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Commercially available intravaginal progesterone (P4) devices differ in shape, surface area and P4 load, which may affect the resulting pregnancy per AI (P/AI) following timed-AI (TAI). The objective of this study was to compare two intravaginal P4 devices on estrus rate, follicular dynamics and P/AI in beef cattle subjected to shortened-TAI protocols. In Expt. 1, nulliparous heifers were randomly assigned to a P4-releasing intravaginal device (PRID-Delta, 1.55 g P4) or a controlled internal drug release (CIDR, 1.38 g P4) at the initiation of a J-synch protocol. Heifers that displayed estrus 72 h following device removal were TAI, or if not in estrus given GnRH at 72 h and TAI at 90 h. In Expt. 2, nulliparous heifers and non-suckling cows were randomly assigned to either PRID or CIDR groups and either 1 or 2 mg of estradiol benzoate (EB) at initiation of a J-synch protocol. All cattle were TAI concurrent with GnRH 72 h after device removal. In Expt. 3, nulliparous heifers and suckling cows were randomly assigned to either PRID or CIDR groups and initiated a 5-d Cosynch protocol, with TAI concurrent with GnRH 72 h following device removal. In each experiment, cattle received estrus detection patches at device removal, which were then scored from 0 to 3 based on color change between initial application and TAI; 0 = unchanged, 1 = ≤50% change, 2 = >50% change, 3 = missing. Estrus was defined to have occurred when the patch was scored 2 or 3. Transrectal ultrasonography was used to determine cyclicity, diagnose pregnancy in all experiments, and the size of the ovulatory follicle in Expt. 3. In Expt. 1, the estrus rate was greater (72.0% vs. 61.0%; P = 0.04) in the PRID compared to the CIDR group. In Expt. 2, a parity by EB dose interaction (P = 0.02) was attributed to an increased estrus rate (52.8% vs. 41.4%; P = 0.05) in heifers given 1 vs. 2 mg EB. In Expt. 3, there was no difference in the ovulatory follicle diameter at device removal (P = 0.22) or TAI (P = 0.28) between P4 groups. Treatment with a PRID tended (P = 0.10) to increase the P/AI in cows compared to a CIDR (73.5% vs. 61.0%). In all experiments combined, the overall P/AI tended to increase (55.2% vs. 51.0%; P = 0.08) and P/AI in cattle exhibiting estrus increased (64.4% vs. 59.7%; P = 0.02) in cattle given a PRID compared to those given a CIDR, respectively. In summary, the type of intravaginal P4 device affected estrus response and P/AI following TAI in beef cows.

Two experiments were conducted to test the effectiveness of a silicone matrix as an intravaginal drug delivery device for letrozole, an aromatase inhibitor used for synchronization protocols in cattle. A wax dip-coat formulation of the intravaginal device used in previous studies was effective in releasing letrozole but was cumbersome to manufacture and deploy, resulting in unwanted variation in drug delivery and circulating concentrations of letrozole. In Experiment 1, a 3 × 3 design was used to test the release kinetics of letrozole from silicone in vitro. Silicone was mixed with 3 different letrozole drug loads (5%, 10%, 15%) and 3 different mineral oil loads (5%, 10%, 15%), and letrozole release into 62.5% ethanol was compared with the wax dip-coat formulation (positive control) by UV spectrophotometry. Letrozole was released from silicone in a dose-dependent manner, with no effect of mineral oil. Release kinetics were then examined in vivo (Experiment 2) in nulliparous beef heifers assigned randomly to six groups (n = 6/group) and given either a large surface area (LSA) with 5% or 15% drug load, a standard surface area (SSA) intravaginal silicone device impregnated with 10% or 15% drug load, a wax dip-coat device (positive control), or a blank device (negative control). Devices were inserted on Day 3 (Day 0 = ovulation) until Day 11. Blood samples were collected at 0, 30 min, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h, and twice daily until Day 11 to determine letrozole plasma concentrations by LC-MS/MS and estradiol plasma concentrations by radioimmunoassay The ovaries were examined once daily from Day 3-13 by ultrasonography to determine follicular and luteal responses to treatment. Letrozole plasma concentrations were higher in heifers given a device with an LSA vs SSA (P 0.05). Plasma concentrations of estradiol decreased the most in heifers given the 15% LSA device (P = 0.06). The interval between emergence of successive follicular waves was longest (P 0.05) in the positive control and the 15% LSA groups. As well, the diameter profiles of the dominant follicle and the corpus luteum were largest (P 0.01) in the positive control and 15% LSA groups. In conclusion, letrozole was released from a silicone matrix in vitro in a dose-dependent manner, and the 15% LSA devices achieved target effects on ovarian function. Results may be used to manufacture a silicone intravaginal device for delivering aromatase inhibitors in a novel synchronization protocol for cattle.

Numerous treatments and protocols have been used to control the reproductive cycle in cattle, with varying effectiveness and many involving the administration of steroid hormones. Steroid hormones, such as estradiol, are perceived as having a negative impact on consumer health. This internationally shared opinion has led to a ban on the use of steroid hormones in food producing animals in many countries (i.e., European Union, New Zealand, and Australia). Letrozole, a non-steroidal aromatase inhibitor, inactivates the aromatase enzyme responsible for the synthesis of estrogens by reversibly binding to the "heme" group of the P450 subunit. Letrozole is approved as an adjuvant or first-line treatment for hormone-dependent breast cancer in post-menopausal women, but has been used increasingly for ovulation induction in the treatment of infertility in women. Using the bovine model to determine the effects on ovarian function, letrozole treatment was found to extend the lifespan of the dominant follicle and thereby delay emergence of the next follicle wave and/or ovulation. Letrozole treatment also had a luteotrophic effect; that is, larger CL and/or higher circulating concentrations of progesterone were detected in letrozole-treated heifers. Results of the initial studies in cattle provided the impetus for the development of aromatase inhibitor-based synchronization and fertility treatment in cattle. Biologically active concentrations of letrozole were achieved via intravenous, intramuscular or intravaginal administration, but the intravaginal route of administration is of particular interest because it permits extended and defined treatment periods, is minimally invasive, and reduces animal handling. Recent results revealed that irrespective of the stage of the cycle, a 4-day letrozole-based protocol induced ovulation in a significantly greater proportion of animals and with significantly greater synchrony than the control treatment. Evidence and reasons for the increasing use of programmed breeding and fixed-time artificial insemination are discussed in this review as a background to current development of an innovative aromatase inhibitor-based protocol as a safe and effective method of controlling the estrous cycle and ovulation in cattle.