2007 Activin regulates estrogen receptor gene expression in the mouse ovary. Journal of Biological Chemistry 282 3675536765 doi:10.1074/jbc.M705143200.

    • Search Google Scholar
    • Export Citation
  • Knight PG & Glister C 2001 Potential local regulatory functions of inhibins, activins and follistatin in the ovary. Reproduction 121 503512 doi:10.1530/rep.0.1210503.

    • Search Google Scholar
    • Export Citation
  • Knight PG & Glister C 2006 TGF-beta superfamily members and ovarian follicle development. Reproduction 132 191206 doi:10.1530/rep.1.01074.

  • Kovanci E, Rohozinski J, Simpson JL, Heard MJ, Bishop CE & Carson SA 2007 Growth differentiating factor-9 mutations may be associated with premature ovarian failure. Fertility and Sterility 87 143146 doi:10.1016/j.fertnstert.2006.05.079.

    • Search Google Scholar
    • Export Citation
  • Kwintkiewicz J & Giudice LC 2009 The interplay of insulin-like growth factors, gonadotropins, and endocrine disruptors in ovarian follicular development and function. Seminars in Reproductive Medicine 27 4351 doi:10.1055/s-0028-1108009.

    • Search Google Scholar
    • Export Citation
  • Laissue P, Christin-Maitre S, Touraine P, Kuttenn F, Ritvos O, Aittomaki K, Bourcigaux N, Jacquesson L, Bouchard P & Frydman R 2006 Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. European Journal of Endocrinology 154 739744 doi:10.1530/eje.1.02135.

    • Search Google Scholar
    • Export Citation
  • Lavoie HA & King SR 2009 Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B. Experimental Biology and Medicine 234 880907 doi:10.3181/0903-MR-97.

    • Search Google Scholar
    • Export Citation
  • Lavranos TC, Rodgers HF, Bertoncello I & Rodgers RJ 1994 Anchorage-independent culture of bovine granulosa cells: the effects of basic fibroblast growth factor and dibutyryl cAMP on cell division and differentiation. Experimental Cell Research 211 245251 doi:10.1006/excr.1994.1084.

    • Search Google Scholar
    • Export Citation
  • Lee WS, Yoon SJ, Yoon TK, Cha KY, Lee SH, Shimasaki S, Lee S & Lee KA 2004 Effects of bone morphogenetic protein-7 (BMP-7) on primordial follicular growth in the mouse ovary. Molecular Reproduction and Development 69 159163 doi:10.1002/mrd.20163.

    • Search Google Scholar
    • Export Citation
  • Li R, Phillips DM & Mather JP 1995 Activin promotes ovarian follicle development in vitro. Endocrinology 136 849856 doi:10.1210/en.136.3.849.

  • Li D, Kubo T, Kim H, Shimasaki S & Erickson GF 1998 Endogenous insulin-like growth factor-I is obligatory for stimulation of rat inhibin alpha-subunit expression by follicle-stimulating hormone. Biology of Reproduction 58 219225 doi:10.1095/biolreprod58.1.219.

    • Search Google Scholar
    • Export Citation
  • Li M, Schatten H & Sun QY 2009a Androgen receptor's destiny in mammalian oocytes: a new hypothesis. Molecular Human Reproduction 15 149154 doi:10.1093/molehr/gap006.

    • Search Google Scholar
    • Export Citation
  • Li Y, Liang XY, Wei LN, Xiong YL, Yang X, Shi HG & Yang ZH 2009b Study of RNA interference inhibiting rat ovarian androgen biosynthesis by depressing 17alpha-hydroxylase/17, 20-lyase activity in vivo. Reproductive Biology and Endocrinology 7 73 doi:10.1186/1477-7827-7-73.

    • Search Google Scholar
    • Export Citation
  • Logan KA, Juengel JL & McNatty KP 2002 Onset of steroidogenic enzyme gene expression during ovarian follicular development in sheep. Biology of Reproduction 66 906916 doi:10.1095/biolreprod66.4.906.

    • Search Google Scholar
    • Export Citation
  • Lundy T, Smith P, O'Connell A, Hudson NL & McNatty KP 1999 Populations of granulosa cells in small follicles of the sheep ovary. Journal of Reproduction and Fertility 115 251262 doi:10.1530/jrf.0.1150251.

    • Search Google Scholar
    • Export Citation
  • Magoffin DA 2005 Ovarian theca cell. International Journal of Biochemistry & Cell Biology 37 13441349 doi:10.1016/j.biocel.2005.01.016.

  • Magoffin DA & Weitsman SR 1993a Differentiation of ovarian theca-interstitial cells in vitro: regulation of 17 alpha-hydroxylase messenger ribonucleic acid expression by luteinizing hormone and insulin-like growth factor-I. Endocrinology 132 19451951 doi:10.1210/en.132.5.1945.

    • Search Google Scholar
    • Export Citation
  • Magoffin DA & Weitsman SR 1993b Effect of insulin-like growth factor-I on cholesterol side-chain cleavage cytochrome P450 messenger ribonucleic acid expression in ovarian theca-interstitial cells stimulated to differentiate in vitro. Molecular and Cellular Endocrinology 96 4551 doi:10.1016/0303-7207(93)90093-Y.

    • Search Google Scholar
    • Export Citation
  • Magoffin DA & Weitsman SR 1993c Insulin-like growth factor-I stimulates the expression of 3 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid in ovarian theca-interstitial cells. Biology of Reproduction 48 11661173 doi:10.1095/biolreprod48.5.1166.

    • Search Google Scholar
    • Export Citation
  • Magoffin DA & Weitsman SR 1994 Insulin-like growth factor-I regulation of luteinizing hormone (LH) receptor messenger ribonucleic acid expression and LH-stimulated signal transduction in rat ovarian theca-interstitial cells. Biology of Reproduction 51 766775 doi:10.1095/biolreprod51.4.766.

    • Search Google Scholar
    • Export Citation
  • Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH & Papadopoulos N 1997 Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277 5560 doi:10.1126/science.277.5322.55.

