The effect of the insulin-sensitizing drug metformin on preovulatory follicle (POF) number, ovulation rate, fetal rate and prolificacy was studied in forty-six cyclic Malpura ewes. After estrus synchronization, the ewes were equally divided into two groups (n = 23). The treatment group (MET) received a daily oral dose of metformin at a rate of 500 mg/animal for approximately 12 weeks, spanning five estrous cycles, as against untreated control (CON). All the ewes were bred to proven rams at the end of treatment. Ovarian ultrasound scans were performed at each estrus and day 9 of each cycle to assess the number and diameter of POFs and corpora lutea (CL), respectively. A comprehensive assessment of circulating hormones including, estradiol, progesterone, androstenedione, and insulin as well as metabolic indicators such as glucose, and lipid profile parameters was performed. At the end of treatment on the day of estrus (E5D0), the treatment showed a stimulatory effect on follicular development with a 53.2% (P < 0.001) increase in the number of POFs. It also increased the ovulation rate by 67.4% (P < 0.01), with a higher proportion (χ2df1 = 10.7, P < 0.001) of ewes in the MET group having multiple ovulations compared to the CON group (82.6 vs. 30.4%). With 1.48 ± 0.12 prolificacy rate in MET ewes, the proportion of ewes giving birth to multiple lambs was 2.9-fold higher than in the CON group. Plasma estradiol, insulin, glucose, total cholesterol, and LDL-cholesterol concentrations were lower (P < 0.05) in the MET ewes than in the CON. The results of the present study indicate that metformin can increase the number of POF, ovulation rate, fetal rate and prolificacy in ewes, while reducing the plasma estradiol, insulin, glucose and cholesterol in MET ewes.

Based on a circular economy approach, we evaluated the possible effect of targeted supplementation with leftover feed from dairy cows (i.e., intensive system) on the reproductive performance of crossbred/rangeland goats (i.e., extensive system) in arid Northern Mexico. During the deep-anestrous season (i.e., March-April, 25° North), multiparous goats (n = 38) with a similar body weight (BW) and body condition score (BCS) were randomly assigned to two groups: (1) supplemented group (SG; n = 19; BCS: 1.76 ± 0.07; BW: 43.7 ± 1.8 kg), receiving 400 g goat d-1 of dairy-cow-feed leftovers prior to grazing; and (2) non-supplemented group (NS; n = 19; BCS: 1.76 ± 0.06; BW: 44.3 ± 2.5 kg). Both groups were directed to the rangeland for a period of ≈8 h. While the experimental period lasted 36 d, the experimental breeding considered 11 d (d0-d10). The anovulatory status of goats was ultrasonographically confirmed on days -20, -10, and -1 prior to male-female interaction. Previously, bucks were separated for 3 weeks from the experimental females and received exogenous testosterone every third day (i.e., 50 mg i.m.) prior to mating. With respect to the response variables, namely BW, BCS, blood glucose levels (BGLs), estrus induction (GIE, %), latency to estrus (LTE, h), estrus duration (ED, h), and luteal tissue volume (LTV, mm), no differences (p > 0.05) occurred between experimental groups. However, the response variables, namely goats ovulating (GO, %; 78.9 vs. 47.3), total number of corpuses luteum (TNCL, n; 27 vs. 13), ovulation rate (OR, n; 1.42 vs. 0.73), multiple ovulation (MO, %; 73.3 vs. 55.5), and pregnancy rate on d 36 (PRd36, %, 68.4 vs. 36.8), favored (p < 0.05) the SG over the NS goats. Our results demonstrate that connecting the circularity of two divergent ruminant production systems (i.e., cow-intensive and goat-extensive) by using dairy cows\' feed leftovers as a targeted supplementation strategy in anestrous goats under a marginal-rangeland production system enhanced out-of-season reproductive outcomes (i.e., ovulation rate and pregnancy rate), thus benefiting marginal goat producers and their families.

