SEARCH

SEARCH BY CITATION

Contents

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

It is generally accepted that progesterone (P4) is a key regulator of reproductive function in mammals. In cattle, the primary focus of P4’s actions has been uterine receptivity and maintenance of pregnancy. Studies in mammalian laboratory species and ovarian derived cell lines also highlight their role in ovarian function. Extensive research in non-mammalian species has elucidated a critical role for P4 and both its nuclear and membrane-bound receptors in oocyte maturation and ovulation. Until recently, such a role in mammalian oocytes has been disputed. However, as oestrous synchronization regimes are constantly tweaked and revised to maximize pregnancy rates to artificial insemination in cattle, the importance of P4 priming of the dominant ingfollicle is once again tak centre stage. Sequencing of the bovine genome and the development of multiple transcriptomic data mining tools have facilitated an explosion in global transcriptome profiling of immature and matured oocytes and their surrounding cumulus cells. Many of the differentially regulated genes and their associated preferentially populated pathways appear to be P4 regulated in other tissues. Therefore, attention is once again turning to a potential role for P4 in ovulatory follicle development and oocyte maturation in cattle. The current review summarizes the most recent findings in these areas.


Introduction

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

The central role of progesterone (P4) in establishing uterine receptivity in mammals, including cattle, has been well described (reviewed by Bazer et al. 2011). However, the role of P4 in mammalian oocyte maturation and its potential impact on oocyte quality have not been well defined. Nonetheless, several lines of evidence support the notion of a role for P4 in oocyte maturation: (i) elevated P4 during development of the ovulatory follicle is associated with improved pregnancy rates (Wiltbank et al. 2011); (ii) the well-described switch from oestradiol (E2) dominance to P4 dominance in the follicular fluid of preovulatory follicles in the period between the LH surge and ovulation (Dieleman et al. 1983), coincident with resumption of meiosis and maturation of the oocyte; (iii) cumulus cells exhibit receptors for P4 and secrete P4 during maturation in vitro; (iv) inhibition of P4 production in vitro is associated with reduced embryo development (Aparicio et al. 2011). The current review focuses on the role of P4 in preovulatory follicle development and oocyte maturation with regard to the pathways and processes involved.

Systemic Progesterone During Development of the Ovulatory Follicle

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Progesterone can affect oocyte quality through its effect on development of the dominant follicle. Pulsatile secretion frequency of gonadotrophin-releasing hormone (GnRH) is regulated by circulating concentrations of P4 during the oestrous cycle, which in turn regulates LH pulse frequency. LH pulse frequency is the primary factor determining whether or not a dominant follicle ovulates; thus, when P4 concentrations are high, LH pulse frequency is low and the dominant follicle undergoes atresia. High LH pulse frequency, as occurs when P4 declines following luteolysis, stimulates continued growth of the dominant follicle, which secretes more oestradiol and inhibin and ultimately ovulates (for reviews, see Roche et al. 1999; Ireland et al. 2000). Very low (subluteal) progesterone concentrations (1–2 ng/ml) are associated with increased LH pulse frequency. However, this increase never reaches follicular-phase-type frequencies that are necessary for the final maturation of the preovulatory follicle and ovulation, and therefore may lead to an extended period of dominance (persistence) of the dominant follicle (Roche et al. 1999). Pregnancy rate is sequentially decreased as the duration of dominance increases from 4 to 8 days and is further significantly reduced if the duration of dominance exceeds 10 days (Mihm et al. 1994), owing to resumption of meiosis in many oocytes (Mihm et al. 1999). Restricting the duration of dominance of the preovulatory follicle to <4 days at oestrus results in a precise onset of oestrus and a high pregnancy rate following a single AI at a detected oestrus (Austin et al. 1999).

The effect of elevated P4 during the growth of the ovulatory follicle has been the subject of several recent reviews (Bisinotto and Santos 2011; Pursley and Martins 2011; Wiltbank et al. 2011). However, Fonseca et al. (1983) was one of the first to report that dairy cows that became pregnant had higher P4 concentrations in a 12-day interval prior to AI compared with cows that did not get pregnant. Increasing P4 before timed AI can result in a substantial increase in fertility, suggesting that reduced fertility in dairy cows may be partly a result of reduced P4 in the period prior to insemination (Inskeep 2004; Wiltbank et al. 2011). In the study of Cunha et al. (2008), cows with low P4 before AI had much lower fertility (37.1%) compared with cows with high P4 (51.0%). Furthermore, there was a positive effect of elevated P4 before AI on pregnancy maintenance after Day 29.

