epidermal-growth-factor and estradiol-3-benzoate

Poor reproductive efficiency is a worldwide problem that has affected the dairy industry during the last several decades. In an attempt to explain the changes in reproductive physiology caused by high milk production, a model of elevated steroid metabolism in lactating dairy cows has been proposed. A slow increase in levels and low peak levels of estradiol (E₂) and progesterone (P₄) characterize endocrine changes in high producing cows. Similar changes have been reported in the repeat breeder cows. The abnormal changes in E₂ and P₄ concentrations of these cows may cause an improper uterine environment due to disturbed expression of growth factors and cytokines in the endometrium. This review focuses on the alteration in epidermal growth factor (EGF) profile in the endometrium during the estrous cycle. The normal cow has two peaks of EGF concentrations on days 2-4 and 13-14. Low concentrations of EGF on these days distinguished both high-producing and repeat breeder cows from normal cows. Alteration of the EGF profile could be found in 70 and 40% of the repeat breeder and high-producing cows, respectively. Treatment with a high dose of estradiol benzoate and an intravaginal progesterone-releasing device restored the normal EGF profile in about 70% of the affected cows. The cows having a normal EGF profile after treatment showed a higher pregnancy rate than the cows with the altered profile. Further studies to understand the etiology of the alteration in the EGF profile are needed to develop another treatment option and preventive management for this problem.

Topics: Administration, Intravaginal; Animals; Cattle; Dairying; Drug Administration Schedule; Drug Delivery Systems; Drug Therapy, Combination; Embryo Loss; Endometrium; Epidermal Growth Factor; Estradiol; Estrous Cycle; Female; Fertility Agents, Female; Infertility, Female; Insemination, Artificial; Lactation; Models, Biological; Ovary; Pregnancy; Progesterone

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.

Topics: Animals; Breeding; Cattle; Endometrium; Epidermal Growth Factor; Estradiol; Estrous Cycle; Female; Fertility; Pregnancy; Progestins

The present study characterized alterations of the endometrial epidermal growth factor (EGF) and examined potential relationships between normalization of the EGF and restoration of fertility in repeat breeder cows. In Experiment 1, endometrial tissues were obtained by biopsy on Days 3, 7 and 14 of the estrous cycle from 99 fertile dairy cows and normal ranges of uterine tissue EGF concentrations were determined. Then, eight fertile cows were examined for endometrial EGF concentrations on Days 3, 7 and 14 during the three consecutive estrous cycles. All eight cows had a normal EGF profile (EGF concentrations were within the normal ranges of all 3 days) in all three estrous cycles and endometrial EGF concentrations were similar among the three estrous cycles. In Experiment 2, 61 repeat breeder cows were examined EGF profile and 43 (70.5%) cows had altered EGF profiles compared with control profiles. A typical alteration was characterized by decreased concentrations on Days 3 and 14 and accounted for 86.0% of all alterations. When repeat breeder cows with altered EGF profiles (n=17) were left untreated, abnormality persisted in 14 (82.4%) cows at the second examination and only 3 animals became pregnant within the next two estrous cycles. Among 15 cows showing a typical alteration at the first examination, 11 (73.3%) cows had the same alteration until the third examination performed after two infertile inseminations following the second examination. When repeat breeder cows with altered EGF profiles (n=26) were given one of four therapeutic treatments, cows in which the EGF profile normalized after treatment had a greater pregnancy rate than those with altered profiles (11/14 animals versus 3/12 animals pregnant; P<0.05). In conclusion, suppressed endometrial EGF concentrations on Days 3 and 14 may be common alterations and persist between estrous cycles in repeat breeder cows. Potential relationship between normalization of the endometrial EGF profile and restoration of fertility was observed. Additional study to confirm results of the treatment is, however, necessary because the present study used a limited number of animals. Nevertheless, current data suggest that normalization of the EGF profile is one of the prerequisite factors to restore fertility.

Topics: Animals; Biopsy; Cattle; Cloprostenol; Endometrium; Epidermal Growth Factor; Estradiol; Estrous Cycle; Female; Fertility Agents, Female; Infertility, Female; Insemination, Artificial; Male; Pregnancy

The pharmacokinetics and time course actions of the soy isoflavone, genistein, and estradiol benzoate (EB) on sex steroid and growth factor signaling were compared in the rat uterus. Following one s.c. injection of 500 mg genistein/kg BW or 500 microg EB/kg BW, AUC for genistein was 20171.8 ng h/ml and was 15.7 ng h/ml for estradiol-17-beta. Estrogen receptor-alpha (ER-alpha) decreased within 2 h of genistein or EB treatment, returning to basal levels within 24 and 48 h, respectively. In response to genistein and EB, progesterone receptors (PRs) A and B increased between 16 and 24 h, with a significant increase at 24 and 48 h. Epidermal growth factor receptor (EGFR) expression peaked 16 h after genistein or EB treatment, inversely correlating with extracellular regulating kinase (ERK) phosphorylation. These effects were inhibited by antiestrogen pretreatment, demonstrating a requirement for ER. At 16 h, uterine weight, epithelial cell height, and cell proliferation increased. While EGFR levels increased, phosphorylated EGFR was not altered. Reduced phosphorylation of downstream kinases corresponded with decreased stromal phosphorylated-ERK (P-ERK) immunolabeling, suggesting signal attenuation. Dynamic profiling of sex steroid receptors and EGF signaling molecules suggest a similar mechanism of action for genistein and EB in the uterus, albeit at approximately 1000-fold concentration.

Topics: Animals; Anticarcinogenic Agents; Area Under Curve; Cell Division; Epidermal Growth Factor; ErbB Receptors; Estradiol; Female; Gene Expression Regulation; Genistein; Immunoblotting; Immunohistochemistry; Injections, Subcutaneous; Organ Size; Phosphorylation; Phytoestrogens; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Signal Transduction; Uterus

Previous studies showed a dramatic increase in EGF gene expression in the endometrial glands of pregnant mares around day 40 after ovulation. To investigate how the steroid hormones of pregnancy might regulate this expression, in situ hybridization was used to monitor the levels of EGF mRNA in endometrial biopsies obtained from seasonally anoestrous or ovariectomised mares given exogenous progesterone and oestrogen, alone or in combination, for up to 46 days. Biopsies were also taken from mares during the non-pregnant cycle, during normal pregnancies and pregnancies compromised by endometrial pathology (endometriosis) or because of incompatible extraspecific embryo transfers (donkey-in-horse pregnancies). Only a few samples showed weak EGF expression during the late luteal phase of the oestrous cycle. During normal pregnancy, the previously observed dramatic increase of expression after day 40 of gestation was confirmed. Although aged mares suffering from endometriosis and mares carrying an extraspecific donkey conceptus showed the same increase of EGF mRNA in normal glands, this was virtually absent from gland cross-sections compromised due to inflammatory or fibrotic changes. Administration of various doses and combinations of progesterone and oestrogen for < 35 days yielded negative or only weakly positive hybridization results, whereas progesterone alone for > or = 40 days upregulated EGF expression strongly irrespective of additional treatment with oestrogen. This is the first experimental evidence that EGF expression in the endometrium can be induced by progesterone alone. The requirement for prolonged progesterone priming is of considerable interest in the context of the unusually late stage of gestation at which placental attachment commences in equids.

Topics: Animals; Endometrium; Epidermal Growth Factor; Estradiol; Female; Gene Expression Regulation; Horses; In Situ Hybridization; Pregnancy; Pregnancy, Animal; Progesterone