    • Search Google Scholar
    • Export Citation
  • Mamluk R, Greber Y & Meidan R 1999 Hormonal regulation of messenger ribonucleic acid expression for steroidogenic factor-1, steroidogenic acute regulatory protein, and cytochrome P450 side-chain cleavage in bovine luteal cells. Biology of Reproduction 60 628634 doi:10.1095/biolreprod60.3.628.

    • Search Google Scholar
    • Export Citation
  • Manna PR, Dyson MT & Stocco DM 2009 Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives. Molecular Human Reproduction 15 321333 doi:10.1093/molehr/gap025.

    • Search Google Scholar
    • Export Citation
  • Manova K, Nocka K, Besmer P & Bachvarova RF 1990 Gonadal expression of c-kit encoded at the W locus of the mouse. Development 110 10571069.

  • Manova K, Huang EJ, Angeles M, De Leon V, Sanchez S, Pronovost SM, Besmer P & Bachvarova RF 1993 The expression pattern of the c-kit ligand in gonads of mice supports a role for the c-kit receptor in oocyte growth and in proliferation of spermatogonia. Developmental Biology 157 8599 doi:10.1006/dbio.1993.1114.

    • Search Google Scholar
    • Export Citation
  • Martelli A, Russo V, Mauro A, Nardinocchi D, Rinaldi C, Bernabo N, Berardinelli P & Mattioli M Role of VEGF in pig preantral follicles Veterinary Research Communications 32 (Supplement 1) 2008 S155S157 doi:10.1007/s11259-008-9114-2.

    • Search Google Scholar
    • Export Citation
  • Mattioli M, Barboni B, Turriani M, Galeati G, Zannoni A, Castellani G, Berardinelli P & Scapolo PA 2001 Follicle activation involves vascular endothelial growth factor production and increased blood vessel extension. Biology of Reproduction 65 10141019 doi:10.1095/biolreprod65.4.1014.

    • Search Google Scholar
    • Export Citation
  • Mazerbourg S & Hsueh AJ 2003 Growth differentiation factor-9 signaling in the ovary. Molecular and Cellular Endocrinology 202 3136 doi:10.1016/S0303-7207(03)00058-3.

    • Search Google Scholar
    • Export Citation
  • McNatty KP, Heath DA, Lundy T, Fidler AE, Quirke L, O'Connell A, Smith P, Groome N & Tisdall DJ 1999 Control of early ovarian follicular development. Journal of Reproduction and Fertility. Supplement 54 316.

    • Search Google Scholar
    • Export Citation
  • McNatty KP, Moore LG, Hudson NL, Quirke LD, Lawrence SB, Reader K, Hanrahan JP, Smith P, Groome NP & Laitinen M 2004 The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology. Reproduction 128 379386 doi:10.1530/rep.1.00280.

    • Search Google Scholar
    • Export Citation
  • McNatty KP, Galloway SM, Wilson T, Smith P, Hudson NL, O'Connell A, Bibby AH, Heath DA, Davis GH & Hanrahan JP Physiological effects of major genes affecting ovulation rate in sheep Genetics, Selection, Evolution 37 Supplement 1 2005 S25S38 doi:10.1186/1297-9686-37-S1-S25.

    • Search Google Scholar
    • Export Citation
  • McNatty KP, Reader K, Smith P, Heath DA & Juengel JL 2007 Control of ovarian follicular development to the gonadotrophin-dependent phase: a 2006 perspective. Society of Reproduction and Fertility Supplement 64 5568.

    • Search Google Scholar
    • Export Citation
  • McNeilly AS 2001 Lactational control of reproduction. Reproduction, Fertility, and Development 13 583590 doi:10.1071/RD01056.

  • McNeilly JR, Saunders PT, Taggart M, Cranfield M, Cooke HJ & McNeilly AS 2000 Loss of oocytes in Dazl knockout mice results in maintained ovarian steroidogenic function but altered gonadotropin secretion in adult animals. Endocrinology 141 42844294 doi:10.1210/en.141.11.4284.

    • Search Google Scholar
    • Export Citation
  • McNeilly AS, Crawford JL, Taragnat C, Nicol L & McNeilly JR 2003 The differential secretion of FSH and LH: regulation through genes, feedback and packaging. Reproduction Supplement 61 463476.

    • Search Google Scholar
    • Export Citation
  • Mizunuma H, Liu X, Andoh K, Abe Y, Kobayashi J, Yamada K, Yokota H, Ibuki Y & Hasegawa Y 1999 Activin from secondary follicles causes small preantral follicles to remain dormant at the resting stage. Endocrinology 140 3742 doi:10.1210/en.140.1.37.

    • Search Google Scholar
    • Export Citation
  • Montgomery GW, Galloway SM, Davis GH & McNatty KP 2001 Genes controlling ovulation rate in sheep. Reproduction 121 843852 doi:10.1530/rep.0.1210843.

  • Moor RM, Hay MF, Dott HM & Cran DG 1978 Macroscopic identification and steroidogenic function of atretic follicles in sheep. Journal of Endocrinology 77 309318 doi:10.1677/joe.0.0770309.

    • Search Google Scholar
    • Export Citation
  • Morley P, Calaresu FR, Barbe GJ & Armstrong DT 1989 Insulin enhances luteinizing hormone-stimulated steroidogenesis by porcine theca cells. Biology of Reproduction 40 735743 doi:10.1095/biolreprod40.4.735.

    • Search Google Scholar
    • Export Citation
  • Motro B & Bernstein A 1993 Dynamic changes in ovarian c-kit and Steel expression during the estrous reproductive cycle. Developmental Dynamics 197 6979 doi:10.1002/aja.1001970107.

    • Search Google Scholar
    • Export Citation
  • Motro B, van der Kooy D, Rossant J, Reith A & Bernstein A 1991 Contiguous patterns of c-kit and steel expression: analysis of mutations at the W and Sl loci. Development 113 12071221.