Cerri et al. (2011a) examined the effects of varying progesterone concentrations during follicle development in unstimulated (single-ovulating) lactating dairy cows on follicular dynamics, fertilization and embryo quality. Reducing progesterone concentrations during the synchronization programme altered concentrations of oestradiol and follicular dynamics, but resulted in similar fertilization and only minor changes in embryo quality. In a second study, the same authors examined the influence of altering the concentrations of progesterone during the development of the ovulatory follicle on the composition of the follicular fluid, circulating LH and PGF(2α) metabolite (PGFM), and expression of endometrial progesterone receptor and oestrogen receptor-α (Cerri et al. 2011b). Reduced concentrations of progesterone during the development of the ovulatory follicle altered follicular dynamics and follicular fluid composition, increased basal LH concentrations, and prematurely increased oestrogen receptor-α abundance and exacerbated PGF(2α) release in the subsequent oestrous cycle. Furthermore, cows with low P4 had altered uterine function in terms of the pathways involved in PGF2alpha secretion. Other studies have demonstrated the importance of elevated P4 during the growth of the ovulatory follicular wave. Cycling cows that began Ovsynch with high P4 had a higher pregnancy rate (43.0%) than those that had low P4 (31.3%). In a second experiment, cows that ovulated the second dominant follicle (high P4 concentrations) had higher pregnancy than cows ovulating the first dominant follicle (41.7 vs 30.4%) (Bisinotto et al. 2010). Thus, increasing P4 during growth of the ovulatory follicle increases fertility to the subsequent timed AI by more than 10%.

Consistent with the above data, Rivera et al. (2011) showed that high P4 during superstimulation of lactating dairy cows increased the quality of embryos collected on Day 7 after oestrus. Superstimulation was initiated during the second follicular wave (high P4), during the first follicular wave (low P4) or during the first wave with P4 supplementation using two P4-releasing devices. Percentages of transferable embryos were 88.5, 55.9 and 78.6%, for high, low and supplemented P4, respectively. Similar data were reported by Nasser et al. (2011) in beef cows when P4 was supplemented during the first follicular wave. These results suggest an effect of elevated P4 during follicle growth on subsequent development after ovulation.

The mechanism of action is unclear. Suboptimal P4 concentrations during follicular growth may alter uterine function (Shaham-Albalancy et al. 1997), endometrial release of PGF2alpha and subsequent luteal lifespan (Shaham-Albalancy et al. 2001; Cerri et al. 2011b) and impaired oocyte competence (Bisinotto et al. 2010). Low P4 during follicular growth increases LH concentrations and the growth of the ovulatory follicle, reduces intrafollicular IGF-I and compromises early stages of embryo development (Cerri et al. 2011a,b; Rivera et al. 2011). Extending follicle dominance under subluteal P4 induces premature resumption of meiosis in oocytes (Revah and Butler 1996; Mihm et al. 1999).

A strategy to improve fertility of cows outside dioestrus would be to supplement P4 during development of the ovulatory follicle, but results from P4 supplementation to high-yielding lactating dairy cows have been inconsistent (summarized by Bisinotto and Santos 2011). The variability in response may be due to the amount of hormone released by the inserts and the resulting peripheral concentrations. Denicol et al. (2012) reported that cows induced to ovulate the first dominant follicle and supplemented with two P4 inserts had similar pregnancy rates to those ovulating a second-wave dominant follicle.

The precise effect of elevated P4 during the growth of the dominant follicle on the oocyte is unknown. Indeed, whereas elevated P4 is clearly important during growth of the ovulatory follicle, as pointed out by Wiltbank et al. (2011), low P4 near the time of AI is crucial; indeed, minor elevations in P4 near AI (perhaps owing to incomplete luteal regression) have been reported to be detrimental to fertility. This raises the question of the potential differing roles of luteal-derived P4 and that produced locally within the follicle by the granulosa and cumulus cells during oocyte maturation.

