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]

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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^[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 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.^[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 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.^[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 immunosuppresant 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 study evaluating EPF levels in women with IUDs concluded that post-fertilization mechanisms contribute significantly to the effectiveness of these devices.^[28]

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 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.^[29]

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).^[30]

Use of EPF has been proposed to distinguish infertility caused by failure to conceive versus infertility caused by failure to implant.^[31] 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.^[32]

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.^[33]

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.^[34]

As a tumour marker

Although almost exclusively associated with pregnancy, EPF-like activity has also been detected in tumors of germ cell origin^[35] and in other types of tumors.^[36] Its utility as a tumour marker, to evaluate the success of surgical treatment, has been suggested.^[37]