    • Search Google Scholar
    • Export Citation
  • Nakamura M, Minegishi T, Hasegawa Y, Nakamura K, Igarashi S, Ito I, Shinozaki H, Miyamoto K, Eto Y & Ibuki Y 1993 Effect of an activin A on follicle-stimulating hormone (FSH) receptor messenger ribonucleic acid levels and FSH receptor expressions in cultured rat granulosa cells. Endocrinology 133 538544 doi:10.1210/en.133.2.538.

    • Search Google Scholar
    • Export Citation
  • Nicol L, Bishop SC, Pong-Wong R, Bendixen C, Holm LE, Rhind SM & McNeilly AS 2009 Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep. Reproduction 138 921933 doi:10.1530/REP-09-0193.

    • Search Google Scholar
    • Export Citation
  • Nilsson EE & Skinner MK 2002 Growth and differentiation factor-9 stimulates progression of early primary but not primordial rat ovarian follicle development. Biology of Reproduction 67 10181024 doi:10.1095/biolreprod.101.002527.

    • Search Google Scholar
    • Export Citation
  • Nilsson EE & Skinner MK 2003 Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development. Biology of Reproduction 69 12651272 doi:10.1095/biolreprod.103.018671.

    • Search Google Scholar
    • Export Citation
  • Nilsson EE & Skinner MK 2004 Kit ligand and basic fibroblast growth factor interactions in the induction of ovarian primordial to primary follicle transition. Molecular and Cellular Endocrinology 214 1925 doi:10.1016/j.mce.2003.12.001.

    • Search Google Scholar
    • Export Citation
  • Nilsson E, Parrott JA & Skinner MK 2001 Basic fibroblast growth factor induces primordial follicle development and initiates folliculogenesis. Molecular and Cellular Endocrinology 175 123130 doi:10.1016/S0303-7207(01)00391-4.

    • Search Google Scholar
    • Export Citation
  • Nilsson EE, Kezele P & Skinner MK 2002 Leukemia inhibitory factor (LIF) promotes the primordial to primary follicle transition in rat ovaries. Molecular and Cellular Endocrinology 188 6573 doi:10.1016/S0303-7207(01)00746-8.

    • Search Google Scholar
    • Export Citation
  • Ogawa T, Yogo K, Ishida N & Takeya T 2003 Synergistic effects of activin and FSH on hyperphosphorylation of Rb and G1/S transition in rat primary granulosa cells. Molecular and Cellular Endocrinology 210 3138 doi:10.1016/j.mce.2003.08.008.

    • Search Google Scholar
    • Export Citation
  • Oliver JE, Aitman TJ, Powell JF, Wilson CA & Clayton RN 1989 Insulin-like growth factor I gene expression in the rat ovary is confined to the granulosa cells of developing follicles. Endocrinology 124 26712679 doi:10.1210/endo-124-6-2671.

    • Search Google Scholar
    • Export Citation
  • Orisaka M, Tajima K, Mizutani T, Miyamoto K, Tsang BK, Fukuda S, Yoshida Y & Kotsuji F 2006 Granulosa cells promote differentiation of cortical stromal cells into theca cells in the bovine ovary. Biology of Reproduction 75 734740 doi:10.1095/biolreprod.105.050344.

    • Search Google Scholar
    • Export Citation
  • Ortega S, Ittmann M, Tsang SH, Ehrlich M & Basilico C 1998 Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. PNAS 95 56725677 doi:10.1073/pnas.95.10.5672.

    • Search Google Scholar
    • Export Citation
  • O'Shea JD, Nightingale MG & Chamley WA 1977 Changes in small blood vessels during cyclical luteal regression in sheep. Biology of Reproduction 17 162177 doi:10.1095/biolreprod17.2.162.

    • Search Google Scholar
    • Export Citation
  • O'Shea JD, Hay MF & Cran DG 1978 Ultrastructural changes in the theca interna during follicular atresia in sheep. Journal of Reproduction and Fertility 54 183187 doi:10.1530/jrf.0.0540183.

    • Search Google Scholar
    • Export Citation
  • Otsuka F, Moore RK & Shimasaki S 2001 Biological function and cellular mechanism of bone morphogenetic protein-6 in the ovary. Journal of Biological Chemistry 276 3288932895 doi:10.1074/jbc.M103212200.

    • Search Google Scholar
    • Export Citation
  • Padmanabhan V & McNeilly AS 2001 Is there an FSH-releasing factor? Reproduction 121 2130 doi:10.1530/rep.0.1210021.

  • Palermo R 2007 Differential actions of FSH and LH during folliculogenesis. Reproductive Biomedicine Online 15 326337 doi:10.1016/S1472-6483(10)60347-1.

    • Search Google Scholar
    • Export Citation
  • Paradis F, Novak S, Murdoch GK, Dyck MK, Dixon WT & Foxcroft GR 2009 Temporal regulation of BMP2, BMP6, BMP15, GDF9, BMPR1A, BMPR1B, BMPR2 and TGFBR1 mRNA expression in the oocyte, granulosa and theca cells of developing preovulatory follicles in the pig. Reproduction 138 115129 doi:10.1530/REP-08-0538.

    • Search Google Scholar
    • Export Citation
  • Park Y, Maizels ET, Feiger ZJ, Alam H, Peters CA, Woodruff TK, Unterman TG, Lee EJ, Jameson JL & Hunzicker-Dunn M 2005 Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad. Journal of Biological Chemistry 280 91359148 doi:10.1074/jbc.M409486200.

    • Search Google Scholar
    • Export Citation
  • Parrott JA & Skinner MK 1997 Direct actions of kit-ligand on theca cell growth and differentiation during follicle development. Endocrinology 138 38193827 doi:10.1210/en.138.9.3819.

    • Search Google Scholar
    • Export Citation
  • Parrott JA & Skinner MK 1998 Thecal cell–granulosa cell interactions involve a positive feedback loop among keratinocyte growth factor, hepatocyte growth factor, and Kit ligand during ovarian follicular development. Endocrinology 139 22402245 doi:10.1210/en.139.5.2240.

