**7. Embryonic losses due to endocrinologic causes**

the continuation of gestation this endometrial PGF2α production must be hindered. Biology of this critical period is complex and affected from very different events. Forming of luteolysis or continuation of gestation is dependent on hormonal, cellular and molecular factors belonging to both mother and the embryo. In order to increase the pregnancy rate in artificial insemina‐ tion and embryo transfer, hCG, eCG and GnRH applications are done in this critical period. In these applications, while increasing progesterone amount, decreasing plasma estradiol 17 beta

Blockage of luteolysis during the recognition of gestation can be possible by inhibition of es‐ tradiol production because existence of estradiol is obligatory for luteolysis. Estradiol indu‐ ces PGF2α secretion. When compared with cyclic animals, follicular development and concentration of plasma estradiol are less in pregnant animals. How does estradiol affects PGF2α secretion in cellular and molecular levels is not known. However, estradiol has got a central role in luteolysis. For this reason; while antilteolytic strategies are developed, for the

Progesterone amount circulating in cows provides maternal recognition. This situation shows the importance of high level progesterone for the recognition of pregnancy in critical period. Another factor for the pregnancy recognition is bovine interferon-tau which is re‐ leased by the embryo. Bovine interferon-tau is also known as bovine trophoblast protein-1 (bTP-1). Bovine interferon-tau which is secreted to lumen of uterus inhibits the release of PGF2α from the endometrium in critical period. Stimulating of progesterone to bovine inter‐ feron-tau is another possible mechanism for the maternal recognition. In the cows, which have higher levels of progesterone in the critical period, more bovine interferon-tau is pro‐

Interferon-tau shows its affect by hindering estradiol receptors. Subsequently, oxytocin recep‐ tors diminish and cyclooxygenase inhibitors get activated. Interferon-tau insures the produc‐ tion of some endometrial proteins crucial for the life of embryo. The first of these proteins is bovine granulocyte protein-2. Second one is ubiquitin cross-reactive protein (UCRP). UCRP conjugates with cytosolic endometrial proteins in response to pregnancy and interferon-tau. Proteins conjugated with UCRP become a target for processing by proteasome. This affect of interferon-tau is mediated by the induction of signal transducer and activation of transcription 1 (STAT-1), STAT-2, and interferon regulatory factor 1. UCRP, alpha chemokines and induc‐

Embryonic death is the most important source of reproductive losses. During the first three weeks of pregnancy embryonic deaths occur by means of several factors. If embryonic deaths take place between the 24th and 50th days, it is called as late embryonic death [4, 13].

amounts and inhibiting PGF2α synthesis from endometrium is aimed [16].

retardation or inhibition of luteolysis decrease of estradiol level is aimed [16].

tion of these transcription factors procure pregnancy recognition by mother [33].

**5. Embryo signals and pregnancy recognition**

76 Success in Artificial Insemination - Quality of Semen and Diagnostics Employed

duced by the embryo [16, 32].

**6. Early embryonic death**

Low progesterone levels lead to death of embryo by causing excessive estradiol and PGF2α secretion. It is required that luteolytic effects of estradiol and PGF2α should be decreased in the early period after insemination in order for maternal recognition of pregnancy [36].

Researchers assert that low progesterone concentration before insemination period causes abnormal follicular development, elicit abnormal oocyte development in ovulatory follicle and ultimately, it causes early embryonic death [37-38].

Adequate secretion of progesterone in luteal period is vital for healthy ovulation, nutrition and survival of developing embryo. Low level of progesterone leads to embryonic death for reasons of:


Oxytocin produced by corpus luteum stimulates the release of PGF2α from endometrium. PGF2α production depends on reaching of oxytocin receptor number to a threshold value. When these receptors in endometrium reaches a sufficient number, pulsatil secretion of PGF2α occurs in response to luteal oxytocin secretion and luteolysis goes after. For this rea‐ son, maternal recognition of pregnancy must take place before luteolysis [32, 40].

1886 were first used. But these drugs formed serious side effects in gastrointestinal system. Aspirin or acetyl salicylic acid was discovered by Felix Hoffman in 1897. It was started to be

For the first time, it has been identified that prostaglandin inhibitors prevent product of Cox by John Vane in 1971 [44]. Later studies have shown that Cox enzymes have different iso‐ forms and have different functions. Cox-1 is found in stomach, intestine, kidney and throm‐ bocytes, and Cox-2 is secreted in platelets, macrophages, endothelial cells [41, 47]. While classic NSAIDs inhibit both enzymes, Cox-2 inhibitors inhibit inducible Cox-2. Thanks to this, Cox-2 inhibitors can show anti-inflammatory effect without forming any side effects in gastrointestinal system and in other tissues [43]. Existence of Cox-3 enzyme was discovered

**Class Active Ingredient Effect**

Diclofenac, Ketorolak, Asetaminofen, Flunixin meglumine.

Nimesulid, Carpofren.

Cox inhibitors are used with different aims in reproductive field. Among these are; blocking of ovulation and implantation, preventing post operative adhesions and hindering of pre‐

A lot of studies have been done to understand the importance of Cox enzyme in implanta‐ tion. It has been found out that COX-2 is produced by uterus luminal epithel and stroma which surround blastocyte during implantation in rats. This situation indicates that COX-2 has a fundamental role in implantation [59-60]. Again in another study, it has been identi‐ fied that female rats which have COX-1 deficiency have normal fertility and young number. Because in the presence of COX-1 enzyme deficiency, COX-2 supplies this deficit [59]. How‐ ever, female rats which have COX-2 deficiency are infertile. Because lacking of COX-2 en‐

Parallel with the studies done on experiment animals, studies searching the effects of NSAIDs on pregnancy rates of livestock have also been done. In these studies, flunixin me‐ glumine, meloxicam, and carprofen have been used in order to increase pregnancy rate in

zyme occurs ovulation, fertilization, implantation and desidualization defects [61].

Cox-1 Specific Agents Low Dose Aspirin It makes COX-1 inhibition without doing COX-2

inhibition.

Nonsteroid Anti-Inflammatory Drugs to Improve Fertility in Cows

http://dx.doi.org/10.5772/51910

79

It inhibits both enzymes.

With Clinic threpautic doses in human and animals, while doing COX-2 inhibition, in increasing doses they cause COX-1 inhibition.

They are agents which do not cuase COX-1 inhibition even in maximum threpautic clinical doses.

sold under the name of Aspirin by Bayer Company in 1899 [46].

by Chandrasekharan et al. in 2002 [48]. See table 1.

COX-2 Selective Agents Meloxicam, Nabumetane,

COX-2 Specific Agents Celecoxib, Rofecoxib.

**Table 1.** Cox inhibitors are classified as below [41, 49]:

mature births (tocolytic) [50-58].

cows.

COX Non-specific Agents

Specific proteins (bTP-1) produced by blastocyst in cows are signals preventing luteolysis. bTP-1, inhibits the endometrium cells' oxytocin receptor production. As a result, oxytocin cannot induce PGF2α release. In addition to this, bTP-1increases protein production from uterine glands. These released proteins into uterus lumen provide nutrition of embryo [32].
