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The alteration of signaling molecules involved in the general metabolism of animals can negatively influence reproduction. In dairy cattle, the development of follicular cysts and the subsequent appearance of ovarian cystic disease (COD) often lead to decreased reproductive efficiency in the herd. The objective of this review is to summarize the contribution of relevant metabolic and nutritional sensors to the development of COD in dairy cows. In particular, we focus on the study of alterations of the insulin signaling pathway, adiponectin, and other sensors and metabolites relevant to ovarian functionality, which may be related to the development of follicular persistence and follicular formation of cysts in dairy cattle. The results of these studies support the hypothesis that systemic factors could alter the local scenario in the follicle, generating an adverse microenvironment for the resumption of ovarian activity and possibly leading to the persistence of follicles and to the development and recurrence of COD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cystic ovarian disease (COD) is an important cause of reproductive failure in dairy cattle. The main aim of this review is to discuss some aspects related to inflammation and angiogenesis that seem to be involved in the development of follicular cysts in domestic animals, with special emphasis on the bovine species, in an attempt to elucidate the relationship between these two processes in the early stages of persistence and in the development of bovine COD. We describe the changes in the expression of cytokines and angiogenic factors that seem to generate disturbances in the intraovarian component underlying the aberrant persistence of follicular cysts. Results show that pro-inflammatory and anti-inflammatory cytokines behave as regulators of angiogenesis through direct and indirect effects, like overexpression of pro-angiogenic factors, particularly in bovine ovarian cells from follicular cysts and persistent follicles. We conclude that, in dairy cattle, an imbalance in the expression of cytokines and pro-angiogenic growth factors related to ovulation and the processes associated with it would contribute to follicular persistence and to the recurrent appearance of COD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cystic ovaries (CO) characterize a disorder frequently found in dairy cattle. However, despite the contributions by several researchers, the mechanism that leads to ovulatory failure has not yet been completely elucidated. Thus, the aim of this study was to examine the mRNA expression of bovine vascular endothelial growth factor (VEGFA)-164, VEGFA-164b and VEGF receptors (VEGFR1 and VEGFR2) by real-time PCR and protein expression by immunohistochemistry, immunofluorescence and Western blot in follicular fluid from dairy cows with spontaneous CO and in an experimental model of follicular persistence induced by prolonged treatment with progesterone. Results showed that both VEGFA isoforms and receptors were coexpressed in granulosa and theca interna cells and in follicular fluid of ovaries from all the groups evaluated. VEGFA-164, VEGFA-164b and VEGFR2 protein expression was higher in theca cells of persistent follicles from group P0 (expected time of ovulation) than in those from dominant follicles (as reference structure) from the control group (p < 0.05). Also, VEGFA-164 expression was higher in theca cells of cysts than in those of dominant follicles of the control group (p < 0.05). In follicular fluid, VEGFA-164 expression was higher in persistent follicles from group P5 (5 days of follicular persistence) than in the control, P0 and P15 groups, and higher in cysts than in dominant follicles from the control group (p < 0.05). This study provides evidence of an altered expression of VEGFA-164, VEGFA-164b and VEGFR2 during the formation of persistent follicles and cysts in cows. Together, these results evidence that early development of CO in cows is concurrent with an altered expression of these growth factors and that these alterations may contribute to the follicular persistence, angiogenic dysregulation and ovulatory failure found in cows with follicular cysts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