    • Search Google Scholar
    • Export Citation
  • Parrott JA & Skinner MK 2000 Kit ligand actions on ovarian stromal cells: effects on theca cell recruitment and steroid production. Molecular Reproduction and Development 55 5564 doi:10.1002/(SICI)1098-2795(200001)55:1<55::AID-MRD8>3.0.CO;2-L.

    • Search Google Scholar
    • Export Citation
  • Parrott JA, Vigne JL, Chu BZ & Skinner MK 1994 Mesenchymal–epithelial interactions in the ovarian follicle involve keratinocyte and hepatocyte growth factor production by thecal cells and their action on granulosa cells. Endocrinology 135 569575 doi:10.1210/en.135.2.569.

    • Search Google Scholar
    • Export Citation
  • Peluso JJ, Downey MC & Gruenberg ML 1984 Role of LH pulse amplitude in controlling rat ovarian oestradiol-17 beta secretion in vitro. Journal of Reproduction and Fertility 71 107112 doi:10.1530/jrf.0.0710107.

    • Search Google Scholar
    • Export Citation
  • Pollack SE, Furth EE, Kallen CB, Arakane F, Kiriakidou M, Kozarsky KF & Strauss JF III 1997 Localization of the steroidogenic acute regulatory protein in human tissues. Journal of Clinical Endocrinology and Metabolism 82 42434251 doi:10.1210/jc.82.12.4243.

    • Search Google Scholar
    • Export Citation
  • Poretsky L, Grigorescu F, Seibel M, Moses AC & Flier JS 1985 Distribution and characterization of insulin and insulin-like growth factor I receptors in normal human ovary. Journal of Clinical Endocrinology and Metabolism 61 728734 doi:10.1210/jcem-61-4-728.

    • Search Google Scholar
    • Export Citation
  • Prodoehl MJ, Irving-Rodgers HF, Bonner WM, Sullivan TM, Micke GC, Gibson MA, Perry VE & Rodgers RJ 2009 Fibrillins and latent TGFbeta binding proteins in bovine ovaries of offspring following high or low protein diets during pregnancy of dams. Molecular and Cellular Endocrinology 307 133141 doi:10.1016/j.mce.2009.03.002.

    • Search Google Scholar
    • Export Citation
  • Ravindranath N, Little-Ihrig L, Phillips HS, Ferrara N & Zeleznik AJ 1992 Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology 131 254260 doi:10.1210/en.131.1.254.

    • Search Google Scholar
    • Export Citation
  • Redmer DA, Doraiswamy V, Bortnem BJ, Fisher K, Jablonka-Shariff A, Grazul-Bilska AT & Reynolds LP 2001 Evidence for a role of capillary pericytes in vascular growth of the developing ovine corpus luteum. Biology of Reproduction 65 879889 doi:10.1095/biolreprod65.3.879.

    • Search Google Scholar
    • Export Citation
  • Ren Y, Cowan RG, Harman RM & Quirk SM 2009 Dominant activation of the hedgehog signaling pathway in the ovary alters theca development and prevents ovulation. Molecular Endocrinology 23 711723 doi:10.1210/me.2008-0391.

    • Search Google Scholar
    • Export Citation
  • Rodgers RJ & Irving-Rodgers HF 2009 The morphological classification of bovine ovarian follicles. Reproduction 139 309318 doi:10.1530/REP-09-0177.

    • Search Google Scholar
    • Export Citation
  • Roh JS, Bondestam J, Mazerbourg S, Kaivo-Oja N, Groome N, Ritvos O & Hsueh AJ 2003 Growth differentiation factor-9 stimulates inhibin production and activates Smad2 in cultured rat granulosa cells. Endocrinology 144 172178 doi:10.1210/en.2002-220618.

    • Search Google Scholar
    • Export Citation
  • Ryan KE, Glister C, Lonergan P, Martin F, Knight PG & Evans AC 2008 Functional significance of the signal transduction pathways Akt and Erk in ovarian follicles: in vitro and in vivo studies in cattle and sheep. Journal of Ovarian Research 1 2 doi:10.1186/1757-2215-1-2.

    • Search Google Scholar
    • Export Citation
  • Scaramuzzi RJ, Adams NR, Baird DT, Campbell BK, Downing JA, Findlay JK, Henderson KM, Martin GB, McNatty KP & McNeilly AS 1993 A model for follicle selection and the determination of ovulation rate in the ewe. Reproduction, Fertility, and Development 5 459478 doi:10.1071/RD9930459.

    • Search Google Scholar
    • Export Citation
  • Schallenberger E, Schams D, Bullermann B & Walters DL 1984 Pulsatile secretion of gonadotrophins, ovarian steroids and ovarian oxytocin during prostaglandin-induced regression of the corpus luteum in the cow. Journal of Reproduction and Fertility 71 493501 doi:10.1530/jrf.0.0710493.

    • Search Google Scholar
    • Export Citation
  • Schams D, Steinberg V, Steffl M, Meyer HH & Berisha B 2009 Expression and possible role of fibroblast growth factor family members in porcine antral follicles during final maturation. Reproduction 138 141149 doi:10.1530/REP-09-0033.

    • Search Google Scholar
    • Export Citation
  • Senger DR, Van de Water L, Brown LF, Nagy JA, Yeo KT, Yeo TK, Berse B, Jackman RW, Dvorak AM & Dvorak HF 1993 Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Reviews 12 303324 doi:10.1007/BF00665960.

    • Search Google Scholar
    • Export Citation
  • Shi FT, Cheung AP, Huang HF & Leung PC 2009a Effects of endogenous growth differentiation factor 9 on activin A-induced inhibin B production in human granulosa-lutein cells. Journal of Clinical Endocrinology and Metabolism 94 51085116 doi:10.1210/jc.2009-1047.

    • Search Google Scholar
    • Export Citation
  • Shi J, Yoshino O, Osuga Y, Koga K, Hirota Y, Hirata T, Yano T, Nishii O & Taketani Y 2009b Bone morphogenetic protein-6 stimulates gene expression of follicle-stimulating hormone receptor, inhibin/activin beta subunits, and anti-Mullerian hormone in human granulosa cells. Fertility and Sterility 92 17941798 doi:10.1016/j.fertnstert.2009.05.004.

