Early pregnancy factor

Early pregnancy factor (EPF) or early conception factor (ECF) is a protein associated with mammalian embryos shortly after fertilization.[1][2] It may be composed of more than one molecule.[3][4] It was first described in 1976.[4]

Detection

Early pregnancy factor is tested for rosette inhibition assay. EPF is present in the maternal serum (blood plasma) shortly after fertilization; EPF is also present in cervical mucus[5] and in amniotic fluid.[6]

EPF may be detected in sheep within 72 hours of mating,[7] in mice within 24 hours of mating,[8] and in samples from media surrounding human embryos fertilized in vitro within 48 hours of fertilization[9] (although another study failed to duplicate this finding for in vitro embryos).[10] EPF has been detected as soon as within six hours of mating.[11]

Because the rosette inhibition assay for EPF is indirect, substances that have similar effects may confound the test. Pig semen, like EPF, has been shown to inhibit rosette formation - the rosette inhibition test was positive for one day in sows mated with a vasectomized boar, but not in sows similarly stimulated without semen exposure.[12] A number of studies in the years after the discovery of EPF were unable to reproduce the consistent detection of EPF in post-conception females, and the validity of the discovery experiments was questioned.[13] However, progress in characterization of EPF has been made and its existence is well-accepted in the scientific community.[3][14]

Origin and function

Early embryos are not believed to directly produce EPF. Rather, embryos are believed to produce some other chemical that induces the maternal system to create EPF.[15] After implantation, EPF may be produced by the conceptus directly.[10]

EPF is an immunosuppressant. Along with other substances associated with early embryos, EPF believed to play a role in preventing the immune system of the pregnant female from attacking the embryo.[11][16] Injecting anti-EPF antibodies into mice after mating significantly reduced the number of successful pregnancies and number of pups;[17] no effect on growth was seen when mice embryos were cultured in media containing anti-EPF antibodies.[18] While some actions of EPF are the same in all mammals (namely rosette inhibition), other immunosuppressant mechanism vary between species.[19]

In mice, EPF levels are high in early pregnancy, but on day 15 decline to levels found in non-pregnant mice.[20] In humans, EPF levels are high for about the first twenty weeks, then decline, becoming undetectable within eight weeks of delivery.[21]

Recent research has suggested that EPF may be associated with cell proliferation in a wide variety of biological situations, not just embryo development.[22]

Clinical utility

Pregnancy testing

In 1979, it was suggested that EPF could be used as a marker for a very early pregnancy test, and as a way to monitor the viability of ongoing pregnancies in livestock.[7] Interest in EPF for this purpose has continued,[23] although current test methods have not proved sufficiently accurate for the requirements of livestock management.[2][24]

In humans, modern pregnancy tests detect human chorionic gonadotropin (hCG). hCG is not present until after implantation, which occurs six to twelve days after fertilization.[25] In contrast, EPF is present within hours of fertilization. While several other pre-implantation signals have been identified, EPF is believed to be the earliest possible marker of pregnancy.[8][26] The accuracy of EPF as a pregnancy test in humans has been found to be high by several studies.[27]

Birth control research

EPF may also be used to determine whether pregnancy prevention mechanism of birth control methods act before or after fertilization. A 1982 study evaluating EPF levels in women with IUDs concluded that post-fertilization mechanisms contribute significantly to the effectiveness of these devices.[28] However, more recent evidence, such as tubal flushing studies indicates that IUDs work by inhibiting fertilization, acting earlier in the reproductive process than previously thought.[29]

For groups that define pregnancy as beginning with fertilization, birth control methods that have postfertilization mechanisms are regarded as abortifacient. There is currently contention over whether hormonal contraception methods have post-fertilization methods, specifically the most popular hormonal method - the combined oral contraceptive pill (COCP). The group Pharmacists for Life has called for a large-scale clinical trial to evaluate EPF in women taking COCPs; this would be the most conclusive evidence available to determine whether COCPs have postfertilization mechanisms.[30]