Follicular Progesterone and Ovulation

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

In cattle, the LH surge induces luteinization, cumulus cell–oocyte complex (COC) expansion, oocyte maturation, ovulation and a change in the follicular endocrine environment from E2 dominance to P4 dominance in the follicular fluid. This is manifested as a rapid, but transient increase in periovulatory follicular P4 concentration, which declines by 12 hours, but rises again at 24 hours, close to the time of ovulation (Dieleman et al. 1983). The mRNA expression level of the nuclear progesterone receptor (PRG) rises in parallel with P4 in both the theca and granulosa cells of periovulatory follicle and appears to be induced by the LH surge rather than P4. These transient and rapid increases imply time-dependent roles for P4 and PGR in the regulation of periovulatory events in cattle (Jo et al. 2002). This is certainly true in rodents where in Pgr-knockout mice (Pgr_/_; PRKO mice) delayed PGR expression results in granulosa cell luteinization but not ovulation (Lydon et al. 1995; Robker et al. 2000) and blocking of P4 in rats inhibits ovulation (Lipner and Greep 1971; Mori et al. 1977; Snyder et al. 1984). Furthermore, P4 has been shown to enhance the activity of proteolytic enzymes important for the rupture of the follicular wall at ovulation (Iwamasa et al. 1992). Consequently, Pgr-knockout mice are infertile and anovulatory (Lydon et al. 1995). However, in cattle, suppression of P4 synthesis in the periovulatory follicle by intrafollicular injection of trilostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase, which catalyses the synthesis of P4 from pregnenolone, did not block ovulation or subsequent CL function. Nevertheless, inhibition of follicular P4 synthesis did block the periovulatory increase in Ptgs2 production by bovine granulosa cells (Li et al. 2007).

Extensive research has led to the identification of the main pathways and processes that occur in the follicle during the periovulatory period; briefly, simultaneous with the induction of P4 synthesis and PGR expression, LH indirectly stimulates granulosa cell PTGS2 synthesis by rapidly inducing the expression of several members of the epidermal growth factor (EGF)-like growth factor family, specifically, amphiregulin (AREG), epiregulin (EREG) and betacellulin (BTC) (see Richards et al. 2008, for a review). These ligands propagate LH signalling throughout the preovulatory follicle by binding EGF-receptors on granulosa and cumulus cells, leading to activation of ERK1/2 and inducing expression of Ptgs2 in both cell types. As Pgr null mice have reduced expression of Areg and Ereg in their COCs and ovaries (Shimada et al. 2006; Park et al. 2004; Hsieh et al. 2007), reviewed by (Robker et al. 2009), a role for P4 and or PGR in their transcriptional regulation is implied. The role of PGR in transcription of ovulatory genes has been investigated using hormone-primed wild-type and PRKO mouse models (Lubahn et al. 1993; Richards et al. 1998; Robker et al. 2000), a diverse set of responsive genes associated with the control of protease activity, cGMP signalling, exocytosis and inflammation have been identified (summarized by Sriraman et al. 2010). As the in vivo experimental models used were dependent on LH/cAMP signalling for the induction of the PGR itself, it is difficult to isolate those genes that are primarily regulated by PGR. Work by Sriraman et al. (2010) sought to address this by infecting primary cultures of mouse granulosa cells with either PGR-A or PGR-B adenoviral vectors in the presence of a P4 agonist R-5020. The majority of genes identified were induced by PGR-A and included Edn1, Apoa1 and Cited1, IPA analysis related the PRG-A induced genes to structural processes including vascular development, tissue and cell morphology, lipid and carbohydrate metabolism, and skeletal and muscular development, whereas the PGR-B induced genes were associated with inflammatory cytokine networks, such as IL1 and TNF (TNFa), which, although relevant to the ovulatory process, are not critical for ovulation (Conneely et al. 2002). Strikingly, the authors did not report regulation of EGFR ligands by the PGRs, highlighting the complexity of the LH, P4, PGR and PGST2 interaction in the periovulatory follicle.