    • Search Google Scholar
    • Export Citation
  • Shikone T, Yamoto M & Nakano R 1992 Follicle-stimulating hormone induces functional receptors for basic fibroblast growth factor in rat granulosa cells. Endocrinology 131 10631068 doi:10.1210/en.131.3.1063.

    • Search Google Scholar
    • Export Citation
  • Shimasaki S, Zachow RJ, Li D, Kim H, Iemura S, Ueno N, Sampath K, Chang RJ & Erickson GF 1999 A functional bone morphogenetic protein system in the ovary. PNAS 96 72827287 doi:10.1073/pnas.96.13.7282.

    • Search Google Scholar
    • Export Citation
  • Shimasaki S, Moore RK, Otsuka F & Erickson GF 2004 The bone morphogenetic protein system in mammalian reproduction. Endocrine Reviews 25 72101 doi:10.1210/er.2003-0007.

    • Search Google Scholar
    • Export Citation
  • Shimizu T, Jiang JY, Sasada H & Sato E 2002 Changes of messenger RNA expression of angiogenic factors and related receptors during follicular development in gilts. Biology of Reproduction 67 18461852 doi:10.1095/biolreprod.102.006734.

    • Search Google Scholar
    • Export Citation
  • Shimizu T, Kawahara M, Abe Y, Yokoo M, Sasada H & Sato E 2003 Follicular microvasculature and angiogenic factors in the ovaries of domestic animals. Journal of Reproduction and Development 49 181192 doi:10.1262/jrd.49.181.

    • Search Google Scholar
    • Export Citation
  • Shukovski L, Dyson M & Findlay JK 1993 The effects of follistatin, activin and inhibin on steroidogenesis by bovine thecal cells. Molecular and Cellular Endocrinology 97 1927 doi:10.1016/0303-7207(93)90207-Z.

    • Search Google Scholar
    • Export Citation
  • Smith AG, Nichols J, Robertson M & Rathjen PD 1992 Differentiation inhibiting activity (DIA/LIF) and mouse development. Developmental Biology 151 339351 doi:10.1016/0012-1606(92)90174-F.

    • Search Google Scholar
    • Export Citation
  • Smith MF, Gutierrez CG, Ricke WA, Armstrong DG & Webb R 2005 Production of matrix metalloproteinases by cultured bovine theca and granulosa cells. Reproduction 129 7587 doi:10.1530/rep.1.00381.

    • Search Google Scholar
    • Export Citation
  • Solovyeva EV, Hayashi M, Margi K, Barkats C, Klein C, Amsterdam A, Hsueh AJ & Tsafriri A 2000 Growth differentiation factor-9 stimulates rat theca-interstitial cell androgen biosynthesis. Biology of Reproduction 63 12141218 doi:10.1095/biolreprod63.4.1214.

    • Search Google Scholar
    • Export Citation
  • Souza CJ, Campbell BK, McNeilly AS & Baird DT 2002 Effect of bone morphogenetic protein 2 (BMP2) on oestradiol and inhibin A production by sheep granulosa cells, and localization of BMP receptors in the ovary by immunohistochemistry. Reproduction 123 363369 doi:10.1530/rep.0.1230363.

    • Search Google Scholar
    • Export Citation
  • Spicer LJ & Chamberlain CS 1998 Influence of cortisol on insulin- and insulin-like growth factor 1 (IGF-1)-induced steroid production and on IGF-1 receptors in cultured bovine granulosa cells and thecal cells. Endocrine 9 153161 doi:10.1385/ENDO:9:2:153.

    • Search Google Scholar
    • Export Citation
  • Spicer LJ, Voge JL & Allen DT 2004 Insulin-like growth factor-II stimulates steroidogenesis in cultured bovine thecal cells. Molecular and Cellular Endocrinology 227 17 doi:10.1016/j.mce.2004.08.003.

    • Search Google Scholar
    • Export Citation
  • Spicer LJ, Aad PY, Allen DT, Mazerbourg S, Payne AH & Hsueh AJ 2008 Growth differentiation factor 9 (GDF9) stimulates proliferation and inhibits steroidogenesis by bovine theca cells: influence of follicle size on responses to GDF9. Biology of Reproduction 78 243253 doi:10.1095/biolreprod.107.063446.

    • Search Google Scholar
    • Export Citation
  • Spicer LJ, Sudo S, Aad PY, Wang LS, Chun SY, Ben-Shlomo I, Klein C & Hsueh AJ 2009 The hedgehog-patched signaling pathway and function in the mammalian ovary: a novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells. Reproduction 138 329339 doi:10.1530/REP-08-0317.

    • Search Google Scholar
    • Export Citation
  • Stewart RE, Spicer LJ, Hamilton TD & Keefer BE 1995 Effects of insulin-like growth factor I and insulin on proliferation and on basal and luteinizing hormone-induced steroidogenesis of bovine thecal cells: involvement of glucose and receptors for insulin-like growth factor I and luteinizing hormone. Journal of Animal Science 73 37193731.

    • Search Google Scholar
    • Export Citation
  • Taylor PD, Hillier SG & Fraser HM 2004 Effects of GnRH antagonist treatment on follicular development and angiogenesis in the primate ovary. Journal of Endocrinology 183 117 doi:10.1677/joe.1.05685.

    • Search Google Scholar
    • Export Citation
  • Telfer EE, McLaughlin M, Ding C & Thong KJ 2008 A two-step serum-free culture system supports development of human oocytes from primordial follicles in the presence of activin. Human Reproduction 23 11511158 doi:10.1093/humrep/den070.

    • Search Google Scholar
    • Export Citation
  • Thomas FH, Armstrong DG & Telfer EE 2003 Activin promotes oocyte development in ovine preantral follicles in vitro. Reproductive Biology and Endocrinology 1 76 doi:10.1186/1477-7827-1-76.