Infertility and early pregnancy loss

EPF is useful when investigating embryo loss prior to implantation. One study in healthy human women seeking pregnancy detected fourteen pregnancies with EPF. Of these, six were lost within ten days of ovulation (43% rate of early conceptus loss).[31]

Use of EPF has been proposed to distinguish infertility caused by failure to conceive versus infertility caused by failure to implant.[32] EPF has also been proposed as a marker of viable pregnancy, more useful in distinguishing ectopic or other nonviable pregnancies than other chemical markers such as hCG and progesterone.[33]

A study of EPF in women taking clomifene to treat infertility found fertilization rates of about 40%-50% per cycle. In cycles where fertilization was detected, nearly 80% resulted in subclinical embryonic loss, a rate much higher than that found in healthy women.[34]

A study of EPF in women undergoing in vitro fertilization (IVF) concluded that, while a significant number of embryos simply failed to implant, an equally significant number of embryos were likely damaged or killed by the transfer process itself. The researchers used these findings to call for more attention to the effective transfer of embryos during IVF procedures.[35]

As a tumour marker

Although almost exclusively associated with pregnancy, EPF-like activity has also been detected in tumors of germ cell origin[36] and in other types of tumors.[37] Its utility as a tumour marker, to evaluate the success of surgical treatment, has been suggested.[38]