Progesterone and Cumulus Expansion

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Cumulus cells respond to the ovulatory LH surge with a unique pattern of gene induction leading to cumulus expansion or mucification (reviewed by Russell and Robker 2007). It is generally accepted that the relationship between cumulus cells and oocytes is important for oocyte cytoplasmic maturation and subsequent developmental competence (Modina et al. 2001; Ali and Sirard 2005; Lodde et al. 2007). In contrast to data from mouse, which indicate that PGR is not normally expressed in cumulus cells of the mouse and cumulus expansion is not affected in Pgr-null mice (Lydon et al. 1995; Robker et al. 2000), inhibition of P4 synthesis or blocking PRG reduced cumulus expansion during in vitro maturation of bovine (Aparicio et al. 2011) and porcine oocytes (Yamashita et al. 2003; Shimada et al. 2004). Similarly, blocking expression of the membrane progesterone receptor beta isoform (mPRβ) during IVM impaired cumulus expansion in porcine COCs (Qiu et al. 2008). Cumulus cell expression of extracellular matrix genes and cumulus cell expansion are activated by ERK signalling, downstream of EGF-L (Areg, Ereg and BC) activation of the EGFR. Both Areg and Ereg mRNA and protein levels were reduced significantly in COCs and ovaries collected from prostaglandin synthase 2 (Ptgs2)-null- and Pgr-null- (PRKO-) human chorionic gonadotropin primed mice (Shimada et al. 2006). In the same study, AREG was shown to induce Ptgs2 expression as well as genes associated with matrix formation and steroidogenesis (StAR, Cyp11a1) in cumulus cells. Work in pigs has indicated a significant role for P4 in the induction and maintenance of TACE/ADAM17, a protease that is required for production of mature forms of AREG and EREG (Yamashita et al. 2010). Thus, it would appear that the P4, PGR and Ptgs2 are active participants in a positive loop of sustained EGFR induced – ERK signalling required for cumulus cell expansion and oocyte maturation during the ovulation process (Shimada et al. 2006; Yamashita et al. 2010). An additional role for P4 as a primary chemoattractant of sperm in the oviduct has been postulated; follicular fluid P4 and P4 synthesized by cumulus cells could form a P4 gradient within and surrounding the cumulus mass in the oviduct. P4 gradients have been shown to produce chemotactic behaviour in human (Teves et al. 2006) and rabbit sperm (Guidobaldi et al. 2008); see Chang and Suarez (2010) for a review.

Progesterone and Oocyte Maturation

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Despite the critical role of P4 in triggering oocyte maturation in frog and fish oocytes, the significance of P4 and PGR signalling for maturation of mammalian oocytes in vitro is a matter of debate. Data from rodents provide little evidence of a similar role in mammalian oocyte maturation (reviewed by Mehlmann 2005), whereas the addition of P4 to the culture medium during bovine oocyte maturation in vitro has been reported to reduce the proportion of embryos forming blastocysts, an effect that was partially reversed by addition of the anti-progestin, mifepristone (RU486) (Silva and Knight 2000). Nevertheless, the switch from oestradiol dominance to P4 dominance in the follicular fluid of mammalian preovulatory follicles in the period between the LH surge and ovulation (Dieleman et al. 1983) and COC cumulus cell P4 synthesis during IVM (Aparicio et al. 2011; Salhab et al. 2011) coincident with resumption of meiosis and maturation of the oocyte, suggests some contribution from P4 in this process.

Bovine COCs express both nuclear (PGR-A, PGR-B) and membrane-bound P4 receptors (mPRα, mPRβ, progesterone receptor membrane component (PGRMC) 1 and PGRMC2) in a cell-dependent (oocyte vs cumulus) and receptor-specific manner (Luciano et al. 2010; Aparicio et al. 2011). Furthermore, the protein expression of these receptors changes dynamically following in vitro maturation and in response to supplementation with LH, FSH or P4 (Aparicio et al. 2011). Additional inhibitory experiments confirmed the functional relevance of P4 and P4 receptor signalling during oocyte maturation to oocyte acquisition of developmental competence. For example, neither P4 synthesis nor PRG signalling by bovine COCs during IVM appears to be important for oocyte meiotic maturation or early cleavage divisions, but blastocyst development rates were dramatically reduced when either cumulus cell P4 synthesis was inhibited using Trilostane, or PRG signalling was blocked using RU 486 during IVM. In contrast the membrane boun receptor PGRMC1 and appear to be involved in oocyte meiotic maturation and first mitosis, respectively, as intracytoplasmic injection of oocytes with an antibody against PGRMC1 affected chromosome segregation during oocyte meiotic maturation (Luciano et al. 2010) and the addition of an mPRα-specific antibody during IVM reduced the percentage of oocytes progressing through the early cleavage stages (Aparicio et al. 2011). Thus, these data clearly demonstrate roles for P4 and P4 receptor signalling at both nuclear and cytoplasmic levels during oocyte maturation.