    • Search Google Scholar
    • Export Citation
  • Tilly JL, Billig H, Kowalski KI & Hsueh AJ 1992 Epidermal growth factor and basic fibroblast growth factor suppress the spontaneous onset of apoptosis in cultured rat ovarian granulosa cells and follicles by a tyrosine kinase-dependent mechanism. Molecular Endocrinology 6 19421950 doi:10.1210/me.6.11.1942.

    • Search Google Scholar
    • Export Citation
  • Tomic D, Brodie SG, Deng C, Hickey RJ, Babus JK, Malkas LH & Flaws JA 2002 Smad 3 may regulate follicular growth in the mouse ovary. Biology of Reproduction 66 917923 doi:10.1095/biolreprod66.4.917.

    • Search Google Scholar
    • Export Citation
  • Vallier L, Reynolds D & Pedersen RA 2004 Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Developmental Biology 275 403421 doi:10.1016/j.ydbio.2004.08.031.

    • Search Google Scholar
    • Export Citation
  • Vallier L, Alexander M & Pedersen RA 2005 Activin/nodal GF pathways cooperate to maintain pluripotency of human embryonic stem cells. Journal of Cell Science 118 44954509 doi:10.1242/jcs.02553.

    • Search Google Scholar
    • Export Citation
  • Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE, Trotter MW, Cho CH, Martinez A & Rugg-Gunn P 2009 Activin/nodal signalling maintains pluripotency by controlling Nanog expression. Development 136 13391349 doi:10.1242/dev.033951.

    • Search Google Scholar
    • Export Citation
  • Van Wezel IL, Dharmarajan AM, Lavranos TC & Rodgers RJ 1999 Evidence for alternative pathways of granulosa cell death in healthy and slightly atretic bovine antral follicles. Endocrinology 140 26022612 doi:10.1210/en.140.6.2602.

    • Search Google Scholar
    • Export Citation
  • Vernon RK & Spicer LJ 1994 Effects of basic fibroblast growth factor and heparin on follicle-stimulating hormone-induced steroidogenesis by bovine granulosa cells. Journal of Animal Science 72 26962702.

    • Search Google Scholar
    • Export Citation
  • Walters DL & Schallenberger E 1984 Pulsatile secretion of gonadotrophins, ovarian steroids and ovarian oxytocin during the periovulatory phase of the oestrous cycle in the cow. Journal of Reproduction and Fertility 71 503512 doi:10.1530/jrf.0.0710503.

    • Search Google Scholar
    • Export Citation
  • Wandji SA, Pelletier G & Sirard MA 1992 Ontogeny and cellular localization of 125I-labeled insulin-like growth factor-I, 125I-labeled follicle-stimulating hormone, and 125I-labeled human chorionic gonadotropin binding sites in ovaries from bovine fetuses and neonatal calves. Biology of Reproduction 47 814822 doi:10.1095/biolreprod47.5.814.

    • Search Google Scholar
    • Export Citation
  • Wang J & Roy SK 2004 Growth differentiation factor-9 and stem cell factor promote primordial follicle formation in the hamster: modulation by follicle-stimulating hormone. Biology of Reproduction 70 577585 doi:10.1095/biolreprod.103.023234.

    • Search Google Scholar
    • Export Citation
  • Wang H, Jiang JY, Zhu C, Peng C & Tsang BK 2006 Role and regulation of nodal/activin receptor-like kinase 7 signaling pathway in the control of ovarian follicular atresia. Molecular Endocrinology 20 24692482 doi:10.1210/me.2005-0446.

    • Search Google Scholar
    • Export Citation
  • Watson ED, Thomson SR & Howie AF 2000 Detection of steroidogenic acute regulatory protein in equine ovaries. Journal of Reproduction and Fertility 119 187192 doi:10.1530/reprod/119.2.187.

    • Search Google Scholar
    • Export Citation
  • Welt C, Sidis Y, Keutmann H & Schneyer A 2002 Activins, inhibins, and follistatins: from endocrinology to signaling. A paradigm for the new millennium. Experimental Biology and Medicine 227 724752.

    • Search Google Scholar
    • Export Citation
  • van Wezel IL, Umapathysivam K, Tilley WD & Rodgers RJ 1995 Immunohistochemical localization of basic fibroblast growth factor in bovine ovarian follicles. Molecular and Cellular Endocrinology 115 133140 doi:10.1016/0303-7207(95)03678-4.

    • Search Google Scholar
    • Export Citation
  • Wiater E & Vale W 2003 Inhibin is an antagonist of bone morphogenetic protein signaling. Journal of Biological Chemistry 278 79347941 doi:10.1074/jbc.M209710200.

    • Search Google Scholar
    • Export Citation
  • Wijgerde M, Ooms M, Hoogerbrugge JW & Grootegoed JA 2005 Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells. Endocrinology 146 35583566 doi:10.1210/en.2005-0311.

    • Search Google Scholar
    • Export Citation
  • Wood JR & Strauss JF III 2002 Multiple signal transduction pathways regulate ovarian steroidogenesis. Reviews in Endocrine & Metabolic Disorders 3 3346 doi:10.1023/A:1012748718150.

    • Search Google Scholar
    • Export Citation
  • Wrathall JH & Knight PG 1995 Effects of inhibin-related peptides and oestradiol on androstenedione and progesterone secretion by bovine theca cells in vitro. Journal of Endocrinology 145 491500 doi:10.1677/joe.0.1450491.

    • Search Google Scholar
    • Export Citation
  • Wu X, Chen L, Brown CA, Yan C & Matzuk MM 2004 Interrelationship of growth differentiation factor 9 and inhibin in early folliculogenesis and ovarian tumorigenesis in mice. Molecular Endocrinology 18 15091519 doi:10.1210/me.2003-0399.

    • Search Google Scholar
    • Export Citation
  • Wulff C, Wiegand SJ, Saunders PT, Scobie GA & Fraser HM 2001a Angiogenesis during follicular development in the primate and its inhibition by treatment with truncated Flt-1-Fc (vascular endothelial growth factor Trap(A40)). Endocrinology 142 32443254 doi:10.1210/en.142.7.3244.