High-producing dairy cows frequently suffer metabolic alterations that cause different diseases, which could decrease the reproductive efficiency of the herd. Among these reproductive disorders, cystic ovarian disease (COD) has been related to alterations in metabolites and hormonal factors such as insulin, adiponectin and leptin. The aim of this study was to determine the protein expression of adiponectin and some of its downstream targets in ovarian follicles of control cows and cows with clinical diagnosis of COD. We also analyzed some key metabolic sensors in plasma and follicular fluid from both groups. In follicular cysts, we detected higher protein expression of adiponectin receptor 2 (AdipoR2), 5' adenosine monophosphate-activated protein kinase (AMPK), carnitine palmitoyl transferase 1 (CPT1) and acyl-coenzyme A oxidase 1 (ACOX1) relative to control antral follicles (p < 0.05). This was related to higher plasma adiponectin concentration in cows with COD than in control cows (p < 0.05). On the other hand, insulin concentrations showed an opposite pattern (p < 0.05). Furthermore, we found alterations in local and systemic concentrations of several metabolites. In this regard, in follicular fluid of cystic cows, the concentrations of non-esterified fatty acids and beta-hydroxybutyrate were higher (p < 0.05), whereas the concentrations of glucose and triacylglycerol were lower than in follicular fluid from control cows (p < 0.05). Besides, in both follicular fluid and plasma of cows with COD, the concentration of cholesterol was higher than in control animals (p < 0.05). These results evidence a local altered scenario of some metabolic sensors in cystic follicles, which could generate an adverse microenvironment for the resumption of ovarian activity, possibly causing the persistence of follicles and the recurrence of COD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The process of transformation of growing bovine follicles into cysts is still a mystery. Local expression of proteins or factors, including transforming growth factor β, growth factors, and transcription factors, plays a central role in mammals. Therefore, in abattoir-derived cystic ovarian follicles and follicular fluid, the role of some transforming growth factor β superfamily proteins, insulinlike growth factor-1 (IGF-1) and GATA-4 and GATA-6, were investigated. The relationship between intrafollicular lipopolysaccharide (LPS) and etiopathogenesis of ovarian cysts was also assessed. Data on the preovulatory follicle and the largest follicle (F1) were compared. The number of intrafollicular LPS-positive samples and LPS concentrations were higher in cysts. Immunohistochemical staining was mildly positive for IGF-1, inhibin alpha, and GATA-4 in thecal cells. Staining for anti-Müllerian hormone (AMH), growth differentiation factor-9, bone morphogenetic protein-6 (BMP-6), and GATA-6 was insufficient for their quantitation, and oocytes could not be stained for any of the proteins tested in the cystic follicles. Expression of BMP-6, inhibin alpha, and IGF-1 was moderately higher in granulosa cells of F1 follicles, and all the proteins were moderately expressed in granulosa cells in preovulatory follicles. However, loss of GATA-6 staining was significant in F1 follicles. Intrafollicular progesterone, IGF-1, and AMH concentrations in cysts and F1 follicles were significantly higher than those in preovulatory follicles. Western blot analyses revealed that follicular fluid inhibin-α was strongly expressed, whereas expression of growth differentiation factor-9, BMP-6, GATA-4 and GATA-6 was lower in cysts than in preovulatory follicles. Also, high intrafollicular AMH concentration and low BMP-6 expression were closely associated with cystic degeneration and atresia. In conclusion, immunohistochemical loss of BMP-6 and GATA-6 in the granulosa cells together with high intrafollicular LPS levels may play important roles in disruption of the ovulatory mechanism and steroidogenic reactions in type 2 cyst. Also, high intrafollicular AMH concentration along with low BMP-6 expression may be used as indicators of the bovine degenarative ovarian follicles., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We examined the hormonal and morphologic changes associated with ovarian cyst formation in high-yielding dairy cows. Follicle fluid was aspirated from 90 cysts and 15 preovulatory and 18 subordinate follicles and used for hormonal determination. Pieces of cystic wall were subjected to morphologic and immunohistochemical evaluation. Cysts were characterized by low concentrations of insulin, insulin-like growth factor-I (IGF-I), and glucose and high activity of IGF binding proteins (IGFBPs). Insulin and IGF-I levels were (mean+/-SEM) 205+/-22 pg/mL and 146+/-42 ng/mL in preovulatory follicles and 3+/-1 pg/mL and 61+/-6 ng/mL in cysts, respectively (P<0.001). Insulin-like growth factor-binding proteins activity was about 10 times higher in cysts than in preovulatory follicles. Cysts were classified into three types according to their estradiol-to-progesterone (E/P) ratio. Type 1 cysts (n=23) exhibited the highest E/P ratio (10.8+/-2.3), partial loss of granulosa cells, and severe morphologic changes in the theca interna. Expression of P(450) side-chain cleavage and P(450) 17 alpha-hydroxylase was noted in theca cells and expression of inhibin-alpha in granulosa cells. Type 2 cysts (n=35) had a low E/P ratio (0.07+/-0.02), and patches of luteal-like tissue in the cystic wall. Type 3 cysts (n=32) had an E/P ratio of 0.91+/-0.17, and no recognizable granulosa or theca cells. In summary, intrafollicular steroid levels as expressed by E/P ratio, together with IGF-I and insulin levels and morphologic changes in the follicular wall, may serve as accurate cyst-classification parameters. Because IGF-I and/or insulin play an essential role in the final stage of follicle development, it can be speculated that abnormal levels of these metabolic hormones might lead to follicle dysfunction, resulting in follicular regression or cyst formation.

The objective of this study was to evaluate the association between the level of milk production on the day of diagnosis of ovarian cysts and treatment response using the Ovsynch protocol. On the day of cyst diagnosis (Day 0), 260 lactating dairy cows with ovarian cysts were treated with gonadotropin-releasing hormone (GnRH), PGF2alpha on Day 7, GnRH on Day 9, and timed inseminated 16-20 h later (Ovsynch protocol). Pregnancy was determined (by transrectal palpation) between 42 and 49 days after insemination. On Day 0, data for milk production (kg/day), parity, days in milk (DIM), and body condition score (BCS) were recorded. Using the median value for milk production on the day of diagnosis, cows were classified as high producers (>28.5 kg) and low producers (or=0.05). Primiparous cows were more likely (adjusted odds ratio: AOR=3.63; 95% CI: 95% confidence intervals=1.28-10.30; P

Prolactin and GH have been detected within the ovary, and it has become increasingly evident that they have a role as intrafollicular regulatory factors. The aim of the present work was to gain an insight into the elements influencing intraovarian GH and PRL in bovine species and to see whether cystic degeneration was accompanied by abnormal bovine GH (bGH) and PRL (bPRL) plasma patterns. We followed the relationships between plasma and ovarian fluid bGH and bPRL concentrations over an entire year in Friesian cows whose ovaries showed distinct types of structures. To assess the presence of bGH and bPRL within ovarian cells, we assayed selected ovarian structures by immunohistochemistry. The results demonstrated that: 1) plasma and ovarian fluid hormonal concentrations were independent, and their ratio was independent of the ovarian structure classes, subclasses and period of the year; 2) in the majority of the cows the concentration of bGH in ovarian fluid was no more than 80% of the level in plasma, whereas in about half the animals bPRL concentrations were higher in the ovary than in peripheral plasma; 3) mean bPRL concentrations in ovarian fluids were significantly higher in summer than in winter; 4) immunoreactive bGH and bPRL were present within granulosa and luteal cells. Thus, it is suggested that in the cow bGH and bPRL levels in the ovary might be regulated in some way independently of the pituitary.