References

  1. ↑ Smart Y, Roberts T, Clancy R, Cripps A (1981). "Early pregnancy factor: its role in mammalian reproduction--research review.". Fertil Steril 35 (4): 397–402. PMID 7011853.
  2. ↑ 2.0 2.1 Greco C, Vivas A, Bosch R (1992). "Evaluation of the method for early pregnancy factor detection (EPF) in swine. Significance in early pregnancy diagnosis". Acta Physiol Pharmacol Ther Latinoam 42 (1): 43–50. PMID 1294272.
  3. ↑ 3.0 3.1 Di Trapani G, Orosco C, Perkins A, Clarke F (1991). "Isolation from human placental extracts of a preparation possessing 'early pregnancy factor' activity and identification of the polypeptide components". Hum Reprod 6 (3): 450–7. PMID 1955557.
  4. ↑ 4.0 4.1 Clarke F (1992). "Identification of molecules and mechanisms involved in the 'early pregnancy factor' system". Reprod Fertil Dev 4 (4): 423–33. doi:10.1071/RD9920423. PMID 1461993.
  5. ↑ Cheng S, Zheng Z (2004). "Early pregnancy factor in cervical mucus of pregnant women". Am J Reprod Immunol 51 (2): 102–5. doi:10.1046/j.8755-8920.2003.00136.x. PMID 14748834.
  6. ↑ Zheng Z, Qin Z, Ma A, Qiao C, Wang H (1990). "Detection of early pregnancy factor-like activity in human amniotic fluid". Am J Reprod Immunol 22 (1–2): 9–11. doi:10.1111/j.1600-0897.1990.tb01025.x. PMID 2346595.
  7. ↑ 7.0 7.1 Morton H, Clunie G, Shaw F (1979). "A test for early pregnancy in sheep". Res Vet Sci 26 (2): 261–2. PMID 262615.
  8. ↑ 8.0 8.1 Cavanagh A, Morton H, Rolfe B, Gidley-Baird A (1982). "Ovum factor: a first signal of pregnancy?". Am J Reprod Immunol 2 (2): 97–101. doi:10.1111/j.1600-0897.1982.tb00093.x. PMID 7102890.
  9. ↑ Smart Y, Cripps A, Clancy R, Roberts T, Lopata A, Shutt D (1981). "Detection of an immunosuppressive factor in human preimplantation embryo cultures". Med J Aust 1 (2): 78–9. PMID 7231254.
  10. ↑ 10.0 10.1 Nahhas F, Barnea E (1990). "Human embryonic origin early pregnancy factor before and after implantation". Am J Reprod Immunol 22 (3–4): 105–8. doi:10.1111/j.1600-0897.1990.tb00651.x. PMID 2375830.
  11. ↑ 11.0 11.1 Shaw F, Morton H (1980). "The immunological approach to pregnancy diagnosis: a review". Vet Rec 106 (12): 268–70. doi:10.1136/vr.106.12.268. PMID 6966439.
  12. ↑ Koch E, Ellendorff F (1985). "Detection of activity similar to that of early pregnancy factor after mating sows with a vasectomized boar". J Reprod Fertil 74 (1): 39–46. doi:10.1530/jrf.0.0740039. PMID 4020773.
  13. ↑ Chard T, Grudzinskas J (1987). "Early pregnancy factor". Biol Res Pregnancy Perinatol 8 (2 2D Half): 53–6. PMID 3322417.
  14. ↑ Cavanagh A (1996). "Identification of early pregnancy factor as chaperonin 10: implications for understanding its role". Rev Reprod 1 (1): 28–32. doi:10.1530/ror.0.0010028. PMID 9414435.
  15. ↑ Orozco C, Perkins T, Clarke F (1986). "Platelet-activating factor induces the expression of early pregnancy factor activity in female mice". J Reprod Fertil 78 (2): 549–55. doi:10.1530/jrf.0.0780549. PMID 3806515.
    Roberts T, Adamson L, Smart Y, Stanger J, Murdoch R (1987). "An evaluation of peripheral blood platelet enumeration as a monitor of fertilization and early pregnancy". Fertil Steril 47 (5): 848–54. PMID 3569561.
    Sueoka K, Dharmarajan A, Miyazaki T, Atlas S, Wallach E (1988). "Platelet activating factor-induced early pregnancy factor activity from the perfused rabbit ovary and oviduct". Am J Obstet Gynecol 159 (6): 1580–4. doi:10.1016/0002-9378(88)90598-4. PMID 3207134.
    Cavanagh A, Morton H, Athanasas-Platsis S, Quinn K, Rolfe B (1991). "Identification of a putative inhibitor of early pregnancy factor in mice". J Reprod Fertil 91 (1): 239–48. doi:10.1530/jrf.0.0910239. PMID 1995852.