A key economic driver of a meat producing sheep flock is the total kilograms of lamb liveweight at weaning per ewe exposed to the ram. Optimization of key reproductive steps is required to achieve peak performance of a sheep flock. The goal of this paper was to use more than 56,000 records from a commercial flock to investigate the key reproductive steps affecting flock reproductive performance. We also applied a maximum-likelihood based technique to predict the embryo survival and ovulation rate for daughters of individual sires based on measurements of the number of fetuses at midpregnancy (detected by ultrasound-scanning). The model was used to determine how changes in premating liveweight, age, predicted ovulation rate, embryo survival, number of fetuses at midpregnancy, lamb survival, and lamb growth rate affect the total lamb liveweight at weaning per ewe exposed to the ram in the flock. The data from the commercial flock was also used to investigate the role of ewe age and premating liveweight on each reproductive step. Sensitivity analyses were performed to identify the key reproductive steps affecting flock reproductive performance. The elasticity for embryo survival was 80% of that for lamb survival. There was also significant between sire variance in the estimates of ovulation rate and embryo survival. The reproductive performance of daughters of sires with high (top 50%) and low (bottom 50%) embryo survival was investigated. Embryo survival was 0.88 in the high group and 0.82 in the low group (a 6% reduction in embryo survival). The expected total weight of lambs weaned per ewe exposed to the ram was 42 kg in the high embryo survival group and 37 kg in the low embryo survival group (a 12% reduction in the total weight of lambs weaned per ewe exposed to the ram). The proportion of twin litters was 70% in the high group and 60% in the low group, highlighting the potential importance of embryo survival for the rate of twinning in flocks with ovulation rates greater than two ova. Although lamb survival was similar between the high and low embryo survival groups, lamb growth was reduced by 10% in the low embryo survival group for the same litter size (P < 0.001). This novel positive phenotypic association between embryo survival and lamb growth rate can potentially be exploited to improve flock performance.

The development and maturation of ovarian follicles is a complex and highly regulated process, which is essential for successful ovulation. During recent decades, several mouse models provided insights into the regulation of folliculogenesis. In contrast to the commonly used transgenic or knockout mouse models, the Dummerstorf high-fertility mouse line 1 (FL1) is a worldwide unique selection experiment for increased female reproductive performance and extraordinary high fertility. Interactions of cycle-related alterations of parameters of the hypothalamic pituitary gonadal axis and molecular factors in the ovary lead to improved follicular development and therefore increased ovulation rates in FL1 mice. FL1 females almost doubled the number of ovulated oocytes compared to the unselected control mouse line. To gain insights into the cellular mechanisms leading to the high fertility phenotype we used granulosa cells isolated from antral follicles for mRNA sequencing. Based on the results of the transcriptome analysis we additionally measured hormones and growth factors associated with follicular development to complement the picture of how the signaling pathways are regulated. While IGF1 levels are decreased in FL1 mice in estrus, we found no differences in insulin, prolactin and oxytocin levels in FL1 mice compared to the control line. The results of the mRNA sequencing approach revealed that the actions of insulin, prolactin and oxytocin are restricted local to the granulosa cells, since hormonal receptor expression is differentially regulated in FL1 mice. Additionally, numerous genes, which are involved in important gonadotropin, apoptotic and metabolic signaling pathways in granulosa cells, are differentially regulated in granulosa cells of FL1 mice.We showed that an overlap of different signaling pathways reflects the crosstalk between gonadotropin and growth factor signaling pathways, follicular atresia in FL1 mice is decreased due to improved granulosa cell survival and by improving the efficiency of intracellular signaling, glucose metabolism and signal transduction, FL1 mice have several advantages in reproductive performance and therefore increased the ovulation rate. Therefore, this worldwide unique high fertility model can provide new insights into different factors leading to improved follicular development and has the potential to improve our understanding of high fertility.

To evaluate whether extending letrozole (LE) treatment duration could induce ovulation in women with polycystic ovary syndrome (PCOS) who previously failed to ovulate after a 5-day regimen of 5 mg LE daily for at least 1 ovulation induction cycle, defined as \"LE resistance\".
Retrospective cohort study.
Tertiary care academic medical center.
A total of 69 women with PCOS and LE resistance were included.
The duration of LE treatment was increased in a stepwise manner (named as \"2-step extended LE regimen\"): a 7-day regimen of 5 mg LE daily was prescribed in the first ovulation induction cycle, and if ovulation did not occur, a 10-day regimen was prescribed in the subsequent cycle.
Ovulation rate was the primary outcome. Clinical pregnancy rate, live birth rate, spontaneous ovulation rate, and ovarian hyperstimulation syndrome rate were the secondary outcomes.
Of the 69 patients, 48 ovulated after the 7-day and 16 after the 10-day regimen. Overall, the cumulative ovulation rate reached 92.75% (64/69) after the 2-step extended LE regimen, with a cumulative clinical pregnancy rate of 31.88% (22/69) and a cumulative live birth rate of 24.63% (17/69). All patients ovulated spontaneously without exogenous trigger agents and none experienced ovarian hyperstimulation syndrome.
Extending LE treatment duration is a feasible method for inducing ovulation in women with PCOS and LE resistance.

