A Progestin-Based Treatment with a High Dose of Estradiol Benzoate Normalizes Cyclic Changes in Endometrial EGF Concentrations and Restores Fertility in Repeat Breeder Cows

Abstract

Abstract. The objective of the present study was to examine the efficacy of a progestin-based treatment with a high dose of estradiol benzoate (EB) to normalize the epidermal growth factor (EGF) profile in the uterine endometrium and restore fertility in repeat breeder cows. Repeat breeder cows without peaks in their endometrial EGF concentrations on Days 3 and 14 of the estrous cycle were used throughout the study. The effect of 1 (standard dose), 2.5 and 5 mg of EB in a progestin-based treatment protocol (EB1, EB2.5 and EB5 treatments, respectively; n=5 for each group) on endometrial EGF concentrations was first examined. The EB1 and EB2.5 treatments in the repeat breeder cows produced a suppressed response in endometrial EGF compared with EB1 treatment in the fertile controls (n=5) and failed to restore the normal EGF profile during the next estrous cycle. However, EB5 treatment produced an increase in EGF concentrations similar to the fertile controls and normalized the endometrial EGF profile. The effects of the EB1 and EB5 treatments (n=30 for each group) on the endometrial EGF profile and fertility were then examined in the repeat breeder cows. The proportion of cows, with an EGF profile normalized by the treatments was higher in the EB5 group (66.7%) than in the EB1 (30.0%) and untreated control (13.3%; n=30) groups (P<0.01). The pregnancy rates of the cows having a normal EGF profile after treatment in the EB1 and EB5 groups were similar (88.9 and 85.0%, respectively) and higher than those of the cows having an abnormal profile within the same groups (19.0 and 30.0%, respectively, P<0.01). In summary, the endometrial response to EB in terms of the EGF concentration was suppressed in repeat breeder cows. A high dose (5 mg) of EB in a progestin-based treatment was found to be effective for restoration of a normal EGF profile and fertility in repeat breeder cows having lesser endometrial EGF concentrations on Days 3 and 14. Key words: Controlled intravaginal drug release (CIDR), Dairy cattle, Epidermal growth factor (EGF), Endometrium, Repeat breeding (J. Reprod. Dev. 54: [473][474][475][476][477][478][479] 2008) rowing evidence indicates that ovarian steroid hormones (i.e., estrogen and progestin) primarily regulate uterine function by stimulating uterine production of growth factors and cytokines, although most of our knowledge in this field has been obtained in mice and rats. Among such local products, epidermal growth factor (EGF) and related ligands that share the EGF receptor have critical functions in the establishment of pregnancy [1,2]. Estrogen stimulates EGF production in the mouse uterus [3][4][5] and human oviducts [6]. Epidermal growth factor replaces estrogen in the stimulation of uterine and vaginal growth and endometrial cell differentiation (e.g., induction of lactoferrin, a major estrogeninducible secretory protein) in mice [7] and in a nidatory estrogen surge that initiates blastocyst attachment to the endometrium in rats [8]. In EGF receptor knockout mice, drastic negative effects o...

Low Incidence of an Altered Endometrial Epidermal Growth Factor (EGF) Profile in Repeat Breeder Holstein Heifers and Differential Effect of Parity on the EGF Profile Between Fertile Holstein (Dairy) and Japanese Black (Beef) Cattle

“…In control cows, endometrial EGF concentrations show 2 peaks, on days 2 to 4 and days 13 to 14, with low concentrations of EGF around day 7. These 2 peaks in the EGF profile were missing in about 70% of repeat breeder cows [5, 6], and normalization of the EGF profile resulted in the restoration of fertility [6, 7]. This alteration in endometrial EGF concentrations has been linked to embryonic death due to the potential role of EGF in the uterus [8, 9] and decreased conception rates after embryo transfer to recipient cows having low EGF peaks on day 3 [10].…”

Endometrial epidermal growth factor profile and its abnormalities in dairy cows

“…In the present study, increased EGF concentrations were observed between Days 2 and 5 in individual cows, and the mean EGF concentrations exhibited an apparent peak on Days 3 and 4. Minor differences in the timing of the first peak found in the 2 studies might not affect the interpretation of our previous findings on the role of altered EGF profiles on reduced fertility in RB and high-yielding dairy cows [1,2,3, 5, 7]. Rather, these results might improve the reliability of our previous studies since these studies used the endometrial EGF concentrations on Day 3 to evaluate the first peak.…”

“…A significant increase in circulating estrogen concentrations and endometrial estrogen receptor levels during estrus in cows [13] should produce a rapid and synchronized transition of the EGF concentrations of the first peak. This was supported by the effect of exogenous estrogen to increase endometrial EGF concentrations in fertile and RB cows [5]. In fertile cows, 1 mg of estradiol benzoate (EB) produced a significant increase in EGF concentrations.…”

“…In addition, we examined the endometrial EGF concentrations on Day 7 in more than 500 RB cows in our previous studies [2, 3, 5]; no cows exhibited peak levels of EGF concentrations. Together, EGF concentrations might remain low between Days 1 and 7 in affected RB cows, but could also be low in high-yielding cows.…”

“…In the RB cows, the alteration in the endometrial EGF concentrations persisted between the estrous cycles when the cows were not treated [3]. The normalization of the EGF profile resulted in the restoration of fertility in RB cows [3, 5]. Thus, these findings support the existence of a potential relationship between the endometrial EGF profile and fertility [1, 3].…”