Early pregnancy factor

Early pregnancy factor (EPF) or early conception factor (ECF) is a protein associated with mammalian embryos shortly after fertilization. [cite journal | author = Smart Y, Roberts T, Clancy R, Cripps A | title = Early pregnancy factor: its role in mammalian reproduction--research review. | journal = Fertil Steril | volume = 35 | issue = 4 | pages = 397–402 | year = 1981 | pmid = 7011853] cite journal | author = Greco C, Vivas A, Bosch R | title = Evaluation of the method for early pregnancy factor detection (EPF) in swine. Significance in early pregnancy diagnosis | journal = Acta Physiol Pharmacol Ther Latinoam | volume = 42 | issue = 1 | pages = 43–50 | year = 1992 | pmid = 1294272] It may be composed of more than one molecule. cite journal | author = Di Trapani G, Orosco C, Perkins A, Clarke F | title = Isolation from human placental extracts of a preparation possessing 'early pregnancy factor' activity and identification of the polypeptide components | journal = Hum Reprod | volume = 6 | issue = 3 | pages = 450–7 | year = 1991 | pmid = 1955557] cite journal | author = Clarke F | title = Identification of molecules and mechanisms involved in the 'early pregnancy factor' system | journal = Reprod Fertil Dev | volume = 4 | issue = 4 | pages = 423–33 | year = 1992 | pmid = 1461993 | doi = 10.1071/RD9920423] It was first described in 1976.

Detection

Early pregnancy factor is tested for rosette inhibition test. EPF is present in the maternal serum (blood plasma) shortly after fertilization; EPF is also present in cervical mucus [cite journal | author = Cheng S, Zheng Z | title = Early pregnancy factor in cervical mucus of pregnant women | journal = Am J Reprod Immunol | volume = 51 | issue = 2 | pages = 102–5 | year = 2004 | pmid = 14748834 | doi = 10.1046/j.8755-8920.2003.00136.x] and in amniotic fluid. [cite journal | author = Zheng Z, Qin Z, Ma A, Qiao C, Wang H | title = Detection of early pregnancy factor-like activity in human amniotic fluid | journal = Am J Reprod Immunol | volume = 22 | issue = 1-2 | pages = 9–11 | year = | pmid = 2346595]

EPF may be detected in sheep within 72 hours of mating, cite journal | author = Morton H, Clunie G, Shaw F | title = A test for early pregnancy in sheep | journal = Res Vet Sci | volume = 26 | issue = 2 | pages = 261–2 | year = 1979 | pmid = 262615] in mice within 24 hours of mating, cite journal | author = Cavanagh A, Morton H, Rolfe B, Gidley-Baird A | title = Ovum factor: a first signal of pregnancy? | journal = Am J Reprod Immunol | volume = 2 | issue = 2 | pages = 97–101 | year = 1982 | pmid = 7102890] and in samples from media surrounding human embryos fertilized in vitro within 48 hours of fertilization [cite journal | author = Smart Y, Cripps A, Clancy R, Roberts T, Lopata A, Shutt D | title = Detection of an immunosuppressive factor in human preimplantation embryo cultures | journal = Med J Aust | volume = 1 | issue = 2 | pages = 78–9 | year = 1981 | pmid = 7231254] (although another study failed to duplicate this finding for "in vitro" embryos). cite journal | author = Nahhas F, Barnea E | title = Human embryonic origin early pregnancy factor before and after implantation | journal = Am J Reprod Immunol | volume = 22 | issue = 3-4 | pages = 105–8 | year = | pmid = 2375830] EPF has been detected as soon as within six hours of mating. cite journal | author = Shaw F, Morton H | title = The immunological approach to pregnancy diagnosis: a review | journal = Vet Rec | volume = 106 | issue = 12 | pages = 268–70 | year = 1980 | pmid = 6966439]

Because the rosette inhibition test 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. [cite journal | author = Koch E, Ellendorff F | title = Detection of activity similar to that of early pregnancy factor after mating sows with a vasectomized boar | journal = J Reprod Fertil | volume = 74 | issue = 1 | pages = 39–46 | year = 1985 | pmid = 4020773] 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. cite journal | author = Chard T, Grudzinskas J | title = Early pregnancy factor | journal = Biol Res Pregnancy Perinatol | volume = 8 | issue = 2 2D Half | pages = 53–6 | year = 1987 | pmid = 3322417] However, progress in characterization of EPF has been made and its existence is well-accepted in the scientific community. [cite journal | author = Cavanagh A | title = Identification of early pregnancy factor as chaperonin 10: implications for understanding its role | journal = Rev Reprod | volume = 1 | issue = 1 | pages = 28–32 | year = 1996 | pmid = 9414435 | doi = 10.1530/ror.0.0010028]