The aim of this study was to evaluate the effectiveness of using different doses of injectable progesterone (P4i) in a new ovulation synchronization protocol in place of progesterone (P4)-releasing intravaginal devices in Bos indicus cows. For this, three experiments were carried out. To determine the P4-release curve (Experiment 1), 55 Bos indicus cows were distributed into 5 experimental groups for the administration of different doses of P4i at D0 (P4i60, n = 11; P4i105, n = 11; P4i150, n = 11; P4i195, n = 11 and P4i240, n = 11) and submitted to the ovulation synchronization protocol (D0: P4i + EB; D8: PGF2α + EC + eCG). Daily blood samples were collected by jugular venipuncture from D0 to D12 for analysis of the serum P4 profile. To evaluate ovarian follicular dynamics and the timing of ovulation (Experiment 2), three studies were conducted with different doses of P4i at the beginning of the ovulation synchronization protocol (Study a: 150 mg and 105 mg P4i; Study b: 75 mg P4i; Study c: 60 mg P4i). At the end of the ovulation synchronization protocol, after ovulation inducing administration, ultrasound examinations were performed every 24 h until 96 h or until ovulation was detected (Studies a, b and c). To evaluate the pregnancy rate (Experiment 3), 132 Bos indicus cows were subjected to an ovulation synchronization protocol using either a 75 mg progesterone injection (Group P4i75) or an intravaginal P4 device (control group) on D0. Pregnancy was determined by ultrasound 30 days after the end of the ovulation synchronization protocol. All statistical analyses were performed by SAS®. In the P4-release curve, the peak occurred on D1 and on D3 all concentrations remained below 1 ng/mL until the end of the study (D12) in all groups. The ovulation rates were similar between the 75 mg dose group and the Control group (P = 0.24 - Experiment 2 - study b), result not observed with other doses of P4i (study a and c). The pregnancy rate (Experiment 3) was greater [P4i Group 27% and Control Group 72.7% (P = 0.0001)] in cows receiving the intravaginal P4 device. In conclusion, the use of long-acting P4i (75 mg) to replace the intravaginal P4 device negatively affects the conception rate of Bos indicus cows submitted to ovulation synchronization protocol.

Twin and multiple births have negative effects on the performance and health of cows and calves. To decipher the genetic architecture of this trait in the two Swiss Brown Swiss cattle populations, we performed various association analyses based on de-regressed breeding values. Genome-wide association analyses were executed using ~600 K imputed SNPs for the maternal multiple birth trait in ~3500 Original Braunvieh and ~7800 Brown Swiss animals. Significantly associated QTL were observed on different chromosomes for both breeds. We have identified on chromosome 11 a QTL that explains ~6% of the total genetic variance of the maternal multiple birth trait in Original Braunvieh. For the Brown Swiss breed, we have discovered a QTL on chromosome 15 that accounts for ~4% of the total genetic variance. For Original Braunvieh, subsequent haplotype analysis revealed a 90-kb window on chromosome 11 at 88 Mb, where a likely regulatory region is located close to the ID2 gene. In Brown Swiss, a 130-kb window at 75 Mb on chromosome 15 was identified. Analysis of whole-genome sequence data using linkage-disequilibrium estimation revealed possible causal variants for the identified QTL. A presumably regulatory variant in the non-coding 5\' region of the ID2 gene was strongly associated with the haplotype for Original Braunvieh. In Brown Swiss, an intron variant in PRDM11, one 3\' UTR variant in SYT13 and three intergenic variants 5\' upstream of SYT13 were identified as candidate variants for the trait multiple birth maternal. In this study, we report for the first time QTL for the trait of multiple births in Original Braunvieh and Brown Swiss cattle. Moreover, our findings are another step towards a better understanding of the complex genetic architecture of this polygenic trait.