Progesterone and Oocyte Developmental Competence

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

The question arises as to whether P4 ‘promotes’ acquisition of developmental competence or simply protects the oocyte from the onset of apoptosis. Indeed, lower rates of apoptosis in cumulus cells have been correlated with developmental potential in both human and cattle oocytes (Lee et al. 2001; Yuan et al. 2005; Salhab et al. 2011). Studies in periovulatory granulosa cells identified P4 as a pro-survival factor and possible mediator of the anti-atretic actions of LH (Svensson et al. 2000, 2001; Friberg et al. 2009). The main anti-apoptotic action of P4 was demonstrated to be mediated via the classical PGR in periovulatory rat granulosa cells (Friberg et al. 2009, 2010), as treatment of these cells with the PGR antagonist Org 31710 induced increased caspase 9 and caspase 3/7 activities (Friberg et al. 2010). Accordingly, treatment of bovine luteal cells, with P4 for 24 h, decreased caspase-3 activity and the ratio of BAX/BCL2 transcripts, while inhibition of CYP11A1 (cytochrome P450scc) increased caspase-3 activity and subsequently apoptosis in these cells (Liszewska et al. 2005). At the level of the COC, Salhab et al. (2011) reported lower rates of cumulus cells apoptosis and higher oocyte competence when COCs were in vitro matured in media, which promoted cumulus cell P4 synthesis, and proposed that P4 is involved in the inhibition of cumulus cells apoptosis through pathways associated with SMAD2, JNK and AKT phosphorylation. In addition, previous studies have described a role for PGRMC1 in the mediation of the anti-apoptotic effects of P4 and sterol metabolism (Gilchrist et al. 2004; Hussein et al. 2005). Indeed, it is likely that anti-apoptotic effects of P4 are not confined to one pathway, but are attributed to the regulation of several key pathways and processes occurring during oocyte maturation.

Oocyte capacitation or cytoplasmic maturation is critical to the oocyte achieving developmental potential and involves numerous morphological and biochemical processes. We have recently carried out a cross-species meta-analysis of micro-array data generated from different models of oocyte competence (O’Shea et al. 2012). Focusing on genes differentially expressed in matured eggs, we identified several biological pathways including Wnt signalling and the antiapoptotic PI3K/Akt pathway as being key to the maturation of a high quality oocyte. The non-canonical Wnt pathway works through tyrosine kinase signalling to activate the Mapk pathway, inducing oocyte maturation and inhibiting caspase activation and subsequent apoptosis. Tight regulation of RNA processing for translation, protein synthesis and degradation were also key processes associated with the acquisition of competence. Studies in other tissues indicate that these are processes that are regulated by P4-responsive genes.

Conclusion

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References

P4 plays a pivotal role across the reproductive axis in mammalian females, including cattle: from P4 priming of the dominant follicle and luteinization of preovulatory granulose cells to promoting oocyte competence, establishing uterine receptivity and maintaining pregnancy, P4 is critical to reproductive success. As all life begins with the egg, investigating the interactions of P4 and P4 receptor signalling with the key pathways and processes of oocyte maturation will allow us to generate new targets for improving oocyte development prospects.