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. [cite journal | author = Orozco C, Perkins T, Clarke F | title = Platelet-activating factor induces the expression of early pregnancy factor activity in female mice | journal = J Reprod Fertil | volume = 78 | issue = 2 | pages = 549–55 | year = 1986 | pmid = 3806515
cite journal | author = Roberts T, Adamson L, Smart Y, Stanger J, Murdoch R | title = An evaluation of peripheral blood platelet enumeration as a monitor of fertilization and early pregnancy | journal = Fertil Steril | volume = 47 | issue = 5 | pages = 848–54 | year = 1987 | pmid = 3569561
cite journal | author = Sueoka K, Dharmarajan A, Miyazaki T, Atlas S, Wallach E | title = Platelet activating factor-induced early pregnancy factor activity from the perfused rabbit ovary and oviduct | journal = Am J Obstet Gynecol | volume = 159 | issue = 6 | pages = 1580–4 | year = 1988 | pmid = 3207134
cite journal | author = Cavanagh A, Morton H, Athanasas-Platsis S, Quinn K, Rolfe B | title = Identification of a putative inhibitor of early pregnancy factor in mice | journal = J Reprod Fertil | volume = 91 | issue = 1 | pages = 239–48 | year = 1991 | pmid = 1995852
cite journal | author = Cavanagh A, Rolfe B, Athanasas-Platsis S, Quinn K, Morton H | title = Relationship between early pregnancy factor, mouse embryo-conditioned medium and platelet-activating factor | journal = J Reprod Fertil | volume = 93 | issue = 2 | pages = 355–65 | year = 1991 | pmid = 1787455] After implantation, EPF may be produced by the conceptus directly.

EPF is an immunosuppresant. 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. [cite journal | author = Bose R, Cheng H, Sabbadini E, McCoshen J, MaHadevan M, Fleetham J | title = Purified human early pregnancy factor from preimplantation embryo possesses immunosuppresive properties | journal = Am J Obstet Gynecol | volume = 160 | issue = 4 | pages = 954–60 | year = 1989 | pmid = 2712125] Injecting anti-EPF antibodies into mice after mating significantly quantify|date=August 2008 reduced the number of successful pregnancies and number of pups; [cite journal | author = Igarashi S | title = Significance of early pregnancy factor (EPF) on reproductive immunology | journal = Nippon Sanka Fujinka Gakkai Zasshi | volume = 39 | issue = 2 | pages = 189–94 | year = 1987 | pmid = 2950188
cite journal | author = Athanasas-Platsis S, Quinn K, Wong T, Rolfe B, Cavanagh A, Morton H | title = Passive immunization of pregnant mice against early pregnancy factor causes loss of embryonic viability | journal = J Reprod Fertil | volume = 87 | issue = 2 | pages = 495–502 | year = 1989 | pmid = 2600905] no effect on growth was seen when mice embryos were cultured in media containing anti-EPF antibodies. [cite journal | author = Athanasas-Platsis S, Morton H, Dunglison G, Kaye P | title = Antibodies to early pregnancy factor retard embryonic development in mice in vivo | journal = J Reprod Fertil | volume = 92 | issue = 2 | pages = 443–51 | year = 1991 | pmid = 1886100] While some actions of EPF are the same in all mammals (namely rosette inhibition), other immunosuppresant mechanism vary between species. [cite journal | author = Rolfe B, Cavanagh A, Quinn K, Morton H | title = Identification of two suppressor factors induced by early pregnancy factor | journal = Clin Exp Immunol | volume = 73 | issue = 2 | pages = 219–25 | year = 1988 | pmid = 3180511]

In mice, EPF levels are high in early pregnancy, but on day 15 decline to levels found in non-pregnant mice. [cite journal | author = Takimoto Y, Hishinuma M, Takahashi Y, Kanagawa H | title = Detection of early pregnancy factor in superovulated mice | journal = Nippon Juigaku Zasshi | volume = 51 | issue = 5 | pages = 879–85 | year = 1989 | pmid = 2607739] In humans, EPF levels are high for about the first twenty weeks, then decline, becoming undetectable within eight weeks of delivery. [cite journal | author = Qin Z, Zheng Z | title = Detection of early pregnancy factor in human sera | journal = Am J Reprod Immunol Microbiol | volume = 13 | issue = 1 | pages = 15–8 | year = 1987 | pmid = 2436493
cite journal | author = Wang H, Zheng Z | title = Detection of early pregnancy factor in fetal sera | journal = Am J Reprod Immunol | volume = 23 | issue = 3 | pages = 69–72 | year = 1990 | pmid = 2257053]