This study examined the effect of glycerin supply strategies in different short-term protocols on follicular dynamics and ovulatory rate in Morada Nova sheep. Eighteen Morada Nova ewes with body condition > 2.9 had their estrus and follicular waves synchronized using three injections of prostaglandin analogue at seven-day intervals. All animals received the same diet during 21 days, which consisted of a total mixed ration (TMR) based on chopped elephant grass and concentrate twice daily. In the control group (n=9), ewes were fed the TMR diet. In the other four groups, ewes received 150 mL of glycerol daily, supplied as an oral drench or mixed in the TMR during three or seven days prior to the application of the third PGF2 alfa analogue. These groups were named as follows: Drench3d (n=10), Drench7d (n=8), TMR3d (n=9) and TMR7d (n=9). Follicle dynamics were monitored by ultrasonography, and plasma glucose and glutathione peroxidase levels were measured at the third prostaglandin administration. Six days after the final PGF2 alfa analogue dose, ovulatory rate was measured by laparoscopy. Glucose was higher (P< 0.001) in the glycerin-treated groups than in control group (83.7 ± 1.7 vs. 68.4 ± 4.5 mg. dL-1; P < 0.001). Ewes in the TMR3d, Drench7d and TMR7d groups had a greater (P < 0.001) number of large follicles (≥ 3 < 5 mm), and the presence of follicles larger than 5 mm was observed. In the same groups, at the third PGF2 alfa analogue dose, a greater (P < 0.001) number of growing follicles (> 3 mm) and a larger size of the largest follicle (P < 0.001) were also recorded. Ovulation rate was 30% higher in the groups that received glycerin for seven days (1.6 ± 0.1 53 vs. 1.1 ± 0.1; P < 0.05), and they also exhibited a 38% reduction in glutathione peroxidase. Thus, the use of glycerin in Morada Nova sheep as a source of energy in short-term supplementation for increase ovulation rate is an efficient strategy when provided for seven days, either orally or in the feed.

The Dummerstorf high-fertility mouse line FL1 is a worldwide unique selection experiment for increased female reproductive performance. After more than 190 generations of selection, these mice doubled the amount of offspring per litter compared to the unselected control line. FL1 females have a superior lifetime fecundity and the highest Silver fecundity index that has been described in mice, while their offspring show no signs of growth retardation. The reasons for the increased reproductive performance remained unclear. Thus, this study aims to characterize the Dummerstorf high-fertility mouse line FL1 on endocrine and molecular levels on the female side. We analyzed parameters of the hypothalamic pituitary gonadal axis on both hormonal and transcriptional levels. Gonadotropin-releasing hormone and follicle-stimulating hormone (FSH) concentrations were decreased in FL1 throughout the whole estrous cycle. Luteinizing hormone (LH) was increased in FL1 mice in estrus. Progesterone concentrations were decreased in estrus in FL1 mice and not affected in diestrus. We used a holistic gene expression approach in the ovary to obtain a global picture of how the high-fertility phenotype is achieved. We found several differentially expressed genes in the ovaries of FL1 mice that are associated with different female fertility traits. Our results indicate that ovulation rates in mice can be increased despite decreased FSH levels. Cycle-related alterations of progesterone and LH levels have the potential to improve follicular maturation, and interactions of endocrine and molecular factors lead to enhanced follicular survival, more successful folliculogenesis and therefore higher ovulation rates in female FL1 mice.

We tested whether short-term nutritional supplementation (500 g lupin grain per head daily) would affect the response of ewes to the ram effect. Experiment 1 (end of non-breeding season): ewes were supplemented for either Days -6 to -1 relative to ram introduction (n = 24) or for 12 days after ram introduction (Days 11 to 22 of the ram-induced cycle; n = 29). Controls (n = 30) were not supplemented. Across all groups, 94-100% of ewes ovulated. Supplementation before ram introduction did not affect ovulation rate at the ram-induced ovulation but increased it during the ram-induced cycle (Control 1.37; supplemented 1.66; p < 0.05). Experiment 2 (the middle of non-breeding season): the supplement was fed for Days -5 to -1 relative to ram introduction. Again, supplementation did not increase number ovulating (Control 16/29; Supplemented 10/29) but it did increase ovulation rate at the ram-induced ovulation (Control 1.31; Supplemented 1.68; p < 0.05). In neither experiment did supplementation affect the frequency of short cycles. Supplementation before ram introduction did not improve the percentage of ewes ovulating or reduce the frequency of short cycles (so will not improve the synchrony of lambing). However, supplementation after ram introduction can increase prolificacy.