142 Evaluation of estrus detection patches as a tool to classify postpartum beef cows as estrous cycling or anestrous prior to the start of the breeding season

Estrus detection patches were evaluated as a tool to classify postpartum cows as estrous cycling or anestrous at the start of the breeding season. EstrotectTM Breeding Indicators were applied to 257 postpartum beef cows in three locations 25 days prior to the start of estrus synchronization. Coincident with the start of estrus synchronization, patches were scored using a 1 to 4 scale (1 = 0–25%; 2 = 25–50%; 3 = 50–75%; 4 = 75–100%) with scores of 3 or 4 considered activated. Blood samples were collected from each cow 10 days prior to, and at the start of the estrus synchronization. Serum progesterone concentrations were determined via radioimmunoassay; cows were considered estrous cycling if one or both samples exceeded a concentration of 0.5 ng/ml. Based on progesterone, 54.9% of cows were estrous cycling at the start of estrus synchronization. When missing patches were considered inconclusive results, use of patches to infer estrous cyclicity resulted in 85.0% sensitivity and 79.2% specificity with a positive predictive value of 87.2%. However, 75.1% of all cows presented with missing patches at the start of synchronization. If missing patches were considered activated, sensitivity was 95.7%, but specificity (16.4%) and PPV (58.2%) were poor, as 47.6% of cows presenting with missing patches were anestrous based on progesterone. Across all cows, pregnancy rate to AI was 58.0% (149/257). Cows with activated patches that were classified as false positives based on serum progesterone concentrations achieved a 71.4% (5/7) pregnancy rate to AI, raising questions as to whether sensitivity was underestimated due to inherent Type II errors in classification of cyclicity via progesterone. In summary, estrus detection aids are a sensitive tool to identify estrous cycling postpartum cows prior to the start of the breeding season; however, poor specificity and patch retention are limitations for this application.

In vivo blockade of ovarian sympathetic activity by Neosaxitoxin prevents polycystic ovary in rats

A high sympathetic tone is observed in the development and maintenance of the polycystic ovary (PCO) phenotype in rats. Neosaxitoxin (NeoSTX) specifically blocks neuronal voltage-dependent Na+ channels, and we studied the capacity of NeoSTX administered into the ovary to block sympathetic nerves and PCO phenotype that is induced by estradiol valerate (EV). The toxin was administered with a minipump inserted into the bursal cavity using two protocols: (1) the same day as EV administration and (2) 30 days after EV to block the final step of cyst development and maintenance of the condition. We studied the estrous cycling activity, follicular morphology, steroid plasma levels, and norepinephrine concentration. NeoSTX administered together with EV decreased NA intraovarian levels that were induced by EV, increased the number of corpora lutea, decreased the number of follicular cyst found after EV administration, and decreased the previously increased testosterone plasma levels induced by the PCO phenotype. Estrous cycling activity also recovered. NeoSTX applied after 30 days of EV administration showed near recovery of ovary function, suggesting that there is a specific window in which follicular development could be protected from cystic development. In addition, plasma testosterone levels decreased while those of progesterone increased. Our data strongly suggest that chronic inhibition of sympathetic nerves by a locally applied long-lasting toxin is a new tool to manage the polycystic phenotype in the rat and could be applied to other mammals depending on sympathetic nerve activity.

Toxicity of Pexacerfont, a Corticotropin-Releasing Factor Type 1 Receptor Antagonist, in Rats and Dogs

Pexacerfont is a corticotropin-releasing factor subtype 1 receptor antagonist that was developed for the treatment of anxiety- and stress-related disorders. This report describes the results of repeat-dose oral toxicity studies in rats (3 and 6 months) and dogs (3 months and 1 year). Pexacerfont was well tolerated in all of these studies at exposures equal to or greater than areas under the curve in humans (clinical dose of 100 mg). Microscopic changes in the liver (hepatocellular hypertrophy), thyroid glands (hypertrophy/hyperplasia and adenomas of follicular cells), and pituitary (hypertrophy/hyperplasia and vacuolation of thyrotrophs) were only observed in rats and were considered adaptive changes in response to hepatic enzyme induction and subsequent alterations in serum thyroid hormone levels. Evidence for hepatic enzyme induction in dogs was limited to increased liver weights and reduced thyroxine (T4) levels. Mammary gland hyperplasia and altered female estrous cycling were only observed in rats, whereas adverse testicular effects (consistent with minimal to moderate degeneration of the germinal epithelium) were only noted following chronic dosing in dogs. The testicular effects were reversible changes with exposure margins of 8× at the no observed adverse effect level. It is not clear whether the changes in mammary gland, estrous cycling, and testes represent secondary hormonal changes due to perturbation of the hypothalamic–pituitary–adrenal axis or are off-target effects. In conclusion, the results of chronic toxicity studies in rats and dogs show that pexacerfont has an acceptable safety profile to support further clinical testing.

High-Fat, High-Sugar Diet Disrupts the Preovulatory Hormone Surge and Induces Cystic Ovaries in Cycling Female Rats

Diet-induced obesity has been associated with various metabolic and reproductive disorders, including polycystic ovary syndrome. However, the mechanisms by which obesity influences the reproductive system are still not fully known. Studies have suggested that impairments in hormone signaling are associated with the development of symptoms such as acyclicity and ovarian cysts. However, these studies have often failed to address how these hormonal changes arise and how they might contribute to the progression of reproductive diseases. In the present study, we used a high-fat, high-sugar (HFHS) diet to induce obesity in a female rodent model to determine the changes in critical reproductive hormones that might contribute to the development of irregular estrous cycling and reproductive cycle termination. The HFHS animals exhibited impaired estradiol, progesterone (P4), and luteinizing hormone (LH) surges before ovulation. The HFHS diet also resulted in altered basal levels of testosterone (T) and LH. Furthermore, alterations in the basal P4/T ratio correlated strongly with ovarian cyst formation in HFHS rats. Thus, this model provides a method to assess the underlying etiology of obesity-related reproductive dysfunction and to examine an acyclic reproductive phenotype as it develops.