Recent research has suggested that EPF may be associated with cell proliferation in a wide variety of biological situations, not just embryo development. [cite journal | author = Cavanagh A, Morton H | title = The purification of early-pregnancy factor to homogeneity from human platelets and identification as chaperonin 10 | journal = Eur J Biochem | volume = 222 | issue = 2 | pages = 551–60 | year = 1994 | pmid = 7912672 | doi = 10.1111/j.1432-1033.1994.tb18897.x]

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. Interest in EPF for this purpose has continued, [cite journal | author = Sakonju I, Enomoto S, Kamimura S, Hamana K | title = Monitoring bovine embryo viability with early pregnancy factor | journal = J Vet Med Sci | volume = 55 | issue = 2 | pages = 271–4 | year = 1993 | pmid = 8513008] although current test methods have not proved sufficiently accurate for the requirements of livestock management. [cite journal | author = Sasser R, Ruder C | title = Detection of early pregnancy in domestic ruminants | journal = J Reprod Fertil Suppl | volume = 34 | issue = | pages = 261–71 | year = | pmid = 3305923
cite journal | author = Gandy B, Tucker W, Ryan P, Williams A, Tucker A, Moore A, Godfrey R, Willard S | title = Evaluation of the early conception factor (ECF) test for the detection of nonpregnancy in dairy cattle | journal = Theriogenology | volume = 56 | issue = 4 | pages = 637–47 | year = 2001 | pmid = 11572444 | doi = 10.1016/S0093-691X(01)00595-7
cite journal | author = Cordoba M, Sartori R, Fricke P | title = Assessment of a commercially available early conception factor (ECF) test for determining pregnancy status of dairy cattle | journal = J Dairy Sci | volume = 84 | issue = 8 | pages = 1884–9 | year = 2001 | pmid = 11518314]

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. [cite journal | author = Wilcox A, Baird D, Weinberg C | title = Time of implantation of the conceptus and loss of pregnancy | journal = N Engl J Med | volume = 340 | issue = 23 | pages = 1796–9 | year = 1999 | pmid = 10362823 | doi = 10.1056/NEJM199906103402304] 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. [cite journal | author = Straube W | title = Early embryonal signals | journal = Zentralbl Gynakol | volume = 111 | issue = 10 | pages = 629–33 | year = 1989 | pmid = 2665388] The accuracy of EPF as a pregnancy test in humans has been found to be high by several studies. [cite journal | author = Smart Y, Roberts T, Fraser I, Cripps A, Clancy R | title = Validation of the rosette inhibition test for the detection of early pregnancy in women | journal = Fertil Steril | volume = 37 | issue = 6 | pages = 779–85 | year = 1982 | pmid = 6177559
cite journal | author = Bessho T, Taira S, Ikuma K, Shigeta M, Koyama K, Isojima S | title = Detection of early pregnancy factor in the sera of conceived women before nidation | journal = Nippon Sanka Fujinka Gakkai Zasshi | volume = 36 | issue = 3 | pages = 391–6 | year = 1984 | pmid = 6715922
cite journal | author = Straube W, Tiemann U, Loh M, Schütz M | title = Detection of early pregnancy factor (EPF) in pregnant and nonpregnant subjects with the rosette inhibition test | journal = Arch Gynecol Obstet | volume = 246 | issue = 3 | pages = 181–7 | year = 1989 | pmid = 2619332 | doi = 10.1007/BF00934079
cite journal | author = Fan X, Zheng Z | title = A study of early pregnancy factor activity in preimplantation | journal = Am J Reprod Immunol | volume = 37 | issue = 5 | pages = 359–64 | year = 1997 | pmid = 9196793]

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 significantlyquantify|date=August 2008 to the effectiveness of these devices. [cite journal | author = Smart Y, Fraser I, Clancy R, Roberts T, Cripps A | title = Early pregnancy factor as a monitor for fertilization in women wearing intrauterine devices | journal = Fertil Steril | volume = 37 | issue = 2 | pages = 201–4 | year = 1982 | pmid = 6174375] 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.cite book |author=Grimes, David |year=2007 |chapter=Intrauterine Devices (IUDs) |editor=Hatcher, Robert A., et al |title=Contraceptive Technology |edition=19th rev. ed. |pages=120 |location=New York |publisher=Ardent Media |id=ISBN 0-9664902-0-7]

For groups that define pregnancy as beginning with fertilization, birth control methods that have postfertilization mechanisms are 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 Pharmicists 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. [cite paper | author = Lloyd J DuPlantis, Jr | title = Early Pregnancy Factor | publisher = Pharmacists for Life, Intl | date = 2001 | url = http://www.lifeissues.net/writers/dup/dup_01earlypregfacts.html | accessdate = 2007-01-01 ]