    • Search Google Scholar
    • Export Citation
  • Wulff C, Wilson H, Rudge JS, Wiegand SJ, Lunn SF & Fraser HM 2001b Luteal angiogenesis: prevention and intervention by treatment with vascular endothelial growth factor trap(A40). Journal of Clinical Endocrinology and Metabolism 86 33773386 doi:10.1210/jc.86.7.3377.

    • Search Google Scholar
    • Export Citation
  • Wulff C, Wilson H, Wiegand SJ, Rudge JS & Fraser HM 2002 Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinology 143 27972807 doi:10.1210/en.143.7.2797.

    • Search Google Scholar
    • Export Citation
  • Xia Y & Schneyer AL 2009 The biology of activin: recent advances in structure, regulation and function. Journal of Endocrinology 202 112 doi:10.1677/JOE-08-0549.

    • Search Google Scholar
    • Export Citation
  • Xu RH, Peck RM, Li DS, Feng X, Ludwig T & Thomson JA 2005 Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nature Methods 2 185190 doi:10.1038/nmeth744.

    • Search Google Scholar
    • Export Citation
  • Xu WW, Kong XB, An LG & Zhang C 2009 Relationship between SnoN expression and mouse follicular development, atresia, and luteinization. Zoological Science 26 6673 doi:10.2108/zsj.26.66.

    • Search Google Scholar
    • Export Citation
  • Yamamoto S, Konishi I, Nanbu K, Komatsu T, Mandai M, Kuroda H, Matsushita K & Mori T 1997 Immunohistochemical localization of basic fibroblast growth factor (bFGF) during folliculogenesis in the human ovary. Gynecological Endocrinology 11 223230 doi:10.3109/09513599709152538.

    • Search Google Scholar
    • Export Citation
  • Yamamoto N, Christenson LK, McAllister JM & Strauss JF III 2002 Growth differentiation factor-9 inhibits 3′5′-adenosine monophosphate-stimulated steroidogenesis in human granulosa and theca cells. Journal of Clinical Endocrinology and Metabolism 87 28492856 doi:10.1210/jc.87.6.2849.

    • Search Google Scholar
    • Export Citation
  • Ying QL, Nichols J, Chambers I & Smith A 2003 BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115 281292 doi:10.1016/S0092-8674(03)00847-X.

    • Search Google Scholar
    • Export Citation
  • Zhao J, Taverne MA, van der Weijden GC, Bevers MM & van den Hurk R 2001 Effect of activin A on in vitro development of rat preantral follicles and localization of activin A and activin receptor II. Biology of Reproduction 65 967977 doi:10.1095/biolreprod65.3.967.

    • Search Google Scholar
    • Export Citation
  • Zsebo KM, Wypych J, McNiece IK, Lu HS, Smith KA, Karkare SB, Sachdev RK, Yuschenkoff VN, Birkett NC & Williams LR 1990 Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver – conditioned medium. Cell 63 195201 doi:10.1016/0092-8674(90)90300-4.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 16815 6387 653
PDF Downloads 1741 814 74
  • View in gallery

    Thecal cell development and function during folliculogenesis. Thecal cells are vital for successful folliculogenesis. A primordial follicle consists of an oocyte and surrounding granulosa cells (GCs), and thecal layers are not formed until the follicle is activated and reaches the secondary stage of development. Thecal cells are required for the production of androgens to provide a structural scaffold, and they form the network of cells that support the vascular system, and after ovulation, thecal cells luteinize and form cells of the corpus luteum.

  • View in gallery

    Modulation of steroidogenic enzymes. Expression levels of genes encoding steroidogenic enzymes are regulated by many different factors within the ovary. The process of androgen production requires the following enzymes: cholesterol side-chain cleavage cytochrome P450 (CYP11A1), 17α-hydroxylase (CYP17) and 3-β-hydroxysteroid dehydrogenase (HSD3B), as well as steroidogenic acute regulatory protein (STAR). Theca cells from sheep, humans, and primates principally produce androstenedione, whereas rodents produce testosterone as precursors for estradiol production in the neighboring granulosa cells. The modulating factors are depicted here, where in green circles the stimulatory factors are shown, and the inhibitory factors are listed in red boxes. BMP, bone morphogenetic protein; GDF9, growth differentiation factor 9; HGF, hepatocyte growth factor; hCG, human chorionic gonadotropin; IGF, insulin-like growth factor; SCF, stem cell factor/kit ligand; TGFB, transforming growth factor β.

  • View in gallery

    Theca cell fate. Atresia during follicle development is a more common fate of thecal cells than progression through to luteinization. In preantral follicles, the oocytes die first, and as follicles progress through development, follicles undergo basal or antral atresia. Thecal cells appear to be more susceptible to cell death early in follicular development, whereas in basally atretic follicles, the thecal layers are disrupted and are less vascular. Throughout all stages of development, antral granulosa cells are commonly the first cells to become atretic; hence, thecal cells are often the last to die during follicle atresia and the entire follicle is degraded during this process. FF, follicular fluid.

  • View in gallery

    Thecal cell recruitment and differentiation. Evidence suggests that thecal stem cells reside in the ovarian stroma and are recruited by factors released from follicles after they are activated. Individual factors may be responsible for the recruitment of these cells, whereas others may promote differentiation and proliferation. The origin of these factors is not currently clear, but it appears that a complex and tightly controlled set of signals from multiple factors is required for thecal recruitment and differentiation. AMH, anti-Müllerian hormone; bFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; GDF9, growth differentiation factor 9; IGF, insulin-like growth factor; KGF, keratinocyte growth factor; LIF, leukemia inhibitory factor; SCF, stem cell factor (kit ligand).

  • View in gallery

    Androgen production from theca cells. Factors released by cells comprising the follicle (granulosa cells, thecal cells, and oocytes) can modulate androgen production in thecal cells in addition to external influences such as gonadotropins and insulin. These molecules can stimulate (green) or inhibit (red) thecal androgen production both directly and/or indirectly. Specific molecules have been observed to act in opposing manners, indicating species-specific differences. bFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; GDF9, growth differentiation factor 9; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IGFBP, IGF-binding protein; IL1, interleukin-1; KGF, keratinocyte growth factor; LIF, leukemia inhibitory factor; SCF, stem cell factor/kit ligand; TGFB, transforming growth factor β; TNF, tumor necrosis factor α.