References

  1. Top of page
  2. Contents
  3. Introduction
  4. Systemic Progesterone During Development of the Ovulatory Follicle
  5. Follicular Progesterone and Ovulation
  6. Progesterone and Cumulus Expansion
  7. Progesterone and Oocyte Maturation
  8. Progesterone and Oocyte Developmental Competence
  9. Conclusion
  10. Acknowledgements
  11. Conflicts of interest
  12. References
  • Ali A, Sirard MA, 2005: Protein kinases influence bovine oocyte competence during short-term treatment with recombinant human follicle stimulating hormone. Reproduction 130, 303310.
  • Aparicio IM, Garcia-Herreros M, O’Shea LC, Hensey C, Lonergan P, Fair T, 2011: Expression, regulation and function of genomic and non-genomic progesterone receptors in bovine cumulus oocyte complexes during in vitro maturation. Biol Reprod 84, 910921.
  • Austin EJ, Mihm M, Ryan MP, Williams DH, Roche JF, 1999: Effect of duration of dominance of the ovulatory follicle on onset of estrus and fertility in heifers. J Anim Sci 77, 22192226.
  • Bazer FW, Spencer TE, Johnson GA, Burghardt RC, 2011: Uterine receptivity to implantation of blastocysts in mammals. Front Biosci (Schol Ed) 3, 745767.
  • Bisinotto RS, Santos JE, 2011: The use of endocrine treatments to improve pregnancy rates in cattle. Reprod Fertil Dev 24, 258266.
  • Bisinotto RS, Chebel RC, Santos JE, 2010: Follicular wave of the ovulatory follicle and not cyclic status influences fertility of dairy cows. J Dairy Sci 93, 35783587.
  • Cerri RL, Chebel RC, Rivera F, Narciso CD, Oliveira RA, Amstalden M, Baez-Sandoval GM, Oliveira LJ, Thatcher WW, Santos JE, 2011a: Concentration of progesterone during the development of the ovulatory follicle: II. Ovarian and uterine responses. J Dairy Sci 94, 33523365.
  • Cerri RL, Chebel RC, Rivera F, Narciso CD, Oliveira RA, Thatcher WW, Santos JE, 2011b: Concentration of progesterone during the development of the ovulatory follicle: I. Ovarian and embryonic responses. J Dairy Sci 94, 33423351.
  • Chang H, Suarez SS, 2010: Rethinking the Relationship Between Hyperactivation and Chemotaxis in Mammalian Sperm. Biol Reprod 83, 507513.
  • Conneely OM, Mulac-Jericevic B, DeMayo F, Lydon JP, O’Malley BW, 2002: Reproductive functions of progesterone receptors. Recent Prog Horm Res 57, 339355.
  • Cunha AP, Guenther JN, Maroney MJ, Giordano JO, Nascimento AB, Bas S, Ayres H, Wiltbank MC, 2008: Effects of high vs. low progesterone concentrations during Ovsynch on double ovulation rate and pregnancies per AI in high producing dairy cows. J Dairy Sci 91(Suppl. 1), 246, [Abstract].
  • Denicol AC, Lopes G Jr, Mendonça LG, Rivera FA, Guagnini F, Perez RV, Lima JR, Bruno RG, Santos JE, Chebel RC, 2012: Low progesterone concentration during the development of the first follicular wave reduces pregnancy per insemination of lactating dairy cows. J Dairy Sci 95, 17941806.
  • Dieleman SJ, Bevers MM, Poortman J, van Tol HT, 1983: Steroid and pituitary hormone concentrations in the fluid of preovulatory bovine follicles relative to the peak of LH in the peripheral blood. J Reprod Fertil 69, 641649.
  • Fonseca FA, Britt JH, McDaniel BT, Wilk JC, Rakes AH, 1983: Reproductive traits of Holsteins and Jerseys. Effects of age, milk yield, and clinical abnormalities on involution of cervix and uterus, ovulation, estrous cycles, detection of estrus, conception rate, and days open. J Dairy Sci 66, 11281147.
  • Friberg PA, Larsson DG, Billig H, 2009: Dominant role of nuclear progesterone receptor in the control of rat periovulatory granulosa cell apoptosis. Biol Reprod 80, 11601167.
  • Friberg PA, Larsson DG, Billig H, 2010: Transcriptional effects of progesterone receptor antagonist in rat granulosa cells. Mol Cell Endocrinol 315, 121130.
  • Gilchrist RB, Ritter LJ, Armstrong DT, 2004: Oocyte-somatic cell interactions during follicle development in mammals. Anim Reprod Sci 82–83, 431446.
  • Guidobaldi HA, Teves ME, Unates DR, Anastasia A, Giojalas LC, 2008: Progesterone from the cumulus cells is the sperm chemoattractant secreted by the rabbit oocyte cumulus complex. PLoS ONE 3, e3040.
  • Hsieh M, Lee D, Panigone S, Horner K, Chen R, Theologis A, Lee DC, Threadgill DW, Conti M, 2007: Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation. Mol Cell Biol 27, 19141924.
  • Hussein TS, Froiland DA, Amato F, Thompson JG, Gilchrist RB, 2005: Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteins. J Cell Sci 118, 52575268.