    Cavanagh A, Rolfe B, Athanasas-Platsis S, Quinn K, Morton H (1991). "Relationship between early pregnancy factor, mouse embryo-conditioned medium and platelet-activating factor". J Reprod Fertil 93 (2): 355–65. doi:10.1530/jrf.0.0930355. PMID 1787455.
  16. ↑ Bose R, Cheng H, Sabbadini E, McCoshen J, MaHadevan M, Fleetham J (1989). "Purified human early pregnancy factor from preimplantation embryo possesses immunosuppresive properties". Am J Obstet Gynecol 160 (4): 954–60. doi:10.1016/0002-9378(89)90316-5. PMID 2712125.
  17. ↑ Igarashi S (1987). "Significance of early pregnancy factor (EPF) on reproductive immunology". Nippon Sanka Fujinka Gakkai Zasshi 39 (2): 189–94. PMID 2950188.
    Athanasas-Platsis S, Quinn K, Wong T, Rolfe B, Cavanagh A, Morton H (1989). "Passive immunization of pregnant mice against early pregnancy factor causes loss of embryonic viability". J Reprod Fertil 87 (2): 495–502. doi:10.1530/jrf.0.0870495. PMID 2600905.
  18. ↑ Athanasas-Platsis S, Morton H, Dunglison G, Kaye P (1991). "Antibodies to early pregnancy factor retard embryonic development in mice in vivo". J Reprod Fertil 92 (2): 443–51. doi:10.1530/jrf.0.0920443. PMID 1886100.
  19. ↑ Rolfe B, Cavanagh A, Quinn K, Morton H (1988). "Identification of two suppressor factors induced by early pregnancy factor". Clin Exp Immunol 73 (2): 219–25. PMC 1541604. PMID 3180511.
  20. ↑ Takimoto Y, Hishinuma M, Takahashi Y, Kanagawa H (1989). "Detection of early pregnancy factor in superovulated mice". Nippon Juigaku Zasshi 51 (5): 879–85. doi:10.1292/jvms1939.51.879. PMID 2607739.
  21. ↑ Qin Z, Zheng Z (1987). "Detection of early pregnancy factor in human sera". Am J Reprod Immunol Microbiol 13 (1): 15–8. PMID 2436493.
    Wang H, Zheng Z (1990). "Detection of early pregnancy factor in fetal sera". Am J Reprod Immunol 23 (3): 69–72. doi:10.1111/j.1600-0897.1990.tb00674.x. PMID 2257053.
  22. ↑ Cavanagh A, Morton H (1994). "The purification of early-pregnancy factor to homogeneity from human platelets and identification as chaperonin 10". Eur J Biochem 222 (2): 551–60. doi:10.1111/j.1432-1033.1994.tb18897.x. PMID 7912672.
  23. ↑ Sakonju I, Enomoto S, Kamimura S, Hamana K (1993). "Monitoring bovine embryo viability with early pregnancy factor". J Vet Med Sci 55 (2): 271–4. PMID 8513008.
  24. ↑ Sasser R, Ruder C (1987). "Detection of early pregnancy in domestic ruminants". J Reprod Fertil Suppl 34: 261–71. PMID 3305923.
    Gandy B, Tucker W, Ryan P, Williams A, Tucker A, Moore A, Godfrey R, Willard S (2001). "Evaluation of the early conception factor (ECF) test for the detection of nonpregnancy in dairy cattle". Theriogenology 56 (4): 637–47. doi:10.1016/S0093-691X(01)00595-7. PMID 11572444.
    Cordoba M, Sartori R, Fricke P (2001). "Assessment of a commercially available early conception factor (ECF) test for determining pregnancy status of dairy cattle". J Dairy Sci 84 (8): 1884–9. doi:10.3168/jds.S0022-0302(01)74629-2. PMID 11518314.
  25. ↑ Wilcox A, Baird D, Weinberg C (1999). "Time of implantation of the conceptus and loss of pregnancy". N Engl J Med 340 (23): 1796–9. doi:10.1056/NEJM199906103402304. PMID 10362823.
  26. ↑ Straube W (1989). "Early embryonal signals". Zentralbl Gynakol 111 (10): 629–33. PMID 2665388.
  27. ↑ Smart Y, Roberts T, Fraser I, Cripps A, Clancy R (1982). "Validation of the rosette inhibition test for the detection of early pregnancy in women". Fertil Steril 37 (6): 779–85. PMID 6177559.
    Bessho T, Taira S, Ikuma K, Shigeta M, Koyama K, Isojima S (1984). "Detection of early pregnancy factor in the sera of conceived women before nidation". Nippon Sanka Fujinka Gakkai Zasshi 36 (3): 391–6. PMID 6715922.