  • Adashi EY, Resnick CE, D'Ercole AJ, Svoboda ME & Van Wyk JJ 1985 Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocrine Reviews 6 400420 doi:10.1210/edrv-6-3-400.

    • Search Google Scholar
    • Export Citation
  • Attia GR, Dooley CA, Rainey WE & Carr BR 2000 Transforming growth factor beta inhibits steroidogenic acute regulatory (StAR) protein expression in human ovarian thecal cells. Molecular and Cellular Endocrinology 170 123129 doi:10.1016/S0303-7207(00)00335-X.

    • Search Google Scholar
    • Export Citation
  • Baird DT, Swanston I & Scaramuzzi RJ 1976 Pulsatile release of LH and secretion of ovarian steroids in sheep during the luteal phase of the estrous cycle. Endocrinology 98 14901496 doi:10.1210/endo-98-6-1490.

    • Search Google Scholar
    • Export Citation
  • Baird DT, Swanston IA & McNeilly AS 1981 Relationship between LH, FSH, and prolactin concentration and the secretion of androgens and estrogens by the preovulatory follicle in the ewe. Biology of Reproduction 24 10131025 doi:10.1095/biolreprod24.5.1013.

    • Search Google Scholar
    • Export Citation
  • Bao B & Garverick HA 1998 Expression of steroidogenic enzyme and gonadotropin receptor genes in bovine follicles during ovarian follicular waves: a review. Journal of Animal Science 76 19031921.

    • Search Google Scholar
    • Export Citation
  • Barbieri RL, Makris A & Ryan KJ 1983 Effects of insulin on steroidogenesis in cultured porcine ovarian theca. Fertility and Sterility 40 237241.

  • Barbieri RL, Makris A & Ryan KJ 1984 Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca. Obstetrics and Gynecology 64 73S80S.

    • Search Google Scholar
    • Export Citation
  • Barboni B, Turriani M, Galeati G, Spinaci M, Bacci ML, Forni M & Mattioli M 2000 Vascular endothelial growth factor production in growing pig antral follicles. Biology of Reproduction 63 858864 doi:10.1095/biolreprod63.3.858.

    • Search Google Scholar
    • Export Citation
  • Barnett KR, Schilling C, Greenfeld CR, Tomic D & Flaws JA 2006 Ovarian follicle development and transgenic mouse models. Human Reproduction Update 12 537555 doi:10.1093/humupd/dml022.

    • Search Google Scholar
    • Export Citation
  • Berisha B, Schams D, Kosmann M, Amselgruber W & Einspanier R 2000 Expression and tissue concentration of vascular endothelial growth factor, its receptors, and localization in the bovine corpus luteum during estrous cycle and pregnancy. Biology of Reproduction 63 11061114 doi:10.1095/biolreprod63.4.1106.

    • Search Google Scholar
    • Export Citation
  • Besmer P 1991 The kit ligand encoded at the murine Steel locus: a pleiotropic growth and differentiation factor. Current Opinion in Cell Biology 3 939946 doi:10.1016/0955-0674(91)90111-B.

    • Search Google Scholar
    • Export Citation
  • Campbell BK, Scaramuzzi RJ & Webb R 1995 Control of antral follicle development and selection in sheep and cattle. Journal of Reproduction and Fertility. Supplement 49 335350.

    • Search Google Scholar
    • Export Citation
  • Campbell BK, Baird DT & Webb R 1998 Effects of dose of LH on androgen production and luteinization of ovine theca cells cultured in a serum-free system. Journal of Reproduction and Fertility 112 6977 doi:10.1530/jrf.0.1120069.

    • Search Google Scholar
    • Export Citation
  • Campbell BK, Souza CJ, Skinner AJ, Webb R & Baird DT 2006 Enhanced response of granulosa and theca cells from sheep carriers of the FecB mutation in vitro to gonadotropins and bone morphogenic protein-2, -4, and -6. Endocrinology 147 16081620 doi:10.1210/en.2005-0604.

    • Search Google Scholar
    • Export Citation
  • Choi J, Lee B, Lee E, Yoon BK & Choi D 2008 Effect of activin A and insulin-like growth factor-I on in vitro development of preantral follicles isolated from cryopreserved ovarian tissues in the mouse. Cryobiology 57 209215 doi:10.1016/j.cryobiol.2008.08.004.

    • Search Google Scholar
    • Export Citation
  • Clark LJ, Irving-Rodgers HF, Dharmarajan AM & Rodgers RJ 2004 Theca interna: the other side of bovine follicular atresia. Biology of Reproduction 71 10711078 doi:10.1095/biolreprod.104.029652.

    • Search Google Scholar
    • Export Citation
  • Connolly DT 1991 Vascular permeability factor: a unique regulator of blood vessel function. Journal of Cellular Biochemistry 47 219223 doi:10.1002/jcb.240470306.

    • Search Google Scholar
    • Export Citation
  • Craig J, Orisaka M, Wang H, Orisaka S, Thompson W, Zhu C, Kotsuji F & Tsang BK 2007 Gonadotropin and intra-ovarian signals regulating follicle development and atresia: the delicate balance between life and death. Frontiers in Bioscience 12 36283639 doi:10.2741/2339.

    • Search Google Scholar
    • Export Citation
  • Deheuninck J & Luo K 2009 Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Research 19 4757 doi:10.1038/cr.2008.324.

  • D'Haeseleer M, Cocquyt G, Van Cruchten S, Simoens P & Van den Broeck W 2006 Cell-specific localisation of apoptosis in the bovine ovary at different stages of the oestrous cycle. Theriogenology 65 757772 doi:10.1016/j.theriogenology.2005.07.008.

    • Search Google Scholar
    • Export Citation
  • Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N & Matzuk MM 1996 Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383 531535 doi:10.1038/383531a0.