  • Inskeep EK, 2004: Preovulatory, postovulatory, and postmaternal recognition effects of concentrations of progesterone on embryonic survival in the cow. J Anim Sci 82, E24E39.
  • Ireland JJ, Mihm M, Austin E, Diskin MG, Roche JF, 2000: Historical perspective of turnover of dominant follicles during the bovine estrous cycle: key concepts, studies, advancements, and terms. J Dairy Sci 83, 16481658.
  • Iwamasa J, Shibata S, Tanaka N, Matsuura K, Okamura H, 1992: The relationship between ovarian progesterone and proteolytic enzyme activity during ovulation in the gonadotropin-treated immature rat. Biol Reprod 46, 309313.
  • Jo M, Komar CM, Fortune JE, 2002: Gonadotropin surge induces two separate increases in messenger RNA for PGR in bovine preovulatory follicles. Biol Reprod 67, 19811988.
  • Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW, 2001: Cumulus cells apoptosis as an indicator to predict the quality of oocytes and the outcome of IVF-ET. J Assist Reprod Genet 18, 490498.
  • Li Q, Jimenez-Krassel F, Bettegowda A, Ireland JJ, Smith GW, 2007: Evidence that the preovulatory rise in intrafollicular progesterone may not be required for ovulation in cattle. J Endocrinol 192, 473483.
  • Lipner H, Greep RO, 1971: Inhibition of steroidogenesis at various sites in the biosynthetic pathway in relation to induced ovulation. Endocrinology 88, 602607.
  • Liszewska E, Rekawiecki R, Kotwica J, 2005: Effect of progesterone on the expression of bax and bcl-2 and on caspase activity in bovine luteal cells. Prostaglandins Other Lipid Mediat 78, 6781.
  • Lodde V, Modina S, Galbusera C, Franciosi F, Luciano AM, 2007: Large-scale chromatin remodeling in germinal vesicle bovine oocytes: interplay with gap junction functionality and developmental competence. Mol Reprod Dev 74, 740749.
  • Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O, 1993: Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci U S A 190, 1116211166.
  • Luciano AM, Lodde V, Franciosi F, Ceciliani F, Peluso JJ, 2010: Progesterone receptor membrane component 1 expression and putative function in bovine oocyte maturation, fertilization, and early embryonic development. Reproduction 140, 663672.
  • Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, Shyamala G, Conneely OM, O’Malley BW, 1995: Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9, 22662278.
  • Mehlmann L, 2005: Stops and starts in mammalian oocytes: recent advances in understanding the regulation of meiotic arrest and oocyte maturation. Reproduction 130, 791799.
  • Mihm M, Baguisi A, Boland MP, Roche JF, 1994: Association between the duration of dominance of the ovulatory follicle and pregnancy rate in beef heifers. J Reprod Fertil 102, 123130.
  • Mihm M, Curran N, Hyttel P, Knight PG, Boland MP, Roche JF, 1999: Effect of dominant follicle persistence on follicular fluid oestradiol and inhibin and on oocyte maturation in heifers. J Reprod Fertil 116, 293304.
  • Modina S, Luciano AM, Vassena R, Baraldi-Scesi L, Lauria A, Gandolfi F, 2001: Oocyte developmental competence after in vitro maturation depends on the persistence of cumulus-oocyte communications which are linked to the intracellular concentration of cAMP. Ital J Anat Embryol 106, 241248.
  • Mori T, Suzuki A, Nishimura T, Kambegawa A, 1977: Inhibition of ovulation in immature rats by anti-progesterone antiserum. J Endocrinol 73, 185186.
  • Nasser LF, Sa′ Filho MF, Reis EL, Rezende CR, Mapletoft RJ, Bo′ GA, Baruselli PS, 2011: Exogenous progesterone enhances ova and embryo quality following superstimulation of the first follicular wave in Nelore (Bos indicus) donors. Theriogenology 76, 320327.
  • O’Shea LC, Mehta J, Lonergan P, Hensey C, Fair T, 2012: Developmental competence in oocytes and cumulus cells: candidate genes and networks. Syst Biol Reprod Med 58, 88101.
  • Park JY, Su YQ, Ariga M, Law E, Jin SL, Conti M, 2004: EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 303, 682684.
  • Pursley JR, Martins JP, 2011: Impact of circulating concentrations of progesterone and antral age of the ovulatory follicle on fertility of high-producing lactating dairy cows. Reprod Fertil Dev 24, 267271.
  • Qiu HB, Lu SS, Ji KL, Song XM, Lu YQ, Zhang M, Lu KH, 2008: Membrane progestin receptor beta (mPR-beta): a protein related to cumulus expansion that is involved in in vitro maturation of pig cumulus-oocyte complexes. Steroids 14, 14161423.
  • Revah I, Butler WR, 1996: Prolonged dominance of follicles and reduced viability of bovine oocytes. J Reprod Fertil 106, 3947.
