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The aim of this study was to determine the pharmacokinetics of letrozole and its effect on FSH and LH concentrations after single (IV, IM, SC) and repeated IV doses in anestrous ewes. This study was conducted in experiments 1 and 2 by randomly dividing 24 healthy Akkaraman ewes in anestrus into two equal groups. In experiment 1, the pharmacokinetics of letrozole following single IV, IM, and SC administration at 1 mg/kg dose and its effect of a single IV dose on plasma FSH and LH concentration were determined. In experiment 2, the effect of repeated IV doses of letrozole on FSH and LH concentrations was established. Plasma concentration of letrozole was measured using high-performance liquid chromatography, and pharmacokinetic parameters were calculated by non-compartmental analysis. FSH and LH concentrations were quantified using ELISA. The elimination half-life (t 1/2ʎz) for IV, IM, and SC routes were 9.94, 37.29, and 41.07 h, respectively. The IV route for letrozole had a total clearance of 0.11 L/h/kg and a volume of distribution at a steady state of 1.50 L/kg. The peak plasma concentration was 0.11 μg/mL for the IM route and 0.14 μg/mL for the SC routes. The bioavailability was 55.18% for the IM route and 75.34% for the SC route. Letrozole following single and repeated (every 24 h for 3 days) IV administrations at 1 mg/kg dose did not affect LH concentration in anestrous ewes but caused an increase in the FSH concentration. This increase in FSH concentration may create a potential for the use of letrozole in ovarian superstimulation protocols. Favorable pharmacokinetic properties (long t 1/2ʎz and good bioavailability) of letrozole for IM and SC routes require further investigation before use in estrus induction or estrus synchronization protocols in sheep. • The pharmacokinetics of letrozole after single and repeated doses in anestrous ewes were evaluated. • The effect of letrozole on plasma concentrations of FSH and LH was established. • The IM and SC administration of letrozole showed a longer elimination half-life than IV. • FSH concentration increased following letrozole treatment while LH concentration remained unchanged. [ABSTRACT FROM AUTHOR]

The objective of this work was to investigate the effect of progesterone (P) and gonadotropin-releasing hormone (GnRH) treatment on estrogen receptor (ER) and P receptor (PR) concentrations in the pituitary gland and uterus of anestrous ewes. Ewes were either not treated (group C, n=4); were treated with 0.33 g P-controlled internal drug release (P-CIDR) for 10 days (group P, n=4), with GnRH, 6.7 ng i.v. injections every 2 h for 18 h followed by a 4 μg bolus administration of Receptal at 20 h (group GnRH, n=4), or with a combination of the P and GnRH treatment (group P+GnRH, n=3). Ewes were humanely killed either at the beginning of the experiment (group C), when the CIDR was removed (group P), or 24 h after the GnRH bolus treatment (groups GnRH and P+GnRH). Progesterone treatment increased serum P concentrations, indicating that the treatment was effective. All GnRH treated ewes had similar luteinizing hormone (LH) surges, which lasted 8 h. At slaughter, estradiol (E2) concentrations in the GnRH group were higher than in groups C, P, and P+GnRH. Treatment with GnRH increased more than 10-fold the content of ER and PR in the pituitary gland without altering steroid receptor concentrations in the uterus. When GnRH was combined with P the uterine receptor contents were higher than with P treatment alone. The treatment with P decreased ER and PR content in the uterus, but had no effect on the pituitary gland. The results show that regulation by P and GnRH of ER and PR content in anestrous ewes is tissue-specific. [Copyright &y& Elsevier]

Reproductive performance in seasonally anestrous ewes is poor even after the use of current controlled breeding protocols. Anestrous ewes treated with a medroxyprogesterone acetate sponge, for 12 or 14 d, and estradiol-17β (E2) have synchronized follicular wave emergence. The objective of this study was to determine the effects of an E2 injection 6 d after CIDR insertion on follicles, E2 and LH concentrations, and estrus in seasonally anestrous ewes. Ewes (n = 13) received CIDRs (Day -12) followed by an injection of eCG (500 IU; i.m.; Day 0) at CIDR removal and an injection of sesame oil without (1 mL; i.m.; Control) or with E2 (350µg; i.m.; Day -6) 6 d before CIDR removal. Treatments were balanced for age, parity, and BCS. Blood samples were collected every 6 h for 48 h after E2 injection and every 3 h for 60 h starting 18 h after eCG injection to determine LH concentrations. Blood samples were collected on Day -6 and 0 and every 6 h for 60 h starting 18 h after eCG injection to determine E2 concentrations. Ovarian ultrasonography was done on Day -6 and 0. A ram was introduced on Day 1 to observe estrus. Ewes treated with E2 had higher LH concentrations (0.37 ± 0.05 ng/mL) than ewes treated with oil alone (0.12±0.05 ng/mL) during the 48 h after E2 injection (P < 0.005). Concentrations of LH were highest at 18 h after E2 injection (1.11 ± 0.12 ng/mL; P < 0.001). Ewes treated with E2 had higher LH concentrations (2.10 ± 0.18 ng/mL) than ewes treated with oil alone (0.12 ± 0.16 ng/mL) at 18 h after E2 injection (P < 0.001). The interval from eCG injection to the start of the pre-ovulatory LH surge was similar (37.1 ± 4.4 h; P > 0.05), but was more synchronized in ewes treated with E2 (2.3 ± 0.6 h) than ewes treated with oil alone (12.0 ± 5.1 h; P < 0.01). Concentrations of E2 were similar between treatments on Day -6 (2.1 ± 0.3 pg/mL; P > 0.05) and Day 0 (2.3 ± 0.4 pg/mL; P > 0.05). Concentrations of E2 tended to be highest at 18 h after eCG injection (3.5 ± 0.5 pg/mL; P = 0.076). Maximum follicular diameter was larger on Day 0 (4.8 ± 0.2 mm) than Day -6 (3.4 ± 0.2 mm; P < 0.001). There were no differences in the interval from eCG treatment to the start (37.6 ± 2.7 h) or end (74.7 ± 1.9 h) of estrus (P > 0.05). Adding an E2 treatment during a CIDR-eCG estrus synchronization protocol increased LH concentrations after E2 treatment and stimulated a more synchronized pre-ovulatory LH surge in seasonally anestrous ewes. [ABSTRACT FROM AUTHOR]