    Straube W, Tiemann U, Loh M, Schütz M (1989). "Detection of early pregnancy factor (EPF) in pregnant and nonpregnant subjects with the rosette inhibition test". Arch Gynecol Obstet 246 (3): 181–7. doi:10.1007/BF00934079. PMID 2619332.
    Fan X, Zheng Z (1997). "A study of early pregnancy factor activity in preimplantation". Am J Reprod Immunol 37 (5): 359–64. doi:10.1111/j.1600-0897.1997.tb00244.x. PMID 9196793.
  28. ↑ Smart Y, Fraser I, Clancy R, Roberts T, Cripps A (1982). "Early pregnancy factor as a monitor for fertilization in women wearing intrauterine devices". Fertil Steril 37 (2): 201–4. PMID 6174375.
  29. ↑ Grimes, David (2007). "Intrauterine Devices (IUDs)". In Hatcher, Robert A. et al. Contraceptive Technology (19th rev. ed.). New York: Ardent Media. p. 120. ISBN 0-9664902-0-7.
  30. ↑ Lloyd J DuPlantis, Jr (2001). "Early Pregnancy Factor". Pharmacists for Life, Intl. Retrieved 2007-01-01.
  31. ↑ Smart Y, Fraser I, Roberts T, Clancy R, Cripps A (1982). "Fertilization and early pregnancy loss in healthy women attempting conception". Clin Reprod Fertil 1 (3): 177–84. PMID 6196101.
  32. ↑ Mesrogli M, Maas D, Schneider J (1988). "Early abortion rate in sterility patients: early pregnancy factor as a parameter". Zentralbl Gynakol 110 (9): 555–61. PMID 3407357.
  33. ↑ Straube W, Loh M, Leipe S (1988). "Significance of the detection of early pregnancy factor for monitoring normal and disordered early pregnancy". Geburtshilfe Frauenheilkd 48 (12): 854–8. doi:10.1055/s-2008-1026640. PMID 2466731.
    Gerhard I, Katzer E, Runnebaum B (1991). "The early pregnancy factor (EPF) in pregnancies of women with habitual abortions". Early Hum Dev 26 (2): 83–92. doi:10.1016/0378-3782(91)90012-R. PMID 1720719.
    Shu-Xin H, Zhen-Qun Z (1993). "A study of early pregnancy factor activity in the sera of patients with unexplained spontaneous abortion". Am J Reprod Immunol 29 (2): 77–81. doi:10.1111/j.1600-0897.1993.tb00569.x. PMID 8329108.
    Shahani S, Moniz C, Bordekar A, Gupta S, Naik K (1994). "Early pregnancy factor as a marker for assessing embryonic viability in threatened and missed abortions". Gynecol Obstet Invest 37 (2): 73–6. doi:10.1159/000292528. PMID 8150373.
  34. ↑ Shahani S, Moniz C, Gokral J, Meherji P (1995). "Early pregnancy factor (EPF) as a marker for detecting subclinical embryonic loss in clomiphene citrate-treated women". Am J Reprod Immunol 33 (5): 350–3. doi:10.1111/j.1600-0897.1995.tb00903.x. PMID 7576116.
  35. ↑ Mesrogli M, Nitsche U, Maas D, Degenhardt F, Dieterle S, Schlösser H (1991). "Rate of early abortion after in vitro fertilization and embryo transfer". Geburtshilfe Frauenheilkd 51 (9): 688–93. doi:10.1055/s-2007-1023817. PMID 1720752.
    Mesrogli M, Dieterle S (1993). "Embryonic losses after in vitro fertilization and embryo transfer". Acta Obstet Gynecol Scand 72 (1): 36–8. doi:10.3109/00016349309013346. PMID 8382429.
  36. ↑ Rolfe B, Morton H, Cavanagh A, Gardiner R (1983). "Detection of an early pregnancy factor-like substance in sera of patients with testicular germ cell tumors". Am J Reprod Immunol 3 (2): 97–100. doi:10.1111/j.1600-0897.1983.tb00223.x. PMID 6859385.
    Mehta A, Shahani S (1987). "Detection of early pregnancy factor-like activity in women with gestational trophoblastic tumors". Am J Reprod Immunol Microbiol 14 (3): 67–9. PMID 2823620.
  37. ↑ Quinn K, Athanasas-Platsis S, Wong T, Rolfe B, Cavanagh A, Morton H (1990). "Monoclonal antibodies to early pregnancy factor perturb tumour cell growth". Clin Exp Immunol 80 (1): 100–8. doi:10.1111/j.1365-2249.1990.tb06448.x. PMC 1535227. PMID 2323098.
  38. ↑ Bojahr B, Straube W, Reddemann H (1993). "Case observations on the significance of early pregnancy factor as a tumor marker". Zentralbl Gynakol 115 (3): 125–8. PMID 7682025.