  • Richards JS, Russell DL, Robker RL, Dajee M, Alliston TN, 1998: Molecular mechanisms of ovulation and luteinization. Mol Cell Endocrinol 145, 4754.
  • Richards JS, Liu Z, Shimada M, 2008: Immune-like mechanisms in ovulation. Trends Endocrinol Metab 6, 191196.
  • Rivera FA, Mendonca LG, Lopes G Jr, Santos JEP, Perez RV, Amstalden M, Correa-Calderon A, Chebel RC, 2011: Reduced progesterone concentration during growth of the first follicular wave affects embryo quality but has no effect on embryo survival post transfer in lactating dairy cows. Reproduction 141, 333342.
  • Robker RL, Russell DL, Espey LL, Lydon JP, O’Malley BW, Richards JS, 2000: Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc Natl Acad Sci U S A 97, 46894694.
  • Robker RL, Akison LK, Russell DL, 2009: Control of oocyte release by progesterone receptor-regulated gene expression. Nucl Recept Signal 7, e012.
  • Roche JF, Austin EJ, Ryan M, O’Rourke M, Mihm M, Diskin MG, 1999: Regulation of follicle waves to maximize fertility in cattle. J Reprod Fertil Suppl 54, 6171.
  • Russell DL, Robker RL, 2007: Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update 13, 289312.
  • Salhab M, Tosca L, Cabau C, Papillier P, Perreau C, Dupont J, Mermillod P, Uzbekova S, 2011: Kinetics of gene expression and signaling in bovine cumulus cells throughout IVM in different mediums in relation to oocyte developmental competence, cumulus apoptosis and P4 secretion. Theriogenology 75, 90104.
  • Shaham-Albalancy A, Nyska A, Kaim M, Rosemberg M, Folman Y, Wolfenson D, 1997: Delayed effect of progesterone on endometrial morphology in dairy cows. Anim Reprod Sci 48, 159174.
  • Shaham-Albalancy A, Folman Y, Kaim M, Rosemberg M, Wolfenson D, 2001: Delayed effect of low progesterone concentrations on bovine uterine PGF(2alpha) secretion in the subsequent estrous cycle. Reproduction 122, 643648.
  • Shimada M, Nihsibori M, Yamashita Y, Ito J, Mori T, Richards JS, 2004: Down-regulated expression of A disintegrin and metalloproteinase with thrombospondin-like repeats-1 by progesterone receptor is associated with impaired expression of porcine cumulus-oocyte complexes. Endocrinology 145, 46034610.
  • Shimada M, Hernandez-Gonzalez I, Gonzalez-Robayna I, Richards JS, 2006: Paracrine and autocrine regulation of epidermal growth factor-like factors in cumulus oocyte complexes and granulosa cells: key roles for prostaglandin synthase 2 and progesterone receptor. Mol Endocrinol 20, 13521365.
  • Silva CC, Knight PG, 2000: Effects of androgens, progesterone and their antagonists on the developmental competence of in vitro matured bovine oocytes. J Reprod Fertil 119, 261269.
  • Snyder BW, Beecham GD, Schane HP, 1984: Inhibition of ovulation in rats with epostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase. Proc Soc Exp Biol Med 176, 238242.
  • Sriraman V, Sinha M, Richards JS, 2010: Progesterone receptor-induced gene expression in primary mouse granulosa cell cultures. Biol Reprod 82, 402412.
  • Svensson EC, Markström E, Andersson M, Billig H, 2000: Progesterone receptor mediated inhibition of apoptosis in granulosa cells isolated from rats treated with human chorionic gonadotropin. Biol Reprod 63, 14571464.
  • Svensson EC, Markström E, Shao R, Andersson M, Billig H, 2001: Progesterone receptor antagonists org 31710 and ru 486 increase apoptosis in human periovulatory granulosa cells. Fertil Steril 76, 12251231.
  • Teves ME, Barbano F, Guidobaldi HA, Sanchez R, Miska W, Giojalas LC, 2006: Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa. Fertil Steril 86, 745749.
  • Wiltbank MC, Souza AH, Carvalho PD, Bender RW, Nascimento AB, 2011: Improving fertility to timed artificial insemination by manipulation of circulating progesterone concentrations in lactating dairy cattle. Reprod Fertil Dev 24, 238243.
  • Yamashita Y, Shimada M, Okazaki T, Maeda T, Terada T, 2003: Production of progesterone from de novo-synthesized cholesterol in cumulus cells and its physiological role during meiotic resumption of porcine oocytes. Biol Reprod 68, 11931198.
  • Yamashita Y, Kawashima I, Gunji Y, Hishinuma M, Shimada M, 2010: Progesterone is essential for maintenance of Tace/Adam17 mRNA expression, but not EGF-like factor, in cumulus cells, which enhances the EGF receptor signaling pathway during in vitro maturation of porcine COCs. J Reprod Dev 56, 315323.
  • Yuan YQ, Van Soom A, Leroy JL, Dewulf J, Van Zeveren A, de Kruif A, Peelman LJ, 2005: Apoptosis in cumulus cells, but not in oocytes, may influence bovine embryonic developmental competence. Theriogenology 63, 21472163.