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). [cite journal | author = Smart Y, Fraser I, Roberts T, Clancy R, Cripps A | title = Fertilization and early pregnancy loss in healthy women attempting conception | journal = Clin Reprod Fertil | volume = 1 | issue = 3 | pages = 177–84 | year = 1982 | pmid = 6196101]

Use of EPF has been proposed to distinguish infertility caused by failure to conceive versus infertility caused by failure to implant. [cite journal | author = Mesrogli M, Maas D, Schneider J | title = Early abortion rate in sterility patients: early pregnancy factor as a parameter | journal = Zentralbl Gynakol | volume = 110 | issue = 9 | pages = 555–61 | year = 1988 | pmid = 3407357] 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. [cite journal | author = Straube W, Loh M, Leipe S | title = Significance of the detection of early pregnancy factor for monitoring normal and disordered early pregnancy | journal = Geburtshilfe Frauenheilkd | volume = 48 | issue = 12 | pages = 854–8 | year = 1988 | pmid = 2466731
cite journal | author = Gerhard I, Katzer E, Runnebaum B | title = The early pregnancy factor (EPF) in pregnancies of women with habitual abortions | journal = Early Hum Dev | volume = 26 | issue = 2 | pages = 83–92 | year = | pmid = 1720719 | doi = 10.1016/0378-3782(91)90012-R
cite journal | author = Shu-Xin H, Zhen-Qun Z | title = A study of early pregnancy factor activity in the sera of patients with unexplained spontaneous abortion | journal = Am J Reprod Immunol | volume = 29 | issue = 2 | pages = 77–81 | year = 1993 | pmid = 8329108
cite journal | author = Shahani S, Moniz C, Bordekar A, Gupta S, Naik K | title = Early pregnancy factor as a marker for assessing embryonic viability in threatened and missed abortions | journal = Gynecol Obstet Invest | volume = 37 | issue = 2 | pages = 73–6 | year = 1994 | pmid = 8150373]

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. [cite journal | author = Shahani S, Moniz C, Gokral J, Meherji P | title = Early pregnancy factor (EPF) as a marker for detecting subclinical embryonic loss in clomiphene citrate-treated women | journal = Am J Reprod Immunol | volume = 33 | issue = 5 | pages = 350–3 | year = 1995 | pmid = 7576116]

A study of EPF in women undergoing in vitro fertilization (IVF) concluded that, while a significant numberquantify|date=August 2008 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. [cite journal | author = Mesrogli M, Nitsche U, Maas D, Degenhardt F, Dieterle S, Schlösser H | title = Rate of early abortion after in vitro fertilization and embryo transfer | journal = Geburtshilfe Frauenheilkd | volume = 51 | issue = 9 | pages = 688–93 | year = 1991 | pmid = 1720752
cite journal | author = Mesrogli M, Dieterle S | title = Embryonic losses after in vitro fertilization and embryo transfer | journal = Acta Obstet Gynecol Scand | volume = 72 | issue = 1 | pages = 36–8 | year = 1993 | pmid = 8382429 | doi = 10.3109/00016349309013346]

As a tumour marker

Although almost exclusively associated with pregnancy, EPF-like activity has also been detected in tumors of germ cell origin [cite journal | author = Rolfe B, Morton H, Cavanagh A, Gardiner R | title = Detection of an early pregnancy factor-like substance in sera of patients with testicular germ cell tumors | journal = Am J Reprod Immunol | volume = 3 | issue = 2 | pages = 97–100 | year = 1983 | pmid = 6859385
cite journal | author = Mehta A, Shahani S | title = Detection of early pregnancy factor-like activity in women with gestational trophoblastic tumors | journal = Am J Reprod Immunol Microbiol | volume = 14 | issue = 3 | pages = 67–9 | year = 1987 | pmid = 2823620] and in other types of tumors. [cite journal | author = Quinn K, Athanasas-Platsis S, Wong T, Rolfe B, Cavanagh A, Morton H | title = Monoclonal antibodies to early pregnancy factor perturb tumour cell growth | journal = Clin Exp Immunol | volume = 80 | issue = 1 | pages = 100–8 | year = 1990 | pmid = 2323098] Its utility as a tumour marker, to evaluate the success of surgical treatment, has been suggested. [cite journal | author = Bojahr B, Straube W, Reddemann H | title = Case observations on the significance of early pregnancy factor as a tumor marker | journal = Zentralbl Gynakol | volume = 115 | issue = 3 | pages = 125–8 | year = 1993 | pmid = 7682025]

References